Vous êtes sur la page 1sur 374



2016 Meet-the-Professor Endocrine Case Management is your source for the
latest updates in the diagnosis and management of a wide range of endocrine
disorders. This valuable resource allows you to evaluate your endocrine
knowledge and gain insight into the strategies used by clinical experts.

Features of Meet-the-Professor Endocrine Case Management 2016 include:

Historical Overview C E L E B R A T I N G A C E N T U R Y O F

Significance of the Clinical Problem
Key Learning Objectives
Strategies for Diagnosis and Management
Clinical Pearls and Pertinent References
Cases and Questions

Endocrine Society
2055 L Street NW, Suite 600
Washington, DC 20036

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

MTP 2016_COVER.Final.R1_2-18-16.indd 1 2/29/16 3:15 PM

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.
2055 L Street, NW, Suite 600
Washington, DC 20036

Other Publications:

The Endocrine Society is the worlds largest, oldest, and most active organization working to advance the clinical practice of
endocrinology and hormone research. Founded in 1916, the Society now has more than 18,000 global members across a range
of disciplines.

The Society has earned an international reputation for excellence in the quality of its peer-reviewed journals, educational
resources, meetings, and programs that improve public health through the practice and science of endocrinology.

Clinical Science Chair, ENDO 2016

Gary D. Hammer, MD, PhD

Physician-In-Practice Chair, ENDO 2016

Michael T. McDermott, MD

The statements and opinions expressed in this publication are those of the individual authors and do not necessarily reflect the
views of the Endocrine Society. The Endocrine Society is not responsible or liable in any way for the currency of the
information, for any errors, omissions or inaccuracies, or for any consequences arising therefrom. With respect to any drugs
mentioned, the reader is advised to refer to the appropriate medical literature and the product information currently provided by
the manufacturer to verify appropriate dosage, method and duration of administration, and other relevant information. In all
instances, it is the responsibility of the treating physician or other health care professional, relying on independent experience
and expertise, as well as knowledge of the patient, to determine the best treatment for the patient.

Copyright 2016 by the Endocrine Society, 2055 L Street, NW, Suite 600, Washington, DC 20036. All rights reserved. No
part of this publication may be reproduced, stored in a retrieval system, posted on the internet, or transmitted in any form, by
any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission of the publisher.

Requests for permission for reproduction should be directed to the Endocrine Society Publications Department: http://www.endo-
society.org/journals/rights.cfm, or send an email to permissions@endo-society.org. For more information or to purchase copies, please
contact Society Services by telephone at 202-971-3646, fax at 202-736-9704, or email at societyservices@endocrine.org or visit the
online store: www.endocrine.org/store.

ISBN: 978-1-943550-02-9
eISBN: 978-1-943550-04-3
Library of Congress Control Number: 2016932453

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2016
DISCLOSURE INDEX ......................................................................................... iv

FOREWORD......................................................................................................... v

TOPIC INDEX ..................................................................................................... vi

SPEAKER HANDOUT INDEX ............................................................................... xi

ADRENAL HPA AXIS .......................................................................................... 1

BONE, CALCIOTROPIC HORMONES, AND VITAMIN D ...................................... 47

DIABETES AND GLUCOSE METABOLISM ......................................................... 83

GENERAL ENDOCRINOLOGY .......................................................................... 143

NEUROENDOCRINOLOGY AND PITUITARY ...................................................... 177

OBESITY AND LIPIDS...................................................................................... 217

PEDIATRIC ENDOCRINOLOGY.......................................................................... 249

REPRODUCTIVE ENDOCRINOLOGY .................................................................. 295

THYROID/HPT AXIS ....................................................................................... 329

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2016
The faculty, committee members, and staff who are in position to control Wang, C: Advisory Board Member and Consultant, Novo Nordisk (spouse);
the content of this activity are required to disclose to the Endocrine Society Advisory Board Member, CSL Behring, Biogen, Baxter (spouse); Medical
and to learners any relevant financial relationship(s) of the individual or Safety Officer-CPC Clinical Research/University of Colorado, Astra
spouse/partner that have occurred within the last 12 months with any Zeneca, Osiris; Speaker, Medical Education Resources. Matsumoto, A:
commercial interest(s) whose products or services are related to the CME Principal Investigator, Abbott Laboratories, GlaxoSmithKline; Advisory
content. Financial relationships are defined by remuneration in any amount Group Member, Abbott Laboratories, Clarus; Ad Hoc Consultant, Endo
from the commercial interest(s) in the form of grants; research support; Pharmaceuticals, Lilly USA, LLC. McCall, A: Clinical Researcher for
consulting fees; salary; ownership interest (e.g., stocks, stock options, or ELIXA Trial (monies paid to university); Clinical Researcher, Lilly USA,
ownership interest excluding diversified mutual funds); honoraria or other LLC; Consultant, Pfizer, Inc. McIver, B: Consultant, Veracyte, Inc.,
payments for participation in speakers bureaus, advisory boards, or boards Asuragen, CBL Path. Nieman, L: Investigator, HRA Pharma. Pinkerton, J:
of directors; or other financial benefits. The intent of this disclosure is not to Consultant, Pfizer, Inc., Noven, Inc., Therapeutic; Investigator,
prevent CME planners with relevant financial relationships from planning or TherapeuticMD. Riddell, M: Speaker, Eli Lilly & Company, Sanofi,
delivery of content, but rather to provide learners with information that Medtronic Minimed. Seaquist, E: Principal Investigator, Amgen, Lilly
allows them to make their own judgments of whether these financial USA, LLC, Merck & Co.; Investigator, Eli Lilly & Company, locemia;
Consultant, locemia; Speaker, Sanofi, Novo Nordisk. Shane, E: Principal
relationships may have influenced the educational activity with regard to
Investigator, Amgen, Lilly USA, LLC, Merck & Co. Trainer, P: Principal
exposition or conclusion.
Investigator, Ipsen, Antisense Therapeutics, Chiasma; Advisory Board
Member, Ipsen, Chiasma. Vella, A: Investigator, GI Dynamics. Verbalis, J:
The Endocrine Society has reviewed all disclosures and resolved or man-
Ad Hoc Consultant, Ferring Pharmaceuticals, Otsuka. Vinik, A: Consultant,
aged all identified conflicts of interest, as applicable.
Merck & Co., Pfizer, Inc., Neurometrix, Pamlab, Principal Investigator,
Tercica, Intarcia, ViroMed, Impeto Medical, Novo Nordisk VeroScience.
The following faculty reported relevant financial relationship, as identi-
Vogiatzi, M: Advisory Group Member, Novo Nordisk. Watts, N: Advisory
fied below: Aronne, L: Grantee, Eisai, Aspire Bariatric; Scientific Board
Group Member, Amgen, Merck & Co.; Scientific Board Member, Abbvie;
Member, Pfizer, Inc. Novo Nordisk, GI Dynamics, Jovia Health, Zafgen,
Speaker Bureau Member, Amgen; Investigator, NPS; Ad Hoc Consultant,
Gelesis; Board Member, Jamieson Labs, MYOS Corp. Auchus, R: Consul-
Sanofi. Young, W: Consultant, Nihon Medi-Physics.
tant, Bluebird Bio. Blonde, L: Principal Investigator, Eli Lilly & Company;
Investigator, Novo Nordisk, Sanofi; Speaker, Astra Zeneca, Jansen Pharma- The following faculty reported no relevant financial relationships:
ceuticals; Consultant, Merck & Co. GlaxoSmithKline, Intarcia. Davis, S:
Lecturer, Abbott Laboratories; Investigator, Trimel Pharmaceuticals, Adler, G; Alter, C; Arafah, B; Bachrach, L; Bantle, J; Barbour, L; Becker,
Lawley Pharmaceuticals. Feingold, K: Speaker, Merck & Co., Amgen, C; Boh, B; Bollerslev, J; Brent, G; Burch, H; Busui, R; Cappola, A;
Sanofi, Regeneron. Feldt-Rasmussen, U: Principal Investigator, Ad Hoc Chamberlain, A; Cornier, M-A; Donahoo, W; Edelman, S; Else, T; Farooki,
Consultant, Novo Nordisk; Advisory Group Member, Pfizer, Inc. Francis, G: A; Farwell, A; Findling, J; Fishbein, L; Habra, MA; Hall, J; Hennessey, J;
Stockholder, Genentech, Inc., Merck & Co.; Principal Investigator, Glaxo- Ho, K; Hodak, S; Holick, M; Jonklaas, J; Kiseljak-Vassiliades, K; Krone,
SmithKline, Novo Nordisk. Gafni, R: Investigator, Shire. Gagel, R: Princi- N; Lopes-Virella, M; McDonnell, M; McMahon, G; Molitch, M; Neggers,
pal Investigator, AstraZeneca. Haugen, B: Investigator, Speaker, Genzyme S; ODorisio, T; ystese, K; Pattison, D; Pearce, E; Pettifor, J; Radovick, S;
Corporation. Husebye, E: Speaker, Shire. Inzucchi, S: Advisory Group Rothman, M; Sabra, M; Safer, J; Sarapura, V; Saunders, K; Schauer, I;
Member, Merck & Co., Jansen Pharmaceuticals; Committee Member, Novo Sheffield-Moore, M; Shukla, A; Silverberg, S; Sparks, L; Sperling, M; Stan,
Nordisk; Speaker, Astra Zeneca, Coinvestigator, Takeda. Kerr, J: Re- M; Urban, R; Vaidya, A; Vincent, A; Wierman, M.
searcher, Novartis Pharmaceuticals. Lane, W: Advisory Group Member,
Novo Nordisk; Investigator, Eli Lilly & Company, Novo Nordisk. Low Endocrine Society staff report no relevant financial relationships.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2016
For 100 years the Endocrine Society has been devoted to educating its
members. According to Albert Einstein, Intellectual growth should com-
mence at birth and cease only at death. The field of endocrinology is
constantly evolving, and as physicians, we want to provide the best
possible care to our patients. To do this, we must engage in lifelong
learning. The Meet-The-Professor Endocrine Case Management book is
designed to provide the clinician with an efficient and high-quality review
of over 70 common and rare endocrine disorders. The expert contributors
have been selected for their deep understanding of the topic, their clinical
experience, and their facility in clearly communicating complex information.

Physicians learn best by active participation in case-based clinical

discussions. When physicians are actively engaged the learning is most
enjoyable and enduring. To this end, we have asked each expert contribu-
tor to provide a historical perspective about the topic, learning objectives,
a concise up-to-date review of their topic, and a summary of cases
followed by a brief discussion of the cases. This format allows the reader
to learn actively by testing their knowledge of clinical endocrinology.

We are deeply grateful to the many experts who contributed to these

sessions and made this book such a valuable learning experience. We are
also thankful to the Endocrine Society staff whose efforts are instrumental
to the successful publication of this book.

Gary D. Hammer, MD, PhD

Clinical Science Chair, ENDO 2016
University of Michigan
Ann Arbor, Michigan 48109

Michael T. McDermott, MD
Physician-In-Practice Chair, ENDO 2016
University of Colorado
Aurora, Colorado 80045

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2016
CMF4 Adrenal Insufficiency, Subclinical and Adrenal Fatigue Page 2
Richard J. Auchus, MD, PhD and James W. Findling, MD

CMF10 Evaluation and Management of the Adrenal Mass Page 10

Anand Vaidya, MD, MMSc and Mouhammed Amir Habra, MD

M01 Management of Classical CAH: From Birth to Adulthood Page 17

Maria G. Vogiatzi, MD

M11 Adrenal Insufficiency: Individualized Management Page 21

Eystein S. Husebye, MD, PhD

M12 Pheochromocytomas and Paragangliomas Page 27

Lauren Fishbein, MD, PhD

M33 Adrenal Insufficiency in Intensive Care Patients Page 32

Baha M. Arafah, MD, FACP

M46 Primary Aldosteronism Page 36

William F. Young, Jr, MD, MSc

M53 Primary Aldosteronism and Cardiometabolic Risk: Approach to Medical Management Page 42
Gail K. Adler, MD, PhD


M02 Applying DXA and Other Imaging to Clinical Conundrums Page 48
Micol S. Rothman, MD

M13 Cancer Treatment and Bone Health Page 51

Azeez Farooki, MD

M23 Hyperparathyroidism Management after Unsuccessful Parathyroid Surgery Page 55

Shonni J. Silverberg, MD

M34 Rickets Page 59

John M. Pettifor, MD, PhD

M35 Osteoporosis in Premenopausal Women Page 64

Elizabeth Shane, MD

M47 Osteoporosis: Managing Patients Who Fracture on Osteoporosis Treatment Page 70

Carolyn B. Becker, MD

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

M51 Osteoporosis Drug Holidays: Data and Opinions Page 75

Nelson B. Watts, MD

M55 Vitamin D Replacement in Patients with Malabsorption Disorders Page 80

Michael F. Holick, MD, PhD


CMF7 ADA and AACE Guidelines for Individualized Diabetes Management n/a
Lawrence Blonde, MD, FACP, FACE and Silvio E. Inzucchi, MD

M03 Using CGM For Day-To-Day Insulin-Dosing Decisions Page 84

Steven Edelman, MD

M10 When and How to Use U500 (or Other Concentrated) Insulin Page 89
Wendy Lane, MD

M14 Exercise Resistance in Type 2 Diabetes Page 96

Lauren M. Sparks, PhD

M15 Diabetic Neuropathies Page 101

Rodica Pop-Busui, MD, PhD

M21 Inpatient Management of Hyperglycemia Page 105

Cecilia C. Low Wang, MD

M22 Management of Hypoglycemia and Impaired Awareness of Hypoglycemia

in Diabetes Page 110
Elizabeth R. Seaquist, MD

M24 Exercise Prescriptions for Patients With DM2 Page 113

Irene Schauer, MD, PhD

M36 Controversies and Consequences of Gestational Diabetes for Mother and Child:
More than Glucose Page 118
Linda A Barbour, MD, MSPH

M37 Management of DM1 in Athletes Page 125

Michael C. Riddell, PhD

M54 Individualizing Management with Insulin Pumps Page 129

Anthony L. McCall, MD, PhD

M56 Diabetes in the Older Patient Page 138

Graham T. McMahon, MD, MMSc

CMF1 Endocrine Tumor Genetics: Challenging Issues Page 144
Tobias Else, MD and Mrta Korbonits, MD, PhD

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

M04 Endocrine Consequences of Opiate Therapy Page 153


M16 Neurohumoral Syndromes Page 157

Aaron Vinik, MD, PhD, FCP, MACP, FACE

M31 Hypoglycemic Disorders Page 167

Adrian Vella, MD

M32 Whats New in the Management of Multiple Endocrine Neoplasia Type 2? Page 172
Robert F. Gagel, MD


CMF6 Acromegaly: Navigating the Difficult Cases Page 178
Katja Kiseljak-Vassiliades, DO and Peter Trainer, MD, FRCP

CMF8 Molecular Imaging and Radionuclide Therapy of Functional Neuroendocrine

Tumors (NETS) Page 184
David Pattison, MBBS, MPH, FRACP, FAANMS and Thomas ODorisio, MD

CMF11 ACTH-Dependent Cushings Syndrome: Challenging Cases Page 191

Lynnette K. Nieman, MD and Janice M. Kerr, MD

M06 Diabetes Insipidus: Principles of Diagnosis and Treatment Page 195

Joseph G. Verbalis, MD

M26 Non-Functioning Pituitary Adenomas and Incidentalomas Page 202

Jens Bollerslev, MD, DMSc and Kristin Astrid Berland ystese, MD

M44 Growth Hormone DeficiencyControversies in the Clinical Management

in Adults Page 206
Ulla Feldt-Rasmussen, MD, DMSc

M48 Traumatic Brain Injury and Fatigue Page 210

Albert Chamberlain, MD, Randall J. Urban, MD, and Melinda Sheffield-Moore, PhD

M57 Prolactinomas Page 214

Mark E. Molitch, MD


M05 Bariatric Surgery Nutritional Management Page 218
William Troy Donahoo, MD

M17 Diet and Exercise Recommendations in Metabolic Disease: Implementing

Effective Behavior Change Page 222
Marie E. McDonnell, MD

M18 Post-Bariatric Surgery Hypoglycemia Page 227

John P. Bantle, MD

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

M25 Advanced Lipoprotein Analysis n/a

Kenneth Feingold, MD

M38 Hypertriglyceridemia and Low HDL Page 232

Maria F. Lopes-Virella, MD, PhD

M39 Obesity Medications Page 239

Katherine H. Saunders, MD, Alpana P. Shukla, MD, MRCP, and Louis J. Aronne, MD, DABOM, FTOS

M52 Management of Severe Hypercholesterolemia Page 244

Marc-Andre Cornier, MD

M09 Thyroid Nodules and Cancer Guidelines in Children Page 250
Gary L. Francis, MD, PhD

M08 Hypoparathyroidism in Children Page 257

Rachel I. Gafni, MD

M42 MODY and Other Monogenic Forms of Diabetes Page 262

Mark A. Sperling, MD

M45 Disorders of Sexual Differentiation in Newborns, Infants, and Children Page 270
Nils P. Krone, MD, FRCPCH

M60 Endocrine Effects of Cancer Treatment Page 277

Sebastian Neggers, MD, PhD

M30 Puberty Disorders in Girls Page 280

Sally Radovick, MD

M29 Bone Fragility in Children: When to Worry and What to Do Page 287
Laura K. Bachrach, MD

M50 Diabetes Insipidus in Children Page 292

Craig A. Alter, MD

CMF5 State-of-the-Art: Use of Hormones in Transgender Individuals Page 296
Benjamin Boh, DO, MS and Joshua D. Safer, MD, FACP

M07 Female Sexual Dysfunction: Do Hormones Help? Page 301

Susan R. Davis, MBBS, FRACP, PhD

M19 Polycystic Ovarian Syndrome Page 306

Margaret E. Wierman, MD

M27 Bioidentical Hormone Replacement Page 310

JoAnn V. Pinkerton, MD

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

M40 Testosterone Replacement Therapy in Men Page 315

Alvin M. Matsumoto, MD

M49 Menopause: Weighing the Options n/a

Janet E Hall, MD, MSc

M58 Care of the Adult Woman with Turner Syndrome Page 322
Amanda Vincent, MBBS, B Med Sci, FRACP, PhD

CMF2 Thyroid Nodules: What Molecular Markers are Most Useful? n/a
Steven Paul Hodak, MD and Bryan McIver, MB, ChB, PhD

CMF3 Thyroid Function Tests That Do Not Make Sense Page 330
Virginia D. Sarapura, MD and Jacqueline Jonklaas, MD, PhD

CMF9 Thyroid Cancer: Advanced Cases Page 334

Mona M. Sabra, MD and Bryan Haugen, MD

CMF12 Nonthyroidal Illness Syndrome: To Treat or Not? Page 338

Gregory A. Brent, MD and Alan P. Farwell, MD, FACE

M20 Thyroid Disease in Pregnancy Page 343

Elizabeth N. Pearce, MD, MSc

M28 Graves Orbitopathy Page 348

Marius N. Stan, MD

M41 Thyrotoxicosis: When Antithyroid Drugs Fail Page 353

Henry B. Burch, MD

M43 Hypothyroidism in the Elderly Page 355

Anne R. Cappola, MD, ScM

M59 Levothyroxine Therapy: When Outcomes Are Less Than Optimal - Optimizing
Patient Care Page 359
James V. Hennessey, MD

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2016
Adler, Gail K. .......................................................... 42 Lane, Wendy S. ........................................................ 89
Alter, Craig A. ........................................................ 292 Lopes-Virella, Maria F. ............................................. 232
Arafah, Baha M. ....................................................... 32 Low Wang, Cecilia C. .............................................. 105
Aronne, Louis J. ...................................................... 239 Matsumoto, Alvin M. ............................................... 315
Auchus, Richard J. ...................................................... 2 McCall, Anthony L. ................................................. 129
Bachrach, Laura K. .................................................. 287 McDonnell, Marie E. ................................................ 222
Bantle, John P. ........................................................ 227 McIver, Bryan ......................................................... n/a
Barbour, Linda A. .................................................... 118 McMahon, Graham T. .............................................. 138
Becker, Carolyn B. .................................................... 70 Molitch, Mark E. ..................................................... 214
Blonde, Lawrence ..................................................... n/a Neggers, Sebastian J.C.M.M. ...................................... 277
Boh, Benjamin ........................................................ 296 Nieman, Lynnette K. ................................................ 191
Bollerslev, Jens ....................................................... 202 ODorisio, Thomas M. .............................................. 184
Brent, Gregory A. .................................................... 338 Aystese, KAB ......................................................... 202
Burch, Henry B. ...................................................... 353 Pattison, David A. ................................................... 184
Busui Pop Rodica .................................................... 101 Pearce, Elizabeth N. ................................................. 343
Cappola, Anne R. .................................................... 355 Pettifor, John M. ....................................................... 59
Chamberlain, Albert ................................................. 210 Pinkerton, JoAnn V. ................................................. 310
Cornier Marc-Andre ................................................. 244 Radovick, Sally ....................................................... 280
Davis, Susan R. ....................................................... 301 Riddell, Michael C. .................................................. 125
Donahoo, William T. ................................................ 218 Rothman, Micol S. .................................................... 48
Edelman, Steven V. ................................................... 84 Sabra, Mona M. ...................................................... 334
Else, Tobias ........................................................... 144 Safer, Joshua D. ...................................................... 296
Farooki, Azeez ......................................................... 51 Sarapura, Virginia D. ............................................... 330
Farwell, Alan P. ...................................................... 338 Saunders, Katherine ................................................. 239
Feingold, Kenneth .................................................... n/a Schauer, Irene E. ..................................................... 113
Feldt-Rasmussen, Ulla .............................................. 206 Seaquist, Elizabeth R. ............................................... 110
Findling, James W. ..................................................... 2 Shane, Elizabeth ....................................................... 64
Fishbein, Lauren M. .................................................. 27 Sheffield-Moore, Melinda .......................................... 210
Francis, Gary L. ...................................................... 250 Shukla, Alpana ........................................................ 239
Gafni, Rachel I. ...................................................... 257 Silverberg, Shonni J. .................................................. 55
Gagel, Robert F. ...................................................... 172 Sparks, Lauren M. ..................................................... 96
Habra, Mouhammed A. .............................................. 10 Sperling, Mark A. .................................................... 262
Hall, Janet E. .......................................................... n/a Stan, Marius N. ....................................................... 348
Haugen, Bryan R. .................................................... 334 Trainer, Peter J. ...................................................... 178
Hennessey, James V. ................................................ 359 Urban, Randall J. ..................................................... 210
Ho, Ken ................................................................ 153 Vaidya, Anand ......................................................... 10
Hodak, Steven P. ...................................................... n/a Vella, Adrian .......................................................... 167
Holick, Michael F. .................................................... 80 Verbalis, Joseph G. .................................................. 195
Husebye, Eystein S. ................................................... 21 Vincent, Amanda ..................................................... 322
Inzucchi, Silvio E. .................................................... n/a Vinik, Aaron I. ....................................................... 157
Jonklaas, Jacqueline ................................................. 330 Vogiatzi, Maria G. .................................................... 17
Kerr, Janice M. ....................................................... 191 Watts, Nelson B. ....................................................... 75
Kiseljak-Vassiliades, Katja ........................................ 178 Wierman, Margaret E. .............................................. 306
Korbonits, Mrta ..................................................... 144 Young, William F. .................................................... 36
Krone, Nils P. ......................................................... 270 n/a Handout not available

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Adrenal Insufficiency, Subclinical and Adrenal Fatigue


Presented, April 1 4, 2016 The concept of adrenal fatigue has been promoted by integra-
tive medicine and naturopathic medicine for several years, and
endocrinologists are often asked for consultation on patients
Richard J. Auchus, MD, PhD; James W. Findling, with presumed subclinical adrenal insufficiency. Many of
MD. Department of Pharmacology & Internal Medicine, these patients are provided with adrenal support and some
Division of Metabolism, Endocrinology & Diabetes, are actually given glucocorticoid therapy based on a salivary
University of Michigan Medical Center, Ann Arbor, cortisol day curve. Few, if any, of these patients have any
Michigan 48109, E-mail: rauchus@med.umich.edu; and biochemical evidence of either ACTH deficiency or cortisol
Medical College of Wisconsin, Milwaukee, Wisconsin deficiency.
Although clinical or relative adrenal insufficiency has
53051, E-mail: jfindling@mcw.edu
been suggested as a possible problem in patients who are either
acutely ill or have undergone chronic stress, there is currently
INTRODUCTION no biochemical criteria that establishes such a problem and
Historical Overview very little clinical evidence of its existence. Nonetheless, there
In 1855, Dr Thomas Addison published his classic work, On are many circumstances in which there is a modest decrease in
the Constitutional and Local Effects of Disease of the Suprare- cortisol secretion and the optimal corticosteroid replacement
nal Capsules, in which he described adrenocortical insuffi- therapy remains controversial.
ciency (1). Thomas Addison was born in April 1793 near New
Castle-upon-Tyne. He studied medicine at the University of LEARNING OBJECTIVES
Edinburgh and was awarded an MD degree in 1815. He even- As a result of participating in this session, learners should be
tually joined the staff at Guys Hospital in London and helped able to:
to elevate the reputation of the medical school there. In addi- Appropriately use and interpret the results of basal and
tion to describing Addisons disease, he also made important dynamic tests of adrenal function.
observations on pneumonia, pulmonary tuberculosis, and fatty Distinguish the clinical and laboratory findings of
liver. Dr Addison also provided the first description of appen- primary and secondary adrenal insufficiency.
dicitis in his and Richard Brights, The Elements of the Prac- Recognize the myth of adrenal fatigue propagated by
tice of Medicine, published in 1839 (2). Twenty-five years after entrepreneurial naturopathic practitioners.
Dr Addisons death, Dr Edward Kendall was born in South List the drugs that interfere with the hypothalamic-
Norwalk, Connecticut in 1886. He received his training at pituitary-adrenal (HPA) axis and cortisol metabolism.
Columbia University and was not only responsible for the Appreciate the degree of cortisol deficiency required for
isolation of T4 while working at Parke-Davis but also discov- clinically meaningful manifestations.
ered and isolated Compound E (cortisone) during a long re-
search career at the Mayo Clinic. The latter discovery earned STRATEGIES FOR DIAGNOSIS, THERAPY,
him the Nobel Prize in 1950 with Phillip Hench and Taddeus AND/OR MANAGEMENT
Reichstein. This remarkable story is beautifully told in The Clinical Presentations of Adrenal Insufficiency
Quest for Cortisone by Thom Rooke from the Mayo Clinic (3). Table 1 summarizes the possible clinical presentations of adre-
nal insufficiency. Constitutional and nonspecific complaints
Dr Kendall was president of the Endocrine Society in
such as fatigue, malaise, nausea, anorexia, and weight loss are
1930 1931.
appreciated but none of them provide very good sensitivity or
Adrenal insufficiency remains a well-appreciated endocri-
specificity. Nonetheless, the diagnosis should be considered in
nopathy whose causes have changed dramatically since the
any patient with unexplained weight loss or hypotension.
mid-19th century. Most cases of adrenal insufficiency are now
An important clinical point is that, in the absence of con-
due to deficiencies of ACTH secretion from the pituitary, comitant conditions such as renal, heart, or liver failure, weight
usually due to iatrogenic factors. Although less common, pri- gain essentially excludes the diagnosis of adrenal insufficiency.
mary adrenal insufficiency (the term for which Addisons dis- The most common clues for the diagnosis are usually from
ease is usually reserved) remains a very important clinic disor- routine laboratory studies. Hyponatremia is a common clinical
der with protean presentations. And the discovery of cortisone manifestation of both primary and secondary adrenal insuffi-
by Dr Kendall provided life-saving therapy for patients with all ciency. Glucocorticoids exert negative feedback on vasopressin
causes of adrenal gland insufficiency. secretion and deficiencies of cortisol may result in nonosmotic

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 1. Clinical Presentations of Adrenal Insufficiency The most common causes of cortisol deficiency are iatro-
Signs/symptoms genic. All exogenously administered glucocorticoids, regard-
Fatigue, malaise, nausea/vomiting, unexplained weight loss less of dose and route of administration, may suppress the HPA
Hypotension, increased skin pigmentation axis. Given that corticosteroids are metabolized by CYP3A4,
Routine laboratory abnormalities drugs that inhibit this hepatic enzyme may reduce metabolic
Hyponatremia, hyperkalemia, hypercalcemia clearance of exogenous steroids and amplify their clinical ef-
Lymphocytosis, eosinophilia fect. It has been shown that endogenous cortisol deficiency will
Drug-induced occur in 50% of patients who receive either intra-articular or
Exogenous corticosteroids (any route of administration), oral glucocorticoids and may even be present in 510% of
medroxyprogesterone acetate patients who receive inhaled or topical corticosteroids. In ad-
Opioids dition, it is less-well appreciated that opioids and some psycho-
CTLA-4 monoclonal antibody-induced hypophysitis (eg, tropic medications may attenuate the pituitary-adrenal axis
ipilimumab) function (4 7). Finally, the diagnosis of adrenal insufficiency
Psychotropic medication may also need to be considered in patients with a genetic
Benzodiazepines (alprazolam), atypical antipsychotics predisposition for adrenal insufficiency including various forms
(onlanzapine, quetiapine)
of congenital adrenal hyperplasia, adrenoleukodystrophy, fa-
Adrenostatic/adrenolytic (etomidate, ketoconazole, metyrapone,
mitotane, osilodrostat)
milial glucocorticoid deficiency (ACTH resistance syndromes),
GR antagonist (mifepristone)
and autoimmune polyglandular syndromes (21).
Imaging abnormalities
Primary: bilateral adrenal enlargement/masses vs atrophic Diagnostic Approach
adrenals History and Physical
Secondary: pituitary mass With the exception of iatrogenic HPA axis suppression by
Hypothalamic-pituitary disease exogenous glucocorticoids, adrenal insufficiency is rare. The
Pituitary tumors, granulomatous diseases, hypophysitis, probability of adrenal insufficiency is extremely low in the
iatrogenic, genetic conditions absence of specific clinical features such as hyperpigmentation,
Genetic disorders hypotension, hypoglycemia, vitiligo, known pituitary disease,
Congenital adrenal hyperplasias weight loss, and anorexia.
Autoimmune polyglandular syndromes
Basal Testing
ACTH insensitivity (familial glucocorticoid deficiency),
Basal Serum Cortisol and Plasma ACTH Values. Basal se-
triple-A syndrome
rum cortisol and plasma ACTH values alone can be used to
Adrenal hypoplasia congenital
exclude all forms of adrenal insufficiency in most patients.
Other transcription factor defects
Because of the strong diurnal rhythm for these hormones, the
Abbreviation: CTLA-4, cytotoxic T-lymphocyte antigen 4. sample is most useful when drawn before 0900 hours; how-
ever, adequate values at any time of day exclude adrenal
insufficiency. A serum cortisol of greater than 14 g/dL (400
nmol/L) is 99% specific for predicting a cortisol increase
greater than 18 g/dL (500 nmol/L) during insulin-induced
stimulation of vasopressin and hyponatremia. Accordingly, the
hypoglycemia (insulin tolerance test [ITT]) (26). Although the
diagnosis of adrenal insufficiency should be considered in any
ACTH value itself is not used to exclude adequate cortisol
patient with unexplained hyponatremia. Hyperkalemia as a
production, when cortisol is low (5 g/dL, 140 nmol/L),
result of mineralocorticoid deficiency may occur in some pa-
the ACTH is used to distinguish primary (100 pg/mL, 20
tients with significant primary adrenal insufficiency. When
pmol/L) from secondary (20 pg/mL, 4.4 pmol/L) adrenal
observed in patients with hyponatremia, the exclusion of the
insufficiency. Basal cortisol values 5-14 g/dL are inconclu-
diagnosis is mandatory.
sive and require additional testing.
Bilateral adrenal enlargement, particularly when the enlarge-
ment coincides with the normal contour of the adrenal glands,
may also be the initial clue to the diagnosis of adrenocortical Random Serum DHEAS. A random serum dehydroepiandrosterone
insufficiency. The presence of adrenal insufficiency in this (DHEA) sulfate (DHEAS) value greater than 60 g/dL (1500
setting is one of the few indications to perform percutaneous nmol/L) also rules out adrenal insufficiency unless the patient
computed tomography (CT) guided biopsy of the adrenal is taking DHEA supplements (24). Unlike cortisol and ACTH,
glands (after pheochromocytoma has been excluded). Of DHEAS is so heavily protein bound that its diurnal rhythm is
course, adrenal insufficiency needs to always be excluded in very slight, permitting use of values obtained any time of day.
patients with hypothalamic-pituitary disease. Because the data supporting its performance vs ITT are sparse,

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

DHEAS is usually used to adjudicate basal cortisol values decrease to less than 5 g/dL to document adequate
slightly less than 14 g/dL (27), particularly when the cortisol 11-hydroxylase inhibition. The criterion for a normal test is a
is drawn after 0900 hours, and caution should be used when serum 11-deoxycortisol greater than 7 g/dL. Note that for
interpreting values close to 60 g/dL. Limitations to DHEAS many commercial cortisol immunoassays, 11-deoxycortisol
include its facile and sustained suppression by exogenous cross-reacts more than 50%; consequently, both cortisol and
glucocorticoids and its normal decline with age, which limits 11-deoxycortisol are best measured by tandem mass spectrom-
its utility in the elderly (age 65 y). etry during this test (23). Conceptually, this test asks whether
the sum of cortisol and cortisol precursors increases to greater
Serum Aldosterone and Plasma Renin. Serum aldosterone and than 12 g/dL (330 nmol/L) when ACTH is elevated by a
plasma renin (activity or mass) are sometimes useful in distin- physiologic stimulus. Based on this logic, the test is unneces-
guishing primary from secondary adrenal insufficiency, but sary when the basal cortisol is itself greater than 12 g/dL. The
aldosterone values are only interpretable when renin is current suppliers of metyrapone for treatment and dynamic
midnormal to high (2 ng/mL/h). testing vary with country, and metyrapone can be expensive
and difficult to obtain.

Dynamic Testing
Standard 250-g Cosyntropin (Short Synachten) ITT Test. The ITT is the gold standard test for all forms of
Stimulation Test. The standard 250 g cosyntropin (short adrenal insufficiency, but it should be restricted to patients with
synachten) stimulation test (CST, SST) is used to definitively suspected secondary adrenal insufficiency and equivocal basal
exclude primary adrenal insufficiency or longstanding second- testing. The ITT has been criticized as nonphysiologic, but
ary adrenal insufficiency. The agent may be administered as an other stimuli that stimulate the HPA axis such as exercise are
iv bolus with sampling as early as 30 minutes or im, when the difficult to standardize and to administer. A bolus of 0.1 0.2
peak is delayed until 45 60 minutes. A peak cortisol value at U/kg of regular insulin is administered by iv bolus in the early
30 60 minutes of greater than 18 g/dL (500 nmol/L) is morning after an overnight fast. Blood samples are obtained for
normal; the change in serum cortisol is highly dependent on the serum cortisol every 15 minutes for 75 minutes. The glucose
basal value, which varies by time of day and clinical status, and nadir should be 40 mg/dL (2.2 mmol/L) to interpret an
should never be used as a diagnostic criterion. Aldosterone abnormal test, and this nadir typically occurs between 30 and
normally doubles in response to cosyntropin, which is help- 45 minutes after the bolus. A cortisol increase to greater than 18
ful in confirming normal adrenal function when cortisol g/dL is normal, and measurement of ACTH does not provide
testing is confounded. additional diagnostic information (28). The test is contraindicated
in patients with seizure disorders, significant cardiovascular dis-
ease, and inability to verbalize symptoms of hypoglycemia.
Low-Dose 1-g CST. The low-dose 1 g CST is popular in
some centers excluding secondary adrenal insufficiency but re-
quires precise timing of samples (30 min) and bolus administra- Special Conditions
tion directly into an iv port with minimal tubing. The exact value Corticosteroid-Binding Deficiency. Corticosteroid-binding
for confidently excluding secondary adrenal insufficiency is prob- globulin (CBG) deficiency is very rare. These patients have low
ably also 18 g/dL, but conflicting numbers are found in the serum cortisol, approximately 0.52 g/dL (15 nmol/L), lack fea-
literature. We have found that this test provides little more infor- tures of adrenal insufficiency, and do not require treatment (20).
mation beyond early morning ACTH, cortisol, and DHEAS mea-
surements, but it can be helpful when a diagnosis is urgently Patients With Critical Illness. Criteria for patients with criti-
needed. In patients with partial central adrenal insufficiency, the cal illness are no different than for outpatients; however, see
DHEA response to low-dose cosyntropin is lost before the cortisol comments about hypoproteinemia and free cortisol below. In
response, so DHEA measurement can be helpful (25). addition, neutrophil elastase cleaves liganded CBG, which re-
leases bound cortisol at sites of inflammation and increases
Overnight Metyrapone Test. The overnight metyrapone test cortisol delivery.
is used to drive the entire HPA axis and to test for secondary
adrenal insufficiency. Metyrapone inhibits 11-hydroxylase Hypoproteinemia. Hypoproteinemia reduces plasma cortisol
(CYP11B1, P450 11B1, P450c11), which acutely lowers cor- binding, elevating the free cortisol fraction and lowering the
tisol with a resultant increase in ACTH and cortisol precursors. total cortisol concentration needed to attenuate ACTH secre-
A bolus dose of 30 mg/kg up to 3 g is given at 2300 hours with tion. In critically ill patients with a serum albumin less than 2.5
food, and a blood sample is obtained at 0800 hours the follow- mg/dL, cosyntropin stimulated total cortisol values as low as 7
ing morning, similar to the overnight dexamethasone suppres- g/dL (200 nmol/L) can be normal, as adjudicated with plasma
sion test. For the test to be valid, the serum cortisol must free cortisol values (1215).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Glucocorticoid Insensitivity Syndrome. Glucocorticoid in- hours achieve serum cortisol concentrations 40 120 g/dL,
sensitivity syndrome is always partial and is likewise very rare. well above those typically achieved by the normal adrenal
These patients have high cortisol and adrenal-derived andro- during critical illness. We tend to give smaller doses more
gens and mineralocorticoids but reach a new set point with frequently, such as 50-mg bolus, then 25 mg every 6 hours,
normal glucocorticoid physiology. Mifepristone is a glucocor- rather than the traditional 100-mg-every-8-hours regimen.
ticoid receptor (GR, NR3C1) antagonist, and mifepristone ad- What is important is that the dosing is continued until the
ministration yields a pharmacologic, partial, and reversible patient is well and can take their usual oral regimen. At these
glucocorticoid insensitivity condition with high serum cortisol doses greater than 40 mg per day, the mineralocorticoid activ-
if the HPA axis is intact. ity of hydrocortisone is sufficient to obviate the need for
fludrocortisone acetate. Alternatively, methylprednisolone (Solu-
Plasma Free Cortisol During CST. The use of plasma free medrol) as a 510-mg bolus followed by 5 mg every 6 8 hours
cortisol during CST has recently shown equivalent if not supe- is plenty, or dexamethasone, 2 mg every 8 12 hours. With
rior performance to total serum cortisol (17), and this type of these alterative glucocorticoids, mineralocorticoid replacement
testing might be useful in certain circumstances, such as might be necessary, and therefore hydrocortisone is preferable.
patients with hypoproteinemia, particularly in critical ill-
ness, or oral contraceptive drug therapy with high CBG (8). Chronic Corticosteroid Replacement
Saliva is an ultrafiltrate of plasma, and thus saliva cortisol Hydrocortisone. Hydrocortisone remains the preferred gluco-
concentrations typically parallel those of plasma free corti- corticoid replacement therapy for adults with all forms of
sol (18, 19). The utility of late-night saliva cortisol in the adrenal insufficiency, because it is the most physiologic of the
diagnosis of Cushings syndrome is well documented, but available treatments and the least likely to cause iatrogenic
fewer studies have addressed its performance and developed Cushing syndrome. Ideally, 1520 mg per day given in three
normative values for diagnosing adrenal insufficiency. divided doses to mimic the normal diurnal rhythm provides the
most physiologic regimen, with the first dose taken on arising
How Much Cortisol Does One Really Need? or at the bedside 30 minutes prior to arising and subsequent
To put the issue in perspective, consider that circulating corti- doses at 1200 1400 hours and a third before 1800 hours if
sol is approximately 10% free hormone and that the affinity of used. Many adults have difficulty remembering all three doses
cortisol for GR is roughly 10 nmol/L. Thus, a serum cortisol of (10-5-5 mg), and two daily doses are usually feasible, such as
7 g/dL (200 nmol/L, free 20 nmol/L) is nearly enough to or 15-5 mg. Rarely, patients with primary adrenal insufficiency
saturate GR. Consequently, even low amounts of cortisol are feel well on a single 20-mg dose on arising, whereas patients
better than none during physiologic stress. Case 2 illustrates with partial central adrenal insufficiency often only need a
this point. single 10- or 15-mg morning dose. Alternatively, a morning
dose of prednisolone or methylprednisolone, 4 8 mg is a
Do Not Forget Etiology and Implications reasonable strategy for patients who cannot take medication
Primary adrenal insufficiency is rare. If a diagnosis is made, the during the day, but synthetic glucocorticoids are more likely to
etiology should be pursued because this information will have cause iatrogenic Cushing syndrome. Prednisone should be
additional consequences for the patient. Young men with primary avoided, given that it is not the active drug and requires
adrenal insufficiency should be screened for adrenoleukodystrophy metabolism to prednisolone in the liver, which is unpredictable
by measuring very-long-chain fatty acids, and all children at the small doses used for adrenal insufficiency. Dexametha-
should be assessed for genetic causes. sone causes even more adverse effects and should be avoided
Finally, the diagnosis of adrenal insufficiency carries pro- for chronic therapy, although its temporary use in moderate
found implications: life-long replacement therapy, medical illness can be beneficial. Sustained-release hydrocortisone
alert identification, increased risk of death (22), limitations for preparations have been developed, and one form (Plenadren)
employment and insurance, etc. is in use in Europe. Glucocorticoid dosing to manage the
Do not label someone with this diagnosis unless you are androgen excess and/or hypertension of congenital adrenal
absolutely certain. hyperplasia is a special situation that is beyond the scope of
this handout.
Acute Management
In the acutely ill patient with adrenal insufficiency, aggressive Fludrocortisone Acetate. Fludrocortisone acetate is the stan-
volume replacement with normal saline is essential. Hydrocor- dard mineralocorticoid replacement therapy, and this is one of
tisone hemisuccinate (Solu-cortef) is given as an iv bolus as the rare drugs for which the dose is similar in infants and
soon as possible, or im if venous access is difficult. The actual adults, 0.1 0.4 mg per day and occasionally more. We find that
amount is not so critical, but at least 20 mg will raise serum most adults with adrenal insufficiency feel better when ad-
cortisol concentrations dramatically. Doses of 50 mg every 6 equately volume replaced with salt and fludrocortisone.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Fludrocortisone acts chronically rather than acutely and has a glucocorticoids. In fact, low-normal or subnormal ACTH lev-
long half-life, so it may be taken any time of day or on els in patients with primary adrenal insufficiency suggest ex-
alternate days when using very low doses. cessive glucocorticoid replacement.

