Thyroid & Parathyroid Gland

Regulasi Aksis Tiroid

PENDRED SYNDROM E

PLASMA
Dietary Iodide Iodide Traping

FOLLICULAR CELL
Iodide Peroxidase Iodine +Tyrosil Residues Iodine + Tyrosil Residues DeiodoTyrosinase MIT + DIT Thyroglobulin MIT + DIT

COLLOID

T4 + T3
Thyroglobulin

T4 + T3

T4 + T3

T4 Protease MIT

T3 DIT

Hypohyroidism Affects Many Body Systems and Overall Health

Thyroid
Thyroid Disease Can Have Widespread Effects

Brain
Depression Decreased Concentration General Lack of Interest

Liver
Increased LDL Cholesterol Elevated Triglycerides

Heart
Decreased Heart Rate Increased/Decreased Blood Pressure Decreased Cardiac Output

Intestines
Constipation Decreased GI Activity

Reproductive System
Decreased Fertility Menstrual Abnormalities May Harm Development of Infant

Kidneys
Decreased Function Fluid Retention and Edema

Prevalence of Elevated Serum TSH by Decade of Age and Gender

NHANES III Study (N=17 353)

18 16 14 12 10 8 6 4 2 0

Males Females

Participants With Elevated TSH, %

At <40 years of age, prevalence is relatively low and similar between males and females At 40 years of age, a higher percentage of female patients have elevated TSH levels

13- 20- 30- 40- 50- 60- 70- >80 19 29 39 49 59 69 79 Age, y

Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

Prevalence of Abnormal Thyroid Function

The Colorado Thyroid Disease Prevalence study
Used thyroid stimulating hormone (TSH) levels as a measure of thyroid function Prevalence of elevated TSH levels (hypothyroidism) was 9.5% and the prevalence of decreased TSH levels (hyperthyroidism) was 2.2% Lipid levels increased as thyroid function declined 40% of patients taking thyroid medications had abnormal TSH levels

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

McDermot MT and Ridgway EC. J Clin Endocrinol Metab 86:4585-4590

Prevalence of Elevated TSH by Gender

Study
Whickham follow-up (1995) Framingham (1987)

Women
8% 5.9% 12%

Men
3% 2.3% NA

Colorado* (2000)
Rotterdam (1993) NHANES* (2002)

4%21% 3%16%
1%13% 1%10%

*Percentage calculated by decade of life.

Sawin CT, et al. Arch Intern Med. 1985;145:1386-1388. Vanderpump MP et al. Clin Endocrinol (Oxf). 1995;43:55-68. Canaris GJ, et al. Arch Intern Med. 2000; 160:526-534. Hak AE, et al. Ann Intern Med. 2000;132:270-278. Hollowell JG, et al. J Clin Endocrinol Metab. 2002;87:489-499.

Thyroid-Stimulating Hormone (TSH) Assays

Key test for diagnosis of hypothyroidism and hyperthyroidism TSH assay sensitivity has improved with subsequent test generations
First generation: RIA Sensitivity: 1.0 IU/mL Second generation: IRMA Sensitivity: 0.1 IU/mL Third generation: ELISA Sensitivity: 0.03 IU/mL

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Zophel K, et al. Nuklearmedizin. 1999;38:150-155.

Thyroid Disease Spectrum

Overt Hypothyroidism TSH >4.0 IU/mL, Free T4 Low Mild Thyroid Failure TSH >4.0 IU/mL, Free T4 Normal Euthyroid TSH 0.4-4.0 IU/mL, Free T4 Normal Thyrotoxicosis TSH <0.4 IU/mL, Free T3/T4 Normal or Elevated

5 TSH, IU/mL

10

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Canaris GJ, et al. Arch Intern Med. 2000;160:526-534. Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.

Screening for Thyroid Dysfunction Recommendations for Asymptomatic Adults

Organization American Thyroid Association Screening Recommendation Women and men >35 years of age should be screened and every 5 years later

American Association of Clinical Endocrinologists

American College of Physicians

Older patients, especially women, should be screened

Women >50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated
Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575. Cooper DS. N Engl J Med. 2001;345:260-265. Ann Intern Med. 1998;129:141-143.

Additional Laboratory Tests for Thyroid Function

Test Serum total T4 Normal Levels 5-11 g/dL When to Use Bound and free T4; use with TSH for diagnosis Use with TSH to assess degree of hypothyroidism In combination with TSH, predictor of disease progression
Endocr Pract. 2002;8:457-469. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Free T4

0.7-1.8 ng/dL

TPOAb, TgAb

Negative

Goals for Treating Thyroid Disease

Hypothyroidism
Restore thyroid hormones to normal levels Levothyroxine sodium is the treatment of choice

Hyperthyroidism
Restore a eumetabolic state 3 treatments available: antithyroid drugs, radioactive iodine (131I), and thyroid surgery
Singer PA, et al. JAMA. 1995;273:808-812.