Sickness and surgery Mineralocorticoid titration. Orthostasis and unexplained fa-

Our sick day rules are very simple: tigue that do not resolve after a hydrocortisone dose suggest
If you are losing fluid faster than you can replace it insufficient fludrocortisone. The goal for fludrocortisone dosing
meaning high fever, diarrhea or vomitingthen double are normal sitting and standing blood pressure (BP) without
(or triple) your glucocorticoid dose until you are orthostatic tachycardia, normal serum potassium, and plasma
completely well for 1 day and then resume your usual renin activity in the normal range or slightly lower. Thus, a
dose without tapering. typical laboratory assessment would be electrolytes, glucose,
If you cannot take your medication orally, take your creatinine, and plasma renin.
emergency hydrocortisone hemisuccinate (100 mg im)
and immediately go to the nearest emergency department
or call an ambulance.
Case 1
For planned surgeries, a 50-mg hydrocortisone You are asked to provide an opinion regarding the diagnosis of
hemisuccinate bolus iv or im prior to induction of adrenal fatigue in a 19-year-old man complaining of anxiety
anesthesia will cover at least 4 hours of surgery well. and panic attacks accompanied by palpitations and weakness.
Depending on the extent of surgery, complications, and He had sought care from a naturopath who made the diagnosis
blood loss, subsequent 25-mg doses every 6 hours is of adrenal fatigue based on salivary cortisol profile, which
usually sufficient until the patient can take medication showed that all his cortisol measurements were below the
orally. Many times, the routine outpatient dose may be reference range. His mother accompanies him at the visit and
resumed the following day, or higher doses are insisted that he see an endocrinologist.
continued when necessary. Fludrocortisone may be His examination showed a healthy-seeming man with nor-
suspended for a few days, particularly when the mal skin pigmentation, BP of 124/74 mm Hg; pulse, 60
hydrocortisone dose is high. For dental procedures, beats/min; and a body mass index of 21.1 kg/m2. His entire
routine colonoscopy, and minor surgeries lasting less examination was completely normal. An early-morning serum
than 2 hours, doubling the morning oral dose before the cortisol level was 1.2 g/dL (33.1 nmol/L).
procedure is usually sufficient, followed by resumption 1. Which of the following tests would you obtain next?
of the usual dosing. A. Plasma ACTH
B. A rapid CST
Glucocorticoid titration C. Pituitary magnetic resonance imaging (MRI)
Unlike T4 replacement in primary hypothyroidism, the titration D. DHEAS
of corticosteroid replacement is mainly based on clinical evalu- A rapid ACTH stimulation test (250 g cosyntropin) yields a
ation rather than laboratory parameters. First and foremost, peak cortisol response of 11.6 g/dL (320 nmol/L) and a basal
evaluation for physical stigmata of iatrogenic Cushing syn- ACTH is less than 5 pg/mL. His total testosterone, free T4, and
drome should be conducted at every visit. Findings such as IGF-I levels are normal.
supraclavicular fat pads, easy bruising and dermal atrophy, 2. Which of the following studies would you secure next?
facial plethora, and worsening glucose tolerance suggest that A. Pituitary MRI
the total glucocorticoid dose is too high. Weight loss, asthenia, B. Insulin-induced hypoglycemia
anorexia, and weakness suggest underdosing. If a patient taking C. Metyrapone stimulation test
two doses of hydrocortisone feels well all morning after the D. CRH stimulation test
first dose but has fatigue and nausea later in the day, consider- A pituitary MRI is normal.
ation should be given to three doses, a larger second dose, or 3. Which of the following studies would you secure in this
switching to a longer-acting glucocorticoid. gentleman?
A serum cortisol measurement after a hydrocortisone dose is A. A measurement of long-chain fatty acids
occasionally useful to document good absorption, but a single B. 21-hydroxylase antibodies
value has limited utility for assessing drug exposure. Some C. A synthetic glucocorticoid screen
clinicians measure day curves with frequent cortisol sam- D. 17-hydroxyprogesterone
pling on the outpatient regimen, but this procedure is generally A synthetic glucocorticoid screen was negative. Exogenous
not feasible in the United States. ACTH measurements are not glucocorticoid therapy is the most common cause of cortisol
helpful in patients with adrenal insufficiency to guide therapy, deficiency. Many patients are not aware of which compounds
as ACTH remains high despite appropriate doses of are being injected in their joints and epidural space. Given that

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

the effect of such injections may suppress the HPA axis for many insufficiency reported. The most likely explanation is that super-
months, the patients may have even forgotten about the steroid imposed acute stressful events seem to probably easily override
treatment. In addition, there are many arthritis remedies from Asia the opioid-induced HPA axis suppression. Moreover, as the opioid
and Latin America (available over the Internet) that may have effect dissipates, there seems to be a very prompt hyper-response
unrecognized and high doses of various synthetic corticosteroids. of the HPA axis function. The accompanying volatility of HPA
A synthetic glucocorticoid screen (Mayo Clinic with tandem mass axis function in patients on chronic opioids makes the assessment
spectroscopy) is commercially available and provides assessment of pituitary adrenal function in these patients very challenging. It
of many common synthetic glucocorticoid products. is not clear whether and how opioid-induced decreases in HPA
4. Two weeks after the initial visit, the patients mother calls axis function should be treated.
you and says she found which of the following in his
dresser drawer? Case 2
A. Marijuana A 64-year old man was found to have bilateral adrenal enlarge-
B. Cocaine ment with a discrete 6.9-cm left adrenal mass on a positron
C. DHEA emission tomography computed tomography (PET/CT) scan
D. Buprenorphine performed for suspected right tonsillar malignancy. Adrenocor-
tical carcinoma (ACC) was suspected, and laparoscopic left
Discussion adrenalectomy was performed. Pathology was interpreted as
The concept of adrenal fatigue is imaginary. There is no scien- having features of low-grade ACC, and he was treated with
tific evidence to support its existence. Adrenal fatigue has been mitotane. Follow-up PET/CT showed increased metabolic ac-
promoted by integrative medicine and naturopathic medicine tivity in the right testicle, and he underwent right orchiectomy.
for many years based on salivary cortisol day curves. These Pathology showed two small yet distinct masses, which were
particular practitioners employ intentionally arbitrary and very interpreted as consistent with metastatic ACC. Upon referral to
narrow reference ranges for these salivary day curves, so that our VA hospital, physical examination showed normal BP, short
most patients will have at least one measurement outside of this stature, normal secondary sexual characteristics, and diffusely
so-called normal range. The idea that chronic stress physi- tanned skin with hyperpigmentation in the surgical scars. Basal
cal or psychological may somehow down regulate the HPA testing at 0800 hours showed plasma ACTH, 1400 pg/mL (300
axis is not supported by any good clinical science. In fact, the pmol/L) and serum cortisol, 2.3 g/dL (30 nmol/L).
contrary is true. Patients with chronic fatigue syndrome have 5. Which of the following tests would you do next?
not been shown to have any consistent dysregulation of A. Stop mitotane and give etoposide, daunorubicin, and
pituitary-adrenal function, and well-designed randomized con- cisplatin (EDP).
trolled trials assessing the use of hydrocortisone in these pa- B. Take a family history and measure serum 17-hydroxypro-
tients have shown only short-term benefit. In addition, patients gesterone.
with post-traumatic stress disorder may have basal cortisol C. Measure DHEAS and corticosteroid-binding globulin.
levels slightly lower than healthy subjects, but there is clearly a D. Perform 250-g CST.
hyper-responsiveness of the HPA axis during periods of stress,
and this heightened sympatho-adrenal response may contribute
to dysphoria and rage seen in some of these patients. Discussion
Although suppression of the hypothalamic-pituitary-gonadal The correct answer is B. This man has four siblings, three with
axis related to opioid use is well known, the potential suppres- short stature who were tall as children, including a sister born
sion of the HPA axis in patients receiving narcotics is much with ambiguous genitalia. Review of the adrenal and testicular
less well appreciated. The interactions of opioids with HPA pathology revealed identical adrenocortical masses with focal
axis are complex and poorly understood. Early studies in pigmentation. The masses lacked the usual features associated
methadone addicts found lower plasma cortisol and ACTH with malignant behavior, such as invasion, high mitotic activ-
responses to naloxone. Approximately 70% of heroin addicts ity, and necrosis. Foci of myelolipoma and tight collections of
have been shown to have an impaired cortisol response to the lymphocytes were also present in the left adrenal mass, and the
CST. The findings for most studies support the concept that testicular masses were testicular adrenal rest tumors. His
opioids act on neurotransmitters that regulate the secretion of 17-hydroxyprogesterone (17-OHP) was 4500 ng/dL (1500
corticotroph-releasing hormone (CRH) thereby suppressing nmol/L), which with the elevated plasma ACTH and serum corti-
ACTH and cortisol. The most likely cause of adrenal insuffi- sol less than 5 g/dL established the diagnosis of classic
ciency in this patient is the surreptitious use of buprenorphine. 21-hydroxylase deficiency (21-OHD). He has classic, not nonclas-
Buprenorphine is a mixed agonist-antagonist effect on the sic, 21-OHD, given that he meets criteria for primary adrenal
and opioid receptors. Given the widespread use of opioids insufficiency, and his 17-OHP is well above 1000 ng/dL.
for chronic pain management, it seems surprising that there Wait a minute! How can he have classic 21-OHD? He
have only been a few cases of opioid-induced clinical adrenal served in the military, survived at least two surgeries, and did

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

not present to endocrine attention until in his 60s. All true. But serious illness is actually accompanied by decreases in plasma
remember, a serum cortisol of 2-3 g/dL will still activate GR ACTH but maintenance of high levels of serum cortisol. This
fairly well and maintain day-to-day physiology in well patients. disassociation of ACTH and cortisol seems to be related, in
Even surgery, if a major body cavity is not entered and blood large part, to decreases in peripheral cortisol metabolism me-
loss is low, is not an extreme stress. Children undergoing minor diated by impaired activity of cortisol-metabolizing enzymes
urologic procedures have a serum cortisol of 3-5 g/dL during in the liver and kidneys (9). Another possible explanation
the procedure with a slight increase upon reversal of anesthesia for this may be increased adrenocortical sensitivity to
(29). He likely has the intron 2 splice mutation or possibly I172N, ACTH or possible changes in post-translational processing
and both of these alleles yield a little 21-hydroxylase activity. It of pro-opiomelanocortin with liberation of fragments of
would be unlikely, however, that he would sustain systemic sepsis ACTH that are biologically active but poorly measured in
or a major myocardial infarction without experiencing an adrenal immunoassays. In addition, serious illness is often accompa-
crisis, unless treated with glucocorticoids. The point of our pre- nied by decreases in protein synthesis of the major binding
senting this case is to emphasize that routine physiology in well protein for cortisol, CBG. This decrease results in high frac-
patients does not require much cortisol. In addition, this case tional concentrations of free circulating cortisol (as might be
should remind you that occasional cases of classic 21-OHD born reflected in salivary cortisol measurements). In sites of inflam-
before newborn screening are still diagnosed late into adulthood mation during critical illness, CBG may actually be an impor-
with incidental adrenal masses. tant carrier protein for cortisol to these sites, where CBG is
cleaved by neutrophil elastase. The real meaning of any corti-
Case 3 sol level during critical illness should probably be assessed by
You are consulted on a 73-year-old man with type 2 diabetes measurements of glucocorticoid-mediated gene expression and
mellitus who represented with lobar pneumonia 6 days prior to signaling pathways, which is not something that can be per-
your consultation. During the past 36 hours he has developed formed clinically. Adrenal androgen and mineralocorticoid
fever, hypotension, and decreased urine output mandating ad- production seem to decrease during prolonged serious illness.
mission to the Intensive Care Unit. Respiratory failure required There is a disassociation between renin and aldosterone during
intubation and mechanical ventilation and sedation. He was critical illness that is not well understood (16).
receiving aggressive iv isotonic fluid replacement, broad- The American College of Critical Care Medicine has pro-
spectrum antibiotics, and a continuous insulin infusion. posed the term critical illness-related corticosteroid insuffi-
His electrolyte composition was normal. He has a total ciency. They have suggested that any random total cortisol
serum calcium of 7.9 mg/dL and a serum albumin of 1.9 less than 10 g/dL (276 nmol/L) during critical illness estab-
mg/dL. Glucose was well controlled with the insulin infusion. lishes the diagnosis of corticosteroid insufficiency. Despite this
The intensivist performed an assessment of adrenal function. A policy, there is not any good evidence that slightly low serum
basal serum cortisol was 11 g/dL (351 nmol/L) with a peak total cortisol is a significant contributing factor to poor out-
response of 17.5 g/dL (407 nmol/L). A serum aldosterone comes or that high-dose hydrocortisone therapy provides any
was 3.5 ng/dL and a plasma renin activity was 12 ng/mL/h. benefit in patients with sepsis. A systematic review of six
Basal plasma ACTH was 17 pg/mL. high-quality randomized trials has not shown any decrease in
6. Which of the following tests would you do next? mortality with hydrocortisone therapy (10), including the CORTICUS
A. Administer hydrocortisone with fludrocortisone trial of 499 randomly assigned patients (11). There is an ongo-
B. Initiate high-dose dexamethasone ing randomized multicenter trial (NCT01448109; ClinicalTrials.gov)
C. Measure plasma free cortisol and/or salivary cortisol that is planning to investigate the effect on 90-day mortality
D. Obtain a pituitary MRI from high-dose hydrocortisone therapy for 1 week in more than
3000 patients with the systemic inflammatory response
Discussion syndrome/sepsis.
Mechanisms to cope with critical illness are mediated by com- In summary, the concept of relative adrenal insufficiency
plex endocrine responses. The HPA axis is an important com- during critical illness is controversial. Free cortisol concentra-
ponent because increased exposure to cortisol is important to tions seem to be quite normal in most these patients, particu-
provide energy and support cardiovascular function as well as larly those with serum albumin less than 2.5 mg/dL, and there
reduce excessive inflammation in seriously ill patients. Failure is very little evidence that exogenous glucocorticoid therapy
of this stress response may have contributed to poor outcomes provides any measurable benefit. Certainly, there are many
in patients, and there has always been concern and controversy things done to seriously ill patients that may attenuate HPA
about the possible presence of relative adrenal insufficiency function including the administration of high-dose corticosteroids as
during critical illness. Acute stress is accompanied by increases well as many psychotropic medications. Nonetheless, it is cer-
in circulating ACTH, and stimulation of steroidogenic enzyme tainly prudent to evaluate the HPA axis in any seriously ill
expression to increase cortisol production. However, protracted hypotensive/febrile patient. Measurement of free cortisol

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

(plasma or saliva) may be necessary to establish an accurate 16. Findling JW, Waters VO, Raff H. The dissociation of renin and aldoste-
rone during critical illness. J Clin Endocrinol Metab. 1987;64:592-595.
assessment of adrenocortical function.
17. Bancos I, Erickson D, Bryant S, et al. Performance of free versus total
cortisol following cosyntropin stimulation testing in an outpatient setting.
REFERENCES Endocr Pract. 2015;21:1353-63.
18. Lewis JG, Bagley CJ, Elder PA, Bachmann AW, Torpy DJ. Plasma free
1. Addison T. On the constitutional and local effects of disease of the
cortisol fraction reflects levels of functioning corticosteroid-binding globu-
suprarenal capsules. London: Samuel Highley, 1855.
lin. Clin Chim Acta. 2005;359:189-194.
2. Bright R, Addison T. The elements of the practice of medicine. London:
19. Aardal-Eriksson E, Karlberg BE, Holm AC. Salivary cortisolan alterna-
Longman, Orme, Brown, Green, and Longmans, 1839.
tive to serum cortisol determinations in dynamic function tests. Clin Chem
3. Rooke T. The quest for cortisone. East Lansing: Michigan State University
Lab Med. 1998;36:215-222.
Press, 2012.
20. Torpy DJ, Bachmann AW, Grice JE, et al. Familial corticosteroid-binding
4. Mussig K, Knaus-Dittmann D, Schmidt H, et al. Secondary adrenal failure
globulin deficiency due to a novel null mutation: association with fatigue
and secondary amenorrhoea following hydromorphone treatment. Clin
and relative hypotension. J Clin Endocrinol Metab. 2001;86:3692-3700.
Endocrinol (Oxf). 2007;66:604-605.
21. Brett EM, Auchus RJ. Genetic forms of adrenal insufficiency. Endocr
5. Oltmanns KM, Fehm HL, Peters A. Chronic fentanyl application induces Pract. 2015;21:395-399.
adrenocortical insufficiency. J Intern Med. 2005;257:478-480. 22. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis
6. Schimke KE, Greminger P, Brandle M. Secondary adrenal insufficiency in educated patients with chronic adrenal insufficiency: A prospective
due to opiate therapy - another differential diagnosis worth consideration. study. J Clin Endocrinol Metab. 2015;100:407-416.
Exp Clin Endocrinol Diabetes. 2009;117:649-651. 23. Monaghan PJ, Owen LJ, Trainer PJ, Brabant G, Keevil BG, Darby D.
7. Facchinetti F, Volpe A, Farci G, et al. Hypothalamus-pituitary-adrenal axis Comparison of serum cortisol measurement by immunoassay and liquid
of heroin addicts. Drug Alcohol Depend. 1985;15:361-366. chromatography-tandem mass spectrometry in patients receiving the
8. Qureshi AC, Bahri A, Breen LA, et al. The influence of the route of 11-hydroxylase inhibitor metyrapone. Ann Clin Biochem. 2011;48:441-446.
oestrogen administration on serum levels of cortisol-binding globulin and 24. Nasrallah MP, Arafah BM. The value of dehydroepiandrosterone sulfate
total cortisol. Clin Endocrinol (Oxf). 2007;66:632-635. measurements in the assessment of adrenal function. J Clin Endocrinol
9. Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism Metab. 2003;88:5293-5298.
during critical illness. N Engl J Med. 2013;368:1477-1488. 25. Sayyed Kassem L, El Sibai K, Chaiban J, Abdelmannan D, Arafah BM.
10. Marik PE. Critical illness-related corticosteroid insufficiency. Chest. Measurements of serum DHEA and DHEA sulphate levels improve the
2009;135:181-182. accuracy of the low-dose cosyntropin test in the diagnosis of central
11. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients adrenal insufficiency. J Clin Endocrinol Metab. 2012;97:3655-3662.
with septic shock. N Engl J Med. 2008;358:111-124. 26. Stewart PM, Corrie J, Seckl JR, Edwards CR, Padfield PL. A rational
12. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free approach for assessing the hypothalamo-pituitary-adrenal axis. Lancet.
cortisol in critically ill patients. N Engl J Med. 2004;350:1629-1638. 1988;1(8596):1208-1210.
13. Raff H, Brock S, Findling JW. Cosyntropin-stimulated salivary cortisol in 27. Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical diagnosis of adre-
hospitalized patients with hypoproteinemia. Endocrine. 2008;34:68-74. nal insufficiency: the added value of dehydroepiandrosterone sulfate mea-
14. Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary surements. Endocr Pract. 2011;17:261-270.
cortisol concentration in the assessment of adrenal function in critically ill 28. Auchus RJ, Shewbridge RK, Shepherd MD. Which patients benefit from
subjects: a surrogate marker of the circulating free cortisol. J Clin provocative adrenal testing after transsphenoidal pituitary surgery? Clin
Endocrinol Metab. 2007;92:2965-2971. Endocrinol (Oxf). 1997;46:21-27.
15. Arafah BM. Hypothalamic pituitary adrenal function during critical ill- 29. Taylor LK, Auchus RJ, Baskin LS, Miller WL. Cortisol response to
ness: limitations of current assessment methods. J Clin Endocrinol Metab. operative stress with anesthesia in healthy children. J Clin Endocrinol
2006;91:3725-3745. Metab. 2013;98:3687-3693.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Evaluation and Management of the Adrenal Mass

CMF10 these components of the adrenal gland produce vital steroid

Presented, April 1 4, 2016 hormones such as cortisol, aldosterone, and sex hormones, as
well as catecholamines such as epinephrine, norepinephrine,
and dopamine.
Anand Vaidya, MD, MMSc; Mouhammed Amir The rapid proliferation of noninvasive imaging has given
Habra, MD. Division of Endocrinology, Diabetes and rise to unexpected and incidentally discovered findings. An
Hypertension, Brigham and Womens Hospital/Harvard incidentally discovered adrenal mass is generally defined as an
Medical School, Boston, Massachusetts 02115, E-mail: adrenal tumor, usually 1 cm or more in diameter, that is
anandvaidya@bwh.harvard.edu; and The University of observed in the absence of signs or symptoms suggestive of
Texas M D Anderson Cancer Center, Department of adrenal disorders by imaging studies ordered for nonadrenal
Endocrine Neoplasia and Hormonal Disorders, Houston, indications. The precise incidence and prevalence of adrenal
Texas 77030, E-mail: mahabra@mdanderson.org tumors is unknown; however, prevalence estimates between 1
and 7% are accepted as a general approximation based on
INTRODUCTION autopsy and imaging series (5 8). Importantly, the prevalence
Historical Overview of adrenal masses is significantly higher with older age. Adre-
The first written description of the adrenal glands as suprarenal nal masses are rare in individuals less than 30 years of age
organs is often attributed to Galen, dating back nearly 2000 (1%), but may be seen in up to 7% of individuals over the
years (1). More detailed anatomical and physiological insights age of 70 years (9). Therefore, in locations where abdominal
into the location and function of the adrenal glands were imaging is frequently used, clinicians should anticipate a sig-
produced over the subsequent centuries, with notable contribu- nificant number of incidentally discovered adrenal masses.
tions by Batholemeus Eustachius in the 1500s, Thomas The assessment of patients with adrenal tumors should in-
Wharton in the 1600s, and Thomas Addison in the 1800s (1, clude evaluation for both the malignant potential of the adrenal
2); however, the first description of an adrenal tumor is attrib- mass as well as the potential for adrenal hormone overproduc-
uted to Felix Frankel in 1886 (3). Dr Frankel described the case tion. Adrenal hormone excess may result in subtle or overt
of Minna Roll, a young woman who died suddenly following clinical manifestations associated with long-term cardiovascu-
repeated attacks of paroxysmal anxiety, in whom bilateral ad- lar, musculoskeletal, and/or metabolic complications. Most ad-
renal tumors were discovered on autopsy. In 2007, a study of renal masses represent benign and nonfunctional entities; how-
Minna Rolls extended family and descendents confirmed ever, the determination of benign or malignant status requires
germline mutations in RET as well as a family history of careful consideration of clinical and radiographic evidence.
medullary thyroid cancer and pheochromocytoma; therefore, Rarely, adrenal masses are malignant. This session will
implicating Minna Roll as the first case of pheochromocytoma review the approach to an incidentally discovered adrenal
described (3, 4). mass, with emphasis on the clinical elucidation of whether a
The advent and proliferation of rapid cross-sectional ab- mass is benign or malignant, and hormonally functional or
dominal imaging in the 20th and 21st centuries has resulted in nonfunctional.
the frequent incidental discovery of adrenal masses, often
termed adrenal incidentalomas. Given that adrenal masses BARRIERS TO OPTIMAL PRACTICE
have the potential to be benign or malignant, as well as hor- Evidence-based guidelines on the management of adrenal
monally active or inactive, practicing clinicians in 2016 are masses rely on small retrospective studies and expert consen-
faced with the challenge of characterizing adrenal masses as sus. There is a lack of longitudinal prospective and intervention
benign and nonfunctional, benign and functional, or malignant. studies to inform the most efficient and cost-effective method
Given the increasing prevalence of incidentally discovered ad- to use imaging in the surveillance of adrenal masses, when to
renal masses, efficient and evidence-based diagnostic and man- employ surgical resection, and regarding the duration and fre-
agement approaches are needed. quency of testing for hormone excess.


Although considered a single organ, the adrenal glands are As a result of participating in this session, learners should be
composed of two distinct areas: the cortex and the medulla. familiar with:
The adrenal cortex serves as a factory for adrenal steroids The differential diagnosis of an adrenal mass.
whereas the medulla originates from neural crest cells and Initiating the biochemical evaluation of an incidentally
produces catecholamines as a neuroendocrine organ. Together, discovered adrenal mass.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Evaluating the radiographic phenotype of an adrenal thought to be nonfunctional may actually produce very small
mass. amounts (or unmeasured forms) of adrenal hormones that con-
The indications for biopsy of an adrenal mass. tribute to subclinical disease (10, 11, 15).
Current evidence regarding the surveillance and Therefore, the diagnostic approach should involve evalua-
management of adrenal masses. tion of three crucial parameters:
Although this session will review the evaluation for The clinical presentation of the patient.
particular states of adrenal hormone excess, this session The biochemical phenotype of the patient to assess for
will not cover the detailed management of disorders of hormone excess.
overt adrenal hormone excess (such as primary The radiographic characteristics to assess for malignant
aldosteronism, Cushings syndrome, or potential.
Clinical Presentation
STRATEGIES FOR DIAGNOSIS, THERAPY, In patients with adrenal masses, detailed medical history is
AND/OR MANAGEMENT essential to guide subsequent testing and management. In par-
Differential Diagnosis and Diagnostic Approach ticular, prior personal history of malignancy (especially breast
The diagnostic approach to an incidentally discovered adrenal cancer, lung cancer, melanoma, colorectal cancer, prostate can-
mass is focused on investigating whether the mass is benign or cer, and renal cell carcinoma) significantly increases the possi-
malignant, and whether it is functional (produces excessive bility of metastasis to the adrenal gland and may warrant
adrenal hormone such as aldosterone, cortisol, or sex steroids) imaging-guided biopsy after excluding pheochromocytoma.
or nonfunctional (Table 1). Excessive cortisol production may Family history is equally important given that adrenal masses
result in the Cushings syndrome, but chronic subclinical originating from the cortex can be seen in multiple hereditary
hypercortisolism is associated with increased risk for cardio- syndromes (multiple endocrine neoplasia type 1, Lynch syn-
vascular and metabolic diseases and death (10 12). Similarly, drome, familial adenomatous polyposis, Li-Fraumeni syn-
excessive aldosterone production in primary aldosteronism can drome, congenital adrenal hyperplasia, and Carneys com-
cause the classic clinical picture of resistant hypertension and plex) whereas tumors originating from the adrenal medulla
hypokalemia, but chronic subclinical exposure to inappropri- (pheochromoctyoma) can be seen in the context of familial
ately high aldosterone may also increase the risk of cardiovas- pheochromocytoma-paraganglioma syndromes associated with
cular and metabolic diseases by activating the mineralocorti- succinate-dehydrogenase mutations, Von-Hipple Lindau syn-
coid receptor (13, 14). Excessive catecholamine production drome, neurofibromatosis type 1, and multiple endocrine neo-
associated with pheochromocytomas can contribute to or worsen
plasia type 2. The clinical assessment for adrenal hormone
cardiovascular and psychiatric diseases. In recent observational
excess should include assessment for features of aldosterone
studies, even adrenal masses with no detectable hormone produc-
excess (resistant or difficult to control hypertension, hypokale-
tion are associated with poorer cardiometabolic profiles and po-
mia), cortisol excess (weight gain, difficulty to control blood
tentially higher cardiovascular risk, suggesting that tumors
pressure [BP], hyperglycemia, ostopenia or osteoporosis, easy
bruising, proximal muscle myopathy, and others), and cate-
TABLE 1. The Differential Diagnosis for an Incidentally cholamine excess (paroxysmal hypertension, anxiety, sweating,
Discovered Adrenal Mass palpitations). Isolated sex hormone excess is extremely rare;
Nonfunctional Functional however, androgen and estrogen excess is not an uncommon
feature of adrenocortical carcinoma (ACC), which may also
Benign Adenoma Adenoma
(aldosterone or present with cortisol excess in more than 50% of cases. Fur-
cortisol producing) ther, a general assessment for features suggestive of malig-
nancy should also be performed (anorexia, weight loss, night
Cyst/pseudocyst Micro- or macronodular
disease (aldosterone sweats, anemia).
Infection (fungal, or cortisol
mycobacterial, producing)
Biochemical Phenotype
hydatid cyst) All adrenal masses should be evaluated for the presence of
Hemangioma Pheochromocytoma cortisol excess even in the absence of clinical signs or symp-
Malignant Adrenocortical carcinoma Adrenocortical toms of Cushings syndrome given the cardiometabolic risks
Neuroblastoma carcinoma
associated with chronic subclinical hypercortisolism (10 12).
Sarcoma This is most commonly assessed using a 1-mg dexamethasone
Primary adrenal lymphoma suppression test (Table 2); however, other methods of assess-
Metastatic cancer from a Pheochromocytoma ing hypercortisolism can also be used, especially when factors
non-adrenal primary
that alter dexamethasone metabolism are present. Most adrenal

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 2. The Suggested Biochemical Screening Tests for Incidentally Discovered Adrenal Masses
Condition Patients Test Interpretation
Cortisol excess All 1-mg dexamethasone 1.8 mcg/dL: excludes cortisol exess
suppression test 1.85.0 mcg/dL: may suggest sub-clinical cortisol excess
5.0 mcg/dL: suggestive of cortisol excess
Catecholamine ALL, except those adrenal masses Plasma fractionated ULN: normal
excess with 10 HU attenuation on metanephrines 12.5 ULN: May represent false positive secondary
non-contrast CT and no or to medications that inhibit catecholamine re-uptake
suggestive clinical signs or 24 h urinary mechanisms or increased sympathoadrenergic tone.
symptoms fractionated May be suggestive of pheochromocytoma in the setting
metanephrines of strongly supportive clinical and radiographic features.
Higher than 4 ULN: strongly suggestive of
Aldosterone Hypertension Serum aldosterone ARR 2025 in the setting of a suppressed plasma renin
excess Hypokalemia to plasma renin activity strongly suggestive of hyperaldosteronism
activity ratio (ARR)
Adrenal androgen Hirsutism or virilization DHEAS Higher than ULN
excess Total testosterone

Abbreviation: ARR, aldosterone renin ratio; ULN, upper limit of normal reference range.

masses should also be screened for catecholamine excess given the mass. In general, the more lipid-rich an adrenal mass is, the
the cardiovascular risks associated with subclinical or clinically more likely it represents a benign entity. An unenhanced CT
apparent pheochromocytoma, and the fact that many patients attenuation of less than 10 HU is strongly supportive of a
with pheochromocytoma present without hypertension or other lipid-rich mass and almost always represents a benign entity
classical symptoms associated with catecholamine excess (16). (19, 20). Very low densities, such as 30 to 50 HU, are
The simplest and most sensitive method to screen for catechol- strongly suggestive of myelolipomas, which are generally be-
amine excess is measurement of plasma-fractionated metanephrines; nign tumors. When unenhanced CT attenuations of greater than
however, 24-hour urinary fractionated metanephrines also pro- 10 HU are encountered, the differential diagnosis includes a
vide highly sensitive and fairly specific results (17). In cases in lipid-poor benign adrenal adenoma, or a more vascular tumor
which the adrenal mass displays a noncontrast computed to- such as a pheochromocytoma, or a malignant entity (either
mography (CT) attenuation of less than 10 Hounsfield units primary adrenal or extra-adrenal metastases) or infiltrative in-
(HU), the probability of a pheochromocytoma is almost zero, fection. In these situations, using an iv contrast adrenal wash-
and in these cases testing for catecholamine excess may be out protocol may be helpful, where postcontrast imaging at 1
deemed unnecessary unless there are other clinical features and 15 minutes to evaluate the contrast avidity of the adrenal
suggestive of pheochromocytoma (18, 19). Screening for hy-
peraldosteronism can be performed with a serum aldosterone-
to-plasma renin ratio and should be particularly considered in TABLE 3. Radiographic Characteristics of Adrenal
patients with an adrenal mass associated with hypertension or Masses to Determine Benign or Malignant Potential
hypokalemia. Testing for adrenal androgens or estrogen should be Likely Potentially
considered when clinical signs of virilization (hirsutism, acne, oily Characteristic Benign Malignant
skin, deepening of the voice) are concerning, and in these situa- Size, cm 4 4-6
tions the concern for ACC should be increased. Attenuation on unenhanced CT, HU 10 10
Contrast washout on CT protocol at 50-60 50
15 min, %
Radiographic Characteristics
MRI chemical shift suggestive of Yes No
The radiographic features of an incidentally discovered adrenal
lipid-rich content
mass provide useful information to determine its etiology and
FDG avidity on PET No Yes
particularly whether it may be benign or malignant. Features
Irregular borders, heterogeneous content, No Yes
such as large size, hetereogeneity, calcifications, necrosis, in- calcifications, necrosis
creased vascularity, and rapid rate of growth are all concerning Rate of growth, cm/y 1 1
for a malignant adrenal tumor or metastases (Table 3).
The most common and well-described imaging modality is Abbreviation: MRI, magnetic resonance imaging.
CT. CT provides excellent information on size, homogeneity, Adapted from Miller and Doherty (22).
calcifications, and valuable information on the lipid content of

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

mass is calculated. Masses that retain less than 50% of contrast of malignant features such as growth of the tumor. There is no
material at 15 minutes (washout 50 60%) are very likely to defined consensus on how long patients should be monitored.
be benign (20, 21). A larger size of the adrenal mass may Expert consensus generally recommends annual evaluation of
increase the risk for malignancy; however, size should be the clinical and biochemical phenotypes for up to 4 years,
evaluated in the context of other features that may support whereas for a stable radiographic phenotype for 2 years may be
malignancy. For example, the risk for a malignant entity in- sufficient (7, 8); however, shorter followup may be considered
creases substantially when an adrenal mass is greater than 4 in those deemed to be very low risk (ie, elderly patients and
cm, but if the mass exhibits an unenhanced CT attenuation those with prior imaging suggesting a chronic process), and
of less than 10 HU and no other malignant radiographic longer followup may be considered in those deemed to be at
characteristics, size by itself may not provide sufficient higher risk (ie, younger patients or irregular radiographic find-
support for a malignant etiology (19, 20). ings that are suspicious but not definitive for malignancy).
Other imaging modalities, such as magnetic resonance im- Longitudinal prospective studies are needed to better define the
aging and positron emission tomography, can also provide optimal surveillance frequency and duration.
valuable information when assessing adrenal masses (22)
(Table 3).
Complications and Prognosis
The health complications of adrenal masses are directly related
Management to their malignant potential or biochemical function. Adrenal
The suggested clinical management and approach to an inci- masses that are assessed to be benign and nonfunctional are
dentally discovered adrenal mass is outlined in Figure 1. Sur- currently considered to not pose any health risks. However, a
gery should be considered when hormone excess is confirmed growing field of research has increasingly observed that some
or when radiographic features suggestive of malignancy are
adrenal masses deemed to be nonfunctional by current stan-
detected. The role of biopsy is typically restricted to scenarios
dards may still produce subclinical levels or adrenal hormones
when the differential diagnosis involves an extra-adrenal me-
that evade detection (such as mineralocorticoid and/or glucocorti-
tastases to the adrenal for which systemic medical therapy
coid agonists), and that this mild hormonal excess may result in
would be the most appropriate next step, there is suspicion for
cardiometabolic diseases over time (10 12, 15). In the rare sce-
adrenal lymphoma or sarcoma, or when an infiltrative infection
nario that an adrenal mass represents an ACC, the complications
(often fungal or mycobacterial infections) is suspected. It is not
can be severe and the prognosis generally very poor.
advised that adrenal mass biopsy be conducted in other situa-
tions given the known difficulties in differentiating primary
benign vs malignant adrenal tumors, the risk of tumor spread in MAIN CONCLUSIONS
primary ACC, and the risk of catecholamine crises in potential With the increasing use of cross-sectional abdominal imaging,
pheochromcytomas. When neither hormone excess nor malig- the prevalence and incidence of incidentally discovered adrenal
nancy are identified, patients should be monitored prospec- masses has grown. A systematic approach for evaluating
tively for incident hormonal functionality and the development whether an adrenal mass is benign or malignant, and hormon-

Adrenal Mass

Clinical Presentation

Biochemical Phenotype (-)

Confirm Hormone
Radiographic Characteristics
Radiographic Phenotype
and Localization Benign Appearing Suspicious
<10HU, non-contrast avid, >10HU, >4-6cm, contrast avid,
homogeneous heterogeneous

Consider surgery
If Unilateral: Consider surgery

Concern for extra-adrenal

If <4cm: Biochemical and
Growth>1cm/year metastases or infection: Biopsy
Suspicious radiographic features
Radiographic Surveillance
Hormonal excess If >4-6cm: Consider surgery

FIGURE 1. Algorithm for Management of Adrenal Masses.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

ally active or inactive, is necessary to efficiently manage pa- headache, or any other significant complaints. Abdominal CT
tient care. We propose evaluation of the clinical presentation revealed a heterogeneous 4-cm left kidney mass and a 3-cm
and biochemical phenotype in each patient to determine the heterogeneous left adrenal mass (precontrast density of 20
risk of hormone excess. We recommend reliance on the radio- HU).
graphic characteristics to determine the malignant potential of This adrenal mass is most likely to be a(n):
the mass. Most adrenal masses will represent benign entities. A. Adrenocortical adenoma
There is a need for more longitudinal and prospective studies to B. Adrenocortical carcinoma
determine the thresholds for subclinical adrenal hormone C. Conns tumor (primary aldosteronism)
excess that should trigger clinical action, and the optimal sur- D. Metastatic breast cancer to the adrenal gland
veillance strategies to follow adrenal masses over time. E. Myelolipoma
F. Pheochromocytoma
Case 1 Case 4
A 50-year-old normotensive woman was incidentally found to A 42-year-old woman is found to have a left adrenal mass after
have a left adrenal mass after undergoing an unenhanced ab- undergoing an unenhanced CT scan of her abdomen. The CT
dominal CT scan for pain. The mass is described as being 1.2 scan was performed after she developed a headache, abdominal
cm in size, round, with a homogenous consistency and attenu- pain, and had a syncopal event. The mass is described as being
ation of 4 HU. The right adrenal gland is normal. Her serum 2.2 cm, round, and with an attenuation of 4 HU. One year prior
potassium is 4.2 mmol/L and she takes no antihypertensive to this incident, she was diagnosed with hypertension and
medications. She has no personal history of cancer. treated with lisinopril. Six months prior to this incident she was
This adrenal mass is most likely to be a(n): advised to augment her antihypertensive regimen to include
A. Adrenocortical adenoma amlodipine. During this incident, her BP was found to be
B. Adrenocortical carcinoma 200/100 mm Hg and her serum potassium was 3.2 mmol/L.
C. Conns tumor (primary aldosteronism) This adrenal mass is most likely to be a(n):
D. Metastatic cancer to the adrenal gland A. Adrenocortical adenoma
E. Myelolipoma B. Adrenocortical carcinoma
F. Pheochromocytoma C. Conns tumor (primary aldosteronism)
D. Metastatic cancer to the adrenal gland
Case 2 E. Myelolipoma
A 71-year-old woman was found to have a new left adrenal F. Pheochromocytoma
mass after undergoing an unenhanced abdominal CT scan to
evaluate for pain. The mass is described as being 3.8 2.9
Case 5
1.9 cm, poorly circumscribed, and with an attenuation of 20
A 30-year-old woman presented with new onset of moderate
HU. On close examination of the right adrenal gland, there is a
hirsutism and acne. Laboratory evaluation showed elevations in
suggestion that it may be thickened. The patient has no history
DHEA-sulfate and total testosterone. CT scan of the abdomen
of hypertension, hypokalemia, or hyperandrogenism, but does
revealed a 7.6-cm right adrenal mass with precontrast density
have a remote history of breast cancer (estrogen receptorposi-
of 45 HU and enhancement washout of 69%. Interestingly, she
tive, progesterone receptorpositive, HER2/neu-negative) dat-
reported a history of abdominal imaging 3 years prior to this
ing back more than 10 years prior this presentation. She was
presentation where an incidental 3-cm right adrenal mass was
treated with lumpectomy, chemotherapy, and 10 years of
aromatase inhibitor therapy and considered to be in complete
This adrenal mass is most likely to be a(n):
remission. Her adrenal glands had been normal on repeated
A. Adrenocortical adenoma
staging imaging during the course of the last 10 years.
B. Adrenocortical carcinoma
This adrenal mass is most likely to be a(n):
C. Conns tumor (primary aldosteronism)
A. Adrenocortical adenoma
D. Metastatic cancer to the adrenal gland
B. Adrenocortical carcinoma
C. Conns tumor (primary aldosteronism) E. Myelolipoma
D. Metastatic cancer to the adrenal gland F. Pheochromocytoma
E. Myelolipoma
Case 1
Case 3 The correct answer is an adrenocortical adenoma. The radio-
A 68-year-old man presented with abdominal pain. He denied graphic characteristics of a small, round, and homogenous mass
any prior history of hypertension, weight changes, palpitations, with a lipid-rich attenuation on unenhanced CT are all supportive

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

of a benign entity. Adrenocortical adenomas are the most common Case 5

benign cause of an adrenal mass. All adenomas should still be The combination of hyperandrogenism and large adrenal mass
evaluated for hormone excess; therefore, this patient should un- (6 cm) is highly suspicious for ACC. Interestingly, some
dergo testing for hypercortisolism, ideally with a 1-mg dexameth- patients with ACC report having prior imaging for other rea-
asone suppression test. Testing for hyperaldosteronism is unlikely sons and this can help documenting the growth rate of the
to be informative given her normal BP and serum potassium, and adrenal mass (23, 24). Adrenal masses that grow more than 1
testing for pheochromocytoma is also unlikely to be informative cm per year raise the suspicion of malignancy and require
given that pheochromocytomas are extremely unlikely when the surgical resection. The diagnosis of ACC is often based on nine
attenuation of a mass is less than 10 HU. pathological features (Weiss criteria) with tumors having
Weiss score of 3 being classified as ACC whereas tumors
Case 2 with a Weiss score of 12 being classified as atypical adeno-
The correct answer is metastatic breast cancer to the adrenal mas (or adrenal neoplasms of undetermined malignant poten-
gland. The radiographic characteristics of a relatively large, heter- tial) such as this case.
ogeneous, and nonlipid-rich mass should raise concern for a ma-
lignant entity. The fact that this mass was not apparent on prior REFERENCES
serial images should raise further concern of a relatively rapid- 1. Leoutsakos B, Leoutsakos A. The adrenal glands: A brief historical per-
spective. Hormones (Athens). 2008;7:334-336.
growing entity. The patients personal history of breast cancer, in 2. Shifrin A. The history of adrenal gland tumors. 2012. Available at:
combination with the fact that the contralateral adrenal gland may http://www.adrenaltumors.org/history.
also be affected, raises the suspicion of metastatic disease to the 3. Neumann HP, Vortmeyer A, Schmidt D, et al. Evidence of MEN-2 in the
original description of classic pheochromocytoma. N Engl J Med.
adrenal glands; however, infiltrative infections should also be 2007;357:1311-1315.
considered in this situation. An adrenal biopsy may be useful in 4. Frankel F. Ein Fall von doppelseitigem, vollig latent verlaufenen
this scenario given that the treatment of stage 4 breast cancer, or Nebennierentumor und gleichzeitiger Nephritis mit Veranderungen am
Circulationsapparat und Retinitis. Arch Pathol Anat Physiol Klin Med.
an infiltrative infection, could alter the subsequent decision to 1886;103:244-263.
pursue medical vs surgical treatments. 5. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural
history of adrenal incidentalomas. Eur J Endocrinol. 2003;149:273-285.
6. Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal
Case 3 incidentaloma in a contemporary computerized tomography series. J
In patients with a history of malignancy known to metastasize Endocrinol Invest. 2006;29:298-302.
to the adrenal gland, the presence of a heterogeneous adrenal 7. Nieman LK. Approach to the patient with an adrenal incidentaloma. J Clin
Endocrinol Metab. 2010;95:4106-4113.
mass is most likely to represent metastasis. The presence of
8. Young WF Jr. Clinical practice. The incidentally discovered adrenal mass.
both a heterogeneous and dense renal mass and adrenal mass N Engl J Med. 2007;356:601-610.
should also raise concern for pheochromocytoma and an inher- 9. Young WF Jr. Management approaches to adrenal incidentalomas. A view
from Rochester, Minnesota. Endocrinol Metab Clin North Am. 2000;29:
itable pheochromocytoma-paraganglioma tumor syndrome. It
159-185, x.
is now estimated that up to 40% of all pheochromocytomas and 10. Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and
paraganglioms are attributed to a germline mutation in one of mortality in patients with adrenal incidentalomas that are either non-
15 genes. A significant number of these gene mutations (VHL, secreting or associated with intermediate phenotype or subclinical
Cushings syndrome: A 15-year retrospective study. Lancet Diabetes
SDHA, SDHB, SDHC, SDHC, TMEM127, FH) also involve a Endocrinol. 2014;2:396-405.
lifetime risk of developing a renal cell carcinoma. Pheochro- 11. Androulakis, II, Kaltsas G, Kollias GE, et al. Patients with apparently
mocytoma can be hard to distinguish radiologically from other non-functioning adrenal incidentalomas may be at increased cardiovascu-
lar risk due to excessive cortisol secretion. J Clin Endocrinol Metab.
heterogeneous adrenal tumors and must be ruled out prior to 2014:jc20134064.
surgery or imaging guided biopsy. 12. Morelli V, Reimondo G, Giordano R, et al. Long-term follow-up in
adrenal incidentalomas: an italian multicenter study. J Clin Endocrinol
Metab. 2014;99:827-834.
Case 4 13. Brown JM, Underwood PC, Ferri C, et al. Aldosterone dysregulation with
The correct answer is a Conns tumor. The radiographic char- aging predicts renal vascular function and cardiovascular risk. Hyperten-
acteristics of a small, round, and lipid-rich mass are supportive sion. 2014;63:1205-1211.
14. Vaidya A, Underwood PC, Hopkins PN, et al. Abnormal aldosterone
of a benign entity. All benign adrenal masses should still physiology and cardiometabolic risk factors. Hypertension. 2013;61:886-
undergo biochemical evaluation for subclinical or overt adrenal 893.
hormone excess. In this case, the history of severe hypertension 15. Tuna MM, Imga NN, Dogan BA, et al. Non-functioning adrenal
incidentalomas are associated with higher hypertension prevalence and
and hypokalemia in this young patient should raise particular
higher risk of atherosclerosis. J Endocrinol Invest. 2014;37(8):765-768.
concern for primary aldosteronism and to a lesser degree 16. Mannelli M, Lenders JW, Pacak K, Parenti G, Eisenhofer G. Subclinical
hypercortisolism or catecholamine excess. The evaluation phaeochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012;26:507-
should include serum aldosterone and plasma renin activity, as 515.
17. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and para-
well as a 1-mg dexamethasone suppression test and plasma- ganglioma: an endocrine society clinical practice guideline. J Clin
fractionated metanephrines. Endocrinol Metab. 2014;99:1915-1942.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

18. Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Com- 21. Caoili EM, Korobkin M, Francis IR, et al. Adrenal masses: Characteriza-
parison of CT findings in symptomatic and incidentally discovered pheo- tion with combined unenhanced and delayed enhanced CT. Radiology.
chromocytomas. AJR Am J Roentgenol. 2005;185:684-688. 2002;222:629-633.
19. Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of 22. Miller BS, Doherty GM. Surgical management of adrenocortical tumours.
Nat Rev Endocrinol. 2014;10:282-292.
noncontrast computed tomography attenuation value (hounsfield units) to
23. Nogueira TM, Lirov R, Caoili EM, et al. Radiographic characteristics of
differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland
adrenal masses preceding the diagnosis of adrenocortical cancer. Horm
Clinic experience. J Clin Endocrinol Metab. 2005;90:871-877. Cancer. 2015;6:176-181.
20. Korobkin M, Brodeur FJ, Yutzy GG, et al. Differentiation of adrenal 24. Ozsari L, Kutahyalioglu M, Elsayes KM, et al. Preexisting adrenal masses
adenomas from nonadenomas using CT attenuation values. AJR Am J in patients with adrenocortical carcinoma: clinical and radiological factors
Roentgenol. 1996;166:531-536. contributing to delayed diagnosis. Endocrine. 2015. [Epub ahead of print].

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Management of Classical CAH: From Birth to Adulthood

M01 complications such as short stature, hypertension (HTN), obe-

Presented, April 1 4, 2016 sity, insulin resistance, and infertility. Furthermore, glucocorti-
coid therapy is far from perfect, resulting in either overtreat-
ment or suboptimal suppression of adrenal androgen secretion.
Maria G. Vogiatzi, MD. Department of Endocrinology Optimizing care and addressing all the medical needs of these
and Diabetes, Childrens Hospital of Philadelphia, patients becomes, therefore, very important.
Philadelphia, Pennsylvania 19104, E-mail: vogiatzim@email.
Children and adults with CAH are at an increased risk for
INTRODUCTION various complications such as short stature, obesity, insulin
Historical Overview resistance, infertility and a reduced quality of life (QOL). These
Congenital adrenal hyperplasia (CAH) was first documented by are related to either excessive treatment with glucocorticoids or ad-
Luigi DeCrecchio, an Italian anatomist, in 1865. Upon autopsy, renal androgen excess.
DeCrecchio found a female patient to have enlarged adrenal The goal of therapy in CAH is to provide optimal control of
glands, male seeming genitals but no testes, and an internal adrenal androgen secretion while avoiding overtreatment with
female reproductive system. There was no effective medical or glucocorticoids. However, recent studies suggest that hormonal
surgical treatment for CAH until 1950 when the discovery was control is frequently not optimal and that many patients are
made independently by Wilkins et al (18) at John Hopkins either overtreated or undertreated.
Hospital and Bartter et al (19) at Massachusetts General
Hospital that cortisone suppressed the elevated urinary
17-ketosteroids. This provided the first clue that the true basis LEARNING OBJECTIVES:
As a result of participating in this session, learners should be
of the disease was inadequate corticoid production. In 1962,
able to:
the 21-hydroxylase deficiency form of CAH was discovered to
Detail the more frequent complications of untreated
be transmitted as a genetic trait that affects both males and
CAH in both children and adults including short stature,
females. A better understanding of the genetic transmission of
HTN, obesity, insulin resistance, infertility, and an
CAH was gained in 1978, when the gene for 21-hydroxylase
impaired QOL.
deficiency was discovered to be located on the short arm of the
sixth chromosome. At an International Newborn Screening Understand the relationship between genotype and
Meeting held in Tokyo in 1982, CAH was recommended as a glucocorticoid therapy with regard to health,
disease that meets the criteria to be included in newborn psychosexual adjustment, and QOL in individuals with
screening systems. classical CAH.


CAH refers to a group of inherited autosomal-recessive disor- AND/OR MANAGEMENT
ders that lead to defective steroidogenesis. The most common Beyond optimizing adrenal control, individuals with CAH have
form of CAH, 21-hydroxylase deficiency (21OHD), accounts multiple medical needs that may vary across life span (Figure
for approximately 95% of all cases. In Its severe form, named 1). Herein, we present various cases to review some frequent or
classical CAH, 21OHD is associated with cortisol and/or newly appreciated complications that occur in patients with
mineralocorticoid deficiency (salt wasting or simple viriliz- classical CAH.
ing types respectively). In this presentation, the term CAH
Classical CAH is a potentially fatal disorder. With the intro- Case 1
duction of glucocorticoid therapy in the 1950s and the applica- A 20-month-old girl with salt-wasting CAH is found to have a
tion of newborn screening, patients with CAH are living lon- blood pressure (BP) of 133/105 mm Hg during a viral illness.
ger. As the number of affected adults is increasing, CAH has Medications: Hydrocortisone, 5 mg twice daily or 18
become a lifelong chronic disease. A number of recent studies mg/m2/d
have shed light into the health and quality of life (QOL) Fludrocortisone, 0.15 mg daily
outcomes of these patients. The results suggest that many live a Na supplements, 500 mg in the morning and 1000 mg in
healthy and productive life and are well adjusted psychoso- the evening
cially. However, a significant number suffer from unwanted Genotype: R356W/Intron 2G

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Figure 1. Medical needs and frequent health concerns in classical CAH from birth to adulthood.

Laboratory results: Na, 142 mEq/L; K, 3.0 mEq/L; 17 is between 9 and 10 years, and height prediction by BP is
hydroxyprogesterone (17 OH Prog), 230 ng/dL; practically unchanged at 168 cm (close to 66).
androstendione, 16 ng/dL; T 3 ng/dL; renin, 0.1 ng/mL/h 4. What is the typical height deficit in CAH and what are
Heart echocardiogram: moderate left ventricular the factors that influence height outcomes?
hypertrophy 5. Is there a role for GH therapy in such cases?
Disposition: fludrocortisone was decreased to 0.05 mg 6. Should he be monitored for central precocious puberty?
Na supplementation was discontinued
She was started on nifedipine and propranolone Discussion
Outcome: HTN resolved after 23 years A recent meta-analysis by Muthusamy et al (1) suggests that
final height in CAH is at 1.38 SDS (1.56 to 1.20; I2
1. What are the rates of HTN in individuals with CAH?
90.2%), whereas final height SDS midparental height SDS is
2. What factors contribute to the development of HTN in
1.03 (1.20 to 0.86; I2 63%). Although there is variability
3. Do rates of HTN increase with age? among studies, final height SDS was not associated with gen-
der, age of onset of puberty, type or dose of steroids. GH,
frequently used in combination with pubertal suppression, im-
proves final height in nonrandomized studies. Most of the
Hypertension is common, particularly in children. Studies
document a relationship to body mass index and children with CAH experience normal puberty, but there is a
fludrocortisone dose. Mineralocorticoid replacement therapy subgroup with sexual precocity. Menarche usually occurs at a
should avoid suppressing plasma levels of renin below the normal age.
normal range, and blood pressure (BP) should be monitored
regularly in both children and adults. Case 3
A 20-year-old noncompliant men with classical CAH com-
Case 2 plains of right testicular pain.
A 6-year-old boy with classical CAH is found to have a bone Sonogram: right testis, 4-mL mass; left testis, 1-mL
age between 8 and 9 years during routine endocrine followup. mass
Physical Examination: Height, 75%; weight, 50th Laboratory results: 17 OH Prog, 4260 mg/dL;
percentile; evidence of adrenarche (Pubic hair Tanner II; androstendione, 440 ng/dL; T, 420 mg/dL; LH, 2.1 IU/L,
testis, 2 mL)
FSH, 3.1 IU/L
Family history: midparental height, 50; height prediction
Sperm Count: moderate oligospermia
by BP, 167 cm (close to 66)
Meds: Hydrocortisone, 18 mg/m2/d; fluodrocortisone, 0.1
Medications: hydrocortisone, 15 mg/m2/d;
fludrocortisone, 0.1 mg daily mg daily
Laboratory results: 17 OH Prog, 1200 ng/dL; 7. What are the rates of Testicular Adrenal Rest Tumor
androstendione, 64 ng/dL; T, 10 ng/dL (TART) and the most appropriate management?
A year later at age 7 years, and after improving adrenal 8. What are the fertility rates in males with classical CAH
control, his growth rate has slowed down, the repeat bone age and the factors leading to reduced fertility?

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 1. Hydrocortisone (HC) Pharmacokinetics in 48 Individuals With Classical CAH (6-20 yr)
Hindmarsh PC Clin Endocrinology 2015
Oral HC (Cmax) (mcg/dl) 28 2.2
(tmax) (min) 66.7 5.9 (range: 20118)
Time to 3.6 mcg/dl (min) 289 15 (range 140540)
IV HC (15 mg/m2) Half-life (min) 76.5 5.2 (range: 40225 min)

Discussion Case 5
Fertility rates are decreased in men with classical CAH; testicular A 4-year-old boy has diagnosed with classical CAH by new-
adrenal rest tumors are a common cause of infertility, require surveil- born screening. He has been treated with glucocorticoids and
lance with repeated ultrasonography, and can respond to therapy with mineralocorticoids since 10 days of life. The family is contem-
glucocorticoids. In addition, dysregulation of hypothalamic-pituitary- plating a second pregnancy. The genotype of the patient was
gonadal axis and Leydig and Sertoli cell dysfunction also contribute performed and revealed a deletion in both CYP21A2 alleles.
to the decreased fertility rates in males. 13. What are the main concerns about prenatal therapy in
14. What is the role of free fetal DNA determination in
Case 4
prenatal diagnosis and therapy?
A 17-year-old girl was diagnosed with classical CAH at birth
when she presented with ambiguous genitalia. She has been
treated with glucocorticoids and mineralocorticoids since 7 Discussion
days of life and underwent genital surgery at first year of life. Dexamethasone is effective in reducing or eliminating viriliza-
tion of affected female fetal genitalia. However, it is a category
The family is very compliant, and except for a body mass index
B drug, whose safety in pregnancy is not established. Systemic
greater than the 95th percentile, the child is doing well and has
review and meta-analysis of publications that examined preg-
never experienced salt wasting. She is now ready to go to
nancy outcomes suggest no statistically significant effect on
college. Parents question the need for fludrocortisone therapy
birth weight and no increased teratogenicity. A small but rig-
and are worried about the long-term effect of surgery and
orous study showed worse verbal working memory, lower
steroids on sexuality and QOL. Genotype of the patient was self-perception of scholastic competency, and increased self-
performed and revealed an Int2 mutation in one CYP21A2 rated anxiety among exposed, unaffected children. It is advised
allele and a deletion in the other. that prenatal therapy to be considered only under internal
9. Is this patient a salt waster? What are the phenotype- review boardapproved protocols. Lately, early sex determina-
genotype correlations in CAH? tion using free fetal DNA in maternal circulation around 5-6
10. Does she need a urological/gyn evaluation? weeks of gestation has been shown to be effective in prevent-
11. Is there an effect of genotype on gender behavior, ing exposure of male fetuses to prenatal dexamethasone. Suc-
sexuality, and family planning? cessful prenatal diagnosis using free fetal DNA has been re-
12. What are the factors that may affect QOL in CAH? ported by Dr News group (15).

Discussion Case 6
A 25-year-old woman with salt-wasting CAH is contemplating
In general, the genotype correlates well with the severity of
cortisone and aldosterone deficiencies, especially in salt-
14. What is true in her case?
wasting and nonclassical (ie, mild) forms. Gender-atypical be-
A. She is at increased risk for miscarriage and other
havior in women with CAH also correlates with genotype.
gestational complications such as diabetes and pre-
However, gender identity disorder is rare in these patients. The
results on QOL in adults are inconsistent. Delayed start to B. She will most likely require cesarean section
sexual activity and fewer relationships have been reported in C. Adrenal androgens increase during pregnancy and
both women and men. Psychosexual difficulties in women have she is likely to have multiple adjustments of her
been linked to genotype and the type of corrective surgery. glucocorticoid doses
However, these results reflect older surgical techniques and D. Babies born to mothers with CAH have low birth
data with most recent techniques are sparse. Finally, certain weight
studies have linked obesity with prednisone or dexamethasone E. Baby girls born to mothers with CAH can be viril-
therapy and impaired QOL. ized if maternal adrenal control is poor

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Discussion born with classic 21-hydroxylase deficiency. A French national survey.

Spontaneous miscarriages have been reported at higher rates J Clin Endocrinol Metab. 2015;100(6):2303-2313.
7. Han TS, Conway GS, Willis DS, et al. Relationship between final height
among glucorticoid-untreated women compared with the gen- and health outcomes in adults with congenital adrenal hyperplasia: United
eral population. Cesarean section is usually performed in indi- Kingdom congenital adrenal hyperplasia adult study executive (CaHASE).
J Clin Endocrinol Metab. 2014;99(8):E1547-E1555.
viduals with prior genital reconstructive surgery. There is no
8. Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital
consensus or established guidelines for the management of adrenal hyperplasia: A cohort study of 203 patients. J Clin Endocrinol
glucocorticoid or mineralocorticoid doses during pregnancy. Metab. 2010;95(11):5110-5121.
9. Volkl TM, Ohl L, Rauh M, Schofl C, Dorr HG. Adrenarche and puberty in
Fetal outcomes are thus far reassuring with lack of fetal
children with classic congenital adrenal hyperplasia due to 21-hydroxylase
masculinization. deficiency. Horm Res Paediatr. 2011;76(6):400-410.
10. Bonfig W, Roehl FW, Riedl S, et al. Blood pressure in a large cohort of
children and adolescents with classic adrenal hyperplasia (CAH) due to
MAIN CONCLUSIONS 21-hydroxylase deficiency. Am J Hypertens. 2015;hpv087. [Epub ahead of
Recent studies suggest that a significant number of children print]
11. Claahsen-van der Grinten HL, Hermus AR, Otten BJ. Testicular adrenal
and adults with classical CAH experience adverse complica- rest tumours in congenital adrenal hyperplasia. Int J Pediatr Endocrinol.
tions related either to the disease itself or the therapy. Therapy 2009:624823.
with glucocorticoids can frequently be challenging and some of 12. Smeets EE, Span PN, van Herwaarden AE, et al. Molecular characteriza-
tion of testicular adrenal rest tumors in congenital adrenal hyperplasia:
these difficulties and variability in outcomes may be related to Lesions with both adrenocortical and Leydig cell features. J Clin
differences in absorption and clearance of administered ste- Endocrinol Metab. 2015100(3):E524-E530.
roids among patients (Table 1). 13. New MI, Abraham M, Gonzalez B, et al. Genotype-phenotype correlation in
1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase
deficiency. Proc Natl Acad Sci U S A. 2013;110(7):2611-2616.
REFERENCES 14. Tardy-Guidollet V, Menassa R, Costa JM, et al. New management strategy
1. Muthusamy K, Elamin MB, Smushkin G, et al. Clinical review: Adult of pregnancies at risk of congenital adrenal hyperplasia using fetal sex
determination in maternal serum: French cohort of 258 cases (2002-2011).
height in patients with congenital adrenal hyperplasia: A systematic review
J Clin Endocrinol Metab. 2014;99(4):1180-1188.
and metaanalysis. J Clin Endocrinol Metab. 2010;95(9):4161-4172.
15. New MI, Tong YK, Yuen T, et al. Noninvasive prenatal diagnosis of
2. Lin-Su K, Harbison MD, Lekarev O, Vogiatzi MG, New MI. Final adult
congenital adrenal hyperplasia using cell-free fetal DNA in maternal
height in children with congenital adrenal hyperplasia treated with growth
plasma. J Clin Endocrinol Metab. 2014;99(6):E1022-E1030.
hormone. J Clin Endocrinol Metab. 2011;96(6):1710-1717.
16. Lekarev O, Lin-Su K, Vogiatzi MG. Infertility and reproductive function
3. Lin-Su K, Vogiatzi MG, Marshall I, et al. Treatment with growth hormone in patients with congenital adrenal hyperplasia: Pathophysiology, advances
and luteinizing hormone releasing hormone analog improves final adult in management, and recent outcomes. Endocrinol Metab Clin N Am. 2015
height in children with congenital adrenal hyperplasia. J Clin Endocrinol 2015;44(4):705-722.
Metab. 2005;90(6):3318-3325. 17. Hindmarsh PC, Charmandari E. Variation in absorption and half-life of
4. Bonfig W, Schwarz HP. Overestimation of final height prediction in hydrocortisone influence plasma cortisol concentrations. Clin Endocrinol
patients with classical congenital adrenal hyperplasia using the Bayley and (Oxf). 2015;82(4):557-561.
Pinneau method. J Pediatr Endocrinol Metab. 2012;25(7-8):645-649. 18. Wilkins L, Lewis RA, Klein R, Rosenberg E. Suppression of androgen
5. Finkielstain GP, Kim MS, Sinaii N, et al. Clinical characteristics of a secretion in congenital adrenal hyperplasia. AMA Am J Dis Child.
cohort of 244 patients with congenital adrenal hyperplasia. J Clin 1950;80(5):883-884.
Endocrinol Metab. 2012;97(12):4429-4438. 19. Bartter FC, Forbes AP, Leaf A. Congenital adrenal hyperplasia associated
6. Bouvattier C, Esterle L, Renoult-Pierre P, et al. Clinical outcome, hor- with the adrenogenital syndrome: an attempt to correct its disordered
monal status, gonadotrope axis, and testicular function in 219 adult men hormonal pattern. J Clin Invest. 1950;29(6):797.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Adrenal Insufficiency: Individualized Management

M11 adrenal crises (4, 5). Increased awareness and improved quality
Presented, April 1 4, 2016 of diagnosis, treatment, and management are needed to reduce
Despite state-of-the-art treatment with corticosteroids, quality
Eystein S. Husebye, MD, PhD. Haukeland University of life and working ability is reduced in a substantial number of
Hospital, University of Bergen, N-5053 Bergen, Norway, patients. Many suffer from other autoimmune conditions (3), add-
E-mail: eystein.husebye@med.uib.no ing to the burden of disease. Overtreatment with glucocorticoids
and mineralocorticoids has potential adverse metabolic conse-
INTRODUCTION quences such as overweight, hypertension, cardiovascular disease,
Historical Overview and osteoporosis, although evidence is still scarce.
Tomas Addison of Guys Hospital in London was the first to Most physicians and even specialists in endocrinology rarely
link the typical symptoms of adrenal insufficiency (AI) to manage more than a few patients. Thus, it is reasonable to believe
disease in the adrenal capsules or glands, first in a paper that procedures for diagnosis, treatment, and followup vary
to the South London Medical Society in 1849, followed by greatly. Endocrine Society Guidelines aimed to improve these
his famous monograph of 1855 in which he captures the shortfalls are about to be published (8).
typical clinical features including hyperpigmentation that is
so typical for primary AI. In Addisons own words, The BARRIERS TO OPTIMAL PRACTICE
leading and characteristic features of the morbid state to Suboptimal treatment of adrenal crisis, including lack of
which I would direct attention are, anemia, general languor adequate education of patients to handle acute crises.
and debility, remarkable feebleness of the hearts action, Unavailability of physiological replacement therapy.
irritability of the stomach, and a peculiar change of color in Lack of parameters to monitor glucocorticoid therapy.
the skin, occurring in connection with a diseased condition
of the supra-renal capsules (1). In his first case of 11
patients, tuberculosis was a major cause; others were infil-
As a result of participating in this session, learners should be
trative tumor growth and probably autoimmunity. Only the
able to:
year after, Trousseau named the disease Addisons disease.
Diagnose AI and generate an appropriate differential
Shortly after, Charles Edouard Brown-Sequard adre-
nectomized rabbits, dogs and cats, claiming that they all
Recognize other autoimmune conditions that may be
died in adrenal failure and that the adrenal glands must
coincident with adrenal failure.
contain a life-preserving material. However, it took 40 years
Develop a long-term treatment plan that will prevent
before a pressor substance was found in the adrenal medulla.
adrenal crises and minimize the untoward effects of
After Swingle and Pfiffner treated adrenalectomized cats
glucocorticoid and mineralocorticoid replacement.
with adrenal extracts and made them survive in 1930 (2),
research was intensified, leading to the isolation of
corticosterone by Kendall (1936), deoxycorticosterone by
Reichstein (1938) and the introduction of cortisone in the
treatment of rheumatoid arthritis by Hench in 1949 (3). At
the same time, cortisone became available for Addison pa-
How to Diagnose AI
tients; later, fludrocortisone was added to the treatment, and
Primary AI can be diagnosed in several ways. The short stan-
the combination of hydrocortisone (HC) or cortisone acetate
dard 250-g Synacthen test is considered the gold standard for
(CA) with fludrocortisone is still the standard treatment for
diagnosis. Given either im or iv, S-cortisol at 30 or 60 minutes
AI. On the diagnostic side, a major breakthrough was the identi-
should reach at least 500 nmol/L (18 g/dL). In most cases of
fication of 21-hydroxylase as the major autoantigen in autoim-
primary AI a paired cortisol and ACTH test will suffice to make
mune Addisons disease (2). It is now a standard part of the
the diagnosis. A random S-cortisol level less than 138 nmol/L (5
workup of Addisons disease to test for these autoantibodies.
g/dL) in the combination of an P-ACTH greater than two times
the upper reference limit is most likely diagnostic, but should be
SIGNIFICANCE OF THE CLINICAL PROBLEM confirmed by a Synacthen test.
AI (Addisons disease) is in many cases diagnosed too late (3). Other typical endocrine test results are elevated plasma
Patients die before the diagnosis is made, and even with known renin activity/renin concentration, low aldosterone, and
adrenal insufficiency, untimely deaths are seen as a result of dehydroepiandrosterone sulfate (DHEA-S). TSH levels can

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

be slightly increased due to lack of cortisol-mediated inhi- In autoantibody-negative individuals genetic causes should
bition of pituitary TSH production. Typical routine labo- be considered in children, particularly adrenoleukodystrophy
ratory findings in untreated AI are hyponatremia, hyperka- (ABCD1 mutations) and adrenal hypoplasia congenital, with
lemia, hypercalcemia, normochromic anemia, sometimes eo- hypogonadotropic hypogonadism (DAX1 mutations). Other causes
sinophilia, and elevated liver transaminases. should be sought guided by medical history, symptoms, and signs
(Causes of adrenal insufficiency, Table 1). The antibody negatives
How to Determine the Cause of AI are more frequent among children and the elderly (age 60 y). A
All patients diagnosed with AI should have its cause determined. computer tomography of the adrenals should be performed. It can
Given that autoimmunity is the overwhelmingly most common reveal atrophy, tumors, calcifications as a sign of tuberculous
cause in Europe and North America it is reasonable to start by adrenalitis, or signs of bleeding. Assay for very long-chain fatty
testing for 21-hydroxylase autoantibodies. Studies from different acids should be performed in all autoantibody-negative males to
European countries have shown a cross-sectional prevalence of identify the X-linked disease adrenoleukodystrophy. Sequencing
80 85% in Addison cohorts (3), and in the newly diagnosed the is available for a number of genetic causes of AI.
percentage is even higher. The typical patient is a female between A commercial assay for autoantibodies against 21-hyd-
20 and 50 years of age, but autoimmune Addisons disease can roxylase is available. In addition, a number of laboratories run
occur at almost any age. Thus, all patients should be tested, in-house assays with comparable performance (sensitivities ap-
possibly with the exception of infants and children less than 3 proximately 90% and specificities close to 100%. Immunofluores-
years of age. Among autoimmune Addisons patients, other cence techniques using adrenal tissue is less sensitive. Autoanti-
organ-specific autoimmune diseases are very common (50%), bodies against interferon alpha and omega are almost always
such as autoimmune thyroid disease, type 1 diabetes, autoimmune positive in APS-1, but are not widely available.
gastritis/pernicious anemia, celiac disease, vitiligo, alopecia, and
ovarian insufficiency (3). These combinations are collectively Therapy
named autoimmune polyendocrine syndrome type 2 (APS-2). Di- How to Administer Corticosteroids in Chronic
agnosis in children and adolescents should raise the question of Replacement Therapy
whether the patient has the monogenic APS type-1 with mutations Patients with Addisons disease require lifelong glucocorticoid
in the autoimmune regulator (AIRE) gene. and mineralocorticoid treatment. Normal cortisol production rates

TABLE 1. Causes of Adrenal Insufficiency

Etiology Pathogenesis Diagnosis/Characteristics
Autoimmunity T and B cell autoimmunity against adrenocortical 21-hydroxylase autoantibodies, most common cause.
cells In children, consider autoimmune polyendocrine
syndrome type 1
Infection Mycobacteria Quantiferon test and PCR
Bacteria (e.g. meningococcus; Haemopholus Adrenal computer tomography
Fungus (e.g. Pneumocystis carinii) Culture
Virus (e.g. HIV, herpes simplex, cytomegalovirus)
Bleeding Anticoagulant therapy Evidence of bleeding on adrenal computer
Anti-phospholipid syndrome
Disseminated intravascular coagulation
Genetic Congenital adrenal hyperplasia, Steroid profile, sequencing of steroidogenic genes
(e.g. CYP21B)
Adrenoleukodystrophy Measure very long-chain fatty acids (X-linked)
Adrenal hypoplasia, congenital with Sequencing of NR0B1 (DAX1, X-linked)
hypogonadotrophic hypogonadism,
Familiar glucocorticoid deficiency (ACTH
resistance syndrome), Smith-Lemli-Opitz
syndrome, Kearns-Sayre syndrome
Surgery Adrenalectomy (e.g. for Cushings syndrome)
Infiltrative disease Bilateral adrenal metastasis or lymphoma, Adrenal computer tomography, investigations
amyloidosis, hemochromatosis xantho- guided by history and clinical findings
Drugs Ketoconazole, etidomate, mitotane metyrapone

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

are between 5 and 10 mg/m2 body surface equivalent to an oral coid and mineralocorticoid replacement a 3-month trial of
replacement dose of 1525 mg per day of HC and 20 30 mg of DHEA replacement could be tried.
CA. CA has a slightly delayed peak but a longer half-life com-
pared with HC. CA is converted to HC by 11-hydroxysteroid Treatment in Special Situations
dehydrogenase type 1. Current treatment is largely empirical; only The Addisons Patient with Hypertension
a few underpowered and often unblinded studies have been per- Essential hypertension in Addisons disease is not uncommon.
formed. Most physicians administer HC and CA in two or three First, mineralocorticoid and glucocorticoid replacement should be
(sometimes four) divided doses, with the first dose upon awaken- carefully evaluated and fine tuned; do not stop mineralocorticoid
ing (even before awaking may work best) and the last dose replacement. If hypertension persists, angiotensin II receptor
approximately 4 6 hours before bedtime. Plenadren, a dual re- blockers or angiotensin-converting enzyme inhibitors can be used;
lease once-daily HC is available in 5- and 20-mg tablets (6). In a likewise, calcium channel blockers. Diuretics should be avoided;
randomized open study, the patients in the Plenadren arm had aldosterone receptor blockers are contraindicated (11).
lower blood pressure (BP) and lower glycated hemoglobin
(HbA1c) both in persons with diabetes and nondiabetics. Dexa- The exercising Addisons patient
methasone has no place in replacement therapy for Addisons There is no evidence supporting that extra HC/CA increase
disease because of the risk of Cushingoid adverse effects. Subcu- performance or lessens postexercise fatigue in short-term
taneous infusion of HC by an insulin pump is safe and can strenuous exercise (12). However, it is many patients experi-
be an alternative in patients with insufficient effects of ence that an extra 510 mg of HC is beneficial, at least for
peroral therapy (7). prolonged strenuous exercise and stress.
Monitoring of glucocorticoid therapy relies on clinical as-
sessment with a keen eye to symptoms and signs of over-
The pregnant Addisons patient
replacement (weight gain, insomnia, recurrent infection, pe-
Free cortisol levels increase during the third trimester (13),
ripheral edema) and under-replacement (lethargy, nausea, poor
resulting in an increased requirement for HC (by 2.5 or 10 mg
appetite, weight loss, hyperpigmentation, joint pain). Detailed
daily). Serum progesterone has antimineralocorticoid effects and
questioning about the patients daily pattern and routines can
hence the fludrocortisone dose may sometimes be increased dur-
help fine-tune doses and times of medication. Some patients
ing late pregnancy. During delivery, a bolus dose of 100 mg
respond better to four (8) or even five small doses of HC or
parenteral HC should be given, and repeated if necessary. The oral
CA. Serum or salivary cortisol day curves can be useful to
dose should be doubled for 24 48 hours postpartum.
monitor treatment. Weight-adjusted dosing makes it easier to
keep serum cortisol within reference ranges (9).
Addisons disease in surgery
The steroid doses during surgery and medical procedures needs
Mineralocorticoid Replacement to be increased according to the degree of stress induced (14).
Mineralocorticoids are vital for maintaining water and ele-
ctrolyte homeostasis. The synthetic mineralocorticoid, 9-
Adrenal Crisis
fludrocortisone is used for replacement. Patients should be
Acute adrenal crisis is a life-threatening emergency that re-
advised to eat salt, and salty foods ad libitum. A once-daily
quires immediate diagnosis and treatment that is not uncom-
dose of 0.05 0.2 mg (most use 0.1 mg) taken in the morning
mon. Six to eight episodes per 100 patient years has been
is usually sufficient for most patients. Mineralocorticoid
reported (15). Especially vomiting and/or diarrhea are com-
replacement is evaluated clinically by asking about salt
monly implicated as a precipitating cause. The symptoms
cravings, orthostatism, and edema. Measuring BP in the
are malaise, nausea, fatigue, vomiting, severe abdominal pain,
supine or sitting and standing positions can help unmask muscle pain, or cramps. Dehydration and hypotension with
under-replacement by revealing BP decreases. Serum so- progression to circulatory shock is not uncommon. Hyperkale-
dium, potassium, and plasma renin activity/renin should be mia can be life threatening.
measured, aiming at a renin in the upper-normal or slightly Diagnosis of AI should never delay treatment if an adre-
elevated range. nal crisis is suspected. A blood sample for serum cortisol,
ACTH (if the diagnosis is not known), sodium, potassium,
Is There an Indication for DHEA Treatment? creatinine, urea, glucose, and other tests for precipitating
Female patients with AI are androgen deficient, and androgen causes (bacterial or viral infections) should be drawn and
levels can be restored by giving oral DHEA. Daily doses of therapy initiated immediately by giving an iv bolus of 100
10 25 mg are usually sufficient to bring T and androstenedione mg HC and saline infusion. Glucose infusion is needed if
back into the reference range. There is limited objective evi- serum glucose is below the reference range. Any treatable
dence of clinical benefits (10). In female patients with lack of triggering condition should be addressed as well. Parenteral
libido and/or low energy levels despite optimized glucocorti- glucocorticoids should be continued at 200 mg/day (either

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

continuous infusion or intermittent treatment) and tapered serum sodium and potassium, and creatinine. Plasma renin
over 13 days if the underlying condition permits. Overdos- activity can be useful to evaluate fludrocortisone replacement
ing may lead to hypokalemia. (Table 2). Other autoimmune comorbidities should also be
The patient should be equipped with a steroid card and a looked for at longer intervals. Women with autoimmune Addi-
glucocorticoid injection kit and educated on the use of stress sons disease have an increased risk of premature ovarian
doses of glucocorticoids. A bilingual European steroid card failure and it is reasonable to inform them that it is not ideal to
was recently endorsed by European Society for Endocrinology postpone planned pregnancies.
and should be suitable for countries outside Europe (16).

The gold standard diagnostic test is the conventional
The annual follow-up (Table 2) should focus on complaints
possibly related to Addisons disease and its treatment. Fur- 250-g Synacthen test, although a paired cortisol and
thermore, it is recommended to focus on subjective health ACTH sample often is sufficient.
perception, weight and appetite, professional activities, and The main cause is autoimmunity revealed by
social life. Questions about episodes of adrenal crisis, medica- autoantibodies against 21-hydroxylase, often as part of
tion, particular extra doses, compliance, timing, and how to and autoimmune polyendocrine syndrome; non-
deal with stress and acute disease are important. All patients autoimmune causes are more frequent in the very young
should be equipped with a steroid card and an injection kit. and old.
Physical examination should include weight, BP, and degree Replacement therapy includes HC or CA in two or three
of pigmentation, keeping in mind the possibilities of autoim- (or four) divided doses, and fludrocortisone without
mune comorbidities. Annual screening for autoimmune thyroid restriction of salt intake. Doses should be individualized
disease, diabetes mellitus, and vitamin B12 deficiency is rec- in terms of numbers and amount. An alternative to
ommended. Routine laboratory analyses include hemogram, regular HC or CA is a duel-release once-daily

Table 2. Suggested Follow-Up Routines for Patients With Adrenal Insufficiency

Action Point Intervention
History History focused on well-being, capacities in work and social life; sexuality, fertility,
adrenal crises; how much and when medication is taken; symptoms and signs of over
and under replacement
Physical examination Weight (height)
Blood pressure sitting/supine and standing
Look for pigmentation changes, alopecia, vitiligo, goiter, and Cushingoid side effects
Recommended annual tests Hemogram
Na, K, creatinine
ferritin and cobalamine
TSH, FT4, anti-TPO
Renin/renin activity
Other tests for consideration Serum or saliva cortisol day curve to check bioavailability
Suspicion of vitamin B 12 deficiency: cobalamine, methylmalonic acid, parietal cell and
intrinsic factor antibodies
Suspicion of celiac disease: transglutaminase antibodies and total IgA (once)
Osteoporosis: bone scan at start of follow-up, around menopause depending on clinical
Other tests dictated by history and findings
Patient (parent/partner) education Steroid emergency card: available and up to date
Self-injection kit: available with vials of hydrocortisone, syringes (alternative is
Sick day rule 1: Need to double the routine oral glucocorticoid dose when the patient
experiences fever, illness requiring bed rest or when requiring antibiotics for an
Sick day rule 2: Need to inject a glucocorticoid preparation intra-muscularly or
intravenously in case of severe illness, trauma, persistent vomiting, when fasting for a
procedure (colonoscopy!) or during surgical intervention

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

formulation of HC; pump treatment is an option for pigmentation. Blood tests reveal a low-normal morning cortisol
those not managing well on tablets. of 167 nmol/L and ACTH of 267 pmol/L.
Annual follow-up visits should focus on steroid 5. Which of the following studies would best guide your
replacement, measures in acute situations, complications, decision on what to do next?
and autoimmune comorbidities. A. Synacthen testing
Patients should be equipped with a steroid card and B. Plasma renin
injectable HC. C. 21-hydroxylase autoantibodies
D. None of the above
CASES 6. How would you handle the case when you received the
Case 1 test result you ordered?
A 62-year-old women was diagnosed with autoimmune Ad- A. Observe, but inform of risk of overt Addisons
disons disease at 27 years of age. She was put on standard disease
replacement with CA and fludrocortisone but experienced B. Observe, but prescribe HC and tell her to start if her
a general lack of energy, fatigue, and joint pain. She had condition worsens
tried various doses and combinations of glucocorticoids C. Start replacement with glucocorticoid
(CA and prednisolone) and when first evaluated by us took D. Start replacement with glucocorticoid and
50 mg CA, 10 mg prednisolone, and 0.1 mg fludrocortisone. mineralocorticoid
Clinically, she was without Cushingoid symptoms and
1. Which of the following studies would best identify
Case 1
whether this patient is properly treated? The 62-year-old woman was followed in our out-patient clinic.
A. Hold CA for 48 hours then check 8 am cortisol and The CA dose was reduced from 50 to 37.5 mg daily divided
ACTH in three doses and predinisolone was discontinued. Clinically
B. Synacthen testing the situation was unchanged. She continued with 0.1 mg
C. Cortisol day curve fludrocortisone. She was offered to participate in a clinical
D. Check for other autoimmune manifestations study testing sc HC pump treatment. She was titrated to a daily
2. You elect to alter her adrenal replacement regimen. dose of 28 mg HC. Immediately she felt that her general
Which of the following approaches would you select at condition improved and she felt energized without the need to
this time? take extra doses of HC. After 3 months she was reverted to her
A. Switch from CA to HC and stop prednisolone previous treatment and her feeling of fatigue returned. After the
B. Slow-release HC trial she was offered pump treatment once again and she has
C. HC sc pump treatment now been treated with continuously sc infusion for 4 years.
D. Switch to dexamethasone
Case 2 1. Answers: D (C). She was checked for autoimmune
A 43-year-old women was diagnosed with autoimmune hypo- comorbidities such as hypothyroidism, celiac disease,
thyroidism at age 21 years, followed by Addisons disease at and vitamin B12 deficiency, but tests were normal. A
25, vitiligo at 37, and celiac disease at 43 years of age. She also cortisol day curve could be useful to check levels and
had vitamin B12 deficiency. Her daughter had vitiligo. compliance. A Syncthen test is not motivated and to
hold CA for 48 could be dangerous.
3. What kind of autoimmune polyendocrine syndrome
does the patient have? 2. Answers: AC could all be correct. In this case we
A. APS-1 tried sc pump treatment with success. One reasonable
B. APS-2 approach could be to first try HC, then slow-release
C. APS-3 HC, and as a third option, pump treatment.
D. The kind of polyendocrine syndrome is irrelevant Dexamethasone is contraindicated due to the high risk
of Cushingoid adverse effects.
4. Should family members be screened for autoimmunity?
A. Yes Case 2
B. No The patient developed several organ-specific autoimmune dis-
eases, of which some were present in family members. Her daugh-
Case 3 ter with vitiligo developed depigmentation in her teens. Her
A 23-year old woman is referred because of fatigue and ac- mother had vitamin B12 deficiency and an aunt had died at 18
cording to her mother who has Addisons disease, increased years of age with an undiagnosed condition that might have been

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Addisons disease. The patient was clearly 21-hydroxylase REFERENCES

autoantibodypositive. Because of familial clustering of organ- 1. Addison T. On the constitutional and local effects of disease of the
specific autoimmunity the AIRE gene was sequenced revealing a suprarenal capsules. In a collection of the published writings of the late
Thomas Addison MD, Physician to Guys Hospital. New Sydenham Soci-
heterozygous mutation in codon 326 (p.P326L) located in the ety (1868) London, Reprinted in Medical Classics 1939.2(244-293).
PHD1 domain. With this information in hand we analyzed a 2. Winqvist O, Karlsson FA, and Kampe O. 21-Hydroxylase, a major
broader spectrum of autoantibodies including interferon omega autoantigen in idiopathic Addisons disease. Lancet. 1992;339(8809):
autoantibodies, but they all turned out negative. Her daughter had 1559-1562.
3. Erichsen MM, Lvs K, Skinningsrud B, et al. Clinical, immunological,
the same mutation and during followup her 7-year-old son also and genetic features of autoimmune primary adrenal insufficiency: Obs-
developed vitiligo. He also had p.P326L. ervations from a Norwegian registry. J Clin Endocrinol Metab. 2009;
4. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis
Answers in educated patients with chronic adrenal insufficiency: A prospective
3. Answer: A. This and similar causes suggest that mono- study. J Clin Endocrinol Metab. 2015;100(2):407-416.
allelic mutations in AIRE might lead to APS-1-like 5. Erichsen MM, Lvs K, Fougner KJ, et al. Normal overall mortality rate in
clinical picture with dominant inheritance, which can be Addisons disease, but young patients are at risk of premature death. Eur J
named Nonclassical APS-1. In vitro transfection of Endocrinol. 2009;160(2):233-237.
6. Johannsson G, Nilsson AG, Bergthorsdottir R, et al. Improved cortisol
mutated and wild-type AIRE reveal that p.P326L have a
exposure-time profile and outcome in patients with adrenal insufficiency:
dominant negative effect on wild-type AIRE-regulated A prospective randomized trial of a novel hydrocortisone dual-release
transcription. formulation. J Clin Endocrinol Metab. 2012;97(2):473-481.
7. ksnes M, Bjornsdottir S, Isaksson M, et al. Continuous subcutaneous
4. Answer: A. Organ-specific autoimmunity often runs in
hydrocortisone infusion versus oral hydrocortisone replacement for treat-
families. There is an approximately 10% risk for a ment of Addisons disease: A randomized clinical trial. J Clin Endocrinol
patient with autoimmune Addisons disease to have Metab. 2014;99(5):1665-1674.
first-degree relative with the same disease. There is also 8. Ekman B, Bachrach-Lindstrom M, Lindstrom T, Wahlberg J, Blomgren J,
increased risk of other organ-specific autoimmune Arnqvist HJ. A randomized, double-blind, crossover study comparing two-
diseases. Thus, the patient should be informed about and four-dose hydrocortisone regimen with regard to quality of life, corti-
this increased risk, and if there is clinical suspicion, sol and ACTH profiles in patients with primary adrenal insufficiency. Clin
Endocrinol (Oxf). 77(1):18-25.
testing can be performed. In this particular case with
9. Mah PM, Jenkins RC, Rostami-Hodjegan A, et al. Weight-related dosing,
dominant inheritance I would opt for familial screening. timing and monitoring hydrocortisone replacement therapy in patients with
adrenal insufficiency. Clin Endocrinol (Oxf). 2004;61(3):367-375.
Case 3 10. Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and
The initial clinical and biochemical evaluation suggested mild meta-analysis of randomized placebo-controlled trials of DHEA treatment
effects on quality of life in women with adrenal insufficiency. J Clin
AI with fatigue and increased pigmentation (due to elevated Endocrinol Metab. 2009;94(10):3676-3681.
ACTH). 11. Inder WJ, Meyer C, Hunt PJ. Management of hypertension and heart
failure in patients with Addisons disease. Clin Endocrinol (Oxf).
Answers 12. Simunkova K, Jovanovic N, Rostrup E, et al. Effect of a pre-exercise
5. Answers: AC. Cortisol is barely in the normal range. hydrocortisone dose on short term physical performance in female patients
Together with a high ACTH level, this strongly with primary adrenal failure. Eur J Endocrinol. 2016;174(1):97-105.
suggests AI. Ideally, a Synacthen test should be 13. Lebbe M, Arlt W. What is the best diagnostic and therapeutic management
strategy for an Addison patient during pregnancy? Clin Endocrinol (Oxf).
performed and the aldosternone reserve determined by
measuring plasma renin. The cause of AI should always 14. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagno-
be determined by measuring 21-hydroxylase sis, treatment and follow-up of patients with primary adrenal insufficiency.
autoantibodies. The risk of other autoimmune J Intern Med. 2014;275(2):104-115.
comorbidities is high. As a minimum, thyroid function 15. Reisch N, Willige M, Kohn D, et al. Frequency and causes of adrenal
and glucose levels should be determined. crises over lifetime in patients with 21-hydroxylase deficiency. Eur J
Endocrinol. 2012;167(1):35-42.
6. Answer: D. She was about to go on her honeymoon 16. Dahlqvist P, Bensing S, Ekwall O, Wahlberg J, Bergthorsdottir R, Hulting
and it was decided to start full replacement therapy AL. 2011. [A national medical emergency card for adrenal insufficiency. A
with CA and fludrocortisone. The patient was instructed new warning card for better management and patient safety]. [Article in
about acute procedures in relation to adrenal crisis and Swedish] Lakartidningen. 2011;108(44):2226-2227.
17. Pearce SH, Mitchell AL, Bennett S, et al. Adrenal steroidogenesis after B
equipped with a steroid card and a HC injection kit.
lymphocyte depletion therapy in new-onset Addisons disease. J Clin
The Synacthen test was postponed due to her travel Endocrinol Metab. 2012;97(10):E1927-E1932.
plans. Two months later it revealed unmeasurable levels 18. Gan EH, MacArthur K, Mitchell AL, et al. Residual adrenal function
of cortisol at baseline and after 250 g Synacthen (20 in autoimmune Addisons disease: Improvement after tetracosactide
nmol/L in all three samples at 0, 30, and 60 min). (ACTH124) treatment. J Clin Endocrinol Metab. 2014;99(1):111-118.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Pheochromocytomas and Paragangliomas

M12 vent morbidity and mortality associated with surgical removal.

Presented, April 1 4, 2016 In addition, all patients with PCC/PGL should be referred for
clinical genetic testing because knowledge of an germline mu-
tation in PCC/PGL susceptibility gene is important for optimal
Lauren Fishbein, MD, PhD. Department of Medicine, surveillance of the patient and his/her family members as most
Division of Endocrinology, Metabolism and Diabetes, gene mutations are associated with risk of multiple primary
University of Colorado School of Medicine, Aurora, PCC/PGL as well as presence of other tumor types. Cost is
Colorado 80045, E-mail: lauren.fishbein@ucdenver.edu thought to be prohibitive to genetic testing in some cases.


The first description of the two distinct layers of the adrenal As a result of participation in this session, learners should be
gland (the cortex and medulla), dates back to the mid 1800s. able to:
Shortly thereafter, the first adrenal medulla tumors were de- Understand how to diagnosis PCC/PGL.
scribed and termed pheochromocytomas (PCCs). Parallel to Understand how to manage perioperative blockade.
this discovery, tumors in ganglia throughout the body were Understand the importance of clinical genetic testing for
termed paragangliomas (PGLs). Until just a few decades ago, patients with PCC/PGL.
the mortality rate for secreting PCCs and PGLs (PCC/PGL)
was quite high, around 30 45% (1). With medical and surgical
advances, particularly with regard to perioperative blockade
regimens, the morbidity has decreased to 0-2.9% (1). The old
Patients with PCC/PGL often present with the classic triad of
rule of tens associated with PCCs is no longer accurate.
headaches, palpitations, and diaphoresis, but many other symp-
Approximately 25% of PCC/PGL are malignant, approxi-
toms and signs can be clues to the diagnosis (Table 1). Screen-
mately 25% are extra-adrenal, and up to 40% are hereditary. In
ing for PCC/PGL also should occur as part of a workup for
the pediatric population, up to 80% of PCC/PGLs may be
patients with secondary hypertension, with an adrenal
hereditary (2).
incidentaloma (with or without hypertension) (4) or with a
known susceptibility gene mutation (5) (Table 2).
SIGNIFICANCE OF THE CLINICAL PROBLEM Both 24-hour urine fractionated and plasma-free met-
PCC/PGLs are neuroendocrine tumors of chromaffin tissue anephrines have over 90% sensitivity for PCC/PGL, but the
which, even when benign, are highly morbid tumors and diag- plasma tests have slightly higher specificity (79 98% vs
nosis can be difficult in some cases. A quarter of tumors are 69 95%) (6). It is recommended that the plasma-free
malignant defined by the World Health Organization as having metanephrines be the first-line screening test. Numerous medi-
distant metastases in nonchromaffin tissue and can occur even cations can interfere with screening and lead to false-positive
up to 20 years after initial diagnosis. There are no curative results including acetaminophen, several classes of antidepres-
therapies for widely metastatic disease, and unfortunately, pa- sants, attention deficit hyperactivity disorder medications
tients with metastatic disease have only a 50% 5-year survival (stimulants) and certain - and - adrenergic blockers (6).
rate (3). In addition, there are no strong predictors of malig- These medications should be held prior to testing if possible. If
nancy; therefore, all patients need life-long screening. Despite the medications cannot be stopped, such as some of the psy-
the high rate of hereditary mutations in patients with chotropic medications, and the plasma metanephrine screen is
PCC/PGL, many patients are not referred for clinical genetic
testing, which can negatively affect the screening and surveil-
TABLE 1. Common Symptoms and Signs Associated
lance of the patient and his/her family members.
Symptoms Signs
Headache Tachycardia
PCC/PGLs are rare tumors, and unless practicing at a referral
Diaphoresis Hypertension
center, many clinicians may see only 1-2 patients with this
Palpitations Hyperglycemia
disease in their career. Often, symptoms of catecholamine
Syncope or presyncope
hypersecretion can go unrecognized as they can mimic many
other conditions. Therefore, including PCC/PGL in the differ-
Weight changes
ential diagnosis is critical. Once diagnosed, clinicians must be
No symptoms
familiar with proper perioperative blockade regimens to pre-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 2. PCC and PGL Susceptibility Genes

Gene Syndrome Protein (Function) Tumor Location Malignancy Rate
NF1 Neurofibromatosis Type 1 Neurofibromin (GTPase which Adrenal (bilateral) 12%
inactivates RAS)
RET Multiple Endocrine Neoplasia RET (transmembrane tyrosine Adrenal (bilateral) 5%
Type 2 kinase)
VHL von Hippel Lindau pVHL (ubiquitin ligase activity) Adrenal (bilateral) 5%
SDHx genes Familial paraganglioma Succinate dehydrogenase complex Any location Low
SDHA syndrome (complex II of the mitochondrial Any location, primarily 23%
SDHB respiratory chain and converts extra adrenal Low
SDHC succinate to fumarate) Head and neck, can be 5%
SDHD SDH subunit A (catalytic subunit) thoracic Low
SDHAF2 (SHD5) SDH subunit B (catalytic subunit) Any location, primarily
SDH subunit C (anchoring subunit) head and neck
SDH subunit D (anchoring subunit) Head and neck (multifocal)
SDH cofactor AF2 (cofactor)
TMEM127 Transmembrane protein 127 Any location, primarily Low
(transmembrane protein) adrenal
MAX MYC-associated protein X Adrenal (bilateral) Intermediate
(transcription factor)
EPAS1 Polycythemia paraganglioma Hypoxia inducible factor 2a Any location Not known
syndrome (transcription factor)
FH Hereditary leiomyomatosis and Fumarate hydratase Any location Possibly high
renal cell carcinoma (converts fumarate to malate)
MDH2 Malate dehydrogenase Any location Not known
(converts malate to oxaloacetate)

positive, it is appropriate to move forward with imaging stud- most appropriate. The Endocrine Society guidelines recommend
ies. Although most PCC/PGLs are secretory, some are not, phenoxybenzamine, a nonselective noncompetitive blocker, as
especially those derived from parasympathetic ganglia such as the first line of treatment and doxazocin or another competitive
in the head and neck. Some nonsecretory PGLs are actually selective -1 blocker, with or without a calcium channel blocker
dopamine-only secreting, which is not picked up with standard as second-line treatment (6) (Table 3). The largest retrospective
biochemical screening. study comparing phenoxybenzamine to competitive selective -1
Cross-sectional imaging with computed tomography (CT) or blockers showed that pheonxybenzamine achieved better preop-
magnetic resonance imaging (MRI) should follow a positive erative and intra-operative blood pressure (BP) control but was
screen for PCC/PGL. The vast majority of tumors are in the associated with more transient postoperative hypotension (8). Full
adrenal gland so abdominal imaging is appropriate to start. Keep -blockade often induces tachycardia and orthostatic hypotension,
in mind that approximately 25% of tumors are located outside the which should be treated with -blockade and hydration with high
adrenal gland, so if there is strong clinical suspicion and no salt intake. These symptoms should not necessarily lead to a dose
adrenal mass, imaging of other locations should be performed, reduction as they imply full -blockade. Remember, -blockers
especially for known susceptibility gene mutation carriers (Table can induce a theoretical unopposed -adrenergic stimulation lead-
2). Functional imaging with 123I-metaiodobenzylguanidine ing to a hypertensive crisis and should not be used until the patient
(MIBG) is not recommended as first line because up to 50% of is fully -blocked. Postoperatively, patients should be screened
normal adrenal glands have increased physiologic uptake, which with plasma metanephrines 4-8 weeks after surgery to ensure
can lead to false-positive results (7), and many PGLs are not complete resection and then annually for life given the potential
MIBG avid. 123I-MIBG imaging can be useful to determine avid- for additional primary tumors, recurrence, and the long latency of
ity in metastatic disease in preparation for possible 131I-MIBG metastatic disease.
treatment. 18F-FDG-PET/CT scanning is recommended for diag- Metastatic PCC/PGL occurs in approximately 10% of PCCs
nosis of metastatic disease, especially for those patients with an and 20% of PGLs (3) and is defined by the presence of distant
inherited Succinate Dehydrogenase Subunit B (SDHB) mutation metastases in nonchromaffin tissue. Metastatic disease can oc-
given that the sensitivity of positron emission tomography imag- cur even up to 20 years after the initial diagnosis and once
ing is 74 100% in this population (6). present, patients have a 50% 5-year survival (3). Predicting
Perioperative blockade is critical to reduce morbidity and mor- metastatic disease is difficult. The risk is increased with the
tality with surgery in patients with PCC/PGL. There are no pro- presence of a germline SDHB mutation, but only half of pa-
spective randomized controlled trials to suggest which regimen is tients with metastatic disease have a mutation in this gene (9).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Table 3. Perioperative Blockade Regimens

Category Drug Dosing Common Adverse Effects
First-line nonselective blocker Phenoxybenzamine 10 mg, 2-3/d Orthostatic hypotension, tachycardia, nasal congestion
(up to 60 mg/d)
Second-line selective -1 blocker Doxazosin 2-4 mg, 2-3 times/d Orthostatic hypotension, tachycardia
Prazosin 1-2 mg, 2 times/d
Terazosin 1-4 mg, once daily
Second-line calcium channel blocker Nicardipine 30 mg 2 times/d Edema, headache
Amlodipine 5-10 mg once daily
-blocker only after full -blockade Metoprolol 25-100 mg, 2 times/d Fatigue, dizziness, asthma exacerbation

Other predictors are tumor size (4 5 cm) or secretion of most common reason for a false-positive screening test is the pres-
methyoxytyramine (not clinically available in most centers) (3, ence of an interfering medication or drug. Blood pressure manage-
10). Histopathologic scoring systems have not been reliable ment with phenoxybenzamine or other blockade is critical
given wide inter- and intra-observer variability (11, 12). Given perioperatively and surrounding treatments for those with metastatic
the difficulty in predicting who will develop metastatic disease, disease. Up to 40% of patients with PCC/PGL have a germline
experts recommend lifelong annual screening for any patient mutation in a known susceptibility gene; therefore, all patients with
who had a PCC/PGL. Many studies are focused on identifying PCC/PGL, regardless of family history, should be referred for clinical
biomarkers for metastatic disease, and new histopathologic genetic testing given the implications for patient and his/her family
scoring systems are being tested (13). Treatments for meta- members.
static disease are not curative but can offer disease control.
These include surgical debulking, chemotherapy with cyclo-
phosphamide, vincristine, dacarbazine (CVD), external beam
Case 1
radiation therapy, or 131I-MIBG treatment) [reviewed in A 54-year-old woman with a past medical history of hepatitis
Fishbein (14)]. Tyrosine kinase inhibitors and other small mol- C, sarcoidosis, hypertension on amlodipine, and hypothyroid-
ecules are being tested in clinical trials. ism status post thyroidectomy for multinodular goiter on
There are more than 13 known susceptibility genes associ- levothyroxine presents for evaluation of palpitations and dia-
ated with an increased risk of PCC/PGL (Table 2) (15). The phoresis. Last menstrual period was 8 years ago. Palpitations
three classic tumor-suppressor genes which, when mutated, occur approximately once a day, last for a few minutes, and are
increase risk of PCC/PGL are NF1, VHL, and RET leading to associated with diaphoresis but no chest pain or shortness of
Neurofibromatosis Type 1, von Hippel Lindau disease, and breath. No headaches. She had a recent normal cardiac stress
Multiple Endocrine Neoplasia Type 2, respectively. More than test. She takes acetaminophen daily and smokes marijuana a
15 years ago, the first Succinate Dehydrogenase (SDH) subunit few times a week to help her chronic pain in her back and
gene was found to be associated with familial PGL syndrome. knees. No known relevant family history. On examination, BP,
We now know that mutations in any of the SDH subunits, A, 142/97 mm Hg; heart rate, 77 bpm; body mass index, 33.4
B, C, and D, and the cofactor AF2 are associated with in- kg/m2. Aside from obesity, the remainder of the physical ex-
creased risk of PCC/PGL. SDHx mutations also increase risk of amination is not significant. Laboratory tests show normal TSH
gastrointestinal stromal tumors and renal cell carcinomas; there of 1.68 mIU/mL (normal range, 0.4-4.5 mIU/mL) and elevated
are reports of associations with some SDH subunit mutations plasma normetanephrines (plasma normetanephrines, 1.15
and pituitary adenomas. In the last few years several other nmol/L [normal range, 0-0.89 nmol/L], plasma metanephrines,
genes have been associated with PCC/PGL although they occur 0.12 nmol/L [normal range, 0-0.49 nmol/L]).
in 2% or less of cases including TMEM127, MAX, EPAS1, FH, Does this woman have a PCC/PGL?
and MDH2 (Table 2). Most of the susceptibility gene mutations
are inherited in an autosomal-dominant pattern meaning off-
Case 2
spring have a 50% chance of inheriting the mutation. SDHD A 43-year-old woman with a past medical history of schizo-
and SDHAF2 mutations also have paternal inheritance; there- phrenia on clozapine and mirtazapine, hypothyroidism well
fore, family history may be misleading. Of the more commonly controlled on levothyroxine and diabetes mellitus type 2 well
mutated genes, SDHB is the only one that carries a significantly controlled on metformin presents for evaluation of an adrenal
increased risk of malignancy. incidentaloma seen on a chest CT. She has rare palpitations.
She denies headaches or diaphoresis. She has no hypertension.
MAIN CONCLUSIONS On examination, her BP is 119/76 mm Hg with heart rate, 70
PCC/PGL can have high morbidity and mortality even when benign bpm. The rest of the physical examination is unremarkable
due to the hypersecretion of catecholamines and metanephrines. The except for a flat affect. On noncontrast CT imaging, the adrenal

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

nodule is 3.5 cm with Hounsfield units (HU) of 8, stable in size DISCUSSION OF CASES AND ANSWERS
over 1 year. Biochemical workup shows normal 24 hour uri- Case 1
nary free cortisol on two occasions and an appropriately sup- Does this woman have a PCC/PGL?
pressed cortisol after a 1 mg overnight dexamethasone suppres- This patient has some of the classic symptoms and signs of
sion test. She has elevated plasma metanephrines (62 pg/mL; PCC/PGL including palpitations, diaphoresis, and hyperten-
normal range 57 pg/mL) and plasma normetanephrine (339 sion, making it appropriate to test for the diagnosis. The plasma
pg/mL; normal range 148 pg/mL). Subsequent 24-hour urine normetanephrine levels returned elevated and could suggest
biochemistries show a mildly elevated urine normetanephrine possible disease. However, she is taking several drugs that
(898 mcg/d; normal range, 82-500 mcg/d) with the rest of the could cause a false-positive elevation of these levels. First,
urine biochemistries within the normal range including urine acetaminophen is a common over-the-counter medication that
metanephrine 174 mcg/d (normal range, 45-290 mcg/d); urine interferes with the assay. Patients should be instructed to re-
epinephrine, 13 mcg/d (normal range, 0-20, mcg/d); urine nor- frain from taking any acetaminophen containing products for
epinephrine, 110 mcg/d (normal range, 0-135 mcg/d); and 5-7 days prior to testing. Secondly, marijuana can cause false-
urine dopamine, 218 mcg/d (normal range, 10-510 mcg/d). positive elevations as well. This patient agreed to retest when
Does this woman have a PCC/PGL? refraining from both drugs for at least a week. Her subsequent
levels of plasma metanephrines returned normal.
Case 3
A 42-year-old man with no known past medical history presented Case 2
Does this woman have a PCC?
with feeling poorly. Through PCP workup, he had a CT abdo-
It can be difficult to determine a diagnosis PCC in patients
men that showed a 5.5-cm retroperitoneal mass thought to be a
with known adrenal nodules and mildly elevated meta-
possible sarcoma. A biopsy of this lesion was aborted due to a
nephrine/normetanephrine levels. First and foremost, drug in-
hypertensive crisis during the procedure. Subsequently, 24-hour
teractions should be noted. In this case, the patient is taking
urinary free metanephrine and catecholamines were checked and
psychiatric medications for schizophrenia which, after discus-
were elevated confirming a diagnosis of a PGL. In retrospect, he
sion with her psychiatrist should not be discontinued for fear of
noted recent intermittent hypertension not on medication and dia-
the patients safety. Therefore, we must rely on other informa-
tion to make an informed decision. HU on CT scan can be
What perioperative blockade regimen is best for patients
helpful with low HU under 10 suggesting a benign cortical
with PCC or PGL?
adenoma. Low contrast uptake and rapid washout (50%), can
What are the next best steps in following this patient after
be suggestive of benign cortical adenomas. MRI imaging can
show lipid-rich signaling suggestive of benign cortical adeno-
mas as well. (PCCs typically have high HU 10, delayed
Case 4 washout 50%, and lipid-poor signal on MRI.) In an experi-
A 16-year-old male with no known past medical history pres- enced center, 123I-MIBG may be helpful, although not all
ents with palpitations, headaches, and syncope while working PCC/PGL are MIBG avid.
out. Cardiac stress test was performed and the patient devel- In this case, the patient was normotensive and had no symp-
oped supraventricular tachycardia during the test. There was a toms, and the CT and 123I-MIBG imaging was suggestive a
plan for an ablation procedure. Family history was significant benign nonfunctional cortical adenoma. The elevated biochem-
for his father recently being diagnosed with a head and neck istry results were attributed to the psychiatric medications. She
PGL and found to have an SDHD mutation. During a conver- continued to be followed over several years with no change in
sation the father was having with his genetic counselor about symptoms or signs, no growth of the adrenal nodule and no
having his children tested for the inherited mutation, he men- change in the laboratory values.
tioned his sons medical issues above. The astute genetic coun-
selor noted that before any procedures were performed on his Case 3
son, that he should be tested for PCC/PGL with plasma What perioperative blockade regimen is best for patients with
metanephrines. The patient was tested and had elevated plasma PCC or PGL?
normetanephrines (13.96 nmol/L; normal range, 0-0.89 Appropriate perioperative blockade is critical before surgery
nmol/L) and normal plasma metanephrines (0.36 nmol/L; nor- or any procedure in patients with PCC/PGL or with metastatic
mal range, 0-0.49 nmol/L). Imaging of the abdomen showed a PCC/PGL. The Endocrine Society guidelines (6) suggest first
peri-aortic mass of 3.9 cm. line-therapy with phenoxybenzamine along with appropriate
Before this patient had symptoms, what was the likelihood hydration and salt loading. -blockade should be used to treat
he had an SDHD mutation and would develop a PCC/PGL? If any tachycardia after full -blockade is achieved.
the patients mother had the SDHD mutation, would his risk be What are the next best steps in following this patient after
the same? surgery?

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

All patients with secreting PCC and PGL should have bio- paternally inherited (with extremely rare exception). When the
chemical testing (plasma or urine metanephrines) checked SDHD mutation is passed along from the mother, the patient
within 4-8 weeks postoperatively to ensure complete resection remains unaffected. Of note, if he inherited the mutation from his
and then annually for life to screen for recurrence, metastatic mother, although he would be unaffected, any of his children who
disease, or additional primary tumors. Given that up to 40% of inherited the mutation would be at risk of developing PCC/PGL.
patients with PCC/PGL have a mutation in a known germline
susceptibility gene, all patients should be referred for clinical
genetic testing. Knowing the presence of a germline mutation 1. Bruynzeel H, Feelders RA, Groenland TH, et al. Risk factors for hemody-
affects the screening and surveillance for the patient and any namic instability during surgery for pheochromocytoma. J Clin Endocrinol
family member with the inherited mutation. Mutation carriers Metab. 2010;95(2):678-685.
are at higher risk for additional primary PCC/PGL and other 2. Bausch B, Wellner U, Bausch D, et al. Long-term prognosis of patients with
pediatric pheochromocytoma. Endocr Relat Cancer. 2014;21(1):17-25.
associated tumors depending on the syndrome (5). In addition,
3. Ayala-Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for
patients with an SDHB mutation are at increased risk of devel- malignancy and overall survival in patients with pheochromocytomas
oping malignancy. and sympathetic paragangliomas: Primary tumor size and primary tu-
This patient had an extra-adrenal PGL that was 5.5 cm. mor location as prognostic indicators. J Clin Endocrinol Metab.
Clinical genetic testing found that he carried an SDHB 2011;96(3):717-725.
4. Zeiger MA, Thompson GB, Duh QY, et al. The American Association of
mutation as did his 15-year-old daughter. There are no
Clinical Endocrinologists and American Association of Endocrine Sur-
formal guidelines for following SDHx mutation carriers, but geons medical guidelines for the management of adrenal incidentalomas.
most experts recommend at least annual biochemical test- Endocr Pract. 2009;15 Suppl 1:1-20.
ing and cross-sectional imaging studies of the neck/ 5. Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: Un-
chest/abdomen/pelvis every 2 years (5). His daughter was derstanding the complexities of the genetic background. Cancer Genet.
screened annually with plasma metanephrines and cat- 6. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and para-
echolamines and full-body MRI every 2 years. The patient ganglioma: An endocrine society clinical practice guideline. J Clin
had biochemical testing 2 months postoperatively, 6 months Endocrinol Metab. 2014;99(6):1915-1942.
postoperatively for the first year, and then annually after that 7. Mozley PD, Kim CK, Mohsin J, Jatlow A, Gosfield E 3rd, Alavi A. The
efficacy of iodine-123-MIBG as a screening test for pheochromocytoma.
with full-body imaging planned every 2 years. Unfortu-
J Nucl Med. 1994;35(7):1138-1144.
nately, 2 years postoperatively he developed back pain and 8. Weingarten TN, Cata JP, OHara JF, et al. Comparison of two preoperative
was found to have a T12 spinal metastasis. This was treated medical management strategies for laparoscopic resection of pheochromo-
with external beam radiation. Within the next year he devel- cytoma. Urology. 2010;76(2):508 e6 e11.
oped several distant metastases in the bone and liver, and he 9. Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL. Inherited
mutations in pheochromocytoma and paraganglioma: Why all patients
was treated with CVD chemotherapy (cyclophosphamide,
should be offered genetic testing. Ann Surg Oncol. 2013;20(5):1444-1450.
dacarbazine, vincristine) as his disease was not MIBG avid. 10. Eisenhofer G, Lenders JW, Siegert G, et al. Plasma methoxytyramine: A
novel biomarker of metastatic pheochromocytoma and paraganglioma in
Case 4 relation to established risk factors of tumour size, location, and SDHB
mutation status. Eur J Cancer. 2012;48(11):1739-1749.
Before this patient had symptoms, what was the likelihood he
11. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score
had an SDHD mutation and would develop a PCC/PGL? (PASS) to separate benign from malignant neoplasms: A clinicopatho-
SDHD mutations are autosomal dominant with a paternal logic and immunophenotypic study of 100 cases. Am J Surg Pathol.
inheritance. The sons risk of being a mutation carrier is 50% 2002;26(5):551-566.
because one of his parents has the mutation, and if he carries 12. Wu D, Tischler AS, Lloyd RV, et al. Observer variation in the application
of the Pheochromocytoma of the Adrenal Gland Scaled Score. Am J Surg
the mutation, he is at high risk of developing PCC/PGL be-
Pathol. 2009;33(4):599-608.
cause of the high penetrance with paternal inheritance. 13. Kimura N, Takayanagi R, Takizawa N, Itagaki E, et al. Pathological
If this patients mother had the SDHD mutation, would his risk grading for predicting metastasis in phaeochromocytoma and paragan-
be the same? glioma. Endocr Relat Cancer. 2014;21(3):405-414.
If this patients mother carried the known familial SDHD mu- 14. Fishbein L. Pheochromocytoma and paraganglioma: Genetics, diagnosis
and treatment. Hematol Oncol Clin North Am. 2016;30(1):135-150.
tation, the patient would still have a 50% risk of carrying the 15. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phae-
mutation; however, he would not be at risk to develop PCC/PGL ochromocytoma: From genetics to personalized medicine. Nat Rev
as the SDHD mutations are associated with PCC/PGL only when Endocrinol. 2015;11(2):101-111.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Adrenal Insufficiency in Intensive Care Patients

M33 tients with Cushings syndrome as it is characterized by

Presented, April 1 4, 2016 710-fold increase in serum free cortisol levels, loss of diurnal
variation, poor suppressibility with dexamethasone, and en-
hanced responsiveness to Cosyntropin. Although increased cor-
Baha M. Arafah, MD, FACP. Case Western tisol secretion is evident, an important factor contributing to the
Reserve University, Cleveland, Ohio 44106, E-mail: high serum cortisol levels in critically ill patients is a decrease
baha.arafah@case.edu in its clearance that is likely due to inhibition of the 11-
hydroxy steroid dehydrogenase-2 enzyme activity.
OF THE CLINICAL PROBLEM Limitations of Current Assessment Approaches of HPA
Although the essential role of the adrenal glands for survival Function in the Critically Ill
had been recognized for centuries, the work of Dr Thomas An important limitation of most published data are the consis-
Addison published in 1855 as a monograph provided the most tently overlooked effect of hypoproteinemia on measured se-
detailed and still accurate description of patients with primary rum cortisol levels. Current thinking suggests that the free
adrenal insufficiency. The biochemical studies conducted in the fraction of the hormone is the biologically active form. Avail-
1930s led to the identification of several adrenocortical steroids able assays for serum cortisol measurements determine the
and culminated in awarding the Noble Prize in Medicine or total (ie, free and bound fractions) concentration. With more
Physiology to three prominent scientists: Edward Kendall, than 90% of cortisol in the circulation being protein bound, it
Tadeus Reichenstein, and Philip Hench. That discovery led to would easy to appreciate the significant effect of alterations in
the synthesis of several steroids including cortisone and hydro- binding proteins (transcortin and albumin) on measured serum
cortisone and subsequently the recognition that their therapeu- total cortisol concentrations. Thus, patients with hypoproteine-
tic potential goes far beyond treating patients with adrenal mia may exhibit lower-than-expected serum total cortisol lev-
insufficiency but also others with a variety of medical disorders els even though they have normal HPA function and normal
such as allergic, autoimmune, and lymphoproliferative dis- free hormone concentrations. The reverse is also true about
eases, to name a few. Over time, physicians not only became patients with increased binding proteins such as those on estro-
aware of glucocorticoid benefits but also of their serious ad- gen therapy and others with hepatitis. Given that critical illness
verse effects. In the early 1990s, the high morbidity and mor- is frequently associated with variable degrees of hypoproteine-
tality in critically ill patients prompted several studies that mia, it would be easy to appreciate its effect in underestimating
examined the presence of adrenal dysfunction in such pa- glucocorticoid secretion in this setting. This invariably leads to
tients and whether treatment with glucocorticoids would be the inaccurate diagnosis of adrenal insufficiency and unneces-
beneficial. Many such studies have serious limitations and sary use of glucocorticoids. In such patients free cortisol levels
provided conflicting results. At this time and despite the large are appropriately elevated.
volume of published data on adrenal function during critical A common and serious concern reported frequently is the
illness, several controversies continue to be debated such as the use of post-Cosyntropin increment in serum cortisol levels of
definition of normal adrenal response, the concept of rela- less than 9 ug/dL as a diagnostic criterion for impaired adrenal
tive adrenal insufficiency and the indications and the doses of function irrespective of the baseline level (the so-called relative
glucocorticoids needed in critically ill patients with impaired adrenal insufficiency). Although that increment might have a
HPA function. prognostic value, it is of no physiologic significance and should
never be used to diagnose adrenal dysfunction or to determine
LEARNING OBJECTIVES: need for glucocorticoids. Most patients who had a post-
After completing this session, the participant will be able to: Cosyntropin increment of less that 9 ug/dL have hypoproteine-
Understand HPA function in critically ill patients. mia and in fact, up to 20% of normal healthy subjects exhibit
Recognize limitations of methods used in assessing HPA the same biochemical feature.
Determine whether glucocorticoid management is Diagnosis of Adrenal Insufficiency During Critical
indicated in a critically ill patient with suspected adrenal Illness
insufficiency. When adrenal insufficiency is partial, biochemical confirmation
of the diagnosis can at times be difficult in ambulatory patients
Normal HPA During Critical Illness and even in those who are critically ill. The variability in
Critically ill patients with normal HPA function have persistent response to stressors and the many confounding factors influ-
hypercortisolemia that is reminiscent of that observed in pa- encing serum cortisol measurements make the biochemical

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

diagnosis of adrenal insufficiency more difficult during critical Management of Adrenal Insufficiency During Critical
illness. One should seriously consider the diagnosis in patients Illness
with symptoms especially those at risk for having adrenal Traditionally, patients with adrenal insufficiency have been
insufficiency. Risk factors include a prior history of using overtreated, particularly during critical illness. Despite the lack
glucocorticoids or drugs that have glucocorticoid activity (eg, of evidence, many textbooks or reviews continue to recom-
mend the use of large dose of hydrocortisone (the so called
Megace) and others that can potentially influence their secre-
stress dose). The latter total dose can reach 300 400 mg daily.
tion such as etomidate. The latter drug is an anesthetic agent
Such doses are clearly associated with adverse events such as
frequently used in critically ill patients to help with intubation
hyperglycemia, hypokalemia, and secondary infections, to
and is known to inhibit the 11- hydroxylase enzyme. Thus,
name a few. Recently however, there is an increasing trend to
patients receiving that drug will have adrenal insufficiency that treat adrenally insufficient subjects with lower doses of hydro-
may persist for up to 24 hours after its administration and cortisone in the ambulatory setting and hopefully during criti-
would therefore need hydrocortisone coverage during that time cal illness as well. We have previously demonstrated that
period. Additional risk factors include a personal or family adrenally insufficient subjects given 50 mg of hydrocortisone
history of autoimmune illnesses, know hypothalamic/pituitary every 6 hours achieve serum cortisol levels that are several-
disease, or brain irradiation to name a few. fold higher than those observed in most critically ill patients. A
When serum-binding proteins (albumin, transcortin) are near decrease in cortisol clearance, which is recently shown to be a
normal (albumin 2.5 g/dL), measurements of total serum feature of critical illness contributes to the high serum levels.
cortisol provide reliable assessment of adrenal function in criti- Currently, there are no data to offer specific guidelines on
cally ill patients, in whom a random serum total cortisol would appropriate glucocorticoid doses during critical illness nor are
be expected to 15 ug/dL in most patients. In hypoproteinemic there any data on the normal HPA function/response to specific
(albumin 2.5 g/dL) critically ill subjects, a random serum illnesses.
total cortisol level is expected to be 11 ug/dL in most pa- Based on our own data, we believe that unless the patient is
in shock, the use of 50 mg of hydrocortisone every 6 hours
tients. There is no need to perform a Cosyntropin stimulation
during any critical illness is excessive and unnecessary. Our
test in the setting of critical illness as this will not provide any
approach is to use lower doses of hydrocortisone during critical
additional meaningful information. However, if the test is per-
illness. Thus, if the critically ill, adrenally insufficient patient is
formed, the postCosyntropin serum total and free cortisol lev-
not in shock, we use a dose of 25 mg every 6 hours and taper
els should be interpreted with the understanding that responses down as clinically indicated. Patients with primary adrenal
in critically ill subjects are higher than those of healthy ambu- insufficiency will not need mineralocorticoid therapy as long as
latory volunteers. The Cosyntropin-induced increment in serum the total dose of hydrocortisone used is greater than 50 mg per
total cortisol should not be used as a criterion for defining day. Critically ill patients in shock have a significant inflam-
normal or abnormal adrenal function, especially in critically ill matory response and might therefore need the higher hydrocor-
patients. We have recently demonstrated that measurements of tisone doses. In that setting, the hydrocortisone is more of an
serum dehydroepiandrosterone sulfate (DHEA-S) are helpful in anti-inflammatory agent than a glucocorticoid replacement.
establishing the diagnosis of adrenal insufficiency in the ambu-
latory setting and to a large degree in the critically ill. Use of Glucocorticoids in the Critically Ill Without
Theoretically, serum free cortisol measurement is the most Adrenal Insufficiency
accurate method to assess adrenal function in critically ill The routine use of glucocorticoids during critical illness is not
hypoproteinemic patients. A random serum free cortisol level justified except in patients where adrenal insufficiency was
is expected to be 1.8 ug/dL in most critically ill patients, properly diagnosed, or in others who are hypotensive, septic,
irrespective of the serum-binding proteins. Given that the free and unresponsive to standard therapy (fluids, antibiotics, and
2 pressors). In the latter setting, one would not be treating an
cortisol assay is not currently available for routine clinical use,
episode of adrenal insufficiency but rather a severe inflamma-
alternative approaches to estimate serum free cortisol can be
tory process resulting from sepsis. The results of the recently
used. These include calculated free cortisol (Coolens method)
published CORTICUS study are supportive of that. Among
and determining the free cortisol index (ratio of serum
available glucocorticoids, hydrocortisone should be the drug of
cortisol/transcortin concentrations). The latter method (index) choice and should be given at the lowest dose and for the
is unreliable and is poorly conceived as it does not have any shortest duration possible. The hydrocortisone dose (50 mg
physiological basis. Recent data suggest that salivary cortisol every 6 h) that is inappropriately labeled as low-dose hydro-
measurements could be a reliable alternative approach to esti- cortisone leads to excessive elevation in serum cortisol levels
mating the free cortisol in the circulation. From a practical and are often associated with significant adverse effects. The
point of view, one would need to rely on total cortisol mea- latter discussion should call into question the current practice
surements and be aware of its limitations as discussed earlier. by many of using such doses of hydrocortisone in any patient

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

even those with true adrenal insufficiency. Hydrocortisone After a few hours in the ICU, she was begun on two pressors
therapy should be tapered and discontinued as clinically indi- and had a stable BP (systolic, 110-115 mm Hg) for several
cated in those who receive the drug without definitive diagno- hours. The ICU team obtained a random and a 30-minute
sis given that prolonged use of the drug can lead to iatrogenic post-Cosyntropin serum cortisol levels that were 19 and 23
HPA suppression. ug/dL, respectively. Her Na was 145 meq/L; the K was 4.4
meq/L, whereas the albumin was 1.7 g/dL.
1. Based on the available data, do you believe that this
patient has adrenal insufficiency?
Case 1
A. Yes
You evaluate a 77-year-old man with persistent postoperative
B. No
hypotension and hypothermia (core temp of 34C) following
C. Cannot determine
triple vessel coronary bypass surgery. His wife stated that he
2. The post-Cosyntropin increment in serum cortisol noted
had surgery to remove a pituitary tumor 10 years earlier, which
in this patient can be:
was followed a year later by gamma knife therapy. He had
A. Observed in ambulatory healthy subjects
complained of fatigue and muscle cramps for several months
B. Always indicative of adrenal dysfunction
and that his primary medical doctor measured a TSH that was
C. Predictive of a potential benefit from hydrocortisone
within the normal range. At the time of your assessment, the
patient is on iv fluids and two pressors with a blood pressure
3. Which of the following is the best interpretation of the
(BP) of 100/65 mm Hg and a heart rate of 75/min in normal
Cosyntropin stimulation test?
sinus rhythm. He looks pale, with diminished body hair, and
A. Normal
exhibits delayed relaxation of his reflexes. Available laboratory
B. Primary adrenal insufficiency
data shows a Na of 133 meq/L, K of 4.1 meq/L, albumin of
C. Secondary adrenal insufficiency
2.8 g/dL, a random cortisol (1230 h) of 6.8 ug/dL, a free T4 of
4. Which of the following is the best next test in this
0.6 ng/dL, and a TSH of 2.9 IU/L. The intensive care unit
patients evaluation?
(ICU) team orders a Cosyntropin test (250 ug iv), which shows
A. Magnetic resonance imaging of pituitary
cortisol levels of 15 and 19 ug/dL at 30 and 60 minutes, B. Computed tomography of adrenal
respectively. C. Random cortisol paired with ACTH level
1. How do you interpret the random cortisol? D. Serum aldosterone paired with plasma renin activity
A. Normal E. No further endocrine testing
B. Suggestive of adrenal insufficiency
C. As expected for a critically ill patient
Case 3
2. The Cosyntropin-stimulated cortisol levels rule out the A 55-year-old man with a history of metastatic small-cell lung
diagnosis of adrenal insufficiency in this patient. cancer was admitted to the ICU with fever, respiratory distress,
A. Yes and hypotension. He has been getting chemotherapy along with
B. No Megace because of anorexia. He was recently diagnosed to
3. Which of the following endocrine disorders were present have hepatitis C but treatment was delayed in light of his
before surgery? progressive and unresponsive lung cancer. In the ICU, he was
A. Adrenal insufficiency started on antibiotics, iv fluids, and two pressors but despite
B. Hypothyroidism that, he remained hypotensive. A random cortisol performed at
C. Hypogonadism 1400 hours was 17 ug/dL. You are asked to interpret the data
D. Diabetes insipidus and offer your opinion on using hydrocortisone in this patient.
4. Which of the following is the best first hormonal treat- Your examination did not reveal any additional finding. Other
ment to administer? laboratory data showed the following: Na, 142 meq/L; K,
A. Hydrocortisone 4.3 meq/L; a total protein of 6.5 g/dL, and an albumin of
B. Thyroid hormone 2.5 g/dL.
C. Testosterone 1. Based on the available data, do you believe that this
D. Flucortisone patient has adrenal insufficiency?
A. Yes
Case 2 B. No
You evaluate a 65-year-old woman who was transferred from C. Maybe
the medical ward to the ICU because of hypotension. She was 2. Which of the following factors should be considered in
admitted a day earlier for suspected pyelonephritis sepsis interpreting cortisol level in this patient?
and was treated with iv fluids and appropriate antibiotics. Her A. Critical illness
blood pressure (BP) decreased to a nadir of 82/60 mm Hg. B. History of lung cancer

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

C. History of hepatitis C. Laboratory error

D. Laboratory error D. Drug effect
E. Drug effect E. Malignant melanoma
3. Which of the following is the best next test in this 3. Which of the following is the most likely cause of the
patients evaluation? polyuria and polydipsia?
A. Magnetic resonance imaging of pituitary A. Central diabetes insipidus
B. Cosyntropin stimulation test B. Nephrogenic diabetes insipidus
C. Measurement of free cortisol, transcortin, and ACTH A. Medication effect
D. Serum aldosterone paired with plasma renin activity D. Osmotic diuresis
4. Which of the following would you recommend to the
A. Await the results of tests that are ordered 1. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free
B. Start hydrocortisone therapy cortisol in critically ill patients. N Engl J Med. 2004;350:1629-1638.
C. Start therapy for hepatitis C 2. Arafah BM. Hypothalamic Pituitary Adrenal Function during Critical
Illness: Limitations of Current Assessment Methods. J Clin Endocrinol
D. Start fludrocortisone
Metab. 2006;91:3725-3745.
3. Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary
Case 4 cortisol concentration in the assessment of adrenal function in critically ill
subjects: A surrogate marker of the circulating free cortisol. J Clin
A 58-year-old woman with malignant melanoma was admitted
Endocrinol Metab. 2007;92:2965-2971.
to the ICU with fever and hypotension. Two weeks earlier she 4. Sprung CL, Annane D, Keh D, et al. CORTICUS Study Group. Hydrocor-
had started complaining of polyuria, polydipsia, headache, tisone therapy for patients with septic shock. N Eng J Med. 2008;358:111-124.
blurry vision, and intermittent diplopia. Ipilimumab was re- 5. Zimmerman JJ, Barker RM, Jack R. Initial observations regarding free
cortisol quantification logistics among critically ill children. Intensive Care
cently initiated to treat metastatic melanoma. A computed to-
Med. 2010;36:1914-1922.
mography scan of the abdomen/chest showed widespread 6. Albert SG, Ariyan S, Rather A. The effect of etomidate on adrenal
metastatic disease and bowel perforation. Her examination function in critical illness: a systematic review. Intensive Care Med.
showed a BP of 80/50 mm Hg, a heart rate of 110/min, with 2011;37:901-910.
7. Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical diagnosis of adre-
poor skin turgor, anisocoria, and a left ptosis. Laboratory data nal insufficiency: the added value of dehydroepiandrosterone sulfate mea-
showed a blood urea nitrogen of 32 mg/L, a creatinine of 1.6 surements. Endocr Pract. 2011;17:261-270.
mg/dL a Na of 148 meq/L, a K of 4.5 meq/L, a random 8. Boonen, E, Vervenne H, Meersseman P, et al. Reduced cortisol metabo-
serum cortisol of 11.1 ug/dL and negative urinalysis. She lism during critical illness. N Engl J Med. 2013;368:1477-1488.
9. Al-Aridi R, El Sibai K, Fu P, Khan M, Selman WR, Arafah BM. Clinical
started on iv saline and antibiotics. and biochemical characteristic features of metastatic cancer to the sella
1. Based on the available data, do you believe that this turcica: An analytical review. Pituitary. 2014;17:575-587.
patient has adrenal insufficiency? 10. Heckmann M, dUscio CH, Steckel H, et al. Reduction in cortisol inacti-
vation is part of the adrenal response to cardiac and noocardiac pediatric
A. Yes
surgery: A prospective study using gas chromatography-mass spectrometry
B. No analysis. Horm Metab Res. 2014;46:677-684.
C. Maybe 11. Boonen E, Van den Berghe G. Endocrine responses to critical illness:
2. Which of the following is the most likely cause of her novel insights and therapeutic implications. J Clin Endocrinol Metab.
clinical picture?
12. Faje AT, Sullivan R, Lawrence D, et al. Ipilimumab-induced hypophysitis:
A. Primary adrenal insufficiency A detailed longitudinal analysis in a large cohort of patients with meta-
B. Secondary adrenal insufficiency static melanoma. J Clin Endocrinol Metab. 2014;99:4078-4085.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Primary Aldosteronism

M46 the immense delight of Conn and those in the operating room,
Presented, April 1 4, 2016 the surgeon, Dr William Baum, encountered a right 13-g adre-
nal tumor, which was removed while leaving the contralateral
gland intact. The patients postoperative studies showed an
William F. Young, Jr, MD, MSc. Division of almost total reversal of the preoperative metabolic and clini-
Endocrinology, Diabetes, Metabolism, and Nutrition, cal abnormalities. Conn had achieved irrefutable proof of
Mayo Clinic, Rochester, Minnesota 55905, E-mail: the validity of his investigative conclusions and established
young.william@mayo.edu for the first time the relationship among adrenal aldosterone-
producing tumors, hypertension, and hypokalemia. A new
INTRODUCTION era had arrived in the study of hypertension and adrenal
Historical Overview mineralocorticoids.
In his presidential address at the Annual Meeting of the Central
Society for Clinical Research in Chicago, Illinois, October 29, SIGNIFICANCE OF THE CLINICAL PROBLEM
1954, Dr Jerome W. Conn stated, I have prepared no compre- Following Conns prismatic case, it became clear that there
hensive review of my personal philosophy of clinical investi- were two major forms of primary aldosteronism (PA): bilateral
gation. Instead, I plan to make a scientific report to you about a idiopathic hyperaldosteronism and aldosterone-producing ad-
clinical syndrome, the investigation of which has been most enoma (APA). Although initially thought to be rare, prevalence
exciting to me since I initiated it in April of this year (1). studies from every continent have now documented that PA is
Conn, a professor of medicine at the University of Michigan, the most common form of secondary hypertension, affecting
had been active in government-funded research on the mecha- 510% of all people with hypertension.
nisms of human acclimatization to humid heat. He established Knowledge gaps among clinicians are prevalent with regard
that the bodys acclimatization response was to rapidly dimin- to the diagnosis and management of patients with PA. For
ish renal salt and water loss and abruptly curtail the salt content example, many clinicians are not aware of the effect of time of
of body sweat and saliva, and he suggested that it was due to day for venipuncture on case detection testing. This is just one
increased adrenocortical function with elaboration of a salt- of more than 20 knowledge gaps that I hope to cover (close)
retaining steroid termed electrocortin, later named aldoste- during this session.
rone. He also showed that im administration of deoxycortico-
sterone acetate produced similar changes in the electrolyte
composition of urine, sweat, and saliva. BARRIERS TO OPTIMAL PRACTICE
The term barriers is continuing professional development
In April 1954, he was asked to see M.W., a 34-year-old
jargon in the United States for identifying issues that prevent or
woman with a 7-year history of muscle spasms, temporary
inhibit clinicians from optimal diagnosis and treatment of a
paralysis, tetany, weakness, and a 4-year history of hyperten-
medical condition. For example, understanding the potential
sion. She had a blood pressure (BP) of 176/104 mm Hg, severe
barriers posed by clinical guidelines for the diagnosis and
hypokalemia (potassium, 1.6-2.5 mEq/L), mild hypernatremia
treatment of PA: How do you confirm PA in a patient on four
(sodium, 146-151 mEq/L), and alkalosis (serum pH, 7.62).
antihypertensive drugs and poor BP control? The clinical
Because there were no signs or symptoms of glucocorticoid or
guidelines suggest that most antihypertensive drugs should be
androgen excess, Conn suspected, on the basis of his past
discontinued in all patients for this confirmatory step. How-
research, that M.W.s clinical presentation could result from
ever, in the clinical setting listed, discontinuing antihyperten-
excess secretion of the adrenal salt-retaining corticoid. Conn
sive medications will put the patient at risk. This issue and
studied M.W. in the Metabolism Research Unit for 227 days.
many others will be discussed during this MTP session.
Using Streetens bioassay technique to measure sodium reten-
tion in adrenalectomized rats after ip injection of human urine,
M.W. averaged 1333 mcg deoxycorticosterone equivalent per LEARNING OBJECTIVES
day compared with normotensive controls at 61.4 mcg per day. As a result of participating in this session, learners should be
In his presidential address, Conn stated, It is believed that able to:
these studies delineate a new clinical syndrome which is des- Recognize when to test for PA
ignated temporarily as primary aldosteronism (1) (The word Implement the key steps to successful case detection
temporarily was used because aldosterone was yet to be testing for PA
measured in any human bodily fluid.) Conn planned for a Discuss the options for confirmatory testing in a patient
bilateral adrenalectomy on December 10, 1954. In the 1995 with PA and select the most appropriate study for a
retelling of the surgical scene, Gittler and Fajans (2) wrote, To particular individual.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Assess the role for subtype testing for PA Step 2: How to Perform Case-Detection Testing
Counsel patients on the treatment options for PA In patients with suspected PA, case-detection testing can be
accomplished by measuring a morning (preferably between
Session Format 0800 and 1000 h) ambulatory paired random plasma aldoste-
We will use a computer-based clinicopathologic conference rone concentration (PAC) and plasma renin activity (PRA).
approach to discuss a patient with suspected PA. The tests This test may be performed while the patient is taking antihy-
performed and the order in which they are obtained will be pertensive medications (with some exceptions [see below]) and
up to the clinicians in the audience. Many potential without posture stimulation. Hypokalemia reduces the secre-
tests/procedures are listed on the test menu (Table 1); however, tion of aldosterone, and it is optimal (but not necessary in most
just because they are listed, it does not mean that they were cases) to restore the serum level of potassium to normal before
actually performed. performing diagnostic studies. Mineralocorticoid receptor
We will then turn to two clinical vignettes (found at the end (MR) antagonists (eg, spironolactone and eplerenone), renin
of this syllabus section on PA) that lead to multiple-choice inhibitors, and high-dose (5 mg/d) amiloride are the only
questions. medications that absolutely interfere with interpretation of the
Finally, if time allows, we will turn to common e-mail ratio in patients with PA and should be discontinued at least 6
questions that I have received with regard to the diagnosis and weeks before testing if clinically feasible. ACE inhibitors,
treatment of PA. angiotensin receptor antagonists (ARBs), and diuretics have the
potential to falsely elevate PRA. Therefore, in a patient
treated with an ACE inhibitor, ARB, or diuretic, the finding of
a detectable PRA level or a low PAC/PRA ratio does not
exclude the diagnosis of PA. However, a very useful clinical
Step 1: When to Test for PA
Patients with hypertension and hypokalemia (regardless of pre- point is that when a PRA level is undetectably low in a patient
sumed cause), treatment-resistant hypertension (three antihy- taking an ACE inhibitor, ARB, or a diuretic, PA should
pertensive drugs and poor control), marked hypertension be highly suspect. Thus, ACE inhibitors, ARBs, and
(150 mm Hg systolic or 100 mm Hg diastolic), hyperten- nonpotassium-sparing diuretics do not need to be discontinued.
sion and an incidental adrenal mass, and onset of hypertension A second important clinical point is that the PRA is suppressed
at a young age should undergo screening for PA. In addition, (1.0 ng/mL/h) in almost all patients with PA. Adrenergic
the diagnosis of PA should be considered whenever performing inhibitors (eg, -adrenergic blockers and central 2 agonists)
a secondary hypertension evaluation (eg, when testing for reno- suppress renin secretion, but also in turn suppress aldosterone
vascular disease or pheochromocytoma). secretion (although to a lesser degree than renin) in normal
individuals; thus, although the PAC/PRA may increase in hy-
pertensive patients without PA treated with adrenergic inhibi-
tors, the PAC remains less than 15 ng/dL (416 pmol/L) and the
TABLE 1. Hyperaldosteronism Test Menu
case detection test is not significantly affected.
Test Menu The PAC/PRA ratio is based on the concept of paired
u Clinical assessment hormone measurements. For example, in a hypertensive hy-
u PAC/PRA ratio pokalemic patient:
u 24-h urinary potassium Secondary hyperaldosteronism should be considered
u Captopril suppression test when both PRA and PAC are increased and the PAC/
u Saline suppression test PRA ratio is less than 10 (277 in SI units) (eg,
u 24-h urine aldosterone on a high-salt diet renovascular disease).
u Fludrocortisone suppression test An alternate source of MR agonism (eg,
u Renal angiogram hypercortisolism) should be considered when both PRA
u Posture test and PAC are suppressed.
u 18-OH B PA should be suspected when PRA is suppressed (1.0
u NP-59 scan ng/mL/h) and PAC is increased.
u CT adrenals/abdomen
u MRI adrenals It is important to understand that the lower limit of detection
u Adrenal vein sampling varies among different PRA assays and can have a dramatic
u GRA test effect on the PAC/PRA ratio. Thus, the cutoff for a high
u Treatment menu PAC/PRA ratio is laboratory dependent and, more specifically,
PRA-assay dependent. In a retrospective study, the combina-
Abbreviation: MRI, magnetic resonance imaging. tion of a PAC/PRA ratio more than 30 (832 in SI units) and
PAC more than 20 ng/dL (555 pmol/L) had a sensitivity of

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

90% and a specificity of 91% for APA. At Mayo Clinic, a PAC testing. Aldosterone suppression testing can be performed with
(in pmol/L)/PRA (in ng/mL/h) ratio of 20 (555 in SI units) or orally administered sodium chloride and measurement of uri-
more and PAC of at least 15 ng/dL (416 pmol/L) are found in nary aldosterone or with iv sodium chloride loading and mea-
more than 90% of patients with surgically confirmed APA. surement of PAC.
Thus, there are patients with PA (especially IHA) who have
PAC levels 15 ng/dL. However, most patients with surgically
Oral Sodium Loading Test
correctable forms of PA will have PACs greater than this After hypertension and hypokalemia are controlled, patients
cutoff. should receive a high-sodium diet (supplemented with sodium
A PAC of 15 ng/dL (416 pmol/L) is in the high-normal chloride tablets if needed) for 3 days, with a goal sodium intake
range (normal range, 121 ng/dL; 28 583 pmol/L). In patients of 218 mmol of sodium (equivalent to 12.8 g sodium chloride).
without PA, most of the variation in PAC/PRA ratios occurs The risk of increasing dietary sodium in patients with severe
within the normal range. A high PAC/PRA ratio is a positive hypertension must be assessed in each case. Because the high-
case detection test result, a finding that warrants further testing. salt diet can increase kaliuresis and hypokalemia, vigorous
It is important for the clinician to recognize that the replacement of potassium chloride may be needed and the
PAC/PRA ratio is only a case-detection tool, and all positive serum level of potassium should be monitored daily. On the
results should be followed by a confirmatory aldosterone sup- third day of the high sodium diet, a 24-hour urine specimen is
pression test to verify autonomous aldosterone production be- collected for measurement of aldosterone, sodium, and creati-
fore treatment is initiated. In a study of 118 subjects with nine. To document adequate sodium repletion, the 24-hour
essential hypertension, neither antihypertensive medications urinary sodium excretion should exceed 200 mmol. Urinary
nor acute variation of dietary sodium affected the accuracy of aldosterone excretion more than 12 mcg/day (33 nmol/d) in
the PAC/PRA ratio adversely, with a sensitivity on and off this setting is consistent with autonomous aldosterone secre-
therapy of 73 and 87%, respectively, and a specificity of 74 and tion. The sensitivity and specificity of the oral sodium loading
75%, respectively (3). test are 96 and 93%, respectively.
The measurement of PRA is time consuming, shows poor
interlaboratory variability, and requires special preanalytical
prerequisites. To overcome these disadvantages, a monoclonal Intravenous Saline Infusion Test
antibody against active renin is being used by several reference The iv saline infusion test has also been used widely for the
laboratories to measure plasma renin concentration (PRC) in- diagnosis of PA. Normal subjects show suppression of PAC
stead of PRA. However, few studies have focused on compar- after volume expansion with isotonic saline; subjects with PA
ing the different methods in the testing for PA and these studies do not show this suppression. The test is done after an over-
lack confirmatory testing. Until such studies are completed it night fast. Two liters of 0.9% sodium chloride solution are
would be reasonable to consider a positive PAC/PRC test when infused iv with an infusion pump over 4 hours into the recum-
the PAC is more than 15 ng/dL (416 pmol/L) and the PRC is bent patient. However, results from a recent study suggest that
below the lower limit of detection for the assay. performing the saline infusion test in the seated position may
improve the accuracy of this test (4). Blood pressure and heart
rate are monitored during the infusion. At the completion of the
Step 3: Confirmatory Testing
An increased PAC/PRA ratio is not diagnostic by itself (sensi- infusion, blood is drawn for measurement of PAC. PAC levels
tivity and specificity are 75%), and PA must be confirmed by in normal subjects decrease to less than 5 ng/dL (139
demonstrating inappropriate aldosterone secretion. The list of pmol/L); most patients with PA do not suppress to less than 10
drugs and hormones capable of affecting the renin-angiotensin- ng/dL (277 pmol/L); postsaline infusion PAC values between
aldosterone axis is extensive, and frequently in patients with 5 and 10 ng/dL (139 and 277 pmol/L) are indeterminate and
severe hypertension, a medication-contaminated evaluation can be seen in patients with IHA.
is unavoidable. Certain calcium channel blockers (eg, vera-
pamil) and 1-adrenergic receptor blockers do not affect the Captopril Stimulation Test and Fludrocortisone
diagnostic accuracy in most cases. It is impossible to interpret Suppression Test
data obtained from patients receiving treatment with MR an- These tests are discussed in more detail elsewhere (5).
tagonists (eg, spironolactone, eplerenone), direct renin inhibi-
tors, or high-dose amiloride when PRA is not suppressed. Step 4: Subtype Testing
Therefore, treatment with a MR antagonist should not be initi- Unilateral adrenalectomy in patients with APA or unilateral
ated until the evaluation has been completed and the final adrenal hyperplasia results in normalization of hypokalemia in
decisions regarding treatment have been made. If PA is sus- all; hypertension is improved in all and is cured in approxi-
pected in a patient receiving treatment with a MR antagonist or mately 30 60% of these patients. In IHA unilateral or bilateral
high-dose amiloride, if clinically feasible, the treatment should adrenalectomy seldom corrects the hypertension. IHA and glu-
be discontinued for at least 6 weeks before further diagnostic cocorticoid remediable aldosteronism (GRA) should be treated

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

medically. Therefore, for those patients who want to pursue a Normalization of BP should not be the only goal in managing
surgical cure, the accurate distinction between the subtypes of the patient with PA. Excess aldosterone is associated with cardio-
PA is a critical step. vascular toxicity; it induces myocardial fibrosis by either stimula-
The subtype evaluation may require one or more tests, the tion of cardiac fibroblasts and/or vascular fibrinoid necrosis.
first of which is imaging the adrenal glands with computed Unilateral laparoscopic adrenalectomy is an excellent treat-
tomography (CT) (Figure 1). When a solitary, hypodense, and ment option for patients with APA or unilateral hyperplasia.
unilateral macroadenoma (1 cm and 2 cm) and normal Although BP control improves in nearly 100% of patients
contralateral adrenal morphology are found on CT in a young postoperatively, average long-term cure rates of hypertension
patient (eg, 35 y) with marked PA (eg, spontaneous hypoka- after unilateral adrenalectomy for APA range from 30 to 60%
lemia and PAC 30 ng/dL), adrenal venous sampling (AVS) (16). Persistent hypertension following adrenalectomy is corre-
may not be needed and consideration should be given to pro- lated directly with having more than one first-degree relative
ceed directly to unilateral laparoscopic adrenalectomy (14). with hypertension, use of more than two antihypertensive
However, in most cases, CT may show normal-seeming agents preoperatively, older age, increased serum creatinine,
adrenals, minimal unilateral adrenal limb thickening, unilateral and duration of hypertension and is most likely due to coexis-
microadenomas (1 cm), or bilateral macroadenomas. In these tent primary hypertension.
cases, if the patient wants to pursue the surgical option, addi- IHA and GRA should be treated medically. In addition,
tional testing is required to determine the source of excess APA patients may be treated medically if the medical treatment
aldosterone secretion (6, 15). includes MR blockade. There have been no placebo-controlled
Although, in general, patients with APA have more severe randomized trials evaluating the relative efficacy of drugs in
PA than patients with IHA, there is no reliable noninvasive the treatment of PA. Spironolactone has been the drug of
clinical predictor profile to make this distinction (7). choice to treat PA for more than three decades. However, it is
For those patients seeking a surgical cure, AVS is an essen- not selective for the MR. For example, antagonism at the T
tial diagnostic step in most patients with PA to distinguish receptor may result in painful gynecomastia, impotence, and
between unilateral and bilateral adrenal aldosterone hyperse- agonism at the progesterone receptor may cause menstrual
cretion (15). We highlighted the keys to successful AVS in a irregularity. Treatment goals are normotension and normokalemia
2009 article (8). without potassium supplementation.
Eplerenone is a competitive and selective MR antagonist
Step 5: Treatment that was approved by the U.S. Food and Drug Administration
The treatment goal is to prevent the morbidity and mortality- for the treatment of uncomplicated essential hypertension and
associated with hypertension, hypokalemia, and cardiovascular congestive heart failure in late 2003.
and renal damage (9). The cause of PA helps to determine the Because of the deleterious cardiovascular and renal effects
appropriate treatment. of excess aldosterone, normalization of circulating aldosterone

Figure 1. Subtype testing and treatment algorithm for primary aldosteronism.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

or MR blockade should be part of the management plan for all tabs, 4 tabs thrice daily (240 mEq/d). Physical examination
patients with PA (17). Unilateral laparoscopic adrenalectomy is showed a normal-seeming young woman with a BP of 146/82
an excellent treatment option for patients with APA or unilat- mm Hg, heart rate 72 bpm, and body mass index of 24.4 kg/m2.
eral hyperplasia. IHA and GRA should be treated medically. In Laboratory studies completed on current medications:
addition, patients with APA may be treated medically if the Sodium 143 mEq/L (mmol/L)
medical treatment includes MR blockade. Potassium 3.2 mEq/L (mmol/L)
Creatinine 1.0 mg/dL (80 mol/L)
Guidelines PAC 51 ng/dL (1415 pmol/L)
The Endocrine Society clinical practice guideline on PA was Plasma renin activity 0.6 ng/mL per hour
published in 2008 (5) and an updated and revised version will
Abdominal CT scan shows a 1.5-cm solitary right adrenal
be published in early 2016.
cortical nodule (precontrast density 5 HU) and the left
adrenal seems normal on all cuts.
Recent Advances 2. The best next step in the management of this patients
The major recent advance in PA has been the detection of
hypertension and hypokalemia is:
somatic mutations in several genes (eg, KCNJ5 potassium
A. Perform a seated saline suppression test
channel mutations, CACNA1D calcium channel mutations,
B. Adrenal venous sampling
ATPase genes ATP1A1 and ATP2B3), which are responsible
C. [6-131I]iodomethyl-19-norcholesterol [NP-59] scin-
for more than 50% of APAs (10-13). However, thus far, the
presence of a somatic mutation in the APA has not provided the
D. Posture stimulation test
clinician with any novel preoperative tests or new treatments.
E. No further tests are needed, proceed to laparoscopic
right adrenalectomy
Case 1
A 28-year-old woman presented to her local physician with
Case 1
new-onset hypertension. There was no family history of hyper-
Correct answer: C. Renin is not suppressed. Therefore, this is
tension. The patient does not use tobacco or alcohol. She was
not PA; rather, this is secondary aldosteronism and in the
taking no medications. Physical examination showed a normal-
clinical setting of a young woman the clinician should suspect
seeming woman with a body mass index of 21 kg/m2. Her BP
fibromuscular dysplasia of one or both renal arteries. Thus, an
was 160/106 mm Hg.
imaging study of the renal arteries is indicated.
The following laboratory studies were obtained at 1030
Sodium 140 mEq/L (mmol/L) Case 2
Correct answer: E. This patient has marked PA and spontaneous
Potassium 3.5 mEq/L (mmol/L)
hypokalemia. Thus, laboratory confirmatory testing is not needed.
Creatinine 1.0 mg/dL (80 mol/L)
This patient can only have one disorder: PA. In addition, in young
PAC 34 ng/dL (943 pmol/L)
people (35 y) with marked PA who have a unilateral
Plasma renin activity 2.6 ng/mL per hour
macroadenoma on adrenal CT, AVS is usually not needed,
The patient is referred to you for further assessment of her whereas in older patients with PA, because of the age-related
hypertension and hypokalemia. development of adrenal nodularity, the findings on CT cannot be
1. The best next step in her evaluation would be to: trusted and AVS is a key and necessary diagnostic step.
A. Perform a seated saline suppression test
B. Repeat the laboratory tests at 0800 hours in the REFERENCES
seated ambulatory patient 1. Conn JW. Presidential address. I. Painting background. II. Primary aldo-
C. Order a magnetic resonance angiogram of the renal steronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3-17.
arteries 2. Gittler RD, Fajans SS. Primary aldosteronism (Conns syndrome). J Clin
Endocrinol Metab. 1995;80:3438-3441.
D. Order a CT scan of the adrenal glands with 2-mm 3. Schwartz GL, Turner ST. Screening for primary aldosteronism in essential
contiguous cuts hypertension: Diagnostic accuracy of the ratio of plasma aldosterone
concentration to plasma renin activity. Clinical Chemistry. 2005;51:386-
Case 2 4. Ahmed AH, Cowley D, Wolley M, Gordon RD, Xu S, Taylor PJ, Stowas-
A 17-year-old woman presented with hypertension of 3 ser M. Seated saline suppression testing for the diagnosis of primary
months duration. Her menstrual cycles were regular and she aldosteronism: A preliminary study. J Clin Endocrinol Metab. 2014;99(8):
had no hirsutism or acne. Her body weight had been stable. She
5. Funder JW, Carey RM, Fardella C, et al. Case Detection, diagnosis, and
is a senior in high school and very active and athletic. treatment of patients with primary aldosteronism: An Endocrine Society
Her medications include amlodipine, 5 mg/d; KCL, 20 mEq Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93:3266-3281.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

6. Rossi GP, Auchus RJ, Brown M, et al. An expert consensus statement on ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and sec-
use of adrenal vein sampling for the subtyping of primary aldosteronism. ondary hypertension. Nat Genet. 2013;45(4):440-444, 444e1 e2.
Hypertension. 2014;63(1):151-160. 12. Scholl UI, Goh G, Stolting G, et al. Somatic and germline CACNA1D
7. Sze WC, Soh LM, Lau JH, et al. Diagnosing unilateral primary calcium channel mutations in aldosterone-producing adenomas and pri-
aldosteronismComparison of a clinical prediction score, computed to- mary aldosteronism. Nat Genet. 2013;45(9):1050-1054.
mography and adrenal venous sampling. Clin Endocrinol (Oxf). 2014;81(1): 13. Williams TA, Monticone S, Schack VR, et al. Somatic ATP1A1, ATP2B3,
25-30. and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension.
8. Young WF, Stanson AW. What are the keys to successful adrenal venous 2014;63(1):188-195.
sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol 14. Lim V, Guo Q, Grant CS, et al. Accuracy of adrenal imaging and adrenal
(Oxf). 2009;70:14-17. venous sampling in predicting surgical cure of primary aldosteronism.
9. Iwakura Y, Morimoto R, Kudo M, et al. Predictors of decreasing glomer- J Clin Endocrinol Metab. 2014;99(8):2712-2719.
ular filtration rate and prevalence of chronic kidney disease after treatment 15. Young WF Jr, Stanson AW, Thompson GB, et al. Role for adrenal venous
of primary aldosteronism: Renal outcome of 213 cases. J Clin Endocrinol sampling in primary aldosteronism. Surgery. 2004;136:1227-1235.
Metab. 2014;99(5):1593-1598. 16. Sawka AM, Young WF Jr., Thompson GB, et al. Primary aldosteronism:
10. Choi M, Scholl UI, Yue P, et al. K channel mutations in adrenal Factors associated with normalization of blood pressure after surgery. Ann
aldosterone-producing adenomas and hereditary hypertension. Science. Intern Med. 2001;135:258-261.
2011;331(6018):768-772. 17. Lim PO, Young WF, MacDonald TM. A review of the medical treatment
11. Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in of primary aldosteronism. J Hypertens. 2001;19:353-361.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Primary Aldosteronism and Cardiometabolic Risk:

Approach to Medical Management

M53 electrolytes (6, 7). Ensuring that patients with PA are treated to
Presented, April 1 4, 2016 minimize all the adverse cardiometabolic effects of aldosterone
is challenging.

Gail K. Adler, MD, PhD. Division of Endocrinology,

Diabetes and Hypertension, Brigham and Womens
To date, we lack prospective studies to identify the best treat-
Hospital, Harvard Medical School, Boston, Massachusetts
ment strategies for the medical management of PA, so medical
02115, E-mail: gadler@partners.org
management of PA is based on expert opinion. Also, an under
appreciation of the full extent of aldosterones adverse
INTRODUCTION cardiometabolic effects hinders care.
Historical Overview
Aldosterone was first isolated and shown to promote renal
sodium retention and potassium loss by Simpson, Tait, and
As a result of participating in this session, learners should be
Bush in 1952 (1). These and subsequent studies established
able to:
aldosterone as a key regulator of blood pressure (BP) and
Define the consequences of excess aldosterone on the
electrolyte balance. The receptor for aldosteronethe miner-
bodys cardiovascular, cerebrovascular, renovascular and
alocorticoid receptor (MR)was isolated and characterized by
metabolic systems.
Rousseau and colleagues in 1972 (2). Jerome Conn (3) de-
Identify the drugs used to treat excess aldosterone.
scribed the first case of primary aldosteronism (PA) due to an
Develop an approach for the medical management of
adrenal cortical tumor in the early 1950s. For decades, PA was
patients with PA.
thought to be rare, affecting approximately 1% of individuals
with hypertension. During the past 15 years, it has become For the diagnosis of PA and determination of whether surgical
clear that PAs contribution to hypertension was grossly therapy is appropriate please refer to the Meet the Professor
underappreciated; it is now thought that PA occurs in approxi- sessions and the 2008 Endocrine Society Clinical Practice
mately 10% of all hypertensives (4). Recently, investigators Guideline: Case Detection, Diagnosis, and Treatment of Pa-
have defined the genetic changes leading to the development of tients with Primary Aldosteronism (9).
over 50% of aldosterone-producing adenomas (5). During the
past 15-20 years it has also become clear that the MR has
multiple cardiometabolic effects that are independent of its
traditional effects on BP and electrolyte homeostasis (6, 7).
Clinical Features
In PA, adrenal overproduction of aldosterone leads to excess
CLINICAL SIGNIFICANCE MR activation. In the renal collecting duct, this leads to epithe-
Hypertension affects 70 million people in the United States (8). lial sodium channel (ENaC) activation and stimulation of so-
PA is a prevalent cause of hypertension, affecting up to 10% of dium retention and potassium excretion (Figure 1). The sodium
all patients with hypertension and 20% of those with resistant retention leads to volume expansion and hypertension, whereas
hypertension (4). the potassium excretion leads to hypokalemia. Thus, patients with
Approximately 50% of patients with PA have bilateral dis- PA have hypertension, elevated aldosterone, increased ratio of
ease on adrenal vein sampling and thus are treated medically, aldosterone to plasma renin activity, and often hypokalemia.
not by unilateral adrenalectomy. In addition, some patients Multiple preclinical studies have shown that excess MR
with PA are not surgical candidates or choose to avoid surgical activation leads to proteinuria, podocyte damage, glomerular
therapy. Given the large numbers of individuals with PA who damage, inflammation, vascular dysfunction, vascular damage,
need medical management, it is important for physicians to stroke, myocardial inflammation, and cardiac fibrosis, through
know how to treat this disease. mechanisms that are independent of BP and potassium homeo-
In recent years, basic and clinical studies have shown that stasis (6, 7). Further, in obese diabetic animal models, MR
aldosterones adverse effects are not limited to its traditionally blockade improves proteinuria, reduces histopathological evi-
known effects of causing hypertension and hypokalemia. dence of renal damage, restores the proinflammatory phenotype
Rather, excess exposure to aldosterone has adverse effects on of visceral adiposity toward that of a lean animal, improves
the vasculature, heart, kidney and metabolism through mecha- glucose metabolism, reduces hepatic steatosis, and reduces
nisms that are independent of aldosterones effects on BP and liver inflammation (7).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Figure 1. Therapeutic interventions to reduce the adverse cardiometabolic and renal effects of excess aldosterone.

Excess MR activation leads to similar cardiometabolic in- with essential hypertension for a median of 12 years after
jury in humans with PA. Retrospective studies have examined diagnosis and treatment, revealed an increased rate of stroke,
the prevalence of metabolic disturbances and cardiovascular arrhythmias, heart failure and type 2 diabetes in PA (12). The
events in patients with PA compared with patients with essen- concept that excess MR activity contributes to cardiovascular
tial hypertension matched for the degree and duration of hyper- disease is supported by landmark clinical trials of patients with
tension (10-13). Patients with PA have an increased prevalence mild, moderate, and severe heart failure, which showed that
of atrial fibrillation (AF), nonfatal myocardial infarction, coro- adding a low dose MR blockade to standard therapy has mini-
nary artery disease, heart failure, stroke, metabolic syndrome, mal effects on BP, but markedly reduces cardiovascular mor-
and abnormal glucose metabolism (Table 1). Treatment of PA bidity and mortality (6). Excess MR activity is also implicated
by resection of an aldosterone-producing adenoma or by ad- in pathophysiology of pulmonary arterial hypertension in hu-
ministration of a MR antagonist reduces the excessive left mans. Increases in aldosterone are associated with insulin re-
ventricular hypertrophy seen in PA (14) and reduces sistance and cardiometabolic risk factors in non-PA patients,
microalbuminuria (15). However, one retrospective study, whereas treatment of PA improves insulin sensitivity [reviewed
which followed individuals with PA and matched individuals in Garg et al (16)]. Finally, recent studies in humans suggest an

TABLE 1: Cardiometabolic Complications in PA

PA, n EH, n PA, % EH, % OR (95% CI) P
Cardio- and cerebro- vascular events
Atrial fibrillation (11) 459 1289 3.9% 1.1% 5.0 (2.0-12.5)b .001
CAD (11) 459 1289 5.7% 2.8% 1.9 (1.1-3.5)b .03
Heart failure (11) 459 1289 4.1% 1.2% 2.9 (1.4-6.0)b .003
Nonfatal MI (11) 459 1289 4.4% 1.7% 2.6 (1.3-5.4)b .01
Stroke (12) 270 810 7.4% 3.5% 2.2 (1.2-4.0) .006
Metabolic disturbances
Metabolic syndrome (13) 85 381 41.1% 29.6% .05
Abnormal glucose metabolism (10) 1283a 2621a 22.4% 16.8% 1.55 (1.01-2.36)

Abbreviations: CAD, coronary artery disease; CI, confidence interval; EH, essential hypertension; MI, myocardial infarction; OR,
odds ratio.
n, total number of participants in a group; %, percentage of individuals experiencing the disease entity; OR, indicates the odds ratio of
experiencing the disease entity; P-value compares EH vs PA.
Meta analysis.
Adjusted for hypertension duration.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

interaction between the renin-angiotensin-aldosterone system spironolactone and eplerenone are steroid-based drugs, finerenone
and PTH with MR blockade reducing PTH, raising the possi- is derived from dihydropyridine.
bility of alterations in bone health in PA (17). These findings The amount of spironolactone or eplerenone needed to treat
suggest that patients with PA are at increased risk of develop- PA varies from one patient to the next. The goal is to use
ing a wide range of cardiometabolic diseases in addition to sufficient MR blockade to raise serum potassium into the nor-
hypertension. mal range and reduce BP into the normal range without adverse
effects. Doses up to 400 mg spironolactone have been used in
Treatment Goals clinical studies of PA (18). However, many patients with PA
It is reasonable to propose that the three key goals for medical have had longstanding hypertension so that even with complete
treatment of PA are to: MR blockade, patients will often require the addition of other
1. Maintain BP in the normal range antihypertensive drugs to control BP. Calcium channel block-
2. Maintain normal serum potassium ers are a reasonable choice. Some physicians recommend a low
3. Reduce the development of target organ damage and dose of hydrochlorothiazide given that PA is a volume-overloaded
adverse metabolic consequences of increased state, but this medication can lower serum potassium. PA is
aldosterone. associated with a low plasma renin activity and low angiotensin II
so angiotensin-converting enzyme inhibitors and angiotensin II
Management: Dietary Sodium Restriction receptor blockers are less likely to reduce BP.
Patients with PA should follow a low-sodium diet. If dietary
sodium is low, there is less sodium to be retained in the Aldosterone Synthase Inhibitors
collecting ducts and therefore less sodium/water retention and Aldosterone synthase inhibitors are under development (18)
less potassium excretion. Thus, dietary sodium restriction low- and have been shown to reduce aldosterone levels in PA.
ers BP and increases serum potassium levels despite continued However, these inhibitors also tend to decrease cortisol. In the
elevations in aldosterone levels. Also, preclinical studies sug- future, we may find that adding a selective aldosterone syn-
gest that the adverse cardiovascular and cerebrovascular effects thase inhibitor to MR blockade is a useful approach to reduce
of excess aldosterone are minimized with a low-sodium diet. MR activation.

Management: Drugs Targeting Excess MR Activation Management: Drugs Targeting Renal Effects of Excess
MR Blockade Aldosterone: ENaC Inhibitors
The mainstay of medical treatment for PA is MR blockade Amiloride and triamterene block the actions of ENaC (18).
[reviewed in Deinum et al (18)]. Spironolactone is the first line Some physicians recommend adding amiloride, if tolerable
of treatment. It is a relatively inexpensive competitive MR doses of MR blockade are insufficient to control BP and hypo-
antagonist. Spironolactone is rapidly metabolized in the liver to kalemia. However, this treatment only blocks the effects of
generate several active metabolites, such as canrenoate. The ENaC leaving individuals exposed to the other tissue effects of
half-life of spironolactone is short (1.4 h), whereas the metabo- excess MR activation.
lites have longer half-lives (16.5 h for canrenoate) allowing for
once-daily dosing. Consuming spironolactone with food im- Management: Treatment of the Cardiometabolic
proves its absorption. Spironolactone also binds to the andro- Abnormalities Associated With PA
gen receptor and the progesterone receptor, although at much PA treatments that reduce aldosterone levels or block the MR
lower affinity than to MR. However, the interaction with these will reduce MR activity in all tissues, whereas those therapies
receptors leads to spironolactones common adverse effects of that block MRs actions in the kidney will leave the rest of the
gynecomastia, breast tenderness, decreased libido, and men- body exposed to excess MR activity. For this reason, I favor
strual irregularities. increasing the doses of spironolactone or eplerenone to achieve
Eplerenone is a newer, more selective competitive inhibitor full MR blockade as tolerated and I am less enthusiastic about
of MR with fewer adverse effects than spironolactone. It is adding ENaC inhibitors to control potassium. I have high hopes
metabolized in the liver to inactive metabolites. Due to its short for aldosterone synthase inhibitors. The adverse cardiovascular
half-life of 4-6 hours, eplerenone should be dosed twice daily. effects of aldosterone seem to be minimized when dietary
Patients unable to tolerate the adverse effects of spironolac- sodium intake is low (7), so I encourage all patients to follow a
tone can be switched to eplerenone. The BP-lowering effect low-sodium diet. Further, I think that physicians should be
of 50 mg spironolactone is roughly equivalent to 75-100 mg proactive in encouraging patients with PA to maintain a
eplerenone. Unfortunately, eplerenone is more costly than healthy lifestyle (healthy weight, good exercise and sleep, and
spironolactone. healthy diet) to reduce the risk of cardiometabolic disease. It is
There are a number of new drugs on the horizon. Finerenone possible that physicians should have a lower threshold for
is a highly potent, highly selective, newly developed MR an- initiating cardiovascular protective therapies (eg, statin or aspi-
tagonist that is not yet available in clinical practice. Although rin) in PA, although there are no studies addressing this ques-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

tion. It is difficult to know whether the patient has achieved Case 3

sufficient MR blockade. Serum potassium is one readout. A A 60-year-old patient with PA has a BP of 154/92 mm Hg, K
detectable plasma renin activity would be consistent with good of 3.5 mmol/L, an estimated glomerular filtration rate (eGFR)
MR blockade, but again there are no studies specifically ad- of 65 mL/min/1.73 m2, and a urinary albumin to creatinine
dressing this issue. ratio of 60 mg/g prior to the initiation of MR blockade. After
initiation of spironolactone, 50 mg daily, BP improves to
131/83 mm Hg, K increases to 4.1 mmol/L, and the urinary
MAIN CONCLUSIONS albumin to creatinine ratio improves to 10 mg/g, but the eGFR
MR blockade is the key medical treatment for PA. The goals decreases to 55 mL/min/1.73 m2. Patients primary care physi-
are to control BP and serum potassium and to prevent the cian calls you because she is concerned that renal function has
development of aldosterone-mediated cardiovascular and met- deteriorated with initiation of the spironolactone. What should
abolic complications. Patients with PA due to bilateral adrenal you do?
production of aldosterone may be treated with MR blockade A. Stop spironolactone and start amiloride
for decades so it is important to maintain adequate blockade B. Stop spironolactone and start eplerenone
and institute preventative strategies to minimize the likelihood C. Continue spironolactone at the current dose
of developing cardiometabolic complications. D. Stop spironolactone and start a calcium channel
A 50-year-old patient with new-onset hypertension is diag- Case 1
nosed with PA and refuses to consider surgery. His BP is The answer to Case 1 is C, Stop spironolactone and start
150/100 mm Hg and his K is 3.1 mmol/L off of all medica- eplerenone, 50 mg bid. Spironolactone was effective at reduc-
tions. You initiate spironolactone, 25 mg daily and up titrate ing the patients BP and raising serum potassium. However,
the dose to 50 mg daily. The patient returns complaining of given that spironolactone can block the androgen receptor,
breast pain and decreased libido. On examination his BP is decreased libido and breast pain are relatively common adverse
137/86 mm Hg and his K is 3.7 mmol/L. effects. Switching to eplerenone, 50 mg bid is roughly equiva-
You would make which of the following medication lent to 50 mg spironolactone in terms of MR blockade, but the
changes? adverse effects of decreased libido and breast pain should
A. Stop spironolactone and start amiloride 5 mg twice a resolve as eplerenones antiandrogen effects are much less than
day (bid) those of spironolactone. A is incorrect given that stopping
B. Stop spironolactone and start eplerenone, 25 mg bid spironolactone and switching to amiloride will only block
ENaC and not protect the rest of the body from excess MR
C. Stop spironolactone and start eplerenone, 50 mg bid
activation. B is incorrect given that 50 mg spironolactone is
D. Decrease spironolactone to 25 mg daily and add KCL,
roughly equivalent to 75-100 mg eplerenone, not 50 mg
20 mEq bid
eplerenone. D is incorrect as 25 mg spironolactone is not likely
E. Stop spironolactone and start calcium channel blockade
to provide sufficient MR blockade to protect the whole body
plus KCL, 20 mEq bid
from excess MR activation. E is incorrect because again cal-
cium channel blockade and KCL will not protect the whole
Case 2 body from excess MR activation.
A 75-year-old man with longstanding PA who has been treated
with MR blockade for several decades, initially spironolactone
Case 2
and now eplerenone, 100 mg bid, sees you as a new patient. He The answer is E, All of the above. Patients with PA com-
has type 2 diabetes, proteinuria, and AF. He also had a stroke several pared with individuals with essential hypertension have an
years ago. He has always been compliant with his medications. He increased risk for stroke, AF, proteinuria and type 2 diabetes,
asks you whether his medical problems are due to his PA. and coronary artery disease. The increase risk for cerebrovas-
Which of the following do you tell him has been associated cular and cardiovascular disease is not due to increased lipids
with PA? so physicians cannot rely on lipid levels to identify individuals
A. Stroke at risk.
B. Atrial fibrillation
C. Proteinuria Case 3
D. Type 2 diabetes mellitus The answer is C, Continue spironolactone at the current
E. All of the above dose. The patient is well controlled on spironolactone with a
F. C and D good BP and serum K without adverse effects associated with

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

androgen receptor blockade. Microalbuminuria has decreased, 7. Garg R, Adler GK. Aldosterone and the mineralocorticoid receptor: Risk
factors for cardiometabolic disorders. Curr Hypertens Rep. 2015;17(7):52.
which is a known benefit to MR blockade in PA. Hyperaldo-
8. Center for Disease Control and Prevention. High Blood Pressure. Accessed
steronism leads to glomerular hyperfiltration. With MR block- from: http://www.cdc.gov/bloodpressure/facts.htm.
ade, the hyperfiltration resolves and the underlying renal injury 9. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and
is apparent. With long-term followup of patients with PA on treatment of patients with primary aldosteronism: an endocrine society clinical
practice guideline. J Clin Endocrinol Metab. 2008;93(9):3266-3281.
MR blockade, eGFR is stable compared with matched patients 10. Chen W, Li F, He C, Zhu Y, Tan W. Elevated prevalence of abnormal
with essential hypertension (15). There is no reason to switch glucose metabolism in patients with primary aldosteronism: A meta-
to eplerenone as all MR antagonists as well as surgical resec- analysis. Ir J Med Sci. 2014;183(2):283-291.
11. Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications
tion of an aldosterone-producing adenoma have similar effects associated with primary aldosteronism: A controlled cross-sectional study.
on eGFR. Hypertension. 2013;62(2):331-336.
12. Mulatero P, Monticone S, Bertello C, et al. Long-term cardio- and cerebro-
vascular events in patients with primary aldosteronism. J Clin Endocrinol
REFERENCES Metab. 2013;98(12):4826-4833.
1. Simpson SA, Tait JF, Bush IE. Secretion of a salt-retaining hormone by 13. Fallo F, Veglio F, Bertello C, et al. Prevalence and characteristics of the
the mammalian adrenal cortex. Lancet. 1952;2(6727):226-228. metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab.
2. Rousseau G, Baxter JD, Funder JW, Edelman IS, Tomkins GM. Glucocor- 2006;91(2):454-459.
ticoid and mineralocorticoid receptors for aldosterone. J Steroid Biochem. 14. Rossi GP, Cesari M, Cuspidi C, et al. Long-term control of arterial
1972;3(2):219-227. hypertension and regression of left ventricular hypertrophy with treatment
3. Conn JW, Louis LH. Primary aldosteronism: A new clinical entity. Trans of primary aldosteronism. Hypertension. 2013;62(1):62-69.
Assoc Am Physicians. 1955;68:215-231; discussion, 231-213. 15. Fourkiotis V, Vonend O, Diederich S, et al. Effectiveness of eplerenone or
4. Piaditis G, Markou A, Papanastasiou L, Androulakis, II, Kaltsas G. Progress spironolactone treatment in preserving renal function in primary aldoste-
in aldosteronism: A review of the prevalence of primary aldosteronism in ronism. Eur J Endocrinol. 2013;168(1):75-81.
pre-hypertension and hypertension. Eur J Endocrinol. 2015;172(5):R191 16. Garg R, Adler GK. Role of mineralocorticoid receptor in insulin resis-
R203. tance. Curr Opin Endocrinol Diabetes Obes. 2012;19(3):168-175.
5. Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mecha- 17. Brown JM, Williams JS, Luther JM, et al. Human interventions to charac-
nisms of primary aldosteronism. J Endocrinol. 2015;224(2):R63R77. terize novel relationships between the renin-angiotensin-aldosterone sys-
6. Parviz Y, Iqbal J, Pitt B, Adlam D, Al-Mohammad A, Zannad F. Emerging tem and parathyroid hormone. Hypertension. 2014;63(2):273-280.
cardiovascular indications of mineralocorticoid receptor antagonists. 18. Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of aldoste-
Trends Endocrinol Metab. 2015;26(4):201-211. rone excess. Pharmacol Ther. 2015;154:120-133.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Applying DXA and Other Imaging to Clinical Conundrums

M02 be used to calculate fracture risk when BMD is not available as

Presented, April 1 4, 2016 well. Bone biopsies give the most direct information about
bone microarchitecture but are invasive procedures. More re-
cently, trabecular bone score (TBS), a gray-level textural mea-
Micol S. Rothman, MD. Division of Endocrinology, surement, has become available and is being used both in
Metabolism, and Diabetes, University of Colorado School research and clinical practice (4). TBS can use lumbar spine
of Medicine, Aurora, Colorado 80045, E-mail: micol. data from standard DXA testing to noninvasively look at bone
rothman@ucdenver.edu microarchitecture. It projects a 3D structure onto a 2D plane
and uses gray-level variation in images of the lumbar spine to
INTRODUCTION calculate a score. This score has been shown to predict fracture
Historical Overview in primary osteoporosis and, more recently, in secondary osteo-
Bone mineral density (BMD) testing by dual-energy x-ray porosis. Other modalities such as quantitative computed to-
absorptiometry (DXA) has been a part of clinical practice since mography can measure volumetric BMD at the spine and hip.
the 1980s. It remains the gold standard for measuring bone Although quantitative computed tomography is thought to be a
density at the spine and hip. BMD is the bone mineral content good measure of bone quality, due to cost and radiation expo-
in g/2D projected area of bone, reported as grams/cm2. In 1994 sure, it is generally only used for research at this time.
the World Health Organization defined osteoporosis on the
basis of BMD testing by DXA and T-score. The T-score BARRIERS TO OPTIMAL PRACTICE
(patients BMD-young normal mean)/SD of young normal. In Although BMD testing is widely used, measurements are fre-
postmenopausal women and men over 50 years of age, a quently not reported in concordance with International Society
T-score of 1.0 and greater is considered normal BMD, less for Clinical Densitometry (ISCD) guidelines. Many clinicians
than 1.0 to 2.5 is defined as low bone mass or osteopenia, are not familiar with how to interpret DXA images in the face
and less or equal to than 2.5 is considered osteoporosis (1). of artifacts and other limitations. In addition, the use of T-
Osteoporosis can also be diagnosed as a low-trauma fracture scores vs Z-scores is often misunderstood. The ISCD suggests
(fall from a standing height.) In younger patients, the Z-score is that only the lowest-site T-score be used for a diagnosis (1).
used to compare patients BMD to others their age. A Z-score That is, one cannot have a hip with osteoporosis but a spine
of less than 2.0 indicates an abnormal BMD for age (1, 2). with osteopenia. Furthermore, many DXA centers do not have
a measurement of least significant change (LSC), which can
SIGNIFICANCE OF THE CLINICAL PROBLEM make it difficult to interpret change in BMD over time.
Osteoporosis is a common bone disease. Fractures affect mor- There are also ongoing controversies about the frequency of
bidity and mortality and cost the health care system billions of DXA for screening and monitoring. Recent publications have
dollars every year. There are more than 2 million fractures in shown conflicting data about when to screen and how often to
the United States each year and the risk of having a broken repeat DXA. Medicare coverage for screening in some groups
bone after age 50 years is 1 in 2 for women and 1 in 4 for men. differs from what the ISCD and National Osteoporosis Foun-
Twenty percent of women will die in the first year after hip dation (NOF) recommend. Many women who are eligible for
fracture and 60% of patients never regain their prefracture level screening DXA still do not receive it. In a study of Medicare
of independence. Osteoporosis in men is often underdiagnosed beneficiaries from 2002-2008, 48% of women had no testing
and undertreated, but a man is more likely than a woman to die performed at all. Less than 4% received four or more DXA
after hip fracture (3). studies, and thus, undertesting may be more of a problem than
Although DXA is still the most widely used clinical tool to overtesting (5).
screen for osteoporosis, it has limitations. Additional tools can
be used to evaluate fracture risk, as many patients who fracture LEARNING OBJECTIVES
have bone density scores in the osteopenic or even normal As a result of participating in this session, learners should be
range. Thus, DXA in combination with Fracture Risk Assess- able to:
ment Tool (FRAX; https://www.shef.ac.uk/FRAX/) is used as a Interpret BMD testing for men and women of all ages
fracture prediction tool for untreated patients with a diagnosis Use DXA to help guide secondary workup of low BMD
of osteopenia. FRAX takes into account BMD independent or bone loss
risks for fracture including: age, glucocorticoid treatment, cur- Be familiar with the guidelines (and controversies)
rent tobacco use, parental history of hip fracture, rheumatoid regarding DXA screening and follow-up intervals
arthritis, and alcohol use, greater than three per day. FRAX can Be familiar with the use of TBS

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

STRATEGIES FOR DIAGNOSIS, THERAPY, Low Z-scores at any age many suggest the need for a
AND/OR MANAGEMENT secondary workup of low bone density.
The NOF Clinicians Guide for 2014 recommends osteoporosis BMD testing should be repeated at a time interval when
screening for all women over age 65 years and men over 70 a change is likely to be significant and/or lead to a
years. They also advise screening for postmenopausal women treatment change. This may vary by patient factors, the
and men above 50 years with other risk factors. In addition, a treatments used and other clinical indicators. For those at
DXA is suggested after a fracture to define the extent of low highest risk, that interval may be 1-2 years. For those at
BMD. The NOF also suggests that DXA be performed at lower risk, it can be longer.
facilities using accepted quality assurance measures. The U.S. Trabecular bone score is a new tool that can help predict
Preventive Services Task Force recommends bone density fracture risk in many groups. It may be of particular use
screening for all women less than 65 years of age (Grade B) in populations where BMD has not historically been
and women less than 65 years of age whose 10-year risk of low.
fracture as calculated by FRAX is greater than a 65-year-old
Caucasian woman without risk factors (9.3%) (Grade B) (6). CASES
The use of additional vertebral imaging for those with low Case 1
BMD is also suggested in the following groups: women greater A 65-year-old woman whose femoral neck T-score lowest site
than 70 years of age and men greater than 80 years of age with is 1.2. How would you decide when to repeat her BMD?
T-scores less than 1.0, women 65-69 years of age and men A. She does not need another BMD ever.
70-79 years of age with T-scores less than 1.5, and men and B. She should have another in 2 years.
women over 50 years of age with adult low-trauma fractures, C. It might be appropriate to extend the screening interval
height loss, and glucocorticoid treatment (3). The NOF advises for this patient, but it depends on her clinical risk
follow-up testing for those on treatment in 1-2 years and every factors.
2 years thereafter, but note that clinical situations may warrant
Answer: C. In 2012, an article by Gourlay et al (7) looked at
more- or less- frequent followup.
the use of screening DXA for osteoporosis. They examined a
Least significant change (LSC) and precision should be
subgroup of women from the Study on Osteoporotic Fractures
calculated by each technician at a site. The technician measures
and looked at the time it took women with normal BMD or
a patient multiple times (15 patients 3 or 30 patients 2) to
osteopenia to transition to osteoporosis. This time varied with
determine precision and, thus, what change in BMD can be
changes in age, estrogen use and body mass index. Less than
interpreted as a true change. There is a formula on the ISCD
5% of the women with mild osteopenia (which would be the
website (ISCD.org) where patients data can be entered and
patient in this case) made the transition to osteoporosis over the
precision for each technician can be calculated. LSC is reported
15-year period. This article does not support retesting in 2
in g/cm2 for hip and spine. T-scores are not used because they
years (answer B) but nor would never testing (answer A) be
can change with alterations in the database reference popula-
appropriate without more knowledge of the clinical scenario.
tion. If a patients change in BMD does not exceed the LSC, it
Patient age and other clinical risks can help determine the
is not considered significant. However, even if changes do
interval. In addition, we should know the LCS for the techni-
exceed LSC, this does not mean they are clinically significant.
cian and machine.
A loss of 12% per year can be seen with normal aging and
We will use this case vignette to discuss the intervals for
BMD testing performed at long intervals may demonstrate loss
screening and also monitoring. We will also talk about LSC
that exceeds LSC, but is not considered pathologic.
and how it is derived.
In the setting of a low T-score (or low Z-score in a young
patient) a workup to rule out secondary causes is advised. This
Case 2
includes looking for common causes of low BMD: renal dis-
A postmenopausal patient has type 2 diabetes. She was previously
ease, liver disease, Vitamin D deficiency, hyperthyroidism,
on thiazolidinedione and currently on sodium/glucose cotran-
hyperparathyroidism, hypogonadism, or hypercalciuria, as well
sporter 2 (SGLT-2)-inhibitor therapy. You decide to obtain a TBS.
as less common causes as clinical suspicion dictates: Cushings
Which of the following is true about/approximately TBS?
syndrome, multiple myeloma, celiac disease, mastocytosis, or
A. TBS requires additional images and radiation exposure
osteogenesis imperfecta.
for the patient.
B. TBS can be used to monitor treatment with
MAIN CONCLUSIONS bisphosphonates.
BMD should be interpreted using T-scores for men 50 C. TBS is associated with an increased risk of
and postmenopausal women. Younger groups should osteoporotic fracture in postmenopausal women with
have Z-scores reported. type 2 diabetes.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

D. A low TBS score is correlated with reduced fracture (thus, answer D is incorrect). In addition, teriparatide is con-
risk. traindicated in young patients (Answer A) as there can still be
concerns for open epiphyses until age 25 years. With a Vitamin
Answer: C. Trabecular bone score is a gray-level textural
D level of 35 ng/ml, further supplementation is unlikely to help
measurement that uses images already obtained by 2D images
his bone health (thus, C is incorrect). Adolescents with chronic
(4, 8). (A is wrong) A high score is indicative of better
illness may have delayed bone age and it is important to keep
microarchitecture (thus, D is wrong) In a study by Leslie et al
this in mind when thinking about DXA Z-scores. Inquiry about
in 2013 (9) postmenopausal women with diabetes had higher
pubertal status with testicular examination and measurement of
BMD but lower TBS than those without diabetes. TBS pre-
T is appropriate. This patient did have pubertal delay. With
dicted fracture in this group and may be particularly useful in
time, good nutrition (weight gain), and initiation of T, his bone
other groups where BMD may be high but fracture risk is
density markedly improved.
increased. At this time, however, changes in TBS have not
been validated to use for monitoring efficacy of therapy (thus, We will use this case vignette to talk about the use of
B is wrong). T-scores and Z-scores in young people and when intervention
This case will serve as a discussion point for talking about would be considered.
the uses and limitations of TBS.
1. ISCD Official Positions. 2015. Accessed from http://iscd.org.
Case 3 2. Lewiecki EM. Bone density measurement and assessment of fracture risk.
A 20-year-old man with a history of severe Crohns disease Clin Obstet Gynecol. 2013;56(4):667-676.
and very low Z-scores: (4.1 in the lumbar spine.) He has not 3. National Osteoporosis Foundation Clinicians Guide. 2014. Accessed
fractured. He is not currently on glucocorticoids. He was from: http://nof.org.
4. Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: A noninva-
known to have Vitamin D deficiency in the past, but recent 25 sive analytical method based upon the DXA image. J Bone Miner Res.
Vitamin D level was 35 ng/mL. He does supplement calcium. 2014;29(3):518-530.
What do you suggest? 5. King AB, Fiorentino DM. Medicare payment cuts for osteoporosis testing
reduced use despite tests benefit in reducing fractures. Health Aff
A. Begin teriparatide. (Millwood). 2011;30(12):2362-2370.
B. Inquire about pubertal status and check T. 6. Golob AL, Laya MB. Osteoporosis: Screening prevention and manage-
C. Add 50 000 IU of Vitamin D once a week. ment. Med Clin N Am. 2015;(99):587-606.
D. Begin alendronate based on low T-score. 7. Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval and
transition to osteoporosis in older women. N Engl J Med. 2012;366(3):225-
Answer: B. This question brings up the larger issue of how to 233.
8. Ulivieri FM, Silva BC, Sardanelli F, Hans D, Bilezikian JP, Caudarella R.
approach low BMD in younger patients. Often, young patients Utility of the trabecular bone score (TBS) in secondary osteoporosis.
with low BMD have not reached peak bone mass and their Endocrine. 2014;47(2):435-448.
bone density must be interpreted with caution. The use of 9. Leslie WD, Aubry-Rozier B, Lamy O, Hans D. TBS (trabecular bone
score) and diabetes-related fracture risk. J Clin Endocrinol Metab.
T-scores in men younger than 50 years of age and premeno-
pausal women is not appropriate and in young patients who are 10. Abraham A, Cohen A, Shane E. Premenopausal bone health: Osteoporosis
not fracturing we try to avoid pharmacologic therapy (10) in premenopausal women. Clin Obstet Gynecol. 2013;56(4):722-729.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Cancer Treatment and Bone Health

M13 retical mechanism to explain this benefit is a favorable altera-

Presented, April 1 4, 2016 tion of the bone microenvironment by bisphosphonates.


Azeez Farooki, MD. Memorial Sloan Kettering Cancer
Numerous cancer therapies can induce bone loss and increase
Center, Department of Endocrinology, New York, New
fracture risk. Aromatase inhibitors are first-line adjuvant
York 10065, E-mail: farookia@mskcc.org
therapy for women with breast cancer and may be continued
for 10 years or more in some patients; this represents a huge
INTRODUCTION population of patients. Recent data from Austria has shown that
Historical Overview the increase in fracture risk resulting from these agents may
The concept of a seed and soil was first proposed by Stephen
have been underestimated. At the present time, physicians
Paget in 1889. This hypothesis proposed that the organ-
(particularly oncologists) are in need of guidance on: 1) how to
preference patterns of tumor metastasis are the product of
manage such patients (which patients to treat and for how long)
favorable interactions between metastatic tumor cells (the
and 2) how to communicate information about risks of
seed) and the microenvironment of a given organ (the
antiresorptive therapies. Endocrinologists should be aware of
soil). In 1980 Ian Hart and Isaiah Fidler (1) grafted kidney,
recent landmark studies specifically in patients with breast
ovary, and lung tissue under the skin or into the muscles of
cancer to give optimal consultative advice. Which FDA-
mice. Injected melanoma cells showed a distinct preference to
approved osteoporosis therapies to use and when to use them
develop in the grafted lung and ovary tissue but not in the renal
are important topics.
tissue, thus providing evidence of a preference for a given
Patients with thyroid cancer with metastatic bone disease are
tissue that was independent of blood supply. Bone matrix
possesses a large amount of potentially growth-stimulating usually managed in part by endocrinologists. It is important to
factors. A vicious cycle was initially proposed by the late Dr implement approved antiresorptive therapy at effective dosing
Greg Mundy in 1997 (2) in which tumor cells activate oste- schedules in such patients to reduce the risk of skeletal com-
oclastic bone resorption (via osteoblast/osteoclast-activating plications.
factors such as PTHrp), which liberates bone-derived growth
factors (IGF-I for example), which in turn promotes tumor-cell BARRIERS TO OPTIMAL PRACTICE
proliferation. Lack of familiarity with data on negative skeletal effects
The iv bisphosphonate pamidronate received approval for of adjuvant cancer therapies (such as aromatase
hypercalcemia of malignancy in 1991, for multiple myeloma in inhibitors) and important considerations when choosing
1995, and for osteolytic bone metastases from breast cancer in an agent to protect bone health.
1996. Zoledronic acid was approved for hypercalcemia of ma- Knowledge gap concerning skeletal morbidity due to
lignancy in August 2001 and for bone metastasis in solid thyroid cancer metastatic to bone.
tumors (a broad indication) in February 2002. In nonmetastatic Lack of familiarity with the clinical data supporting use
patients with cancer, the United States Food and Drug Admin- of iv bisphosphonates and denosumab in patients with
istration (FDA) approved denosumab (Prolia) in 2011 in the thyroid cancer metastatic to bone.
context of adjuvant endocrine therapy to increase bone mass
in patients who are at high risk of fracture from: 1) receiving
androgen deprivation therapy for nonmetastatic prostate cancer LEARNING OBJECTIVES
or, 2) adjuvant aromatase inhibitor (AI) therapy for breast As a result of participating in this session, learners should be
cancer. able to:
An exciting question that has been the subject of numerous Understand how adjuvant aromatase inhibitors induce
randomized trials over the years in patients with breast cancer bone loss and increase fracture risk and choose
is whether bisphosphonates can prevent seeding and/or appropriate agents to treat this problem.
propagation in bone of nascent micrometastases; is there an Appreciate new data showing a potential adjuvant
adjuvant effect of bisphosphonates? In breast cancer, this story benefit to bisphosphonate therapy in postmenopausal
has culminated with the 2015 publication of a meta-analysis of patients with breast cancer.
these trials in the Lancet (3) demonstrating, in postmenopausal Appreciate that skeletal-related events (SREs), a
patients only, a reduction in bone recurrence and a highly composite endpoint of skeletal morbidity, are common
significant improvement in cancer-specific survival. One theo- and repetitive in thyroid cancer metastatic to bone.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Treat patients with metastatic thyroid cancer to bone CASES WITH QUESTIONS
with the appropriate dosing schedule of antiresorptive Case 1
therapy to prevent SREs. A 51-year-old Caucasian woman was diagnosed with invasive
breast carcinoma, ER PR HER2-negative, and underwent
chemotherapy 1 year prior. She was not treated with radiation
therapy. Her menses have not returned since chemotherapy and
she is now going to be treated with an adjuvant aromatase
Patients treated with adjuvant aromatase inhibitors in the setting of
inhibitor to reduce her risk of recurrence. Her T-scores are
breast cancer are at risk for rapid bone loss and increased fracture
2.0 at the lumbar spine, femoral neck, and total hip sites.
risk. Over 5 years, The Arimidex, Tamoxifen, Alone or in Com-
FRAX risk calculates at below country-specific treatment
bination (ATAC) trial showed a reduction in bone mineral density
(BMD) at the lumbar spine equal to 6.1% and a reduction at the
1. What is her risk for bone loss? Risk for fracture?
total hip equal to 7.2% (4). Oral and iv bisphosphonates have been
2. For what duration of therapy should this patient be
shown to protect BMD in these patients; denosumab has not only
been shown to protect BMD but also to reduce fracture risk in
3. Choice of agent?
aromatase inhibitortreated patients (5). In conclusion, clinicians
4. How would you answer the patient if she asks, How
should have a lower threshold to treat patients receiving adjuvant
will this affect my cancer?
aromatase inhibitors with antiresorptive therapy (bisphosphonates
or denosumab) with the goals of preventing bone loss and reduc-
ing fracture risk. Case 2
A meta-analysis has shown that bisphosphonates may re- A 62-year-old female with metastatic poorly differentiated thy-
duce the risk of bone recurrence and breast cancer-specific roid cancer was diagnosed 2.5 years ago. Current imaging
mortality (3). These data are often very useful when discussing reveals multiple widespread pulmonary nodules ( 1 cm) and
treatment decisions with patients. an unchanged lytic metastasis in the left T12 pedicle. Sorafenib
Thyroid cancer patients with metastatic bone disease are at was considered but not given due to Hepatitis B and increased
high risk for skeletal morbidity (captured in a composite end- liver function tests; subsequently, the hepatitis was treated and
point known as SREs) and should benefit from antiresorptive sorafenib is being considered.
therapy to protect them from SREs (pathologic fracture, the Laboratory tests: TSH 0.23 mcU/mL, Tg 916 ng/mL,
need for radiation, or surgery to bone, spinal cord compression) 25(OH)D 35 ng/mL, glomerular filtration rate is normal,
and, to potentially reduce pain. Although no randomized con- calcium and total alkaline phosphatase are normal.
trolled trials exist in thyroid cancer specifically, data both with
zoledronic acid and denosumab has confirmed the clinical utility Chronology:
of these potent antiresorptives in various solid tumors metastatic June 2013: Lytic lesion in R arm found on x-ray after she was
to bone (6, 7) in reducing he risk of SREs. Data in these patients bumped on a bus and had severe pain.
employed much more intensive dosing schedules compared with 08/2013: MRI showed a large lesion in the right proximal
that employed in osteoporosis patients (Figure 1). humerus that did not extend into the joint.


4 mg 120 mg 5 mg 60 mg
zoledronic zoledronic
denosumab denosumab
acid acid
Dosing interval monthly* monthly yearly q6 months
Bone Metastases YES YES - -
Hypercalcemia of Malignancy YES YES - -
Mulple Myeloma YES - - -
Endocrine-therapy induced osteoporosis/penia** YES - - YES
Giant Cell Tumor of the Bone - YES - -
Post-Menopausal Osteoporosis in Women - - YES YES#
Prevenon of Post-Menopausal Osteoporosis in
- - YES -
Senile Osteoporosis in Men - - YES -
Glucocorcoid-induced Osteoporosis - - YES -
* New randomized data (not yet peer reviewed) demonstrates non-inferiority to every 3 month dosing
** Every 6 month dosing was studied in this context
# In paents with 1) high-risk of fracture, 2) documented failure of bisphosphonate, or 3) a CrCl < 35 mL/min

Figure 1. FDA-approved therapies and schedules for benign and malignant bone disease.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

11/2013: Computed tomography guided biopsy consistent absorptiometry scan after taking the AI for 1 year. A large loss
with metastatic thyroid carcinoma, most likely follicular. of BMD would prompt initiation of antiresorptive therapy.
2/27/2014: Resection of the right humeral metastasis and a Among the several FDA-approved options for osteoporosis
right shoulder hemiarthroplasty. therapy, bisphosphonates or denosumab are preferable for this
5/15/2014: Total thyroidectomy for a 5.0-cm poorly differ- patient. This patient should not be treated with raloxifene
entiated thyroid carcinoma, extensive capsular invasion into therapy due to findings from the ATAC study, which demon-
fibroadipose tissue, extensive blood vessel invasion with more strated that combining a SERM (tamoxifen) with an AI was
than 8 foci of vascular invasion, including invasion of large inferior (from a cancer standpoint) to using an AI alone.
extrathyroid vessels. One benign lymph node was resected. Teriparatide use is also an uncertain area due to theoretical
7/2014: 290 mCi radioiodine. Post-therapy uptake in lesions of concerns of stimulating occult micrometastases (8) and should
frontal brain, T12 and L4, in a lytic lesion in the right mandibular be avoided at this early point in the patients cancer course.
condyle, and diffusely in lungs and in small lung nodules. Bisphosphonate and denosumab are both valid options for this
7/2014: Magnetic resonance (MR) image of spine. Diffuse patient. Although the patient is not osteoporotic, denosumab,
infiltrative lesion in anterior half of L4, and in the pedicle, 60 mg every 6 months would be an FDA-approved option
facet, and posterior vertebral body of T12. Both of these under the indication for endocrine therapyinduced bone
lesions were raidioactive iodine (RAI) avid in the post-therapy loss. Also, zoledronic acid may be given at 3-4 mg every 6
scan. A sclerotic lesion in the alar of S2S3 that was not RAI months in this context (9, 10) although 5 mg yearly may also
avid was also noted. be sufficient. The duration of treatment is debatable and in
7/2014: MR brain. Dural-based lesion measuring 2.5 part depends on the duration of aromatase inhibitor therapy;
1.8 1.9 cm above the right anterior cranial fossa adjacent to a 3-year treatment duration followed by reassessment is
right orbit. This lesion was RAI avid on the post-treatment reasonable.
scan. The patient can be educated on the recent meta-analysis of
8/2014: Hyperfractionated radiotherapy to T12 and L4. randomized trials of bisphosphonate use in nonmetastatic
9/2014: Craniotomy for removal of frontal dural-based breast cancer (18 766 subjects), which demonstrated (only for
metastatic lesion. postmenopausal patients) a significantly decreased risk of
breast cancer bone recurrence and a significant improvement in
10/2014: Stereotactic radiosurgery to right frontal resection bed.
cancer-specific mortality (3). Although a meta-analysis not
1. Is this patient at risk for malignant bone disease
definitive, it is suggestive that adjuvant bisphosphonate
causing fractures and other types of skeletal morbidity
therapy (iv or oral) may improve cancer-specific mortality to a
magnitude similar to that of adjuvant chemotherapy. The pa-
2. Does this patient have an indication to be treated with
tient will have to interpret this information in light of their own
iv bisphosphonate or denosumab therapy?
beliefs and preferences about medication. Of note, a large
3. If yes, at what dose and schedule? For how long?
randomized trial with adjuvant denosumab examining breast
4. If the patient had a severe reaction to iv zoledronic
cancer recurrence is currently pending.
acid, what would you offer next?

Case 2
DISCUSSION In the oncologic literature, a composite endpoint known as
Case 1 SRE is used to capture the morbidity associated with metastatic
This patient is at high risk for bone loss due to her recent bone disease. This endpoint consists of: pathologic fractures,
chemotherapy-induced menopause and also the initiation of the need for radiation therapy to bone, surgery due to impend-
aromatase inhibitor (AI) therapy. The slope of the bone loss ing fracture, and spinal cord compression. This patient has
related to AI therapy seems to be greatest in the first 2-3 years already suffered an SRE (radiation to bone) and is at risk for
of use. The patients 10-year fracture risk via a FRAX calcu- future SREs. A retrospective analysis of 245 patients with
lation is not high enough to treat although this calculation does differentiated thyroid carcinoma metastatic to bone has shown
not account for the effect of the aromatase inhibitor (given that that 78% of the patients either presented with an SRE or
the secondary cause button in FRAX adds nothing if one developed an SRE over a median followup of 3.4 years (11).
inputs the BMD). The recent paper by Gnant et al (5) demon- Of the patients who sustained an initial SRE, 65% went on to
strated a higher-than-expected risk of fracture in women initi- sustain a second SRE. One small nonrandomized trial of iv
ating adjuvant AIs; surprisingly, on subgroup analysis, fracture pamidronate in differentiated thyroid carcinoma has shown a
risk in the placebo group seemed similar across different ages significant decrease in bone pain and a trend toward improve-
and, for normal or osteopenic BMDs, respectively. ment in performance status (12), and another nonrandomized
The two options here are to watch and wait or treat now. If study has suggested benefit from zoledronic acid in reducing
the patients strong preference was to watch and wait, a rea- SREs (13). Both zoledronic acid, 4 mg monthly and
sonable option would be to repeat the duel-energy x-ray denosumab, 120 mg monthly have been approved in solid

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

tumors metastatic to bone (a small number of thyroid cancer mineral density: 5-year results from the anastrozole, tamoxifen, alone or in
combination trial. J Clin Oncol. 2008;26(7):1051-1057.
patients were enrolled onto these trials) based on a delay in
5. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast
time to first SRE and decreased incidence of SREs. Recent cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-
randomized data with zoledronic acid in breast, prostate, and controlled trial. Lancet. 2015;386(9992):433-443.
myeloma patients has evaluated a less intensive dosing 6. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus
placebo in the treatment of skeletal metastases in patients with lung cancer
schedule of zoledronic acid, 4 mg every 3 months vs the and other solid tumors: A phase III, double-blind, randomized trialThe
standard of care, 4 mg monthly. These data have been pre- Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group.
sented in abstract form and showed no difference in SREs J Clin Oncol. 2003;21(16):3150-3157.
7. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study
between once-monthly and once-every-3-month dosing of of denosumab versus zoledronic acid in the treatment of bone metastases
zoledronic acid. There was also no difference in bone turnover in patients with advanced cancer (excluding breast and prostate cancer) or
markers at the end of the study (14). The case patient should be multiple myeloma. J Clin Oncol. 2011;20;29(9):1125-1132.
8. Farooki A, Fornier M, Girotra M. Anabolic therapies for osteoporosis.
offered either of the FDA-approved options in solid tumors: N Engl J Med. 2007;357(23):2410-2411.
zoledronic acid, 4 mg or denosumab, 120 mg (an 9. Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant
every-3-month dosing interval seems to be noninferior to letrozole-induced bone loss in postmenopausal women with early breast
cancer. J Clin Oncol. 2007;25:829-836.
monthly dosing for zoledronic acid but there is no such data 10. Bundred NJ, Campbell ID, Davidson N, et al. Effective inhibition of
with denosumab). The duration of therapy in this setting is an aromatase inhibitor-associated bone loss by zoledronic acid in post-
open question and probably should depend on the activity of menopausal women with early breast cancer receiving adjuvant
letrozole: ZO-FAST Study results. Cancer. 2008;112:1001-1010.
the bone lesions. With long-term use, there is some risk of
11. Farooki A, Leung V, Tala H, Tuttle RM. Skeletal-related events due to
osteonecrosis of the jaw and atypical femur fracture (15). In the bone metastases from differentiated thyroid cancer. J Clin Endocrinol
setting of thyroid cancer, if there is any significant degree of Metab 2012;97(7):2433-2439.
hypoparathyroidism, these potent antiresorptive agents should 12. Vitale G, Fonderico F, Martignetti A, et al. Pamidronate improves the
quality of life and induces clinical remission of bone metastases in patients
not be used (or be used with great caution) due to risk of severe with thyroid cancer. Br J Cancer. 2001;84(12):1586.
hypocalcemia. 13. Orita Y, Sugitani I, Toda K, Manabe J, Fujimoto Y. Zoledronic acid in the
treatment of bone metastases from differentiated thyroid carcinoma. Thy-
roid. 2011;21:31-35.
REFERENCES 14. Himelstein AL, Qin R, Novotny PJ, et al. CALGB 70604 (Alliance): A
1. Hart IR, Fidler IJ. Role of organ selectivity in the determination of randomized phase III study of standard dosing vs. longer interval dosing of
metastatic patterns of B16 melanoma. Cancer Res. 1980;40:2281-2287. zoledronic acid in metastatic cancer. J Clin Oncol. 2015;33(suppl; abstr
2. Mundy GR. Mechanisms of bone metastasis. Cancer. 1997;80:1546-1556. 9501).
3. Coleman R, Powles T, Paterson A, et al. Adjuvant bisphosphonate treat- 15. Puhaindran ME, Farooki A, Steensma MR, Hameed M, Healey JH, Boland
ment in early breast cancer: Meta-analyses of individual patient data from PJ. Atypical subtrochanteric femoral fractures in patients with skeletal
randomised trials. Lancet. 2015;3;386(10001):1353-1361. malignant involvement treated with intravenous bisphosphonates. J Bone
4. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone Joint Surg Am. 2011;93:1235-1242.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Hyperparathyroidism Management after Unsuccessful

Parathyroid Surgery


Presented, April 1 4, 2016 As a result of participating in this session, learners should be
able to:
Understand the definition of terms used in this clinical
Shonni J. Silverberg, MD. Division of Endocrinology, context (failed PTX, persistent PHPT, recurrent PHPT,
Department of Medicine, Columbia University College of post-PTX hyperparathyroidism).
Physicians and Surgeons, New York City, New York Use a stepwise approach to determining management.
10032, E-mail: sjs5@cumc.columbia.edu
Historical Overview Some Definitions
Primary hyperparathyroidism (PHPT) has evolved in its pre- It is first necessary to decide whether surgery has in fact been
sentation from a highly symptomatic disease to one that pres- unsuccessful. Beyond reviewing the surgical pathology (if no
ents with asymptomatic hypercalcemia in a majority of patients parathyroid tissue was removed, it is unlikely that the patient
in the United States. Parathyroidectomy (PTX) remains the was cured), it is necessary to obtain postoperative laboratory
only option for cure of PHPT. All patients with the classical values. Persistent PHPT is said to exist when the postopera-
PHPT described by Fuller Albright as a disease of bones tive serum calcium never normalizes (7). This differs from
(osteitis fibrosa cystica), stones, and psychic groans were con- Recurrent PHPT, which describes a patient in whom serum
sidered for surgery, and symptomatic patients today are as calcium normalizes after PTX, but who becomes hypercalce-
well. Today, a more nuanced approach is taken to the decision mic again greater than 6 months after surgery. PTH levels may
about surgery in asymptomatic patients, with four sets (1990, or may not normalize in the early-postoperative period, and a
2002, 2009, 2014) of guidelines for surgery in the asymptom- normal PTH is not required in a cured patient under all circum-
atic patient published as knowledge of the disorder has in- stances. In some studies, PTH remains elevated in as many as
creased (1 4). The problem of managing the patient after 40% of patients after successful PTX (8, 9). If the calcium is
unsuccessful parathyroid surgery is an old one. The most fa- normal and PTH remains elevated, a search for secondary
mous patient with PHPT, Dr Albrights patient, Captain causes of hyperparathyroidism should be undertaken. Any
Martell, underwent seven operations before his ectopic para- identified cause(s) must be addressed before the PTH will
thyroid was found. The patients presenting for surgery are
normalize. The exception to this is seen in patients with
much changed, as the 17 patients described in Albrights study
normocalcemic PHPT. If these patients undergo parathyroidec-
had average serum calcium of 13.9 mg/dL and average gland
tomy, they cannot be considered cured until and unless their
weight of 11 g (5).
PTH levels are normal, as their calcium level was not abnormal
to begin with. Generally speaking, final determination regard-
SIGNIFICANCE OF THE CLINICAL PROBLEM ing cure vs persistent PHPT is made at the 6-month follow up
Today, improved preoperative imaging and surgical advances visit, although the diagnosis may be obvious earlier (10)
have led to a success rate for parathyroidectomy that is over
95% when surgery is done by an experienced parathyroid Confirm the Diagnosis of PHPT
surgeon. However, there are compelling data that less experi- It is important to review the original diagnosis of PHPT and
enced surgeons have a higher failure rate (6). Even in the best confirm hypercalcemia with elevated or nonsuppressed PTH
hands, cure is not always achieved, often because of unrecog- levels. Alternative causes of hypercalcemia should be consid-
nized multiglandular disease where imaging is notoriously un- ered. Familial hypocalciuric hypercalcemia should also be con-
reliable. sidered given that surgery does not cure this syndrome.

BARRIERS TO OPTIMAL PRACTICE Review the Preoperative Imaging

Physicians must fully understand the implications of Was appropriate preoperative imaging performed if a mini-
postsurgical laboratory values in patients who have mally invasive approach was used? There are real limitations to
undergone parathyroid surgery. preoperative imaging, and the surgeon must be prepared to
There are no clear guidelines for which patients should consider a bilateral approach if imaging is negative, or to look
be followed expectantly after unsuccessful surgery, and further if an abnormal gland is not found at the site identified
which should be sent for reoperation. on imaging in a minimally invasive operation.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Review the Surgery Itself Localize

If a minimally invasive approach was used, was intraoperative Not only an imaging issue. Localize the best parathyroid sur-
PTH (ioPTH) measurement available? If so, what was the geon possible. Data clearly show that failure and complication
observed PTH decline? The dictum that a 50% decline in PTH rates are inversely associated with the number of parathyroid
indicates cure is problematic in cases where the baseline PTH procedures the surgeon does (6, 14).
is very elevated, and a 50% decline is nowhere close to the
normal range. Even if an enlarged gland is removed, a second Management of Those Who Are Not Surgical
involved gland or four-gland disease may exist. Many surgeons Candidates or Who Choose Not to Have Surgery
are now using dual protocols, which call for further ioPTH Review observation vs pharmacologic intervention. Specifi-
testing if the PTH does not decrease into the normal range (11). cally, review International Consensus Conference Guidelines
When PTH does not decrease appropriately, did the surgeon for following nonoperative patients (3). Pharmacologic agents
convert to look for diseased glands in other usual locations? are not curative in PHPT. Rather, medication can address some
Ultimately, if the abnormal parathyroid gland was not found in individual sequelae of the hyperparathyroid process. Options
the usual location, was an ectopic parathyroid looked for? All for the latter include oral bisphosphonates (not U.S. Food and
this will allow the endocrinologist to make an assessment
Drug Administration [FDA] approved specifically for PHPT)
regarding the adequacy of the initial surgery, and perhaps point
to treat low bone mineral density (BMD) (15, 16). Also, the
to the potential difficulty or ease of a repeat surgical procedure.
calcimimetic, cinacalcet, is FDA approved to treat patients with
moderately severe hypercalcemia in PHPT. However, cinacalcet
Does the Patient Have Any Classical Symptoms of
does not improve BMD, nor does it lower urinary calcium excre-
tion in PHPT patients (17).
If so, reoperation should be considered in all patients who are
operative candidates. There is good observational data that
patients with overt symptoms (such as nephrolithiasis) have Normocalcemic PHPT
clear evidence of progressive disease when followed without It is important to remember that there are no evidence-based
surgery (12, 13). guidelines for surgery in this phenotype of the disease (3, 18).
Threshold higher for reoperation?
Does the Patient have Asymptomatic PHPT?
If so, review the latest International Consensus Conference Parathyroid cancer
Guidelines for Parathyroidectomy to determine whether the Parathyroid cancer is a special circumstance (19). If there is
patient meets surgical guidelines (3). evidence for parathyroid cancer, reoperation should be considered.


If the patient is symptomatic or if the patient meets surgical In a patient whose PTH levels are elevated after surgery, it is
guidelines or if the patient and his/her physician are interested important to determine the correct diagnosis to allow appropri-
in pursuing a cure of PHPT, reoperation can be considered. In ate management.
asymptomatic patients, a higher threshold is often used before a Reoperation is an appropriate approach to the
decision to operate is made. This is appropriate given higher management of some but not all patients whose
failure rates and higher complication rates in repeat vs initial parathyroid disease is not cured by initial surgery,
parathyroid surgery. Review timing: there is rarely a reason to
depending on severity of the disease and likelihood of
consider reoperation emergently or even hastily.
cure based upon preoperative localization studies.
Watchful waiting or medical management of some
Preoperative Localization manifestations of PHPT (hypercalcemia or osteoporosis)
Although preoperative localization testing is desirable before
can be an alternative to reoperation in some patients.
an initial parathyroid surgery if a minimally invasive approach
is being considered, it is a necessity prior to a reoperation.
Noninvasive imaging should be performed first but invasive CASES AND DISCUSSION
imaging should be considered if surgery is contemplated and Case 1
noninvasive studies are unrevealing. Success of preoperative A 64-year-old man was diagnosed with PHPT (calcium, 10.4
imaging varies from center to center with greatest success at mg/dL; PTH, 142 pg/mL; 25(OH)D, 22 ng/mL) and underwent
high-volume centers, so a referral to such a center is an option parathyroidectomy. Instructions from the surgeon were to take
if testing is unrevealing. Most surgeons will require at least one calcium, 600 mg 4 times daily for a week after surgery. Labs at
positive localization study before a repeat PTX, and some his 3-week postoperative visit: calcium, 8.9 mg/dL; PTH, 112
require two concordant studies. pg/mL.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Questions Questions
1. What is the likely diagnosis at the postoperative visit? 3. What is her diagnosis in 2011? Persistent or recurrent
A. Persistent PHPT PHPT?
B. Recurrent PHPT 4. Which of the following diagnoses would be correct in
C. Normocalcemic PHPT 2014?
D. Secondary hyperparathyroidism A. Persistent PHPT
2. What is the best approach to management of this patient? B. Recurrent PHPT
A. Repeat labs 3 months postoperatively to see whether C. Normocalcemic PHPT
PTH normalizes. D. Primary plus secondary hyperparathyroidism
B. Resume calcium supplementation to 1 g/d between 5. What options would you consider for her after the 2015
diet and supplements and repeat labs at 3 months to studies? Repeat neck computed tomography (CT)? Mini-
see if PTH normalizes. mally invasive parathyroidectomy (MIP)? Bilateral neck
C. Treat vitamin D deficiency and repeat labs at 3
exploration? Medical approach to osteoporosis?
months to see whether PTH normalizes.
D. Treat vitamin D deficiency and resume calcium
supplementation to 1 g/d between diet and supple- Answers
ments. Repeat labs at 3 months to see whther PTH Question 3. Recurrent
Question 4. Recurrent PHPT and primary plus secondary hy-
Answers perparathyroidism. She is vitamin D deficient, which both
Question 1. Answer D is correct. This was not an unsuccess- further raises her PTH levels and lowers her calcium into the
ful parathyroidectomy. Calcium level is now in the lower end normal range.
of the normal range. The persistently elevated PTH level is
likely due to his vitamin D deficiency.
Question 5. Although repeat CT and MIP are incorrect an-
swers, either of the other two approaches could be considered.
Question 2. Answer D is correct. PTH will not completely She clearly meets surgical guidelines. However, in the absence
normalize in the face of significant vitamin D deficiency. It is of positive localizing studies, treating her osteoporosis medi-
important to assure calcium sufficiency after parathyroidec- cally is a safe and acceptable choice.
tomy as well.
Case 3
Case 2 A 60-year-old woman was diagnosed with PHPT (calcium,
A 55-year-old woman was diagnosed with PHPT in 2006. She 10.5 mg/dL; PTH, 64 pg/mL; 25(OH)D, 35 ng/mL) and osteo-
had PTX in early 2007 and 132 mg right upper parathyroid porosis. Sestamibi suggested a left upper-gland adenoma.
adenoma removed. Postoperative calcium and PTH were nor- Left-sided MIP performed with removal of a 400-mg
mal. In 2008, she had an anterior wall myocardial infarction. In adenoma. Normal left lower gland left in place.
2009 she had a metatarsal fracture with minimal trauma and
Intraoperative PTH: baseline, 188 pg/ml; 5 minutes, 147;
BMD showed osteoporosis. The patient was treated with
10 minutes, 133.
zoledronic acid once. Laboratory values on followup are show
Converted to bilateral PTX and right upper (70 mg) and
in Table 1.
right lower (190 mg) glands removed.
Intraoperative PTH: baseline, 242 pg/ml; 5 minutes, 146;
10 minutes, 106; 30 minutes, 68.
Table 1. Case 2 Three-week postoperative visit: calcium, 10.5 mg/dL;
Calcium, PTH, 25(OH)D, PTH, 58 pg/mL; 25(OH)D, 56 ng/mL.
Year mg/dL pg/mL ng/mL Studies
2010 10.0 53
2011 10.5 65 Spine T-score, 2.5
6. What is her diagnosis at the postoperative visit? Persis-
2014 9.5 95 22 Sestamibi negative
CT: Borderline tent or recurrent PHPT?
enlarged right lower 7. How do you interpret her intraoperative PTH levels?
gland, nl left upper A. Left side: insufficient response; right side: sufficient
gland response.
2015 10.5 68 37 Bilat venous sampling B. Left side: sufficient response; right side: sufficient

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

C. Left side: insufficient response; right side: sufficient 4. Potts JT Jr, Fradkin JE, Aurbach GD, Bilezikian JP, Raisz LG. Proceed-
ings of the NIH consensus development conference on diagnosis and
management of asymptomatic primary hyperparathyroidism. J Bone Miner
D. Left side: insufficient response; right side: insuffi- Res. 1991;6:Suppl 2.
cient response. 5. Albright F, Aub JC, Bauer W. Hyperparathyroidism: A common and
E. Left side: insufficient response; right side: equivocal polymorphic condition as illustrated by seventeen proved cases from one
clinic. JAMA. 1934;102:1276-1287.
6. Stavrakis AI, Ituarte PH, Ko CY, Yeh MW. Surgeon volume as a predictor
8. After allowing her to heal from surgery, what options of outcomes in inpatient and outpatient endocrine surgery. Surgery.
would you consider for her management? Repeat neck 2007;142(6):887-899; discussion 887-899.
CT? MIP? Bilateral neck exploration? Medical approach 7. Udelsman R. Approach to the patient with persistent or recurrent primary
hyperparathyroidism. J Clin Endocrinol Metab. 2011;96(10):2950-2958.
to osteoporosis?
8. Duh QY, Arnaud CD, Levin KE, Clark OH. Parathyroid hormone: Before
and after parathyroidectomy. Surgery. 1986;100(6):1021-1031.
9. Oltmann SC, Maalouf NM, Holt S. Significance of elevated parathyroid
hormone after parathyroidectomy for primary hyperparathyroidism.
Question 6. Persistent PHPT. She was never cured. Endocr Pract. 2011;17 Suppl 1:57-62.
10. Witteveen JE, Kievit J, Morreau H, Romijn JA, Hamdy NA. No recurrence
of sporadic primary hyperparathyroidism when cure is established 6
Question 7. Answer E is correct. Although the PTH level months after parathyroidectomy. Eur J Endocrinol. 2010;162(2):399-406.
decreased by well over 50% (from 242 to 68 pg/mL) and the 11. Richards ML, Thompson GB, Farley DR, Grant CS. An optimal algorithm
patient may be cured, the PTH did not completely normalize. for intraoperative parathyroid hormone monitoring. Arch Surg.
12. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year
Question 8. Although there are no real guidelines for consid- prospective study of primary hyperparathyroidism with or without para-
ering repeat surgery, and this, like Question 3 in Case 1, is thyroid surgery. N Engl J Med. 1999;341(17):1249-1255.
13. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of
therefore a judgment call. The patient meets surgical guidelines primary hyperparathyroidism with or without parathyroid surgery after 15
(osteoporotic). However, she only has one small parathyroid years. J Clin Endocrinol Metab. 2008;93(9):3462-3470.
left. I would therefore favor medical treatment of her osteopo- 14. Abdulla AG, Ituarte PH, Harari A, Wu JX, Yeh MW. Trends in the
rosis at this time. Surgery can always be considered if her frequency and quality of parathyroid surgery: Analysis of 17,082 cases
over 10 years. Ann Surg. 2015;261(4):746-750.
clinical situation changed. 15. Chow CC, Chan WB, Li JK, et al. Oral alendronate increases bone mineral
density in postmenopausal women with primary hyperparathyroidism.
REFERENCES J Clin Endocrinol Metab. 2003;88(2):581-587.
1. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management 16. Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in primary hyper-
of asymptomatic primary hyperparathyroidism: Summary statement from parathyroidism: A double-blind, randomized, placebo-controlled trial.
the Fourth International Workshop. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 2004;89(7):3319-3325.
2014;99(10):3561-3569. 17. Peacock M, Bolognese MA, Borofsky M, et al. Cinacalcet treatment of primary
2. Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of hyperparathyroidism: Biochemical and bone densitometric outcomes in a five-year
asymptomatic primary hyperparathyroidism: Summary statement from the study. J Clin Endocrinol Metab. 2009;94(12):4860-4867.
third international workshop. J Clin Endocrinol Metab. 2009;94(2):335-339. 18. Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcemic primary hyper-
3. Bilezikian JP, Potts JT Jr, Fuleihan GH, et al. Summary statement from a parathyroidism. J Clin Densitom. 2013;16(1):33-39.
workshop on asymptomatic primary hyperparathyroidism: A perspective 19. Cetani F, Marcocci C. Parathyroid cancer. In: Bilezikian JP, ed. The
for the 21st century. J Bone Miner Res. 2002;17 Suppl 2:N2N11. Parathyroids, 3rd edition. Cambridge, MA: Academic Press, 2015.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.


M34 erties. Following the clear evidence that vitamin D could be

Presented, April 3rd, 2016 used not only to prevent but also to treat rickets, public health
programs, which included food fortification and supplementa-
tion, dramatically reduced the prevalence of the disease to such
John M. Pettifor, MD, PhD. Medical Research Council/ an extent that it was suggested that rickets had been all but
Wits Developmental Pathways for Health Research Unit, eradicated from the United States.
Faculty of Health Sciences, University of the The almost complete eradication of vitamin D deficiency
Witwatersrand, Johannesburg 2193, South Africa, E-mail: rickets from the United States and a number of European
john.pettifor@wits.ac.za countries brought cases of so called vitamin D-resistant rick-
ets to the fore. Since Albrights classic description of X-linked
hypophosphatemic rickets some 15 years after McCollums
discovery of vitamin D, a much clearer understanding of the
Rickets has been a public health problem for centuries among
pathogenesis of the various forms of rickets has developed (4).
children in the temperate zones of the world. Although it has
In particular, the central role that fibroblast growth factor 23
been reported that rickets may have occurred in a Neolithic
and other paracrine hormones play in a number of the
female, whose skeleton was discovered on a Hebridean island
phosphopenic forms of the disease has been elucidated.
off Scotland, and has been described in manuscripts from the
Greco-Roman empires around the Mediterranean Sea during
the first and second centuries AD, the first detailed reports from
The prevalence of rickets in children varies from country to
Europe were described in several theses and books in the
country, because the prevalence of vitamin D deficiency de-
middle of the 17th century. At that time, the disease appeared
pends on a number of factors such as the extent and duration of
to have a predilection for children of well-to-do families, spar-
the childs skin exposure to UV radiation, the amount of UV
ing the middle classes, but also affecting the poor. It was not
radiation reaching the earth, the season of the year, the latitude
until the industrial revolution several centuries later, that large
of the country, the amount of food fortification in the normal
numbers of children of working class families were affected
diet, and the use of vitamin D supplements. Furthermore, in
(1). In Europe, the disease was so widespread that in many less affluent countries, it appears that low dietary calcium
European cities at the end of the first World War most children intakes either by themselves or in combination with poor vita-
were affected with the disease that began within the first 6 min D status may result in the development of active rickets
months of life. and bony deformities (5).
In the North-Eastern United States, the pattern of rickets was There are relatively few countries that have accurate infor-
similar to that seen in Europe, with the disease being particu- mation on the prevalence of rickets within different communi-
larly noted in children of European immigrants (2). It was ties, because the diagnosis of active rickets is dependent on
estimated that at the beginning of the 20th century up to 80% obtaining radiographic evidence, which is often not available
of children in Boston had rickets. during community surveys. There is also uncertainty as to how
The pathogenesis of the endemic form of rickets (nutritional best to screen for active rickets in communities (6). In the few
rickets) had a number of fanciful explanations until the discov- studies that have compared the prevalence of suspected rickets
ery of vitamin D in the third decade of the 20th century. It was using clinical findings, biochemical abnormalities, and radio-
considered to be due to bad air, to dampness and cold, or to graphic features, the figures have varied markedly with clinical
infection, among many other explanations. Despite a lack of features generally greatly overestimating the prevalence that is
understanding of the causes of rickets, cod liver and shark liver found when using a radiographic diagnosis.
oil had been suggested as effective treatments in the 18th There is a need to be aware of the possibility of rickets in
century, and in the next century, the benefits of sunlight were infants and children living in at-risk communities, because
expounded. At the end of the first World War, the British rickets not only can lead to hospital admission for hypocal-
Medical Research Council sent Harriet Chick to Vienna to caemic symptoms such as convulsions and apnoeic episodes,
establish the cause of the high prevalence of rickets in children but also to poor growth, bony deformities, and impaired
in that city. Using controlled trials, she was able to establish immunity resulting in increased risk of respiratory infec-
that rickets was a seasonal disease and that cod liver oil and tions, in particular.
sunlight were effective in not only preventing the disease but
also healing it (3). In 1922, McCollum named the factor in cod BARRIERS TO OPTIMAL PRACTICE
liver oil that healed rickets vitamin D after having differenti- 1. The lack of consensus among scientists as to what
ated it from vitamin A through the formers heat stable prop- constitutes vitamin D deficiency in infants and children,

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

although there is more consensus around 25- Dietary calcium intakes to prevent rickets:
hydroxyvitamin D (25OHD) levels associated with
For infants between 0 6 months and 6 12 months an
active vitamin D deficiency rickets.
adequate calcium intake is 200 and 260 mg/d, respec-
2. The lack of uniform policy guidelines in many
countries to address the high prevalence of vitamin D
For children more than 12 months of age, a dietary
deficiency in women of child bearing age and to
calcium intake of less than 300 mg/d increases the risk of
prevent vitamin D deficiency during infancy.
rickets independent of serum 25OHD levels
3. The lack of availability of cheap and accessible forms
For children 12 months, the panel recommends the
of calcium to supplement diets of young children in
following classification of dietary calcium intake:
less affluent countries where low dietary calcium
f Sufficiency more than 500 mg/d
intakes are the norm rather than the exception.
f Insufficiency 300 500 mg/d

f Deficiency 300 mg/d

LEARNING OBJECTIVES In regard to fractures and rickets, the panel concluded
As a result of participating in this session, learners should be that children with radiographically confirmed rickets
able to: have an increased risk of fractures, but children with
Understand the recommendations made by a global subclinical vitamin D deficiency do not.
pediatric consensus group on the prevention, diagnosis,
and management of nutritional rickets.
Appreciate the difficulties associated with the screening 2. Prevention and treatment of nutrition rickets
of at-risk children in a community to determine the The panel recommended for the prevention of rickets
that all infants within the first year of life should receive
prevalence of rickets in a community.
vitamin D supplements of 400 IU/d, irrespective of the
method of feeding, and that infants and children beyond
Diagnosis, Prevention, and Management of Nutritional 12 months of age should receive 600 IU/d, made up of
Rickets dietary intake and/or sunlight exposure.
Despite effective means of preventing nutritional rickets, it In healthy children, routine 25OHD screening is not
remains a public health problem in many countries, where it recommended. Children in high-risk groups can be
has a major impact on the health of those affected, through the identified based on clinical profile and should be
consequences of hypocalcemia, bony deformities, failure to supplemented irrespective of the 25OHD levels.
thrive, motor delay, altered immune status, and dilated cardio- For the treatment of nutritional rickets, the minimum
myopathy. Furthermore, the consequences may be felt many recommended dose of vitamin D2 or D3 is 2000 IU/d.
years after the active rickets has healed, through its effects on Calcium intake should be ensured at 500 mg/d through
limb and pelvic deformities. diet and/or supplements.
The following consensus was developed by a group of With regard to the route of administration and duration
pediatric endocrinologists and nutritionists from a number of of therapy, the panel recommends that for vitamin D the
societies and groups globally to obtain an international guide- oral rather than im route should be used, that when
line on the diagnosis, prevention, and management of nutri- administered daily vitamins D2 and D3 are equally
effective in treating the disease, and that treatment
tional rickets (7). The publication contains the evidence from
should be given for a minimum of 12 weeks.
which the guidelines were derived.

3. Prevention of nutritional rickets: identification of risk

1. Defining nutritional rickets and the interplay between
vitamin D status and calcium intake
Maternal vitamin D deficiency should be avoided by
Nutritional rickets is a disorder of defective chondrocyte
ensuring that all pregnant women meet the intake of 600
differentiation and mineralization of the growth plate and
is caused by inadequate 25OHD concentrations and/or
Complementary foods introduced no later than 26 weeks
low dietary calcium intakes in children.
of life should include sources rich in calcium.
Although the diagnosis of nutritional rickets can be
Restricting exposure to sunlight increases the risk of
suspected on the basis of history, physical examination
vitamin D deficiency and nutritional rickets.
and biochemical testing, its confirmation requires the use
Environmental factors such as latitude, season, time of
of radiographs.
day, cloud cover, and pollution affect the availability of
The panel recommends the following classification of
vitamin D status based on serum 25OHD levels: UVB, whereas personal factors such as the time spent
outdoors, skin pigmentation, skin coverage, body
Sufficiency 25OHD more than 50 nmol/L (20 ng/mL) composition, and genetics affect the dose response to
Insufficiency 25OHD 20 50 nmol/L (1220 ng/mL) UVB and circulating 25OHD. It is important to reiterate
Deficiency 25OHD less than 30 nmol/L (12 ng/mL) that there is no safe threshold of UV exposure that

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

allows for sufficient vitamin D synthesis without CONCLUSIONS

increasing skin cancer risk. Vitamin D deficiency should be considered a major global
public health priority. Nutritional rickets can have severe con-
4. Prevention of osteomalacia during pregnancy and sequences, including death. Clinical rickets represents the tip
lactation and congenital rickets of the iceberg, and its resurgence indicates widespread vita-
Maternal vitamin D deficiency increases the risk of min D deficiency and/or low dietary calcium intakes. The
elevated cord blood alkaline phosphatase, increased disease is fully preventable, thus the panel recommends the
neonatal anterior fontanelle size, neonatal hypocalcemia, eradication of rickets through implementation of international
and impaired dental enamel formation, thus maternal vitamin D supplementation and food fortification programs.
vitamin D deficiency should be prevented during
pregnancy. There is little evidence to suggest that Case 1
maternal supplementation increases birth anthropometry A 4-year-old boy is brought by his mother to a primary health
or improves short or long-term bone mass in the care clinic in rural Mpumalanga (latitude 27S), South Africa,
offspring. because she is worried by the progressive deformities develop-
There is no evidence that increased calcium intake
ing in the lower limbs for the past year. She has also noticed
(through diet and/or supplementation) in pregnancy
that the child is less active and complains of pain in the legs
above recommended nonpregnant intakes is beneficial
when walking. Examination revealed a short, well-nourished
for neonatal bone.
looking child (height for age z-score 2.1, weight for height
Vitamin D intake during lactation influences breastmilk
z-score 0.5), who had typical knock knees with an intermal-
vitamin D concentrations, thus breastfeeding infants of
mothers who receive vitamin D 2000 IU/d during leolar distance of 15 cm.
lactation have serum 25OHD levels similar to infants Question 1: Which other clinical features suggestive of rick-
who are directly supplemented with 400 IU/d. However, ets would you look for in this age group child, that would
maternal dietary calcium or vitamin D intakes do not strengthen the likelihood of the child having active rickets?
influence breastmilk calcium concentration. Question 2: Which 2 questions would you ask the mother to
Congential rickets is uncommon and is usually try and establish a cause for the rickets?
associated with mothers who have severe osteomalacia. Question 3: Is it possible to grade the severity of rickets
It is effectively prevented by ensuring maternal vitamin based on radiographs of the wrists and knees?
D sufficiency during pregnancy. Question 4: Which biochemical tests would you consider to
be essential to help in establishing the pathogenesis of the bone
5. Assessing the burden of nutritional rickets and public disease?
health strategies for prevention Question 5: How would you treat the child?
The prevalence of rickets in a community should be
determined by population-based samples, case reports Case 2
from sentinel centers, or by mandatory reporting. An 18-month-old girl, who lives with her single parent in a
Screening for rickets should be based on clinical high-rise block of apartments in the densely residential area of
features, followed by radiographic confirmation of downtown Johannesburg (latitude 26S), is not walking yet.
suspected cases. The panel made the point that screening Her mother emigrated from Zimbabwe several years ago in the
with serum 25OHD, alkaline phosphatase, or radiographs hope of getting employment in South Africa. She breastfeeds
is not indicated. her infant, who has for the past year been cared for by a
Rickets prevention involves universal vitamin D childminder in the same apartment block during the day while
supplementation of all infants between birth and 12
the mother works. Examination reveals a hypotonic toddler
months of age, and the supplementation of children at
with a relatively large skull (circumference 48.8 cm) and an
high risk over 12 months of age. Vitamin D supplements
open anterior fontanelle. She has enlarged wrists and readily
should be incorporated into primary health care
palpable costochondral junctions. Radiographs of the wrists
programs. These programs should be accompanied by
appropriate monitoring, advocacy, and publicity, reveal severe rickets. On more general enquiry, the mother
particularly in communities at high risk of vitamin D comments that there are a number of small children in the
deficiency or low dietary calcium intakes. community who have bracket legs.
Consideration should be given to the fortification of Question 1: Which factors predisposed this child to develop
appropriate foods based on dietary patterns of the target rickets?
populations. Food fortification can prevent rickets and Question 2: From a public health perspective, how would
improve vitamin D status. It should be accompanied by you prevent vitamin D deficiency rickets among the children in
relevant legislation and monitoring. this community?

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Answers to case 1 likely cause is nutritional rickets (due to vitamin D or dietary

Question 1: There have been very few studies on the reliability calcium deficiency), and treatment consists of both vitamin D
of various clinical signs in predicting the presence of active and calcium supplements. Only if the child is unresponsive to
radiographic rickets in children outside the infant/toddler age therapy for nutritional rickets, should the child be investigated
range. Thacher et al (8) used data obtained from a study of for the rarer causes of calciopenic rickets.
children who had suspected rachitic leg deformities in Nigeria Question 5: The general consensus is that nutritional rickets
to determine the usefulness of various signs in predicting the should be treated with a combination of vitamin D and calcium
presence of active rickets in children older than 18 months of supplements, thus differentiating between vitamin D deficiency
age. Wrist and costochondral junction enlargement had the and dietary calcium deficiency through measuring 25OHD and
greatest sensitivity and specificity. Age less than 5 years, 1,25(OH)2D levels is unwarranted in most situations. The ac-
height for age z-score less than 2, leg pain on walking, wrist tual doses of vitamin D and/or calcium to be given are influ-
enlargement, and costochondral enlargement were each inde- enced by the age of the child and the likely compliance with
pendently predictive of active rickets. Any 3 of these signs daily therapy (11). It is generally believed that daily therapy is
accurately identified 87% of children with active rickets. better than intermittent therapy, but both are effective in heal-
Question 2: Because only a very few foods in South Africa ing rickets. Similarly, although there might be theoretical rea-
are vitamin D fortified (as is the case in many countries), sons why D3 is better than D2, both have been shown to be
children are dependent on sunlight (UVB radiation) to maintain equally effective in healing rickets in the clinical situation.
their vitamin D status. One should also consider that low
dietary calcium intakes may be in part or wholly responsible Answers to case 2
for the bone deformities. Thus, the 2 important questions that Question 1: The factors probably predisposing the child to
should be asked to help establish the pathogenesis are 1) how rickets include:
much time does the child spend playing outside the house, and Lack of exposure to UVB radiation due to living in an
how much skin is exposed to UVB radiation (short-sleeve apartment block with no access to a yard, being looked
shirts and legs and face exposed)? and 2) does the child drink after by a childminder in the same building and thus not
milk or eat dairy products at home on a regular basis? Dietary getting outside.
calcium intakes in many less affluent societies average approxi- Minimal dietary vitamin D intake, as mother continues
mately 300 mg/d, but children who are suspected of having to breastfeed, although not during the day. Few foods,
dietary calcium deficiency rickets uniformly have calcium in- besides infant formulas, are vitamin D fortified in South
takes of 200 mg/d or less (5). Africa.
Question 3: The possibility of being able to grade the sever-
ity of radiological rickets has important implications, because it The mother is Zimbabwean and thus darkly pigmented. She
provides the ability to assess the response of patients with probably has relatively poor vitamin D status due to limited
rickets to treatment over time. A similar longitudinal assess- access to sun exposure, thus limited amounts of vitamin D
ment could be made using the changes in serum alkaline cross in her breastmilk. Darker pigmented individuals are gen-
phosphatase. Thacher et al have developed a 10 point scoring erally more at risk of vitamin D deficiency, as highlighted by
system based on the radiographic severity of rickets at the the fact that it is mainly darker pigmented immigrant children
distal radius and ulna and around the knee (9). A maximum of who are at risk of vitamin D deficiency rickets in temperate
4 points is allocated to the wrist and 6 points to the knee. The climates. It is possible that the child has a relatively low-
average radiographic score correlated reasonably well with calcium intake as breastfeeding is infrequent. Usually on wean-
serum alkaline phosphatase levels (r 0.58). ing, cows milk or milk formulas are not continued, thus
Question 4: In any child with a diagnosis of rickets, the first dietary calcium intakes are low, particularly as the family pot is
steps are to establish that the child has active rickets and then corn based. Children who do not consume dairy products may
to determine whether the child has calciopenic or phosphopenic have calcium intakes of less than 300 mg/d. The panel recom-
rickets (10). Thus, once a radiograph establishes the presence mends a calcium intake for infants 0 6 months of age of 200
of active rickets, the type of rickets can be determined by mg/d, for infants 6 12 months of age of 260 mg/d, and for
measuring serum calcium, phosphorus, and PTH concentra- children older than 12 months of more than 500 mg/d.
tions. Calciopenic rickets is associated with an inability to Question 2: To reduce the prevalence of rickets in the
maintain serum calcium concentrations and thus is typically residential community in the inner city apartments, several
associated with low or low-normal calcium values and elevated approaches can be combined:
PTH levels. Serum phosphorus levels are typically low, but Vitamin D supplementation should be routine for all
these are secondary to high PTH levels. In phosphopenic rick- infants less than 12 months of age. In this community,
ets, serum calcium and PTH values are typically normal but the children are at high risk of developing rickets, and
phosphorus values low. Once calciopenic rickets is diagnosed, thus vitamin D supplementation should be continued
there is generally no need for further investigations as the most after 12 months of age.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

As part of the mothers antenatal and postnatal care, she 3. Chick DH. Study of rickets in Vienna 1919-1922. Med Hist.
should have received vitamin D supplements, because
4. Levine BS, Kleeman CR, Felsenfeld AJ. The journey from vitamin D-
she is at high risk of having a poor vitamin D status. resistant rickets to the regulation of renal phosphate transport. Clin J Am
Because the neighborhood is a high-risk community, an Soc Nephrol. 2009;4(11):1866-1877.
education program highlighting the risks of vitamin D 5. Pettifor JM. Calcium and vitamin D metabolism in children in developing
deficiency and emphasizing the importance of using countries. Ann Nutr Metab. 2014;64(suppl 2):15-22.
6. Pettifor JM. Screening for nutritional rickets in a community. J Steroid
parks for the children during the day and the need for Biochem Mol Biol. 2016. In press.
vitamin D supplementation. 7. Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on
The importance of an adequate calcium intake should prevention and managmeent of nutritional rickets. J Clin Endocrinol
also be emphasized, because it is likely that poor Metab. 2016. In press.
8. Thacher TD, Fischer PR, Pettifor JM. The usefulness of clinical features to
vitamin D status and low dietary calcium intakes identify active rickets. Ann Trop Paediatr. 2002;22(3):229-237.
combine to exacerbate the prevalence of rickets. 9. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Manaster BJ, Reading
JC. Radiographic scoring method for the assessment of the severity of
REFERENCES nutritional rickets. J Trop Pediatr. 2000;46(3):132-139.
1. ORiordan JL, Bijvoet OL. Rickets before the discovery of vitamin D. 10. Rajah J, Thandrayen K, Pettifor JM. Clinical practice: diagnostic approach
Bonekey Rep. 2014;3:478. to the reachitic child. Eur J Pediatr. 2011;170(9):1089-1096.
2. Weick MT. A history of rickets in the United States. Am J Clin Nutr. 11. Shaw NJ, Mughal MZ. Vitamin D and child health part 1 (skeletal
1967;20(11):1234-1241. aspects). Arch Dis Child. 2013;98(5):363-367.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Osteoporosis in Premenopausal Women

M35 Lack of awareness of the clinical significance of low

Presented, April 1 4, 2016 trauma fractures in premenopausal women
Lack of awareness of diseases and medications that can
result in low peak bone mass or accelerated or premature
Elizabeth Shane, MD. Department of Medicine, bone loss in premenopausal women
Columbia University College of Physicians and Surgeons, Lack of clinical trial data on treatment of osteoporosis in
New York City, New York 10032, E-mail: premenopausal women, particularly clinical trials that
es54@columbia.edu include low trauma fracture as an outcome


Historical Overview As a result of participating in this session, learners should be
Osteoporosis is a common clinical problem in postmenopausal able to:
women and older men, and data from many large observational Understand the clinical significance of low BMD and
and randomized controlled clinical trials are available to guide fractures in premenopausal women
physician management of this common disease of aging. In Understand the causes of low BMD and fractures in
contrast, it is distinctly uncommon for premenopausal women premenopausal women
to present with low bone mass or fractures, and few data exist Understand the principles of management of osteoporosis
to guide physicians in the diagnosis and management of osteo- in premenopausal women with secondary osteoporosis
porosis in this age group. One of the earliest epidemiological and idiopathic osteoporosis.
studies of fractures and bone mineral density (BMD) by dual
x-ray absorptiometry (DXA) published in 1988 demonstrated
that fracture incidence is much lower in young women than
older women, even when BMD is comparably low (1). Another
study published in 1994 demonstrated that 90% of people
Postmenopausal Women
age 20-44 years who presented with low BMD and fractures
In postmenopausal women, osteoporosis is defined as a BMD
have a secondary cause of osteoporosis (2). In the 1990s,
of the spine, hip, or forearm more than 2.5 SD below the
several studies delineated features of unexplained osteoporosis
young-adult mean (T-score 2.5), with or without the pres-
in young men, namely low bone formation that was directly
ence of a major low trauma fracture (forearm, humerus, spine,
associated with low serum IGF-I. However, it was not until
hip, femur, pelvis); Low bone mass (osteopenia) refers to T
after 2000 that data on bone quality (microarchitecture, remod-
scores between 1.0 and 2.5.
eling, collagen properties, marrow adipocytes) and response to
osteoanabolic therapy began to emerge in young women with
osteoporosis (3). Premenopausal Women
In premenopausal women, the International Society for Clinical
Densitometry (ISCD) recommends that T scores not be used to
SIGNIFICANCE OF THE CLINICAL PROBLEM categorize BMD. z scores compare a young womans BMD to
The diagnosis of osteoporosis is difficult in premenopausal the mean of an age- and sex-matched reference population. The
women because the relationship between bone density and ISCD recommendations are that z scores should be used in-
incident fractures is unclear. The treatment of osteoporosis in stead of T scores to categorize BMD measurements and that a
this age group is also difficult because none of the interventional z score that is less than or equal to 2.0 should be designated
studies have a fracture outcome. Most premenopausal women low bone density or below expected for age (4). In con-
with osteoporosis (90%) have an underlying disease or medi- trast, the International Osteoporosis Foundation (IOF) recom-
cation exposure that causes bone loss or skeletal fragility. mends that the use of z scores be confined to women below age
Unexplained (idiopathic) osteoporosis (IOP) in premenopausal 30 years, who may not have reached peak bone mass, and that
women is unusual, but such patients present even greater chal- T scores should be used in women over age 30 years, in whom
lenges in diagnosis and management. peak bone mass has been reached (5).
The z score is a statistical definition that encompasses 95%
BARRIERS TO OPTIMAL PRACTICE of the normal population. Thus, by definition, the ISCD recom-
Lack of data on clinical significance of low BMD mendations mean that 2.5% of premenopausal women will
measurements in premenopausal women, particularly as have a z score less than 2.0, and thus considered to have low
they relate to short-term (510 y) fracture risk bone density or bone density that is below expected for age.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Use of the T-score would restrict the definition of low bone Lactation is associated with losses of 310% at the spine and
density to 0.5% of the general population, which is probably hip over the first 3 6 months with recovery after weaning over
wise because the clinical significance of isolated low BMD the next 1218 months (11). Therefore, BMD measurements
measurements is uncertain, and the extent to which isolated should not performed for at least a year after pregnancy or
low BMD measurements predict short-term (510 y) fracture lactation, during this period of transient loss and recovery.
incidence in young women is unknown. Both the ISCD and the Routine BMD screening of premenopausal or perimenopausal
IOF concur that the term osteoporosis should be avoided in women is not recommended unless there is a history of fragility
premenopausal women with isolated low BMD measurements fracture(s), or a medical conditions or medication exposure
and the term osteopenia should not be used at all. associated with low bone mass or bone loss (estrogen defi-
ciency, glucocorticoids, etc.) (Table 2).
Etiology of Low BMD in Premenopausal Women Premenopausal women with a low trauma fracture or z score
Some premenopausal women with small skeletons may seem to below 2.0 should have a thorough history, physical examination,
have low BMD, because DXA scanners measure areal BMD and laboratory evaluation to identify potential secondary causes of
(g/cm2) rather than true volumetric BMD (g/cm3). DXA cannot bone loss such as renal or liver disease, hyperthyroidism, hyper-
distinguish between small bones and less dense bones. Pre- parathyroidism, Cushings syndrome, early menopause, or other
menopausal women may have low BMD because: disorders associated with estrogen deficiency, such as anorexia,
They have genetically determined low peak bone mass celiac disease and other forms of malabsorption, idiopathic
They are thin and their skeletons are adapted to carrying hypercalciuria, or connective tissue disorders (Table 1).
lower loads
They have a syndrome known as constitutional leanness, Idiopathic Osteoporosis in Premenopausal Women
a nonpathological state of low body weight with normal Premenopausal women with no identifiable etiology after ex-
menses that is often familial (6, 7). tensive evaluation for secondary causes are said to have IOP.
IOP primarily affects Caucasians, men and women equally.
Although it is generally assumed that such women have normal
Fractures may be multiple, occurring over a 5-10-year period.
bone quality (normal trabecular and cortical volumetric BMD,
Women may present with acute vertebral compression frac-
microarchitecture, and strength), there are few data to support
tures during pregnancy or lactation, but may also present with
this. In fact, the opposite may be true. For example, in pre-
fractures temporally unrelated to pregnancy. The mean age at
menopausal women with constitutional leanness and low
diagnosis is in the mid thirties. Abnormalities of osteoblast
areal BMD by DXA, advanced imaging by high-resolution
function and decreased IGF-I have been found in most studies
peripheral quantitative computed tomography (HR-QCT) has
of men with IOP. In a recent bone biopsy study of women with
shown that volumetric BMD is also low, with disrupted
IOP, both those with fractures and those with z scores less than
microarchitecture (8). Moreover, in our study of premeno-
or equal to 2.0 but no fractures had evidence of low volu-
pausal idiopathic osteoporosis (IOP), young women with low
metric BMD of the hip and spine (by central QCT) (9), distal
BMD by DXA and no history of adult low trauma fractures, the
radius, and tibia (by HR-p QCT) (10) and iliac crest bone
positive predictive value of a low areal BMD by DXA for low
biopsies (by microCT) (12). In addition, both those with frac-
volumetric BMD by central QCT was 95% at the lumbar spine,
tures and those with low BMD had comparable
90% at the total hip, and 86% at the femoral neck (9). They also
microarchitectural disruption and reduced estimated strength
had abnormal cortical and trabecular microarchitecture at the dis-
(by finite element analysis). In addition, both groups of af-
tal radius and tibia (10). Thus, low BMD by DXA may accurately
fected women had increased marrow fat (independent of bone
reflect skeletal integrity (volumetric BMD, microarchitecture, and
volume fraction) (13), reduced bone mineralization density
strength) in premenopausal women.
distribution (by quantitative backscattered electron imaging),
Other reasons for low BMD in premenopausal women in-
and abnormal bone matrix (by Fourier transform infrared spec-
clude low peak bone mass due to reduced bone acquisition
troscopy) (14). Bone turnover was heterogeneous, but those in
during adolescence secondary to:
the lowest tertile of bone turnover had the most marked deficits
Lifestyle choices (eg, excessive alcohol, tobacco
in volumetric BMD, microarchitecture, and strength (12). Se-
exposure, low calcium intake, physical inactivity)
rum IGF-I was higher in the women in the lowest tertile of
Underlying illnesses (eg, eating disorders, estrogen
bone formation rate, suggesting that they may have IGF-I
deficiency, celiac disease, inflammatory bowel disease)
resistance at the osteoblast level (12). There were virtually no
Exposure to certain medications (eg, glucocorticoids,
differences between premenopausal women with IOP who had
Depo-Provera) may interfere with peak bone mass
fractures and those with only low BMD. However, whether
these women with low BMD reflect the larger population of
Such secondary causes of osteoporosis (Table 1) may also premenopausal women with low BMD is unknown. It is pos-
cause excessive bone loss after adolescence, and may be asso- sible that the lack of detectable differences may represent
ciated with abnormal bone quality, although there are few data. ascertainment bias, as women with a family history of osteo-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

porosis or some other reason to suspect poor bone health may Teriparatide has been shown to prevent bone loss in
have been more likely to participate. premenopausal women on GnRH agonists for
endometriosis (16), to increase BMD in premenopausal
Management women with glucocorticoid-induced osteoporosis, and with
There are no official guidelines for management of premeno- IOP (17), and with pregnancy- and lactation-associated
pausal women with low bone mass or osteoporosis. All recom- osteoporosis (18).
mendations are thus based upon expert opinion (3, 5).
Aggressive therapy with antiosteoporosis agents may be
Lifestyle modifications should be encouraged for all women
necessary for women with glucocorticoid-induced osteoporo-
with low bone mass given that peak bone mass may improve
sis. However, the 2010 American College of Rheumatology
into the fourth decade. The following should be encouraged:
guidelines do not recommend pharmacologic therapy for pre-
Adequate calcium intake (1000 1200 mg elemental
vention and treatment of glucocorticoid-induced osteoporosis
calcium daily), preferably from dietary sources
patients under age 50 years unless they have a history of spine
Adequate vitamin D intake (400-800 IU vitamin D3
or hip fracture and have taken or will be taking at least 7.5 mg
daily) or sufficient to maintain serum 25-OHD levels
of prednisone or equivalent daily for at least 90 days.
above 20-30 ng/mL
Premenopausal women receiving chemotherapy for breast
Regular physical activity, particularly weight-bearing
cancer represent another group at risk for rapid bone loss,
primarily related to induction of premature menopause. Pro-
Cessation of smoking
spective studies demonstrate bone loss at 1 year of 4 8% in
Avoidance of excessive dieting
the spine and 2 4% at the hip in premenopausal women who
Maintenance of normal body weight
become menopausal after receiving adjuvant chemotherapy.
Avoidance of excess alcohol, caffeine and phosphorus
Intravenous bisphosphonates prevent bone loss in premeno-
containing drinks.
pausal women with chemotherapy-induced amenorrhea.
A study of 16 premenopausal women with IOP treated only Premenopausal women with osteogenesis imperfecta can be
with increased dietary calcium and physical activity revealed treated with either oral alendronate or iv pamidronate.
small but significant increases in lumbar spine and femoral In our recent pilot study of teriparatide in 21 premenopausal
neck BMD after 2 or 3 years and no new fractures (15). women with IOP, there were large and highly significant increases
When a secondary cause of osteoporosis is detected in pre- (10%) in lumbar spine BMD, with smaller but also significant
menopausal women, treatment should be targeted to that dis- increases at the femoral neck and total hip, and no change at the
ease or abnormality. Examples of specific approaches that have radius (17). Teriparatide was also associated with marked im-
been shown to lead to increases in BMD include: provements in trabecular volumetric BMD and microarchitecture
Institution of a gluten-free diet in celiac disease and cortical thickness on iliac crest bone biopsies (17). Approxi-
Parathyroidectomy in patients with primary mately 20% of the women, however, did not respond (no change
hyperparathyroidism in BMD at any site). The nonresponsive women had markedly
Discontinuation of medroxyprogesterone acetate lower bone turnover at baseline based on serum bone turnover
Oral contraceptives for women with oligo- or markers and lower bone formation rate on iliac crest bone biop-
amenorrhea, on GnRH therapy with perimenopausal sies. They also had significantly smaller and delayed increases in
bone loss serum P1NP and C-telopeptide during teriparatide therapy, and
significantly higher serum IGF-I levels, more evidence for IGF-I
Pharmacologic therapy should be avoided unless the patient
resistance at the osteoblast level (17). Teriparatide has the advan-
is losing bone or fracturing. Ferrari et al (5) recently summa-
tage of not being retained in the skeleton. However, a subset
rized effects of bisphosphonates and teriparatide in premeno-
of women in the pilot study, re-evaluated approximately 2
pausal women with osteoporosis.
years after completing teriparatide, showed partial loss of
Selective estrogen receptor modulators (SERMs) such as
bone mass at the spine, but stable BMD at the hip. Those who
raloxifene should not be used in premenopausal women;
lost significant bone mass were older (46 vs 38 y; P .05)
they block estrogen action on bone, leading to further
(19). Thus, antiresorptive therapy may be required after stop-
ping teriparatide in premenopausal women, just as it is in
Bisphosphonates carry a category C rating for safety in
postmenopausal women and men.
pregnancy as they cross the placenta and accumulate in
fetal bones in an experimental rat model. Although they
are probably safe, their long half-life in bone makes MAIN CONCLUSIONS
their use in reproductive-age women a concern. In Although most premenopausal women with osteoporosis have
premenopausal women without fractures or known a secondary disorder that negatively affect bone health, a sig-
secondary causes for fractures, bisphosphonates are nificant proportion of those presenting to tertiary care institu-
generally not indicated. tions have IOP.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

IOP is likely to be a disorder of heterogeneous etiology, TABLE 1. Common Secondary Causes of Osteoporosis in
with some women having very low bone formation rates and Premenopausal Women
others having normal or high bone formation rates. The etiol- Cause
ogy of bone loss may vary according to bone turnover status. In Anorexia nervosa
our study, those with low bone formation have slightly GI malabsorption (eg. celiac disease, postoperative states)
HIGHER serum IGF-I concentrations and may manifest a form Vitamin D and/or calcium deficiency
of IGF-I resistance at the osteoblast level. Those with high Hyperthyroidism
bone formation rates may have a mild form of idiopathic Hyperparathyroidism
hypercalciuria. Bone biopsy is necessary to determine whether Cushings syndrome
bone formation is high or low as serum bone turnover markers Hypogonadism
were not predictive in our studies. We found, albeit in a small Hypercalciuria
sample, that women with unexplained low BMD had just as Rheumatoid arthritis and other inflammatory conditions
bad bone quality as those with low trauma fractures. Alcoholism
In general, conservative therapy is best for young women. Renal disease
Management of osteoporosis in premenopausal women with sec- Liver disease
ondary osteoporosis should focus on diagnosis and specific tar- Osteogenesis imperfecta
geted therapy of the secondary cause. Pharmacologic therapy should Marfans syndrome
be reserved for the most severely affected women, who have Homocystinuria
very low BMD (z scores 2.5), declining BMD on conser- Medications
vative therapy or major fractures. Management of IOP could Glucocorticoids
include antiresorptive therapy if appropriate to the patients age Immunosuppressants (cyclosporine)
and bone remodeling status or osteoanabolic therapy. Antiseizure medications (particularly phenobarbital and
GnRH agonists (when used to suppress ovulation)
Case 1
Cancer chemotherapy
A 31-year-old woman is referred with a history of multiple
vertebral fractures. At age 29 years she was involved in a
Depot medroxyprogesterone acetate
motor vehicle accident. Four months later she developed severe
Excess thyroid hormone
back pain and was found to have compression fractures of T8,
T10, L1, and L4. One year later back pain recurred and new
Abbreviation: SSRIs, selective serotonin reuptake
fractures of T11, L2, and L3 were documented, along with inhibitors.
multiple rib fractures and 2 inches of height loss.
1. What additional history would you seek?
2. What physical examination findings would you look for?
3. Which laboratory tests would you order? Question 3
4. She is anxious to have a child. What would you advise Certainly a DXA scan, CBC, chemistry panel including total
her regarding breast feeding? alkaline phosphatase, serum 25-OHD and 1,25(OH)2D, PTH,
5. Would you recommend therapy? If so, which therapy 24-hour urine calcium and free cortisol, celiac screen and other
and why? tests as appropriate.

Discussion Question 4
Question 1 In general, I suggest such women avoid breast feeding, as the
You should focus your questions on any prior history of frac- rapid decrease in BMD could exacerbate their problems and
tures in her past, any diseases (eg, celiac disease, cystic fibro- perhaps precipitate more fractures. That being said, many pa-
sis, anorexia nervosa) or medication exposures (eg, tients insist on breast feeding and in my clinical experience,
glucocorticoids, anticonvulsants) during childhood or adoles- many do not go on to have more fractures.
cence that could have negatively affected bone health. A family
history of fractures and nephrolithiasis is important. A detailed
Question 5
menstrual/reproductive history and alcohol history is key.
Management depends on whether there is any secondary cause;
if so, it should be treated directly if possible. Conservative
Question 2 management with adequate calcium, vitamin D, and weight-
Signs of Cushings Syndrome, osteogenesis imperfecta, kypho- bearing exercise. SERMs should be avoided. If she is menstru-
sis, mastocytosis. ating normally, there is probably no point in oral contraceptive

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 2. Guidelines for BMD Testing in Premenopausal serum 25-OHD of 22 ng/mL (normal range, 20 50
Women mg/dL), an intact PTH of 59 pg/mL (normal range,
History of fragility fracture 14 64 mg/dL) and a 24-hour urinary calcium of 70
Diseases or conditions associated with low bone mass or bone loss mg on an adequate collection (normal range, 100 250
Premenopausal estrogen deficiency (eg, hyperprolactinemia, mg). How do you interpret these results? Would you
athletic triad, prolonged amenorrhea) measure bone turnover markers? What would you do
Eating disorders next?
Chronic obstructive pulmonary disease
Cystic fibrosis Discussion
Hyperparathyroidism Question 6
Rheumatoid arthritis You should not recommend alendronate in a premenopausal
Inflammatory bowel disease woman with low bone mass contemplating pregnancy in the near
Celiac disease future. Bisphosphonates carry a category C rating for safety in
Medications that cause bone loss pregnancy because they cross the placenta and accumulate in fetal
Glucocorticoids bones in an experimental rat model. Although they are probably
Depot progesterone safe, their long half-life in bone makes their use in reproductive-
GnRH agonists age women a concern. In premenopausal women without fractures
Aromatase inhibitors or known secondary causes for fractures, bisphosphonates are gen-
Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine, erally not indicated.
If pharmacologic therapy of osteoporosis is being considered
Question 7
Being monitored for effectiveness of pharmacologic therapy for
osteoporosis A DXA scan is not an appropriate test for evaluation of back
pain and should not have been ordered for that purpose. The
ISCD does not recommend the use of T-scores or the term
osteopenia in premenopausal women. They recommend that
pills. Bisphosphonates should be avoided at this age and if z scores be used to categorize BMD measurements and that z
imminent childbearing is being considered. Teriparatide may score that is less than or equal to 2.0 should be designated
be of some help, but there are few data on how long the effect low bone density or below expected for age. Practically
of the drug lasts, and antiresorptive therapy may be required speaking, it does not matter very much which is used, because
after completion of teriparatide to consolidate gains in BMD. at age 32 years, T- and z scores will be very concordant. This
There are no data on whether treatment of osteoporosis in patient is likely to have z scores that are the same as her T
premenopausal women reduces the risk of future fractures. scores, which means that her BMD is within the normal range
for her age.
Case 2
A 32-year-old woman is referred for evaluation and manage-
Question 8
ment of osteopenia. A DXA scan, ordered because she com-
Although her BMD is within the normal range for her age and
plained of low back pain, revealed that she had T scores of 1.9
we do not recommend bone density screening for young
at the lumbar spine, 1.8 at the femoral neck and total hip, and
women, her BMD is at the very low end of the normal range
1.1 at the 13 radius. She was told she had severe osteopenia
for her age. Given that you know this, it is appropriate to
and prescribed alendronate. However, she was planning to
evaluate her with a history and physical examination, your goal
become pregnant and was concerned that alendronate might
being to determine whether there is any condition that could be
affect the baby.
adversely affecting her skeleton. You may elect to obtain a few
6. Do you agree with the recommendation of
basic laboratory tests, as suggested by the history and physical
examination. The history should address detailed menstrual/
7. How would you counsel her about the results of her
reproductive history, history or family history of fractures, any
DXA scan?
diseases (eg, celiac disease, cystic fibrosis, anorexia nervosa),
8. Would you recommend any evaluation?
lifestyle choices (dieting, avoidance of calcium containing foods,
9. Her history is unremarkable excepting for the
tobacco and alcohol exposure) or medication exposures (eg,
occurrence of a femoral neck stress fracture while
glucocorticoids, anticonvulsants) during childhood or adolescence
running in a half-marathon at age 25 years. Does this
that could have negatively affected bone health.
change your thinking?
10. A biochemical evaluation reveals a serum calcium of
8.7 mg/dL (normal range, 8.6 10.2 mg/dL), serum Question 9
PO4 of 2.5 mg/dL (normal range, 2.5 4.5 mg/dL), a A femoral stress fracture is distinctly unusual and warrants a

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

more careful evaluation of her bone health. Stress fractures subjects and anorexia nervosa. Am J Physiol Endocrinol Metab. 2007;292:
may be due to either repetitive overuse of a normal bone or
7. Fernandez-Garca D, Rodrguez M, Garca Aleman J, et al. Thin healthy
normal use of a weak (osteoporotic) bone. A history of a stress women have a similar low bone mass to women with anorexia nervosa.
fracture may suggest that although her BMD is within the Br J Nutr. 2009;102:709-714.
normal range for age, that her bone strength is not normal, 8. Galusca B, Zouch M, Germain N, et al. Constitutional thinness: Unusual
human phenotype of low bone quality. J Clin Endocrinol Metab. 2008;93:
especially if the amount of running does not seem excessive 110-117.
(granted, this may be a subjective assessment). 9. Cohen A, Lang TF, McMahon DJ, et al. Central QCT reveals lower
volumetric BMD and stiffness in premenopausal women with idiopathic
osteoporosis, regardless of fracture history. J Clin Endocrinol Metab.
Question 10 2012;97:4244-4252.
Although the serum results are all within the normal range, the 10. Cohen A, Liu XS, Stein EM, et al. Bone microarchitecture and stiffness in
premenopausal women with idiopathic osteoporosis. J Clin Endocrinol
urinary calcium excretion is low. The pattern (low-normal
Metab. 2009;94:4351-4360.
serum calcium, PO4, serum 25-OHD; high-normal PTH) is 11. Kovacs CS. Osteoporosis presenting in pregnancy, puerperium, and lacta-
consistent with mild, compensated secondary hyperparathy- tion. Curr Opin Endocrinol Diabetes Obes. 2014;21:468-475.
roidism. Together with a low urinary calcium, this suggests 12. Cohen A, Dempster DW, Recker RR, et al. Abnormal bone microarchitecture and
evidence of osteoblast dysfunction in premenopausal women with idio-
intestinal malabsorption. You should query the patient about pathic osteoporosis. J Clin Endocrinol Metab. 2011;96:3095-3105.
gastrointestinal (GI) symptoms, weight loss, and family history 13. Cohen A, Dempster DW, Stein EM, et al. Increased marrow adiposity in
of GI diseases such as celiac disease, and obtain celiac serolo- premenopausal women with idiopathic osteoporosis. J Clin Endocrinol
gies. Metab 2012;97:2782-2791.
14. Misof BM, Gamsjaeger S, Cohen A, et al. Bone material properties in
premenopausal women with idiopathic osteoporosis. J Bone Miner Res.
REFERENCES 2012;27:2551-2561.
1. Hui SL, Slemenda CW, Johnston CC, Jr. Age and bone mass as predictors 15. Peris P, Monegal A, Martnez MA, Moll C, Pons F, Guanabens N. Bone
of fracture in a prospective study. J Clin Invest. 1988;81:1804-1809. mineral density evolution in young premenopausal women with idiopathic
2. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton LJ 3rd. Epi- osteoporosis. Clin Rheumatol. 2007;26:958-961.
demiology and clinical features of osteoporosis in young individuals. 16. Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD, Neer
Bone. 1994;15:551-555. RM. Prevention of estrogen deficiency-related bone loss with human
3. Cohen A, Shane E. Evaluation and management of the premenopausal parathyroid hormone-(1-34): A randomized controlled trial. JAMA. 1998;
woman with low BMD. Curr Osteoporos Rep. 2013;11:276-285. 280:1067-1073.
4. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of 17. Cohen A, Stein EM, Recker RR, et al. Teriparatide for idiopathic osteo-
the 2013 International Society for Clinical Densitometry Position Devel- porosis in premenopausal women: A pilot study. J Clin Endocrinol Metab.
opment Conference on bone densitometry. J Clin Densitom. 2013;16:455- 2013;98:1971-1981.
466. 18. Choe EY, Song JE, Park KH, et al. Effect of teriparatide on pregnancy and
5. Ferrari S, Bianchi ML, Eisman JA, et al. Osteoporosis in young adults: lactation-associated osteoporosis with multiple vertebral fractures. J Bone
Pathophysiology, diagnosis, and management. Osteoporos Int. 2012;23: Miner Metab. 2012;30:596-601.
2735-2748. 19. Cohen A, Kamanda-Kosseh M, Recker R, et al. Bone density after
6. Bossu C, Galusca B, Normand S, et al. Energy expenditure adjusted for teriparatide discontinuation in premenopausal idiopathic osteoporosis.
body composition differentiates constitutional thinness from both normal J Clin Endocrinol Metab. 2015;100:4208-4214.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Osteoporosis: Managing Patients Who Fracture

on Osteoporosis Treatment

M47 nonvertebral fractures, and approximately 1.3% for hip frac-

Presented, April 1 4, 2016 tures after 3-6 years of treatment (5, 6). Similarly, patients
receiving denosumab (DMAB) in the pivotal and extension
trials had incident vertebral fracture rates of approximately
Carolyn B. Becker, MD. Brigham and Womens Hospital, 3.5% and nonvertebral fracture rates of approximately 6.5 and
Department of Endocrinology, Diabetes and Hypertension, 3.8% at 3 and 6 years, respectively (7, 8).
Boston, Massachusetts 02115, E-mail: cbbecker@partners.org In the real world of patient care, fractures that occur while
on therapy may be much higher. For example, in one observa-
INTRODUCTION tional study, nearly 19% of postmenopausal women on oral OT
Historical Overview sustained one or more fractures over 3 years of therapy. All of
Twenty years ago, alendronate (ALN) was the first the fractures were morphometric vertebral fractures picked up
bisphosphonate shown to reduce osteoporotic fractures in on imaging, not clinical fractures (9). In another observational
postmenopausal women (1, 2). This revolutionized the era of study, women with severe osteoporosis on oral OT for an
osteoporosis research and led to rapid development of new average of 26 months had a subsequent risk of incident fracture
therapies. Since then, bisphosphonates have truly become the of 9.5% per year on continued therapy (10). This led the
backbone of osteoporosis therapy (OT). The historical devel- authors to surmise that effectiveness of oral OT may wane
opment of bisphosphonates is a fascinating example of bench over time. In a national patient registry of 38 000 patients
to bedside research and fruitful collaborations between indus- beginning ALN therapy and maintaining greater than 80%
try, academia, and clinicians. The story began with the search adherence, 9.4% sustained a major osteoporotic fracture 6
for agents that could prevent dental caries and work as better months or more after starting the therapy (11). In contrast, a
detergents (by chelating calcium and magnesium). Scientists at longitudinal survey of 5500 women with osteoporosis found
Procter and Gamble in Cincinnati noted the strong affinity of that only 6.5% sustained a single fracture and 1.3% sustained
bisphosphonates for hydroxyapatite crystal, a property that two or more new fractures while taking oral OT continuously
would come to have broad implications for skeletal metabo- for 3 years (12). These were self-reported fractures and not
lism. Collaborative work among scientists and clinicians on confirmed with radiographic imaging.
both sides of the Atlantic ocean resulted in development of
etidronate, the first bisphosphonate used in clinical medicine. BARRIERS TO OPTIMAL PRACTICE
In 1968, etidronate saved the life of a 16-month-old girl with The reality is that no currently available treatment for osteopo-
myositis ossificans progressiva, a disease causing widespread rosis can completely eliminate the risk of fracture.
muscle calcification. Today, bisphosphonates are used all over Reasons for this include low adherence and persistence with
the world as radionuclide bone scanning agents as well as medications, inadequate absorption (in the case of oral
treatments for osteoporosis, Pagets disease, hypercalcemia of bisphosphonates), failure to diagnose and treat secondary causes
malignancy, and multiple myeloma (3). of osteoporosis, intervention that is too little or too late to reverse
existing defects in bone mass and/or bone quality, and the inability
SIGNIFICANCE OF THE CLINICAL PROBLEM of our treatments to address nonskeletal risk factors such as frailty
We have made great progress in diagnosing, preventing, and and falls (13, 14). Additional barriers to optimal treatment include
treating osteoporosis, yet fragility fractures remain a major the high cost of many pharmaceutical agents as well as tier-based,
clinical and public health issue. At best, our current interven- sequential reimbursement policies that discourage individualized
tions reduce the relative risk of fragility fractures by 30 70% approaches to care. In fairness, very few clinical trials comparing
at the spine, 1525% at nonvertebral sites, and 40% at the hip. active therapies or combinations of therapies exist. This means
OT reduces the risk of multiple fractures by 80 90% compared that sequential treatment failures rather than clinical trial evi-
with placebo (4). dence may direct much of our decision making.
Poor compliance with self-administered medications (see Given that fragility fractures occur among a significant pro-
Barriers to Optimal Practice) can greatly lower the effective- portion of patients being treated for osteoporosis, it is surpris-
ness of OT. But even in trials in which drugs are administered ing how few guidelines exist to help clinicians manage these
by healthcare personnel, fractures still occur. For example, in patients. In 2012, a working group of the International Osteo-
the pivotal and extension trials for iv zoledronic acid (ZA), porosis Foundation tried to fill this gap by publishing prag-
new fracture rates in the active treatment arms were approxi- matic advice for clinicians managing patients with osteoporosis
mately 3% for morphometric vertebral fractures, 8% for treatment failure. Alhough based largely on limited data and

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

expert opinion, this position paper represents a starting point If the therapy is self administered, is the patient actually
for the clinical care of patients who fracture on OT (4). taking the drug?
Is she taking it properly (particularly critical with oral
Is she missing 20% of the doses (the threshold for
As a result of participating in this session, learners should be able to:
adequate adherence)?
Decide when a new fragility fracture truly represents
Is she getting sufficient calcium and vitamin D?
treatment failure.
Decide which workup needs to be performed. Studies have shown that persistence with OT is often dismal.
Decide rationally which therapeutic changes, if any, Among 451 000 new oral bisphosphonate users, only 63%
should be made. persisted with therapy at 1 year, 46% at 2 years, and less than
25% at 5 years (16). Other studies have shown that up to half
of patients starting on oral bisphosphonates stop therapy within
3-6 months (17). A recent pharmacy review of 127 000 patients
starting on oral OT or teriparatide (TPT) found that persistence
Fragility Fracture with medication at 1 year was only 40% for monthly
A fragility fracture occurs spontaneously or after falling from a risedronate (RIS), 39.9% for weekly ALN, 22.7% for
standing height. Certain fracture sites are excluded from this raloxifene, and 34% for TPT (18).
definition because they are not typically associated with osteo- Once compliance issues have been addressed, the second
porosis and/or are less responsive to OT. These include frac- step is to determine whether the patient has primary or
tures of the hands, skull, digits, feet, and ankles (4). secondary osteoporosis. This involves a careful history and
Treatment failure for patients on OT is defined as (4): physical examination as well as additional laboratory testing.
Two or more incident fragility fractures. Listed in Table 1 are diseases to be considered in the differen-
tial diagnosis when a patient fails to respond to OT.
One incident fracture and an elevated baseline serum collagen
Type 1 C-telopeptide (CTX) that does not decrease by 25%
while on antiresorptive therapy (or, a serum N-terminal Testing for Patients Fracturing on OT
propeptide of Type 1 collagen [P1NP] that does not increase Complete blood count, serum calcium, phosphorus,
creatinine, 25(OH)D, alkaline phosphatase, celiac
by 25% while on anabolic therapy).
antibodies, TSH, liver enzymes, and 24-hour urine for
One incident fracture and a clinically significant decrease in
calcium, sodium, creatinine, and free cortisol.
bone mineral density (BMD) at the spine (5%), or at the hip Additional testing could include intact PTH, serum and
(4%). urine protein electrophoresis, and sex steroid levels.
Persistently elevated bone turnover markers (BTM) Serum or urine markers of bone turnover (eg, serum
accompanied by a clinically significant decrease in BMD. CTX or P1NP for antiresorptive and anabolic therapy,
respectively) may be helpful, particularly when
compared with baseline values prior to therapy. Note
that BTMs must be collected under proper conditions
Compliance is the degree to which a patient correctly follows
and using the same assay to be fully comparable (13).
medical advice; for medications, this includes timing, dosage, Finally, a repeat measurement of BMD using dual-energy
and frequency. x-ray absorptiometry (DXA) can be supportive evidence
showing inadequate response to medication therapy. A
Adherence clinically significant decline in BMD coupled with a new
Adherence and compliance are often used interchangeably fracture strongly supports the need to rule out compliance
issues and secondary causes of osteoporosis. It also
though adherence may imply that the patient is in agreement
suggests that a change in therapy is warranted.
with the treatment plan or intervention.

Changing Therapy: A Rational Approach

Persistence Table 2 shows the seven major osteoporosis therapies available in
Persistence is time from initiation of therapy to discontinuation the United States. The numbers in the boxes represent statistically
of that therapy. significant relative risk reductions in spine, nonvertebral, and hip
In general, 6 12 months of uninterrupted OT are necessary fractures based on meta-analyses or randomized clinical trials.
before concluding that an OT is not effective or that the patient The most effective agents for reducing spinal fractures are
is a nonresponder (4, 10, 11). ZA, DMAB, and teriparatide. For nonvertebral fractures, re-
sults are much more modest and not all agents are effective.
Clinical Assessment of the Patient Who Fractures on OT Finally, ALN, RIS, ZA, and DMAB are the sole agents to have
The first step is to review compliance (15). significantly reduced hip fractures in clinical trials.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

TABLE 1. Secondary Causes for Osteoporosis/Fractures*

Inherited Nutritional Endocrine Medications Other
Osteogenesis imperfecta Malabsorption- Hypogonadism Glucocorticoids Multiple myeloma
Homocysteinuria Alcoholism Hyperthyroidism Anticonvulsants Rheumatoid arthritis
Marfans syndrome Calcium deficit Cushings Heparin Mastocytosis
Vitamin D deficit Anorexia Excess thyroid Immobilization
Hypercalciuria PHPT GnRH agonists
Hepatic disease HAART
Aromatase inhibitors
Proton pump inhibitors

Abbreviations: PHPT, primary hyperparathyroidism; GnRH, gonadotropin-releasing hormone; HAART, highly active anti-retroviral
*Adapted from Lewiecki EM 2003 (15).

TABLE 2. Statistically Significant Relative Risk

Reductions in Fractures (N/S not significant) greater patient satisfaction (21) when switched to DMAB
compared with those switched to oral ibandronate. Simi-
Spine Non-vertebral Hip
Drug Fractures Fxs Fractures larly, in another study, patients switched to DMAB had
significant decreases in BTMs and significant increases in
Alendronate 0.55 0.84 0.61
BMD at both spine and hip after 12 months, compared with
Risedronate 0.63 0.80 0.74
those continuing on ALN (23).
Zoledronic Acid 0.30 0.75 0.59
Bottom line: DMAB leads to greater suppression of BTMs
Ibandronate 0.48 N/S N/S
as well as generalized improvements in BMD within 1 year of
Raloxifene 0.70 N/S N/S
switching from chronic ALN.
Denosumab 0.32 0.80 0.60
Teriparatide 0.35 0.62 N/S
Switching from ALN or RIS to TPT
After 12 months, patients previously on RIS showed signifi-
cantly greater gains in BMD at both spine and hip on TPT
Only 11 studies, mainly open label, short duration (2 y), compared with those previously on ALN (24).
and with small sample sizes, have been performed to evaluate
outcomes when transitioning from oral bisphosphonates (ALN Switching from ALN or Raloxifene (RLX) to TPT vs
or RIS) to other agents (19). None of these studies include adding TPT to oral drug
fracture outcomes. A brief synopsis of results from some of the Addition of TPT to ALN increased BMD at spine and hip
larger trials is outlined below. significantly more than stopping ALN and starting TPT by
itself. With RLX, either adding or switching to TPT led to
equivalent gains in BMD at the spine and hip (25).
Switching from ALN to another oral bisphosphonate
In general, switching poorly compliant patients from ALN to
another oral bisphosphonate, such as RIS (20) or ibandronate Other combination therapies (26)
Adding TPT to ALN or ZA increases BMD at the hip beyond
(21) does not lead to any measurable improvements.
PTH alone; at the spine, however, there is no additive effect of
combination therapy.
Switching from ALN to ZA vs continuing ALN DMAB plus TPT shows additive effects at BMD of spine
Women on long-term ALN who switched over to ZA had and hip compared with either drug alone.
significantly lower BTMs at 3 months compared with those In the opinion of one expert: for patients previously
continuing on ALN. At 1 year, however, there were no differ- treated with bisphosphonates who suffer hip fractures or who
ences in BMD or bone biopsies (22). have very low or declining BMD at the hip, strong consider-
Bottom line: Oral ALN may not maximally suppress bone ation should be given to starting TPT and continuing a potent
resorption, even after 4 years of therapy. ZA leads to greater antiresorptive therapy (possibly switching to ZA or DMAB) to
suppression of BTMs in the short term but no change in BMD. improve hip BMD and strength quickly. (27)


Patients with poor adherence to ALN had significant de- A significant proportion of patients on OT will continue
creases in BTMs, significant increases in BMD (21, 21) and to fracture.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

No currently available therapy can completely C. Check additional laboratory tests to rule out secondary
eliminate the risk of fracture. causes of osteoporosis.
D. Stop ALN and switch to iv ZA.
A rational approach to patients who fracture after at least 6 12
mo of OT is outlined below:
Assess for compliance and absorption (particularly if Case 2
A healthy 70-year-old woman returns for followup of general-
patient is on an oral bisphosphonate).
ized osteoporosis. She has been on ALN, 70 mg by mouth
Assess for secondary causes of osteoporosis via history,
weekly with excellent compliance for 4 years as well as ad-
physical examination, and selected laboratory testing.
equate calcium and vitamin D. A repeat DXA shows stable
Assess BTMs (serum CTX for antiresorptive and serum
values at all sites with T-scores of 2.8 at the spine (8%
P1NP for anabolic therapy), preferably with baseline
increase since baseline), 3.0 at the FN, and 2.8 at the TH
measurements for comparison.
(4.5% increase since baseline). After sustaining a wrist fracture
Assess BMD via DXA if at least 12 mo have passed
at age 65, she has done well. Two months after seeing you, she
since the previous scan.
trips over a branch while hiking in the woods, fracturing her
If there is evidence of poor compliance, malabsorption,
left humerus. Laboratory work-up reveals normal CBC, Ca,
inadequate BTM response, or significant decline in BMD
Phos, creatinine, 25OHD, serum and urine protein electropho-
in addition to a single fragility fracture, then therapy
resis, alk phos, and urinary calcium excretion. A fasting serum
should be changed. This also applies if patients sustain
CTX comes back in the lowest 25th percentile for premeno-
two or more incident fractures on a particular therapy.
pausal women.
In general, when changing OT: What is the most appropriate management?
Replace a weaker antiresorptive agent (eg, raloxifene) A. Stop ALN and begin teriparatide.
with a more potent antiresorptive agent (eg, B. Stop ALN and begin ZA.
bisphosphonate) (4). C. Stop ALN and begin DMA.B
Substituting one oral bisphosphonate for another may not D. Continue ALN for now.
improve efficacy against subsequent fractures.
Replace an oral drug with an injected drug (eg, ZA or Case 3
DMAB) (4). A 72-year-old woman with osteoporosis comes to see you with
Replace a strong antiresorptive (eg, ZA or DMAB) with acute midback pain after lifting a bag of mulch. She had taken
an anabolic (TPT) (4). ALN 70 mg weekly for 4 years followed by DMAB 60 mg sc
In cases in which hip fracture is a particular risk, consider every 6 months for the past 18 months. On examination, her
combination therapy with ALN, ZA, or DMAB TPT midback is tender and she has lost 1 in in height. Imaging
(27). Focus on modifiable risk factors such as smoking shows an acute biconcave vertebral compression fracture at
cessation, correction of vitamin D deficiency, and T10 and mild-to-moderate anterior wedge compression frac-
reducing or stopping unnecessary medications (eg, tures at 2 other vertebrae that seem to be old. Her last DXA
proton pump inhibitors). from 6 months ago revealed T-scores of 2.5 at L1-L4, 2.8 at
the left FN, and 2.5 at the left TH. All were significantly
CASES WITH QUESTIONS improved compared with the previous scan. An extensive lab-
Case 1 oratory work up including 24 hour urine free cortisol, serum
A 66-year-old woman is diagnosed with osteoporosis on a tryptase, serum and urine protein electrophoresis, and PTH
screening DXA. Her T-scores are 3.5, 3.2, and 3.0 at comes back negative. Fasting serum CTX is suppressed.
L1L4, left femoral neck (FN), and left total hip (TH), respec- What is the most appropriate management?
tively. She is 15 years postmenopausal and on no medications. A. Stop DMAB and switch to ZA.
She has no toxic habits, exercises regularly, and has never B. Stop DMAB and switch to teriparatide.
fractured. She gets adequate calcium in her diet and takes C. Switch to ZA and add teriparatide.
vitamin D, 800 IU daily. Physical examination is negative for D. Continue DMAB and add teriparatide.
kyphosis or loss of height. Her body mass index is 21 kg/m2.
CBC, serum calcium, phosphate, creatinine, 25(OH)D, and DISCUSSION
hepatic panel are normal. You start her on ALN, 70 mg by Case 1
mouth weekly. Four months later she slips on ice, falls, and There are two teaching points from this case. The first point
breaks her left wrist. is that 6 12 months of treatment are required before one can
What is the most appropriate management? call OT a failure or deem the patient a nonresponder. Four
A. Assess her compliance with the current regimen. months is too short a time and there is no need for further
B. Check a serum or urine marker of bone resorption. laboratory testing or switching to a new therapy. Bone

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

turnover markers would be useful in comparison with base- acid for treatment of postmenopausal osteoporosis. N Engl J Med.
line levels but BTMs were not obtained at baseline. The 6. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of
second point is that a review of compliance with oral zoledronic acid treatment of osteoporosis: A randomized extension to
bisphosphonates is always warranted given that poor com- the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res.
pliance is so common with self-administered OT. 7. Cummings SR, San Martin J, McClung MR, et al. Denosumab for preven-
tion of fractures in postmenopausal women with osteoporosis. N Engl
Case 2 J Med. 2009;361(8):756-765.
8. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of
This case explores what to do when a patient on potent denosumab treatment in postmenopausal women with osteoporosis:
antiresorptive therapy fractures, despite improvements in BMD Results from the FREEDOM extension study. Osteoporos Int. 2015;26
and suppression of BTMs. According to the International Os- (12):2773-2783.
9. Cairoli E, Eller-Vainicher C, Ulivieri FM, et al. Factors associated with
teoporosis Foundation Position Paper (4), she does not warrant bisphosphonate treatment failure in postmenopausal women with primary
a change in therapy unless the wrist fracture occurred after osteoporosis. Osteoporos Int. 2014;25:1401-1410.
6 12 months on OT (which it did not). However, in the real 10. Adami S, Isaia G, Luisetto G, et al. Osteoporosis treatment and fracture
incidence: The ICARO longitudinal study. Osteoporos Int. 2008;19:
world, this would clearly be a disappointing result for both 1219-1223.
patient and physician. Teriparatide significantly reduces 11. Abrahamsen B, Rubin KH, Eiken PA, et al. Characteristics of patients
nonvertebral fractures but its effect on hip fractures is not who suffer major osteoporotic fractures despite adhering to alendronate
treatment: A national prescription registry study. Osteoporos Int.
established. Intravenous ZA will not increase BMD in patients 2013;24:321-328.
already responding to ALN. In contrast, DMAB has been 12. Dez-Perez A, Adachi JD, Adami S, et al. Risk factors for treatment failure
shown to significantly increase BMD at the spine and hip, even with antiosteoporosis medication: The global longitudinal study of osteo-
porosis in women (GLOW). J Bone Miner Res. 2014;29:260-267.
in patients coming off of long-term ALN. We have no fracture 13. Lewiecki EM, Watts NB. Assessing response to osteoporosis therapy.
outcomes to support this change but extension studies suggest Osteoporos Int. 2008;19:1363-1368.
that DMAB may be superior to bisphosphonates in the long 14. Carey JJ. What is a failure of bisphosphonate therapy for osteoporosis?
Cleve Clin J Med. 2005;72:1033-1039.
term. After 8 years of DMAB, BMD continues to increase at 15. Lewiecki EM. Nonresponders to osteoporosis therapy. J Clin Densitom.
both spine and hip while TH BMD plateaus at a lower level 2003;6:307-314.
after only 4.5 years on ZA (28). 16. Burden AM, Paterson JM, Solomon DH, et al. Bisphosphonate prescrib-
ing, persistence and cumulative exposure in Ontario, Canada. Osteoporos
Int. 2012;23:1075-1082.
Case 3 17. Sheehy O, et al. Differences in persistence among different weekly oral
bisphosphonate medications. Osteoporos Int. 2009;20(8):1369-1376.
This case illustrates the patient who clearly meets criteria for a 18. Carbonell-Abella C, Pages-Castella A, Javaid MK, et al. Early (1-year)
change in therapy. She has fractured on two potent antiresorp- discontinuation of different anti-osteoporosis medications compared: A
tive agents, ALN and DMAB. Compliance is not an issue and population-based cohort study. Calcif Tissue Int. 2015;97(6):535-541.
19. Eiken P, Vestergaard P. Treatment of osteoporosis after alendronate or
her workup for secondary causes is negative. She needs ana- risedronate [published online October 5, 2015]. Osteoporos Int. doi:
bolic therapy. However, she has osteoporosis at the hip sites 10.1007/s00198-015-3334-4.
and thus is at high risk for a hip fracture. Teriparatide has not 20. Roux C, Hofbauer LC, Ho PR, et al. Denosumab compared with
risedronate in postmenopausal women suboptimally adherent to alendro-
shown efficacy against hip fractures and can lead to declines in nate therapy: Efficacy and safety results from a randomized open-label
BMD at the femoral neck. In this particular situation, combi- study. Bone. 2014;58:48-54.
nation therapy with DMAB plus TPT should be strongly con- 21. Recknor C, Czerwinski E, Bone HG, et al. Denosumab compared with
ibandronate in postmenopausal women previously treated with bis-
sidered. In clinical trials, this combination seems to lead to the phosphonate therapy: A randomized open-label trial. Obstet Gynecol.
most robust improvements in BMD at both spine and hip 2013;121:1291-1299.
although no fracture data are available. Changing to ZA would 22. McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5 mg in
the treatment of postmenopausal women with low bone density previously
not offer any added value in this situation. treated with alendronate. Bone. 2007;41:122-128.
23. Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone
mineral density and bone turnover in postmenopausal women transitioning
REFERENCES from alendronate therapy. J Bone Miner Res. 2010;25:72-81.
1. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone 24. Miller PD, Delmas PD, Lindsay R, et al. Early responsiveness of women
mineral density and the incidence of fractures in postmenopausal osteopo- with osteoporosis to teriparatide after therapy with alendronate or
rosis. N Engl J Med. 1995;333:1437-1443. risedronate. J Clin Endocr Metab. 2008;93:3785-3793.
2. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of 25. Cosman F, Wermers RA, Recknor C, et al. Effects of teriparatide in
alendronate on risk of fracture in women with existing vertebral fractures. postmenopausal women with osteoporosis on prior alendronate or
Lancet. 1996;348(9041):1535-1541. raloxifene: Differences between stopping and continuing the antiresorptive
3. Francis MD, Valent DJ. Historical perspectives on the clinical dev- agent. J Clin Endocr Metab. 2009;94:3772-3780.
elopment of bisphosphonates in the treatment of bone diseases. 26. Cosman F. Combination therapy for osteoporosis: A reappraisal. Bonekey
J Musculoskelet Neuronal Interact. 2007;7(1):2-8. Rep. 2014;3:518.
4. Diez-Perez A, Adachi JD, Agnusdei D, et al. Treatment failure in osteo- 27. Cosman F. Anabolic and antiresorptive therapy for osteoporosis: Combi-
porosis. Osteoporos Int. 2012;23:2769-2774. nation and sequential approaches. Curr Osteoporos Rep. 2014;12:385-395.
5. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic 28. Reid IR. Denosumab after 8 years. Osteoporos Int. 2015;26:2759-2761.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Osteoporosis Drug Holidays: Data and Opinions

M51 United States, four bisphosphonates are approved for the

Presented, April 1 4, 2016 prevention and/or treatment of postmenopausal osteoporo-
sis, osteoporosis in men, and osteoporosis due to long-term
glucocorticoid therapy. Alendronate and risedronate can be
Nelson B. Watts, MD. Osteoporosis and Bone Health given orally daily, weekly, or monthly; zoledronate is a
Services, Mercy Health, Cincinnati, Ohio 45242, E-mail: once-yearly iv infusion and ibandronate can be given either
nelson.watts@hotmail.com orally (monthly) or intravenously (every third month).
Bisphosphonates bind strongly to hydroxyapatite crystals
INTRODUCTION in bone (zoledronate most strongly, risedronate least
Historical Overview strongly; alendronate and ibandronate have intermediate af-
Osteoporosis has been clinically recognized for centuries. In the finity for bone). Drug that does not bind with bone is rapidly
1940s, Fuller Albright made the connection between osteoporosis excreted by the kidneys. In the process of bone resorption,
and estrogen loss with menopause, and for many years, estrogen bisphosphonates are released from the bone and enter the
was the treatment of choice. Bisphosphonates are compounds with osteoclasts, causing loss of resorptive function and acceler-
several different commercial and medical uses. First available in ating apoptosis. There is a rapid and substantial decrease in
the mid 1990s, they have been the most widely used agents for bone turnover markers with a maximum effect in 3 6
prevention and treatment of osteoporosis. months and modest increases in bone density in the first few
years of treatment (35%) that then plateau. With continued
treatment, the new steady state is maintained for 10 years (2,
Osteoporosis is a common disorder, one of several risk Bisphosphonates have proven efficacy for prevention of
factors for fracture risk. Fractures cause significant disabil- bone loss due to aging, estrogen deficiency, and glucocorti-
ity and even death. Bisphosphonates are unique in that they coid use. Three of the four (alendronate, risedronate, and
accumulate in bone so after a loading dose it might be zoledronate) have been shown in placebo-controlled trials to
possible to discontinue treatment, at least temporarily, with prevent fractures of the spine, hip, and other nonvertebral
maintenance of a therapeutic benefit. Also, there are con- sites (4 6). Because of this broad-spectrum antifracture
cerns that long-term treatment (5 y) increases the risk of efficacy, bisphosphonates have been the agents of choice for
osteonecrosis of the jaw (ONJ) and atypical femur fractures, most patients with osteoporosis.
although the risk remains small. Orally administered bisphosphonates are usually well toler-
ated but may irritate the esophagus and should not be used by
BARRIERS TO OPTIMAL PRACTICE patients who cannot remain upright, who have active upper
There is confusion and concerns among providers and pa- gastrointestinal symptoms, or have delayed esophageal empty-
tients regarding safety of bisphosphonate treatment and op- ing. Up to one third of patients receiving their first iv dose of
timal duration. zoledronate or monthly oral dose of ibandronate or risedronate
experience one or more symptoms of acute-phase reactions
(fever, muscle aches, etc.) (79), but these are usually mild,
LEARNING OBJECTIVES resolve within a few days, and rarely recur with repeated
As a result of participating in this session, learners should be
administration. Hypocalcemia may occur but is usually mild
able to:
and not clinically recognized (10). Iritis has been described
Describe the benefits and risks of bisphosphonate
with bisphosphonates (more with iv than oral) but is rare (1
per 1000).
Describe the rationale for drug holidays from
Although there is no evidence of renal toxicity from oral
bisphosphonates, the only route of elimination is by the
Review data regarding when a drug holiday should be
kidneys, so they should be used with caution if at all by
offered and opinion as to how long a holiday should
patients with reduced kidney function. Renal toxicity may
occur with rapid iv administration of zoledronate; its use is
contraindicated for patients with creatinine clearance less
AND/OR MANAGEMENT Bisphosphonates used in the United States were approved
Bisphosphonates have been widely used for treatment of based on placebo-controlled trials of 3 4 years duration. Sev-
osteoporosis and other metabolic bone diseases (1). In the eral of these studies have been extended, with two alendronate

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

cohorts followed for 10 years (2, 3), risedronate cohorts fol- for osteoporosis or Pagets disease. Retrospective review of
lowed for 4 (11) and 7 years (12), and zoledronate cohorts records from the HORIZON trial with iv zoledronate for
followed for 6 years (12). No new safety concerns have been osteoporosis, two cases of ONJ were identified: one who
found in these studies. Although there have been some con- received zoledronate and one who received placebo. It is
cerns about possible oversuppression of bone turnover, iliac estimated that there have been more than 200 million pre-
crest biopsies after up to 10 years of treatment have not shown scriptions in the United States for oral bisphosphonates and
oversuppression (2). more than 6 million patients treated with iv bisphosphonates
Since their approval and widespread use, a number of for cancer worldwide. Epidemiologic data suggest an inci-
potential safety concerns have been identified but with no dence of ONJ in oral bisphosphonate users ranging from
clear cause-and-effect relationship but at least some evi- 1:10 000 to 1:250 000 (14).
dence of increased risk (albeit rare) with therapy of 5 years A causal link between bisphosphonate use and ONJ is likely
or longer. These include musculoskeletal pain, atrial fibril- but has not been conclusively established. ONJ has also been
lation, esophageal cancer, ONJ, and atypical femur frac- seen in patients receiving high-dose denosumab for treatment
tures. The latter two have been subject to close scrutiny and of advanced cancer spread to bone (15). Possible mechanisms
widespread discussion in the medical literature and in the include oversuppression of bone turnover (failure of osteoclasts
lay press. to remove diseased necrotic bone) or interference with clear-
ance of microfilms.
ONJ The American Society for Bone and Mineral Research
In 2003, a letter to the editor reported ONJ in 36 patients with Task Force performed a comprehensive review (13) and the
advanced cancer who were being treated with high doses of iv American Dental Association published guidelines in 2011
bisphosphonates (approximately 10 times higher than the doses (16). Patients receiving bisphosphonates should be informed
used to treat osteoporosis). Subsequent reports included pa- that there are risks of any treatment, including a low risk of
tients receiving lower doses of bisphosphonates for treatment ONJ with long-term therapy. Regular dental visits and main-
of osteoporosis, but, to date, well over 90% of reported cases tenance of good oral hygiene including routine dental clean-
have been in patients with cancer. This subject was extensively ing and needed restorative procedures are important. Ideally,
addressed by a Task Force of the American Society for Bone patients who need invasive dental procedures should have
and Mineral Research (14). procedures performed and healing complete before starting
This condition has received considerable public exposure, bisphosphonate therapy, if circumstances permit. Patients
which caused misconceptions among medical and dental pro- already taking a bisphosphonate may elect to take some time
fessionals as well as the public regarding the seriousness and off therapy, although there is no evidence that this will
frequency of this condition. Some patients decided to stop improve outcomes.
bisphosphonate treatment although they were at high risk of
fracture and low risk of ONJ. Atypical Femur Fractures
ONJ is a clinical diagnosis: Although bisphosphonates reduce the rates of fractures due
Exposed necrotic bone in the maxillofacial region not to osteoporosis, reports have suggested a link between
healing after 8 weeks of appropriate therapy in patients bisphosphonate use and the development of so called atypi-
with no history of craniofacial radiation (14). cal insufficiency fractures.
The bone may be yellow or white, the borders smooth or Proximal femur fractures (hip) due to osteoporosis have
ragged. no warning symptoms, are unilateral (on the side of a
ONJ often follows an invasive procedure, such as dental fall), have an acute angle, and may be comminuted.
extraction, or occurs in patients with poorly fitting Atypical fractures are often preceded by weeks of
dentures or bony exostoses. months of prodromal pain in the thigh or groin, require
There may be pain, swelling, paresthesias, drainage, soft little or no trauma.
tissue ulceration, sinus tracks, and loosening of teeth but Thirty percent of atypical fractures are bilateral.
many patients are asymptomatic.
The location is in the subtrochanteric region of the
Some lesions heal slowly or not at all, but healing has
femoral shaft.
been reported and is probably the rule rather than the
They are transverse or oblique angle with a medial spike
and little or no comminution.
ONJ has been seen in subjects not using
They begin as a localized periosteal reaction of the
bisphosphonates, but the background incidence is not
lateral cortex.
Cortical bone is unusually thick (and this is not a
ONJ was not identified prospectively in any of the clinical something that bisphosphonates do) and healing is often
trials that included more than 60 000 patient-years in studies delayed.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Bone biopsies in such patients often show severely reduced used to decide when to end a drug holiday, but the
bone turnover, although I have seen a patient with one of risedronate study showed that fracture risk remained re-
these subtrochanteric fractures whose iliac crest biopsy was duced despite what seemed to be unfavorable changes in
completely normal. Several retrospective studies have also these parameters (11). Conversely, there is no evidence that,
suggested an association between bisphosphonate use and off treatment, fracture risk is reduced if BMD is stable or
atypical fractures (1720). The association between long- bone turnover marker is low.
term bisphosphonate use and atypical fractures does not
demonstrate causality. Additional large-scale studies are Monitoring Therapy
needed to further clarify this issue. BMD by dual-energy x-ray absorptiometry has been the
accepted technique for monitoring therapy, usually per-
Possible Side Benefits of Bisphosphonate Therapy formed every 12 years. Although treatments produce, on
Not all the news about long-term bisphosphonate use is bad. average, gains in BMD (more for some agents than for
There is evidence from controlled trials and observational others), the association between BMD gains and fracture
studies that bisphosphonate treatment is associated with a risk reductions are, for the most part, not terribly strong, and
decreased risk of breast cancer (2124), colorectal cancer not linear. I tell my patients that Im happy if BMD is not
(25), gastric cancer (26), stroke (27), and myocardial infarc- going down. One of my patients said it well: If youre not
tion (28), as well as improved survival (29). losing, youre winning.

Drug Holidays
Bisphosphonates are unique in that the drugs accumulate in MAIN CONCLUSIONS
bone and there seems to be residual benefit in terms of In my view, once we start treatment for osteoporosis, we
fracture reduction for some time after a 35-year course of must continue doing something to reduce fracture risk in-
bisphosphonate treatment (11). definitely and therapy be monitored by serial BMD testing.
The few data we have suggest that for higher-risk pa- Because bisphosphonates are avidly bound to bone, a reser-
tients, continuing treatment for 6 10 years is better than voir of drug accumulates after years of treatment that is
stopping after 35 years (3, 13, 30). Although the drug gradually released over months or years and seems to result
holiday concept has been widely accepted (31), data are not in a lingering antifracture benefit for some time after therapy
robust regarding how long to treat, how long the holiday is stopped. This makes it possible to consider drug
should be, when the holiday should be stopped, or effective- holidaystime off bisphosphonate therapy (but possibly on
ness of treatment after restarting). The good news is that a another agent, but not another potent antiresorptive drug)
break in bisphosphonate therapy may reset the clock on and then resuming therapy. Although there is no strong
ONJ and atypical femur fractures. science to guide us, we believe that some time off treat-
The American Society for Bone and Mineral Research con- ment should be offered to most patients on long-term
vened a task force on this issue (32). The algorithm they bisphosphonate therapy. The duration of treatment and the
produced is shown in Figure 1. length of the holiday should be tailored to individual patient
It has been suggested that a decrease in bone mineral circumstances, including the risk of fracture and the binding
density (BMD) or increase in bone turnover marker might be affinity of the particular bisphosphonate used.

FIGURE 1: ASBMR Task Force on Long-term Bisphosphonate Use Recommendations for Patient Management.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

CASES alendronate on risk of fracture in women with existing vertebral fractures.

Lancet. 1996;348:1535-1541.
Case 1 is a 52-year-old woman diagnosed with osteopenia 4
5. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on
years ago (femoral neck T-score, 2.2). She has been treated vertebral and nonvertebral fractures in women with postmenopausal osteopo-
with a weekly oral bisphosphonate since then with no signifi- rosis: A randomized controlled trial. Vertebral Efficacy With Risedronate
Therapy (VERT) Study Group. JAMA. 1999;282(14):1344-1352.
cant change in her BMD. Is this an appropriate patient for a
6. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for
drug holiday? treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:
Case 2 is a 70-year-old woman who has been on a weekly 1809-1822.
oral bisphosphonate for 5 years. Her baseline femoral neck 7. Adami S, Bhalla AK, Dorizzi R, et al. The acute-phase response after
bisphosphonate administration. Calcif Tissue Int. 1987;41:326-331.
T-score was 2.8 and now is 1.8. Is this an appropriate 8. Gallacher SJ, Ralston SH, Patel U, Boyle IT. Side-effects of pamidronate.
patient for a drug holiday? Lancet 1989;2:42-43.
Case 3 is a 70-year-old woman who has been on 9. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug thera-
pies for hypercalcaemia of malignancy. Drug Safety. 1999;21(5):389-406.
denosumab, 60 mg twice yearly for 4 years. Her baseline 10. Maalouf NM, Heller HJ, Odvina CV, Kim PJ, Sakhaee K.
femoral neck T-score was 2.8 and now is 1.8. Is this an Bisphosphonate-induced hypocalcemia: Report of 3 cases and review
appropriate patient for a drug holiday? of literature. Endocrine Practice. 2006;12:48-53.
11. Watts NB, Chines A, Olszynski WP, et al. Fracture risk remains reduced one
Case 4 is a 70-year-old woman who has been on a weekly year after discontinuation of risedronate. Osteoporos Int. 2008;19:365-372.
oral bisphosphonate for 5 years. Her baseline femoral neck 12. Mellstrom DD, Sorensen OH, Goemaere S, Roux C, Johnson TD, Chines
T-score was 2.8 and now is 2.8. Is this an appropriate AA. Seven years of treatment with risedronate in women with postmeno-
pausal osteoporosis. Calcif Tissue Int J. 2004;75(6):462-468.
patient for a drug holiday? 13. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of
Case 5 is a 75-year-old woman who was has taken weekly zoledronic acid treatment of osteoporosis: A randomized extension to
alendronate for 13 years. Her baseline femoral neck T-score the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res.
was 5.1. Her most recent femoral neck T-score was 4.8. Is
14. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteone-
this an appropriate patient for a drug holiday? What other crosis of the jaw: Report of a task force of the American Society for
options should be considered? Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491.
15. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and
outcomes of osteonecrosis of the jaw: Integrated analysis from three
DISCUSSION OF CASES AND ANSWERS blinded active-controlled phase III trials in cancer patients with bone
metastases. Ann Oncol. 2012;23:1341-1347.
Case 1 met the guidelines for pharmacologic therapy prior to 16. Hellstein JW, Adler RA, Edwards B, et al. Managing the care of
2008 but does not meet the current guidelines. I would stop her patients receiving antiresorptive therapy for prevention and treatment
bisphosphonate therapy but not for a drug holiday because she of osteoporosis: Executive summary of recommendations from the
American Dental Association Council on Scientific Affairs. J Am Dent
does not need it.
Assoc. 2011;142:1243-1251.
Case 2 has had a nice increase in BMD with 5 years of 17. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures
bisphosphonate treatment, is no longer at high risk of fracture, in patients on alendronate therapy: A caution. J Bone Joint Surg Br.
and is a good candidate for a drug holiday. 2007;89(3):349-353.
18. Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-
Case 3 has had a nice increase in BMD with 4 years of energy femoral shaft fractures associated with alendronate use. J Orthop
denosumab therapy but denosumab effects go away very Trauma. 2008;22:346-350.
quickly so she is not a candidate for a drug holiday. 19. Lenart BA, Neviaser AS, Lyman S. et al. Association of low-energy
femoral fractures with prolonged bisphosphonate use: A case control
Case 4 has avoided the loss of bone that would have been study. Osteoporos Int. 2009;20:1353-1362.
expected but is still at high risk. Studies suggest that pa- 20. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use
tients like this do better with treatment of longer duration. and the risk of subtrochanteric or femoral shaft fractures in older women.
JAMA. 2011;305:783-789.
Case 5 remains at high risk despite 13 years of treatment 21. Vestergaard P, Fischer L, Mele M, Mosekilde L, Christiansen P. Use of
with bisphosphonate. I would give her a bisphosphonate bisphosphonates and risk of breast cancer. Calcif Tiss Int. 2011;88:255-262.
holiday but treat her with teriparatide for 2 years after 22. Dreyfuss JH. Oral bisphosphonate use associated with a decreased risk of
breast cancer. Cancer. 2010;60:343-344.
stopping her bisphosphonate and reconsider treatment op- 23. Cheblowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate use and
tions when the 2 years of teriparatide are up. breast cancer incidence in postmenopausal women. J Clin Oncol.
24. Rennert G, Pinchev M, Rennert HS. Use of bisphosphonates and risk of
REFERENCES postmenopausal breast cancer. J Clin Oncol. 2010;28:3577-3581.
1. Russell RG, Rogers MJ. Bisphosphonates: From the laboratory to the 25. Rennert G, Pinchey M, Rennert HS, Gruber SB. Use of bisphosphonates and
clinic and back again. Bone. 1999;25(1):97-106. reduced risk of colorectal cancer. J Clin Oncol. 2011;29:1146-1150.
2. Bone HG, Hosking D, Devogelaer JP, et al. Ten years experience with 26. Abrahamsen B, Pazianas M, Eiken P, Russell RG, Eastell R. Esophageal
alendronate for osteoporosis in postmenopausal women. New Engl J Med. and gastric cancer incidence and mortality in alendronate users. J Bone
2004;350:1189-1199. Miner Res. 2012;27:679-686.
3. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or 27. Steinbuch M, DAgostino RB, Mandel JS, et al. Assessment of mortal-
stopping alendronate after 5 years of treatment: The Fracture Interven- ity in patients enrolled in a risedronate clinical trial program: A retro-
tion Trial Long-term Extension (FLEX): A randomized trial. JAMA. spective cohort study. Regul Toxicol Pharmacol. 2002;35(3):320-326.
2006;296:2927-2938. 28. Wolfe F, Bolster MB, OConnor CM, Michaud K, Lyles KW, Colon-
4. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of Emeric CS. Bisphosphonate use is associated with reduced risk of

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

myocardial infarction in patients with rheumatoid arthritis. J Bone Miner 31. Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for
Res. 2013;28:984-991. osteoporosisWhere do we go from here? N Engl J Med. 2012;366:
29. Grey A, Bolland MJ. The effect of treatments for osteoporosis on 2048-2051.
mortality. Osteoporos Int. 2013;24:1-6. 32. Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in
30. Schwartz AV, Bauer DC, Cauley JA, et al. Efficacy of continued alendro- patients on long-term bisphosphonate treatment: Report of a Task Force
nate for fractures in women without prevalent vertebral fracture: The of the American Society for Bone and Mineral Research [published
FLEX trial (abstract). J Bone Miner Res. 2010;25(5):976-982. online September 9, 2015]. J Bone Miner Res. doi:10.1002/jbmr.2708.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Vitamin D Replacement in Patients With Malabsorption Disorders

M55 25-hydroxyvitamin D of 40 60 ng/mL and recognized up to

Presented, April 1 4, 2016 100 ng/mL is safe; toxicity is usually seen when blood levels
are greater than 150 ng/mL. Whereas the IOM recommended
that most children and all adults up to age 70 years require only
Michael F. Holick, MD, PhD. Section of Endocrinology, 600 IU of vitamin D daily the Endocrine Society recommended
Nutrition and Diabetes, Department of Medicine, Boston that children should receive 600 1000 IU daily and adults
University Medical Center, Boston, Massachusetts 02118, 1500 2000 IU daily. Obese adults required 23 times more
E-mail: mfholick@bu.edu vitamin D to satisfy their requirement.
The Endocrine Society recommends that treating vitamin D
INTRODUCTION deficiency with 50 000 IU of vitamin D2 once a week for 8
Historical Overview weeks is effective. To prevent recurrence the recommendation
Vitamin D deficiency became a major health problem for is to maintain patients on 50 000 IU of vitamin D every 2
industrialized countries beginning in the mid 1600s. By the weeks or approximately 1500-2000 IU daily.
turn of the last century upwards of 90% of children living in
northeastern United States and in the industrialized centers in
Europe had evidence of the bone-deforming disease, rickets.
One of the major barriers is to obtain a blood level of
The discovery that cod liver oil and sunlight were both effec-
25-hydroxyvitamin D to determine the patients vitamin D
tive in preventing this devastating disease resulted in the forti-
status. This can be caused by lack of knowledge or interest by
fication of milk with vitamin D and government agencies
the physician or a problem with the insurance company reim-
recommending that infants and children be exposed to sensible
bursing for the test. Both the IOM and Endocrine Society do
sun light. Vitamin D fortification became extremely popular in
not recommend broad screening for vitamin D status. The
the 1930s and 1940s and not only milk but also bread, custard,
assay for 25-hydroxyvitamin D should be used in circum-
shaving cream, hot dogs, and even beer were fortified with
stances for patients who were at risk for vitamin D deficiency
vitamin D. However, an outbreak of infantile hypercalcemia
or for patients who may have a metabolic abnormality making
that was associated with mental retardation, facial abnormali-
them sensitive to vitamin D therapy. Risk factors would include
ties, and heart problems in Great Britain, which was incorrectly
fat malabsorption syndromes, obesity, and medications that influ-
thought to be due to over fortification of milk with vitamin D,
ence vitamin D metabolism. Patients with granulomatous disor-
led to the banning of vitamin D fortification throughout Europe
and most of the rest of the world with the exception of the ders such as sarcoidosis must be monitored carefully to prevent
United States and Canada. Its likely that this was due to the hypercalcemia.
rare genetic disorder, Williams syndrome. Children with this Another barrier is that there are a variety of vitamin D
disorder have elfin facies, mild mental retardation, heart prob- supplements available and that the only pharmaceutical form
lems, and a hypersensitivity to vitamin D that can cause hyper- available is vitamin D2. There has been a lot of controversy and
calcemia. misconception that vitamin D2 was less effective than vitamin
D3 in maintaining blood levels of 25-hydroxyvitamin D. Sev-
eral studies, however, have demonstrated that vitamin D2 is as
SIGNIFICANCE OF THE CLINICAL PROBLEM effective in maintaining 25-hydroxyvitamin D levels in the
Concern that sun exposure increases risk for the most common
preferred range of 40-60 ng/mL as vitamin D3.
cancer (ie, skin cancer) has led to widespread use of sunscreens
and the recommendation to avoid all direct sun exposure. This has
led to a worldwide vitamin D deficiency epidemic. It is now LEARNING OBJECTIVES
estimated that 40 and 60% of children and adults throughout the As a result of participating in this session, learner should be
world are vitamin D deficient and insufficient, respectively. able to:
In 2010 The Institute of Medicine (IOM) made recommen- 1. Learn how to determine a persons vitamin D status
dations using a population model for vitamin D intake for and how to use the serum 25-hydroxyvitamin D assay
children and adults in the United States. They recommended in a clinical setting.
that to maximize bone health a 25-hydroxyvitamin D should be 2. Learn how to treat and prevent vitamin D deficiency in
greater than 20 ng/mL. The Endocrine Society recommended children and adults.
that vitamin D deficiency should be defined as a 25-hydroxyvitamin 3. Learn how to use the assay for 1,25-dihydroxyvitamin
D less than 20 ng/mL; insufficiency, 2129 ng/mL; and suffi- D when evaluating patients with calcium, phosphate,
ciency 30 ng/mL. They recommended the preferred level of and bone metabolism disorders.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

4. Learn how to treat and prevent vitamin D deficiency with vitamin D. However, caution is required in treating vita-
the in patients with malabsorption syndromes. min D deficiency in patients with chronic granulomatous dis-
orders such as sarcoidosis and tuberculosis. They have in their
granuloma-activated macrophages that efficiently convert
25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3. This ac-
tive metabolite enters the circulation and can result in hypercalciuria
25-Hydroxyvitamin D is the major circulating form of vitamin D
and hypercalcemia.
that should be used for the purpose of evaluating a persons
Patients with vitamin D deficiency often have high-normal or
vitamin D status. Blood levels of 1,25-dihydroxyvitamin D are
elevated levels of PTH. Chronic vitamin D deficiency can result in
often normal or elevated in a vitamin D deficient state and thus
significant parathyroid hyperplasia, which can ultimately results in
provide no value when determining a persons vitamin D status.
autonomy causing tertiary hyperparathyroidism.
This assay, however, can be of value in acquired and inherited
Patients with chronic kidney disease, no matter what the
disorders of calcium and phosphate metabolism associated with
degree of renal failure, should be treated for vitamin D defi-
alterations in the production of 1,25-dihydroxyvitamin D.
ciency and maintain a blood level of 25-hydroxyvitamin D
Vitamin D deficiency is common in both children and
of at least 30 ng/mL. This may help reduce the development of
adults. In the United States the U.S. Centers for Disease Con-
secondary hyperparathyroidism. Patients with early stages of
trol and Prevention reported that 32% of children and adults are
Chronic Kidney Disease (CKD) that cannot adequately excrete
at risk for vitamin D deficiency (ie, a 25-hydroxyvitamin D
phosphate results in an increase in serum phosphate levels.
20 ng/mL). Based on the literature regarding blood levels of
This provides a signal to osteocytes to produce fibroblast
25-hydroxyvitamin D that is not associated with the vitamin D
growth factor 23, which travels to the kidney to increase
deficiency metabolic bone disease osteomalacia and the plateau
phosphate excretion by internalizing the sodium-phosphate
of PTH levels as it relates to blood levels of 25-hydroxyvitamin
cotransporter. It unfortunately also inhibits the renal production
D, the Endocrine Society in its guidelines recommended that of 1,25-dihydroxyvitamin D. This sets up a vicious cycle, ie, a
for maximum bone health, a 25-hydroxyvitamin D should be at decrease in 1,25-dihydroxyvitamin D results in a decrease in in-
least 30 ng/mL. The Endocrine Society also recommended that testinal calcium absorption. The resulting transient decrease in
maintenance of a 25-hydroxyvitamin D of at least 30 ng/mL the ionized calcium is recognized by the calcium sensor in the
was associated with improved muscle function, especially in parathyroid glands resulting in an increase in the production
the elderly. and secretion of PTH. The constant stimulation of the parathy-
There are a variety of strategies to treat and prevent vitamin roid glands can lead to parathyroid hyperplasia. Patients with
D deficiency in children and adults. For infants who may be end-stage renal disease are unable to produce an adequate amount
only seen once in the emergency department or by their pedia- of 1,25-dihydroxyvitamin D3 even when the blood phosphate level
trician, a single 250 000-IU dose of vitamin D orally or im has is normal. These patients require treatment with either
been effective in helping to reduce risk for rickets and is 1,25-dihydroxyvitamin D3 or one of its active analogs.
known as Stoss therapy. The Endocrine Society recommends Patients with hypoparathyroidism and pseudohypoparathyroid-
that all infants from the time they are born should receive ism have a decreased capacity to produce 1,25-dihydroxyvitamin
400-1000 IU daily. This is especially important for infants who D. These patients should be treated with vitamin D for vitamin D
were being breast fed given that human breast milk contains deficiency as well as with 1,25-dihydroxyvitamin D3 to reduce
very little vitamin D, usually not more than 25 IU/L. For risk for hypocalcemia.
children over 1 year of age 50 000 IU of vitamin D once a Patients with chronic granulomatous disorders are at risk for
week for 6 weeks or 2000 IU daily is effective. A maintenance developing hypercalciuria and hypercalcemia when blood lev-
dose of 600-1000 IU is recommended to prevent recurrence. els of 25-hydroxyvitamin D are greater than 30 ng/mL. These
For all adults 50 000 IU of vitamin D once a week for 8 weeks patients, however, should not be made vitamin D deficient and
is effective in correcting vitamin D deficiency. To prevent this can lead to the painful bone disease osteomalacia and
recurrence 50 000 IU of vitamin D every 2 weeks for up to 6 severe proximal muscle weakness. These patients are treated
years has been effective. For obese adults with a body mass with lower doses of vitamin D to maintain blood levels of
index greater than 30 kg/m2, 23 times more vitamin D is often 25-hydroxyvitamin D in the range of 20-29 ng/mL. Serum
required to treat and prevent vitamin D deficiency. Patients calcium levels should be carefully monitored to be sure that the
with fat malabsorption syndromes or who are on medications patient does not become hypercalcemic.
such as glucocorticoids, antiseizure medications, and AIDS There are several genetic disorders affecting production or
medications often required significantly more vitamin D to recognition of 1,25-dihydroxyvitamin D. Pseudovitamin D de-
treat and prevent vitamin D deficiency. Patients with primary ficiency rickets is caused by a mutation of the renal 1 alpha
hyperparathyroidism should be treated for vitamin D deficiency hydroxylase. There is a rare genetic disorder of the hepatic
given that it has been demonstrated that they will not signifi- 25-hydroxylase that can cause rickets. A 24-hydroxylase defi-
cantly increased their serum calcium when they are treated ciency has been associated with hypercalcemia during infancy.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Older children and adults who present with a history of kidney vitamin D, an alternative is to use the U.S. Food and Drug
stones, hypercalciuria, and hypercalcemia should be evaluated Administrationsanctioned Sperti lamp. This lamp emits UVB
for a 24-Hydroxylase deficiency. radiation and is effective in raising blood levels of 25-hydroxyvitamin
D and maintaining these levels in patients with that malabsorp-
tion syndromes.
Case 1
Case 3: Mystery Case
A 35-year-old white female with long-standing history of
A 45-year-old male presents with a serum calcium of 13.5 mg/dL
Crohns disease with multiple surgeries resulting in a short
and a PTH of 30 pg/mL. An ultrasound and sestamibi scan
bowel syndrome with only 4 feet of small intestine presented
suggested a possible parathyroid adenoma and it was surgically
with excruciating unrelenting aches and pains in her bones and
removed. Intraoperative PTH level decreased from 30 to 10
muscles. A serum 25-hydroxyvitamin D was undetectable and
pg/mL. Twenty-four hours after surgery serum calcium was 11.0
her PTH level was 560 pg/mL. mg/dL with a PTH of 25 pg/mL. A repeat sestamibi scan sug-
1. What is the most likely cause for her global aches and gested another possible foci and he underwent a surgical explora-
pains? tion and a parathyroid gland was removed. Twenty-four hours
2. What strategies can be used to improve her vitamin D after surgery his PTH was undetectable and he had a calcium of
status? 10.9 mg/dL. A serum 25-hydroxyvitamin D was 57 ng/mL and
1,25-dihydroxyvitamin D was 57 pg/mL. The patient denies tak-
Case 2 ing any calcium or vitamin D supplementation.
A 55-year-old white female who underwent gastric bypass 5. What additional testing would be appropriate to
surgery presents with a serum 25-hydroxyvitamin D of 5 ng/mL and determine the cause of his persistent hypercalcemia?
PTH of 120 pg/mL. Her bone mineral density revealed T-scores,
0.5 and 3.0 in the lumbosacral spine and femoral neck. REFERENCES
3. What strategies would you use to treat her vitamin D 1. Farraye FA, Nimitphong H, Stucchi A, et al. Use of a novel vitamin D
bioavailability test demonstrates that vitamin D absorption is decreased in
patients with quiescent Crohns disease. Inflamm Bowel Dis. 2011;17:2116-
4. Why is there such a discrepancy in the T-scores for the 2121.
lumbosacral spine and femoral neck? 2. Koutkia P, Lu Z, Chen TC, Holick MF. Treatment of vitamin D deficiency due
to Crohns disease with tanning bed ultraviolet B radiation. Gastroenterol.
Conclusions 3. Pramyothin P, Biancuzzo RM, Lu Z, Hess DT, Apovian CM, Holick MF.
There are several strategies for treating and preventing vitamin Vitamin D in adipose tissue and serum 25-hydroxyvitamin D After Roux-en-Y
gastric bypass. Obesity. 2011;19(11):2228-2234.
D deficiency in patients with malabsorption syndromes. A
4. Pramyothin P, Holick MF. Vitamin D supplementation: Guidelines and
vitamin D absorption test has been developed which can help evidence for subclinical deficiency. Curr Opin Gastroenterol. 2012; 28(2):
the clinician in evaluating whether a patient with a malabsorp- 139-150.
tion syndrome is able to absorb any vitamin D. If so pharma- 5. Dabai NS, Pramyothin P Holick MF. The effect of ultraviolet radiation from
a novel portable fluorescent lamp on serum 25-hydroxyvitamin D3 levels in
cologic doses of vitamin D may be appropriate. However for healthy adults with Fitzpatrick skin types II and III. Photodermatol
patients who are unable to absorb any dietary or supplemental Photoimmunol Photomed. 2012;28(6):307-311.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Using CGM For Day-To-Day Insulin-Dosing Decisions

M03 days but sometimes weeks or months later would review its
Presented, April 1 4, 2016 data retrospectively, after the wear period.
The first unblended (real-time) CGM devices did not arrive
until the mid 2000s with the MiniMed Guardian RT-System
Steven Edelman, MD. Taking Control of Your and the Dexcom STS-CGM. Such real-time CGMs are now
Diabetes, University of CaliforniaSan Diego, Del Mar, available for both short-term professional trials and long-
California 92014, E-mail: sedelman@ucsd.edu term personal use (Dexcom).


Historical Overview
Understand the significance of CGM in the management
Diabetes management focuses on achieving target hemoglo-
of type 1 diabetes.
bin A1c (HbA1c) levels to reduce acute and chronic com-
plications. Self monitoring of blood glucose (SMBG) with Explain why the trend arrow is so important in day to
glucose meters remains the mainstay of glycemic monitor- day insulin adjustments made by patients.
ing in most people with type 1 and type 2 diabetes but has Review the pitfalls of using blinded CGM in patients
major drawbacks. By simply reporting one blood glucose with type 1 diabetes.
(BG) reading at a single point in time, SMBG fails to
provide information about direction, both from where the SIGNIFICANCE OF THE CLINICAL PROBLEM
BG is coming from and to where it is going. Even testing AND BARRIERS TO OPTIMAL PRACTICE
with SMBG four to six times each day, which is much Since its introduction, real-time CGM use has been vali-
greater than the national average, can miss persistent hyper- dated by multiple studies to improve glycemic control in
glycemia and potentially dangerous hypoglycemia.
both children and adults, while concurrently reducing the
In contrast, continuous glucose monitors (CGM) sample
incidence of hypoglycemia. As a result, real-time CGM is
interstitial glucose every 5 minutes (288 readings each day),
now endorsed by leading organizations such as the ADA,
providing extensive analytics including glucose variability,
AACE, and The Endocrine Society as a component of stan-
hourly statistics and trends, modal day views, and estimated
dard of care management for diabetes.
A1c values, all of which are extremely accurate and helpful
to the patient primarily and provider secondarily. Recent Despite the increased availability and demonstrated effec-
advances in sensor accuracy have lowered the mean absolute tiveness of real-time CGM, providers continue to use
relative difference of current generation CGMs (Dexcom blinded CGM during short-term wear periods. Unlike the
G5) to less than 10%, matching that of glucose meters. multiple studies supporting real-time CGM, the evidence
When first introduced in 1999, CGMs were exclusively regarding blinded, professional CGM use is less conclusive.
used for short-term, blinded, professional use. The For short-term professional wear periods, a common ar-
Minimed (Medtronic) CGMs was worn for 3 days, but its gument for using blinded CGM is that it better captures a
BG measurements were hidden from the patient. Then, the patients regular day, when their behavior is uninfluenced
device would be returned and a health care provider usually by knowledge of their BG data. When analyzing the data

FIGURE 1. Scenarios in which respondents continuous glucose monitoring device showed a glucose value of 110 mg/dL
and they were planning to eat 50 g of carbohydrates (two arrows up/two arrows down).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

FIGURE 2. Impact of the direction and rate of glucose change on a mealtime insulin dose at euglycemia (110 mg/dL).
Left panel (A) indicates the percentage of respondents who increased their insulin dosages 0 to 400% when 2 UP arrows
were displayed. Right panel (B) indicates the percentage of respondents who decreased their insulin dosages 0 to 100%
when 2 DOWN arrows were displayed.

retrospectively, the provider hopes to unearth hidden trends coefficient of variation from day-to-day pharmacodynamics
of glycemic variability that will inform interventions that within the same patient to be between 27 and 59% for basal
optimize diabetes management. insulins and 20 30% for short-acting insulins.
Although these intentions are noble, there is unfortunately In addition, a short 37-day trial presents an extremely
no such thing as a regular day of BG values in type 1 limited sample size for capturing a regular day. A given
diabetes. Intrapatient variability of subcutaneously injected 72-hour trial period can easily span both workweek and
insulin can vary greatly in their rate of absorption and time weekend days, active and inactive days, and days with
course of action. Glucose clamp studies have measured the different food portion sizes, compositions, and timings.

FIGURE 3. Glucose levels captured by the retrospective continuous subcutaneous glucose monitoring system (CGMS)
for the evening before and the morning of the patients death. The calibrations measured and entered by the patient are
represented by the 4 circles. The timing of the patients meals, exercise, and correction insulin boluses are represented
by the bars along the bottom of the graph. The precipitous decrease in glucose level after the correction doses can be
observed to start just after midnight, and possible counterregulatory efforts are noted once the glucose level declined to
below 30 mg/dL shortly after 2 AM.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.


Real-time Monitoring Is an Intervention 1). The respondents were asked how they would adjust their
In contrast, the full potential of CGM lies in its ability to insulin dose in each scenario.
empower and educate patients in real time, a goal that can Shown in Figure 2, more than two thirds of respondents
effectively improve long-term glucose control. would increase their dose by over 40% in response to having
A recent survey of approximately 300 successful CGM users two up arrows, and nearly 90% would decrease their dose
(mean A1c of 6.9% with minimal hypoglycemia) with type 1 and with two down arrows (15% of whom would not take any
type 2 diabetes detailed how the real-time display of glucose insulin at all). Such varied reactions to the same BG reveal
information such as BG and trend arrows provided actionable how valuable real-time CGM data can be.
insights. A majority of respondents reported initiating therapeutic In fact, the survey of successful regular CGM users re-
interventions overnight after being awoken by CGM alarms for vealed that more than 80% of respondents found that real-
both hypoglycemia and hyperglycemia. A majority of users in this time analysis of their CGM data was more useful than
survey reported more frequent insulin boluses or injections per retrospective analysis. The limitations of retrospective anal-
day after starting CGM. Respondents also reported that continu- ysis are further highlighted by the fact that 19% of those
ous glucose data led to adjustments in the timing and quantity of surveyed never or rarely downloaded their CGM data during
insulin doses before meals and at times when they were correcting clinician office visits. If the overwhelming benefit to CGM
for elevated glucose values. wearers lies in real-time analysis, why should we restrict
this feature?
Example of Strategies for Management of Insulin
Adjustments Protection Against Hypoglycemia and the Dead-in-Bed
The survey quantified these adjustments by presenting the Syndrome
above scenarios, which paired the same euglycemic BG of 110 CGM has proven to be an invaluable tool to protect against
mg/dL with a different glucose curve and trend arrows (Figure hypoglycemia, both mild and especially severe hypoglyce-


The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

they deal with their disease day in and day out. As such,
except for research studies, all usage of CGM should be
For type 1 diabetes, unblended CGM is the standard of care
plain and simple. If circumstances require the use of short-term
CGM, then unblended CGM should be selected. Real-time
availability of hypoglycemic alarms and trend arrows add in-
formation that is exponentially more insightful than a static
glucose meter reading.
Thanks to David Ahn, MD for his help in preparing this

CASE 4. Case 1
Example of how a static BG measurement can lead to over-
and underdosing of insulin.
mia. This factor is of extreme importance in patients with
hypoglycemia unawareness. Case 2A: Jeremy
A case report documents a 23-year-old with type 1 diabe-
tes who suffered a lethal hypoglycemic event in his sleep Case 2B
while undergoing an observation period with blinded, short- The correct answer is D. A common but wrong answer is C.
term professional CGM to investigate recurrent severe hy- Because the BG value is increasing dramatically (3 mg/dL/min)
poglycemia (Figure 3; Ref. 7). On the first evening of his giving a correction based solely on the correction factor will
trial, he exercised at the gym after dinner and then went to underdose the patient. If the trend arrow had been horizontal
bed. At approximately 0900 hours the next morning, he was then 3.3 U would have been the correct answer.
discovered by his family to be dead in bed. He unfortunately
did not respond to glucagon or resuscitative efforts by para- Case 3: Robyn
medics. Robyn looks at her Dexcom (CGM) at 0300 hours and her
Postmortem analysis of his insulin pump and blinded CGM BS was now greater than 350 mg/dL and she gave herself
device revealed glucose readings showing severe hypoglyce- another Rage Bolus 5.0 U. At 0800 hours she had a
mia (50 mg/dL), highlighted by the arrows on the graph, hypoglycemic reaction and needed to ingest glucose tabs.
for at least 3 hours prior to his death. Had he been wearing Robyn did stack her insulin dose, which is not uncommon in
an unblended CGM, a hypoglycemic alarm would have CGM users as they do not see their BG values changing fast
sounded at a higher glucose threshold, likely triggering a enough after a bolus. SQ insulin just has too slow an onset and
life-saving intervention by the patient himself or a nearby hangs around for an extended period of time leading to exces-
family member. sive delayed hypoglycemia.
Although this case of dead-in-bed syndrome is admittedly Barbara is a 69-year-old female who was diagnosed with
a worst-case scenario, severe hypoglycemic or hyperglycemic type 1 diabetes 7 years ago. She is on an Omnipod with
events that occur during a blinded CGM wear period lead to insulin aspart (CHO, 12:1 and CF, 1:40). She is also on
financially and emotionally costly events that are easily pre- pramlintide premeals.
vented by unblinding the CGM. In the United States and Barbara ate a late dinner at 2000 hours.
around the world there are frequent cases of patients passing Predinner BS was 205 mg/dL.
away from severe hypoglycemia. In fact, recent studies suggest She planned on eating 70g CHO.
that 4 10% of deaths in people with type 1 diabetes are due to Premeal does of fast acting insulin: 6 2 8 U.
Case 4: Barbara (continued)
I believe that many of the underlying motivations for using 1. Tamborlane WV, Beck RW, Bode BW, et al. Continuous glucose monitor-
blinded professional CGM are rooted in the paternalistic and ing and intensive treatment of type 1 diabetes. N Engl J Med.
anachronistic perspective that the practitioner always knows
2. Battelino T, Conget I, Olsen B, et al. The use and efficacy of continuous
best. I also believe that the most valuable and sustaining glucose monitoring in type 1 diabetes treated with insulin pump therapy:
interventions empower and further educate the patient as A randomised controlled trial. Diabetologia. 2012;55:3155-3162.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

3. Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor- Care in Diabetes2015. Diabetes Care. 2015;38(Suppl 1):S33-S40.
augmented insulin-pump therapy in type 1 diabetes. N Engl J Med. 6. Pettus J, Price DA, Edelman SV. How patients with type 1 diabetes
2010;363:311-320. translate continuous glucose monitoring data into diabetes management
4. Klonoff DC, Buckingham B, Christiansen JS, et al. Continuous glucose decisions. Endocr Pract. 2015;21:613-620.
monitoring: an Endocrine Society Clinical Practice Guideline. J Clin 7. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in
Endocrinol Metab. 2011;96:2968-2979. the dead-in-bed syndrome, as captured by a retrospective continuous
5. American Diabetes Association. Glycemic targets. Sec. 6 in Standards of Medical glucose monitoring system. Endocr Pract. 2010;16:244-248.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

When and How to Use U500 (or Other Concentrated) Insulin

M10 insulin per day (4). Severe insulin resistance is somewhat

Presented, April 1 4, 2016 arbitrarily defined in the medical literature as an insulin re-
quirement of more than 200 U per day or more than 2 U per
kilogram of body weight daily (1). With increasing obesity,
Wendy Lane, MD. Mountain Diabetes and Endocrine patients with type 2 diabetes may require several hundred units
Center, Asheville, North Carolina 28803, E-mail: of insulin per day. Most patients with type 2 diabetes are not
mountaindiabetes@msn.com meeting glycemic targets, and in patients with increasing insu-
lin resistance driving the need for large doses of insulin, gly-
INTRODUCTION cemic control becomes even more suboptimal (5).
Historical Overview
U500R insulin, a product of Eli Lilly and Company, is 5-fold BARRIERS TO OPTIMAL PRACTICE
concentrated regular insulin containing 500 U of insulin per High insulin doses are clinically challenging to deliver. Insulin
mL vs the standard U100 or 100 U/mL insulin. It was first syringes only hold up to 1 mL of insulin, which contains 100 U
introduced into clinical practice in 1952 to address the high of a U100 insulin preparation. In a patient requiring more than
insulin requirements of patients with diabetes who had devel- 100 U of basal insulin daily, this would require two or more
oped severe insulin resistance caused by high titers of insulin insulin injections to deliver the basal insulin dose alone. Insulin
antibodies to nonhuman insulin preparations (1). U500R insu- pens can only deliver 80 U of basal insulin analogs glargine (in
lin was originally a beef insulin, which was replaced by pork either its U100 or U300 formulation) or detemir with a single
U500R insulin in 1980 and subsequently by U500R human injection. Only insulin degludec, recently marketed as Tresiba
insulin in 1997. U500 insulin usage declined with the develop- by Novo Nordisk, is available in a U200 formulation in a pen
ment of recombinant DNA technology and the manufacturing capable of delivering 160 U (0.8 mL) with a single injection.
of human regular insulin in 1982 as insulin antibody-mediated Large insulin depots can be poorly absorbed and painful to
insulin resistance was no longer a common problem for inject, leading to glycemic variability and suboptimal glycemic
insulin-treated patients. The increase of the obesity epidemic control both from incomplete absorption and from patient non-
over the past 25 years gave rise to a twin epidemic of insulin compliance owing to the discomfort of the large-volume injec-
resistance, reviving the need for a concentrated insulin to meet tion (1, 6). Thus, there is a need for the development of
the insulin needs of an increasingly obese diabetic population. concentrated insulin to reduce the number of insulin injections
Novo Nordisk also produced a concentrated human insulin required daily as well as the insulin volume itself in patients
formulation, Actrapid U-500, which was withdrawn from the with large insulin requirements. In 2015, the first concentrated
European market in 2008. From 2008 through 2015, U500R rapid-acting insulin analog, U200 lispro, also became available
insulin was the only commercially available concentrated insu- to address the mealtime insulin needs of many patients with
lin worldwide to address the needs of patients with high insulin average-to-high insulin requirements on basal/bolus insulin
requirements on the basis of severe insulin resistance (1). In therapy.
2015, several other concentrated insulin preparations became Continuous subcutaneous insulin infusion (CSII), or insu-
available, including U300 glargine (Toujeo, Sanofi Aventis), lin pump therapy, has been shown to improve glycemic
U200 lispro (Humalog, Eli Lilly), and most recently U200 control in patients with type 1 and type 2 diabetes (7, 8), and
degludec (Tresiba, Novo Nordisk). to reduce complications of diabetes and diabetes-related
morbidity and mortality in patients with type 1 diabetes (7,
SIGNIFICANCE OF THE CLINICAL PROBLEM 9). However, delivering large insulin doses by CSII is chal-
The global obesity epidemic has given rise to an epidemic of lenging because of the limited size of the insulin reservoir of
insulin resistance and type 2 diabetes, and increasing body most pumps (1.8 3 mL, with a capacity of 180 to 300 U of
mass index (BMI) is accompanied by a parallel increase in a U100 rapid-acting insulin analog). Thus, patients requiring
insulin doses in insulin-treated patients. In one recent study of more than 200 300 U of insulin daily would need to change
patients with type 2 diabetes, approximately 35% of patients the pump reservoir daily. Furthermore, high basal insulin
required maintenance basal insulin doses of 60 U of insulin or delivery rates by pump (3.5 4 U/h) may cause induration
more (2). In another treat-to-target basal insulin trial involving and scarring of the sc tissue, and the large-volume insulin
insulin-nave patients, 21% of subjects required more than 80 boluses for meals can also have incomplete or inconsistent
U of basal insulin by the end of the trial (3). Market research absorption, leading to glycemic instability (1). Furthermore,
for an insulin delivery system has revealed that 17% of insulin- high insulin delivery rates require frequent battery and res-
treated patients with type 2 diabetes use more than 100 U of ervoir changes of the insulin pump, driving up the cost of

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

this already-expensive therapy. For these reasons, there has (1), protease inhibitors (13), atypical antipsychotics
been increasing use of concentrated U500 insulin via CSII in (14)].
high-dose insulin users during the past 10 years (10). Sev- Gestational diabetes or type 2 diabetes and pregnancy.
eral small case series (11) and a small, single, uncontrolled Congenital or acquired lipodystropy with severe insulin
prospective trial (12) have shown that U500 delivered by resistance.
CSII in patients with high insulin requirements (an off-label Acquired endocrinopathy (Cushings disease,
use of U500 insulin) results in improved glycemic control acromegaly, glucagonoma, pheochromocytoma).
(11, 12), reduced glycemic variability by continuous glucose
monitoring (12), and improved patient satisfaction (12). Pharmacokinetic and Pharmacodynamic (PK/PD)
These studies have led to an ongoing large, randomized, Properties of U500 Insulin
prospective multicenter study to evaluate the safety of U500 Compared with U100 regular insulin, U500 insulin has a time-
insulin in CSII compared with multiple daily injections action profile with an extended duration or tail. Insulin clamp
(MDI) (Eli Lilly; NCT02561078; ClinicalTrials.gov). Tan- studies have shown the time to onset is within 30 minutes,
similar to U100 regular insulin, with peak insulin levels at a
dem, Inc has created an insulin pump with a 480 U insulin
mean of 3 hours, peak glucose infusion rate at 3.5 4.5 hours,
reservoir, the t:flex, to address the needs of insulin pump
and duration of action 6.510 hours after sc injection (15).
patients with higher insulin requirements. The larger reser-
Thus, U500 insulin has a similar time to onset and slightly
voir would reduce the frequency of insulin cartridge changes
slower time-to-peak than U100 regular insulin and a duration
in this population, but the problems associated with high
of action similar to NPH insulin. This gives U500 insulin both
basal insulin delivery rates and large volume boluses of the
basal and bolus insulin characteristics, making it suitable for
current rapid-acting U100 insulin analogs would still be
use as an insulin monotherapy.
problematic for the reasons stated above, even using a
larger-reservoir insulin pump.
U500 Studies
Clinical studies of U500 insulin have consisted mostly of
LEARNING OBJECTIVES retrospective case series (11) and one small uncontrolled pro-
As a result of participating in this session, learners should be spective trial (12). A recent meta-analysis and review of the
able to: U500 medical literature reviewed nine MDI studies and six
Identify appropriate candidates for U500/concentrated CSII studies of U500 insulin. Nine MDI studies involving 310
insulin therapy. patients showed an HbA1c reduction of 1.59% upon conver-
Describe the PK/PD profile of U500 insulin. sion from U100 to U500 insulin (95% confidence interval [CI],
Convert U100 insulin regimens to U500 insulin 1.26 1.92), which was associated with a mean weight gain of
regimens, including both MDI and pump therapy. 4.38 kg (95% CI, 2.35 6.41). Six CSII studies involving 55
Recognize the new concentrated insulin analogs and patients showed a 1.64% overall reduction in HbA1c (95% CI,
detail medical situations warranting their potential use. 1.14 2.14) and was associated with a 2.99 kg weight gain
Appreciate the benefits of combining insulin-sparing (95% CI, 1.837.81; not significant) (11).
therapies with insulin and detail medical situations
warranting their potential use. Dosing of U500 Insulin
U500 insulin is dosed according to total daily insulin require-
ment. If the baseline HbA1c is less than 8.0%, it is recom-
MANAGEMENT OF THE PATIENT WITH mended to reduce the total daily insulin dose by 10 20%; if the
TYPE 2 DIABETES AND HIGH INSULIN baseline HbA1c is greater than 10%, the dose should be in-
REQUIREMENTS creased 10 20%. For baseline HbA1c between 8 and 10%, the
Appropriate Candidates for U500/Concentrated Insulin baseline total daily insulin dose should be converted to U500
Patients with type 2 diabetes who require more than 2 U/kg or insulin on a unit-per-unit basis (1). It is common to see im-
more than 200 U of insulin daily on the basis of obesity proved absorption with conversion to U500 insulin, which may
without any secondary factor increasing insulin resistance are result in a lowered insulin dose after conversion.
candidates for U500 insulin. However, patients with moderate U500 insulin may be dosed using either a U100 insulin
insulin-dose requirements (100 U/d of insulin) under circum- syringe or a tuberculin syringe. There is no U500 insulin
stances of illness or stress may have worsening insulin resis- syringe; thus, unit markings on an insulin syringe must be
tance and require higher-than-usual insulin doses, which may multiplied by 5 to show the actual number of insulin units
become high enough to require the use of concentrated insulin being delivered. The prescription should be written volu-
therapy. Such conditions may include (1): metrically (in mL) as well as in unit markings on an insulin
Medications that worsen insulin resistance [high-dose syringe and stating the actual number of units to be delivered.
glucocorticoids, post-transplant antirejection medications Thus, if the insulin dose is 50 U prior to each meal, the

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

prescription should be written thus: U500 insulin: Inject 0.1 ity factor should be set at 100, the usual blood glucose target is
mL or 10 U markings on an insulin syringe, 50 U, prior to 100 mg/dL, and the insulin-on-board time should be set at 6
each meal. Patients should be carefully instructed where to hours for U500 insulin.
draw up the insulin on the syringe to avoid overdosing errors. Patients should monitor blood glucose levels at least 4 times
Patients with insulin requirements between 150 and 300 U per day upon conversion to U500 insulin, and check occasional
per day may use either of the following regimens: 0200 0300 hours blood glucose (BG) readings when night
Twice-daily regimen: 60% of the total daily dose before infusion rate changes are made.
breakfast and 40% of the total daily dose before the Patients should be educated on signs and symptoms of
evening meal. hypoglycemia and instructed in the treatment of hypoglycemia.
Thrice-daily regimen: 40% of the total daily dose before Patients beginning U500 insulin should be given prescriptions
breakfast, 30 40% before the noon meal, and 20 30% for glucagon for emergency use.
before the evening meal.
A recent 24-week prospective trial comparing the efficacy and Other Currently Available Concentrated Insulin
safety of twice-daily U500 to twice-daily U500 insulin showed
U300 Glargine
no difference in glycemic control between the two regimens,
U300 glargine (Toujeo, Sanofi Aventis) is identical to 100
but the thrice-daily regimen was associated with a lower inci-
glargine (Lantus) in formulation but the injection volume is
dence of hypoglycemia (16).
reduced by 2/3 (ie, 1 mL contains 300 U glargine instead of
Patients with insulin requirements between 300 and 600 U
100 U). This three-times concentrated glargine formulation has
should use the thrice-daily regimen as described above. If
a flatter pharmacokinetic profile than U100 insulin glargine
fasting blood glucose levels are above target, a fourth injection
with a longer duration of action (24 h) with a lower incidence
consisting of 10% of the total daily insulin dose may be
of nocturnal hypoglycemia than U100 glargine (17). U300
administered at bedtime (with 30% of the total daily dose given
glargine is less bioavailable than U100 glargine in glucose
before each meal).
clamp studies and in clinical trials, with 27% lower area under
Patients requiring more than 600 U of insulin per day should
the curve glucose infusion rate over 24 hours in glucose clamp
use four daily injections as described above.
studies (Toujeo PI) (18) and requires an 1117% higher dose
compared with U100 glargine in clinical trials (17). Also, it is
Dosing U500 Insulin in CSII currently only available in an injection pen, which can deliver
Patients already using U500 insulin in an MDI regimen may
a maximum of 80 U of insulin (no dose conversion necessary;
convert to insulin pump settings by using the following algo-
the pen reads the actual number of units of insulin glargine).
rithm: take 50% of the total daily insulin dose, divide by 24,
Each pen contains 1.5 mL of U300 glargine, or a total of 450
and administer as a single basal hourly infusion rate via insulin
U. The fact that U300 glargine requires an increased dose
pump with the other 50% of the total daily insulin dose distributed
compared with the U100 preparation and that patients requiring
as premeal insulin boluses. At first, it is prudent to reduce the
more than 80 U of basal insulin will still need two basal insulin
nocturnal basal rate between midnight and 0600 hours by 10 15%
injections make this option of limited use in the high-dose
to avoid nocturnal hypoglycemia, as insulin absorption may fur-
insulin-requiring patient.
ther improve when converting U500 from MDI to CSII.
For patients using U100 insulin regimens who are going to
be using U500 insulin by CSII, the total daily insulin dose must U200 Lispro
first be divided by 5, then divided again by 24 to yield the U200 lispro (U200 Humalog, Eli Lilly): This is a twice-
initial hourly U500 infusion rate. Currently, no insulin pumps concentrated, rapid-acting insulin analog for prandial use that
are able to convert pump settings for U500 insulin (which is contains 200 U of lispro insulin per mL vs 100 U. It is of equal
not U.S. Food and Drug Administrationapproved for use with bioavailability to U100 lispro (19), reduces the volume of
an insulin pump). Therefore, it must be recognized that in mealtime insulin by half, and is available only in a pen. No
patients using U500 insulin in CSII, the pump will be deliver- dose conversion from U100 lispro is necessary. The pen con-
ing five times the amount of insulin per hour shown as the tains a total of 600 U of insulin lispro in 3 mL. This may be a
hourly basal rate, and 5 times the number of units shown by the good option for patients on MDI regimens who require high
pump for meal boluses. doses of basal and bolus insulin. This insulin is not available in
Patients who use carbohydrate counting should multiply a vial, and has not been studied in CSII.
their carbohydrate factor by 5. For example, if a patient uses 1
U of insulin per 3 g of carbohydrate, this will become an U200 Degludec
insulin-to-carbohydrate ratio of 1:15 in the pump. Patients U200 degludec (Tresiba, Novo Nordisk): Degludec is an
using preset meal boluses should divide the bolus amount by 5 ultra-long-acting basal insulin analog that forms soluble
for the corresponding U500 meal boluses. The initial sensitiv- multihexamers upon injection from which insulin hexamers

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

are slowly and steadily released into the circulation. There is nightly glargine and lispro insulin, but she required more than
a secondary albumin-binding effect that further protracts the 100 U of basal insulin per day, was taking six insulin injections
action of the insulin, giving it a duration of action of up to per day, and still experienced fasting hyperglycemia with fast-
42 hours (20). Degludec is available in injection pens in ing BGs from 150 200 mg/dL. Therefore, her PCP switched
both U100 and U200 formulations. Degludec has a her to NPH and regular insulin with a total of 90 U of NPH and
pharmacokinetic profile that is flatter and longer in duration 70 U of regular insulin in four injections per day (50 of N with
than U100 glargine; it has not been studied in a head-to- 20 of R before breakfast, 20 of R with lunch and supper, and
head trial against U300 glargine. U200 degludec has been 40 of N with 10 of R at bedtime.). She monitors BGs reliably
shown to be equivalent in bioavailability and PK profile to four times per day and is compliant with her insulin regimen.
the U100 formulation in glucose clamp studies (21), unlike Although she has fairly good control on this regimen (HbA1c
U300 glargine. There is an approximately 10% lower basal 7.1%) she is referred for a more convenient regimen and for
insulin dose requirement for insulin degludec vs 100 insulin consideration of insulin pump therapy.
glargine in patients with type 1 diabetes (22).

Question 1
Adjunct (Insulin-Sparing) Agents in Patients With
What are the shortcomings of insulin glargine in a patient
High-Dose Insulin Requirements
Adjunct therapies to insulin can be useful in patients with high requiring insulin doses like Marys?
insulin requirements to lower the insulin dose, reduce insulin- High doses of insulin glargine can be poorly absorbed and
associated weight gain (excepting the thiazolidinediones), and require multiple injections per dose. This can occur with doses
in some cases, reduce the glycemic variability associated with greater than 60 U per dose.
insulin therapy. Oral agents that reduce weight when added to
high-dose insulin therapy include metformin and the SGLT-2 Question 2
inhibitors. Although the thiazolidinediones have an insulin- Is Mary a feasible insulin pump candidate? What barriers does
sparing effect, their use in combination with high-dose insulin she have to initiation of CSII?
therapy is associated with edema, weight gain, and heart failure Mary is a good pump candidate. She is compliant with a
(23) and therefore is not recommended. The GLP-1 receptor complex insulin regimen, monitoring BGs regularly and moti-
agonist liraglutide has been successfully combined with U500 vated to improve and maintain good glycemic control. How-
insulin and has resulted in improved glycemic control, weight ever, her large insulin requirement will make insulin pump
loss, and lower insulin doses (24) as well as reduced glycemic therapy with a U100 insulin analog impractical because she
variability by continuous glucose monitoring (25). will require a basal insulin rate of 3 4 U per hour, boluses that
may sometimes be greater than 30 U and exceed the bolus
MAIN CONCLUSIONS capability of the pump, and she will require a cartridge change
Patients with type 2 diabetes and large insulin requirements every 11.5 days using a U100 insulin analog.
present a therapeutic challenge. These patients may improve
glycemic control, weight, and glycemic variability by use of
concentrated insulin with adjunct insulin-sparing therapies. Un-
Insulin (N and R, total 170 180 U, approximately 1.8 U/kg),
til 2015, the only concentrated insulin available in the United
furosemide, benazepril, metformin, amitriptyline, atorvastatin,
States was U500 regular human insulin, and the author and
others have accumulated a body of clinical experience showing
best clinical practices in using U500 insulin in the insulin-
resistant patient with type 2 diabetes with large insulin require- Physical Examination
ments. Newer concentrated insulins have recently become Height, 65; weight, 221 lbs; BMI, 36.8 kg/m2; normal fundi;
commercially available, and it is now our task to discover how normal thyroid; lungs clear; cardiac examination showed regu-
to optimally use these in our patients requiring delivery of large lar rhythm without murmur; abdomen obese and nontender;
insulin doses. dusky rubor of both legs and feet without edema or lesions;
pulses in feet diminished; knee and ankle jerk reflexes are
absent over the feet and monofilament and bone vibratory
Case 1: Mary sensation are absent to the ankle.
Mary is a 59-year-old woman with a 17-year history of type 2
diabetes with microalbuminuria and advanced peripheral neu- Plan
ropathy, hypertension, dyslipidemia, and recurrent urinary tract Begin CSII with U500 insulin. Initial pump settings:
infections. She had failed oral agents 1 year prior and had been Basal rate 0.6 pump units per hour (equivalent to
begun on an intensive insulin regimen that initially involved 3.0 U/h) 24 hours.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Meal doses: set meal doses of 5 pump units (25 tor less attractive as an adjunct therapy. She is a good candidate
actual units) U500 for breakfast and lunch, 7 pump for addition of a GLP-1 RA to U500 insulin by CSII.
units (35 actual units) for supper. Plan: begin liraglutide at 0.6 mg sq qd, increasing to 1.2 mg
Target BG, 100 mg/dL; insulin sensitivity factor, 100. sq in 1 week.
Continue metformin.

Question 6
Question 3 How should Marys U500 pump settings be reduced upon
Marys basal insulin setting by pump is equivalent to 72 U per
addition of liraglutide to her regimen?
24 hours, in contrast with the 90 U of basal insulin she took in
Mary has good glycemic control on her present U500 insulin
her MDI regimen. Why was this reduced?
doses by CSII. Liraglutide is a long-acting GLP-1 RA that
Mary has fairly good glycemic control already prior to
reduces both basal and bolus insulin requirements. Mary
initiation U500 by CSII. Thus, a 20% insulin reduction at the
should have her U500 basal and meal boluses reduced by
initiation of U500 pump therapy is a prudent initial reduction,
1525% upon initiation of liraglutide. Her present U500 set-
as she is likely to improve her insulin absorption, moving from
tings are MN-6 am: 0.6 pump units (3.0 U/h) and 6 am-MN,
glargine to U500 by CSII and require 10 20% less insulin.
0.7 pump units (3.5 U/h). She is using preset meal boluses of
This also will reduce the chance that she will experience
35 pump units (1525 U) for meals. Her basal pump settings
hypoglycemia upon conversion to U500 by CSII.
should be reduced to MN-6 am: 0.5 pump units (2.5 U/h); 6
am-MN, 0.6 pump units (3.0 U/h). Her meal boluses are re-
Question 4 duced to 2 4 pump units. Her correction dose remains the same
What other instructions should Mary receive upon initiation of (target BG, 100 mg/dL; insulin sensitivity factor, 100).
U500 via insulin pump?
Mary should be instructed in recognition and treatment of
Follow-up Visits
hypoglycemia and have glucagon prescribed. She should be
Follow-up visit 4 weeks later: HbA1c, 6.0%; weight, 223 lbs.
provided with contact information for the insulin pump nurse
Follow-up visit 4 weeks later: HbA1c, 5.4%. Weight, 221
or CDE and instructed to contact her with BG readings in
lbs. Having some mild-to-moderate nocturnal hypoglycemia
24 48 hours, as insulin requirements may decrease dramati-
(lowest BG, 52 mg/dL; several BGs in 60s). Basal rates and
cally and quickly upon conversion from U100 insulin to U500
bolus doses reduced.
Follow-up visit 3 months later: HbA1c, 5.8%; weight,
215 lbs.
Follow-up Visits Next 5 years of followup: Mary remains on CSII with U500
Follow-up visit 3 months later: HbA1c, 6.0%. No hypoglyce- insulin by CSII with liraglutide, with stabilized basal infusion
mia (lowest BGs in 60s and occur with exercise only). Weight, rates of 0.35 0.45 pump units per hour and preset meal
226 lbs. Mary states, I love the pump! boluses on average of 3 pump units, ie, 15 U per meal. Her
Follow-up visit 6 months later: HbA1c, 5.8%. No significant HbA1cs have ranged from 5.8 6.9%. Her weight has ranged
hypoglycemia. Weight, 221 lbs. from 215220 lbs. She is pleased with the comfort and conve-
Follow-up visits over next 5 years: HbA1c, 5.0 6.7%; BGs nience of her insulin regimen.
stable and well controlled without hypoglycemia. Weight in-
creases gradually to 230 lbs. She requires a slight increase of Case 2: Rodney
basal rate (now has two basal rates of 0.6 pump units (3.0 U), Rodney is a 42-year-old man with a 15-year history of type 2
from MN-6 am and 0.7 pump units (3.5 U) per hour from 6 diabetes. He failed oral combination therapy with metformin
am-MN to maintain euglycemia. Mary is concerned about her and glyburide, so basal insulin (glargine) was added and
gradual increase in her insulin dose, weight, and HbA1c (now titrated to 100 U per day without therapeutic benefit; all his
at its highest since beginning U500 by CSII at 6.7%). BGs on oral agents plus glargine remained greater than 200
mg/dL. Six weeks ago, Rodneys PCP intensified his insulin
Question 5 regimen to a regimen of glulisine, 20 U prior to meals and
What adjunct therapies are options for Mary to limit insulin- U300 glargine, 100 U at bedtime (a total of five daily injections),
induced weight gain, lower her insulin dose, and lower her in combination with maximal metformin and glyburide. Rodney
HbA1c? monitors BGs three times per day; all readings range from
Adjunct therapies to high-dose insulin that reduce insulin 250 350 mg/dL. Rodney has never experienced hypoglycemia.
dose and weight include metformin, GLP-1 receptor agonists, Rodneys medications include insulin (1.3 U/kg): U300
and SGLT-2 inhibitors. Mary is already on her maximal- glargine, 100 U/d; glulisine, 20 U before meals three times
tolerated dose of metformin, and has a history of recurrent daily; metformin, glyburide, losartan, omeprazole, atorvastatin,
urinary tract infections, making addition of an SGLT-2 inhibi- sertraline, vitamin D, and aspirin.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.

Examination and supper. Instruct Rodney to consume three meals equal in

Height, 70; weight, 280 lbs; BMI, 40.6 kg/m2; blood carbohydrate content approximately 5 6 hours apart (ie, 0700,
pressure (BP), 140/100 mm Hg. Examination is 1200, 1800 h).
unremarkable except for abdominal obesity and absence
of ankle jerk reflexes. HbA1c is 8.3%. Renal function is
normal. Question 10
Which adjunct glucose-lowering therapies should Rodney be
treated with?
Question 7
Rodney should continue metformin. In addition, Rodney
Discuss Rodneys insulin regimen. Assuming he is taking his
should try a long-acting GLP-1 RA. He will begin dulaglutide,
insulin as directed and not eating between meals, what prob-
0.75 mg injected once per week in combination with his new
lems could be associated with his present insulin regimen?
U500 insulin regimen.
What, if any, adjunct therapies to insulin might be of benefit to
Rodney requires a high dose of basal insulin. Insulin Question 11
glargine is poorly absorbed at high doses, and U300 glargine How should Rodney be followed?
has lower bioavailability than U100 glargine, making it even Rodney will continue to monitor his BGs three or more
less efficient in delivering a high basal insulin dose. Rodney times daily and phone, fax, or email them to clinic for review
also is on relatively low mealtime insulin doses compared with and insulin adjustment weekly. He should be educated on
his basal insulin dose, and is likely to require higher mealtime signs, symptoms, and treatment of hypoglycemia, and in-
insulin doses than he is currently taking. structed to call the clinic if he experiences any hypoglycemia.
Rodney is not likely to be obtaining benefit from glyburide
while taking high-dose insulin therapy, and this medication, Followup
which also has an adverse cardiovascular safety profile, should Rodney begins his U500 insulin regimen in combination with
be discontinued. Rodney is likely to be obtaining benefit from dulaglutide and continues metformin. He faxes his BGs weekly
the insulin-sparing effects of metformin as well as nonglycemic for review. On his initial U500 insulin doses, glucose readings
anti-inflammatory benefits of this agent, and should continue improve and range from 103300 mg/dL. Rodney tolerates
metformin. dulaglutide (0.75 mg). During the next several weeks, U500
Liraglutide would have been a good adjunct therapy for
insulin doses are increased to 125 U three times daily before
Rodney in that it might have lowered his insulin dose, contrib-
meals (25 U markings on insulin syringe) and dulaglutide is
uted to glycemic control, and helped mitigate insulin-
increased to 1.5 mg per week.
associated weight gain, but he was unable to tolerate it. He
might be able to tolerate another GLP-1 RA, however, and
combining a once-weekly GLP-1 RA with an intensive insulin Discussion of Rodneys Insulin Doses
regimen and metformin would be the optimal treatment regi- Rodney is now on a total of 375 U of insulin (as U500 insulin)
men for Rodney. Rodney is also a candidate for addition of an daily. He is on three insulin injections daily, and a GLP-1 RA
SGLT-2 inhibitor, especially in light of his elevated BP. Rod- weekly. He is now absorbing his insulin doses and insulin
neys BP management should also be intensified. titration is now resulting in glycemic improvement. When he
was on glargine, despite insulin up-titration, Rodney did not
show further glycemic improvement owing to the poor absorp-
Question 8
tion of high doses of glargine.
Is Rodney a candidate for U500 insulin?
Rodney currently uses 160 U of insulin per day, but is
presently underinsulinized. He also is showing poor Three-Month Followup
absorption/action of his basal insulin. He is likely to require Rodneys BGs are now close to 100% at target (range: 94 180
much more insulin than he is presently taking, and thus is mg/dL) on 125 U of U500 insulin (25 U markings on insulin
likely to require greater than 200 U of insulin per day when syringe) before meals three times daily, metformin and
optimally insulinized. He is thus an appropriate candidate dulaglutide, 1.5 mg per week. Rodney has not had any episodes
for U500 insulin. of hypoglycemia. He is pleased with his glycemic control and
reports feeling better with more energy. His weight is up 10 lbs
to 290 lbs; HbA1c, 5.9%.
Question 9
How would we convert Rodneys insulin regimen to a U500
insulin regimen? Question 12
Begin U500 insulin at 50 U (10 U markings) on an insulin What additional treatment options (if any) are appropriate for
syringe before breakfast and 45 U (9 U markings) before lunch Rodney at this time?

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 January 2017. at 12:19 For personal use only. No other uses without permission. . All rights reserved.