Types of Hypothyroidism
Primary hypothyroidism: caused by decreased production of T4 and T3 due to thyroid dysfunction Secondary hypothyroidism: caused by decreased thyroidal stimulation by TSH; may be caused by pituitary (TSH) or hypothalamic (TRH) disease
Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Causes of primary hypothyroidism

Common
Autoimmune lymphocytic thyroiditis (Hahimoto) Radioiodine Thyroid surgery Drugs: antithyroid drugs (PTU,Crbimazole),amioda rone, lithium.

Rare
Infiltration Dysgensis Thyroid hormone resistance Iodine deficiency Iodine excess (WolffChaikoff effect)

Chew and Leslie. Clinical Endocrinology and Daiabetes,2006

Clinical Manifestations of Hypothyroidism

Fatigue Weight gain Dry skin and cold intolerance Yellowing or yellow hue of the skin Coarseness or loss of hair Hoarseness Goiter Delayed relaxation of deep tendon reflexes Ataxia Constipation Memory and mental impairment Decreased concentration Depression Irregular or heavy menses and infertility Myalgias Hyperlipidemia Bradycardia and hypothermia Myxedema

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Cholesterol Levels Elevate With Increasing TSH Levels

280 270 260 250 240

Mean Total Cholesterol Level, mg/dL

Abnormal Euthyroid

270

267

238

239

230 226 223 216 220 210 209 200 <0.3 0.3- >5.1- >10- >15- >20- >40- >60- >80 5.1 10 15 20 40 60 80
TSH, IU/mL

229

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Correlation of Serum TSH and Cholesterol in Hypothyroid Patients

Patients (n) 390 130 130 81 115 99 73 TSH Range (IU/mL 1.1 to 5.0 5.1 to 10.0 10.1 to 15.0 15.1 to 20.0 20.1 to 40.0 40.1 to 80.0 >80.0 Mean Cholesterol (mg/dL) 231 244* 252* 248* 260* 310* 347*

*Statistically significantly (P<.05) different from TSH 1.1 to 5.0 group

Elder J, et al. Ann Clin Biochem. 1990;27:110-113.

Hypothyroidism and Depression Have Many Common Features

Depression Hypothyroidism
Constipation Appetite decrease Decreased concentration Decreased libido Delusions Depressed mood Diminished interest Sleep increase Weight increase Fatigue

Sleep decrease Suicidal ideation Weight loss Appetite increase/ decrease

Bradycardia Cardiac and lipid abnormalities Cold intolerance Delayed reflexes Goiter Hair and skin changes

Nemeroff CB, J Clin Psychiatry. 1989;50(suppl):13-20.

Hypothyroidism Treatment Goal Euthyroidism

The goal of hypothyroidism therapy is to replace thyroxine to mimic normal, physiologic levels and alleviate signs, symptoms, and biochemical abnormalities

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Treatment of Hypothyroidism Thyroid Hormone Replacement

Treatment of choice: levothyroxine (synthetic

levothyroxine, LT4)
Chemically stable T4 converted to T3 in periphery

Other therapies (T3 or T3 and T4 mixtures) Thyroid USP, liothyronine, liotrix, thyroglobulin Some disadvantages, no advantages versus levothyroxine
Singer PA, et al. JAMA. 1995;273:808-812.

Endocr Pract. 2002;8:457-469.

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Recommendations for Treatment of Hypothyroidism

AACE guidelines:
AACE advocates the use of a high-quality brand preparation of levothyroxine. It is preferable to maintain the patient on the same brand of levothyroxine throughout treatment. Importantly, patients should be reevaluated and retitrated after an interval of at least 6 weeks following any change in levothyroxine brand or dose.

American Thyroid Association recommendations:

For patients who have recently started receiving

levothyroxine or who have had their dosage, type, or brand of thyroid preparation changed, the TSH concentration should be measured after 8 to 12 weeks.

Endocr Pract. 2002;8:457-469.

Singer PA, et al. JAMA. 1995;273:808-812.

Diagnosis Algorithm for Hypothyroidism

Suspect Hypothyroid? Test TSH

TSH <0.4 IU/mL

TSH 0.4 to 4.0 IU/mL

TSH >4.0 IU/mL

Patient Hyperthyroid? Consult Hyperthyroidism Diagnosis Algorithms

Patient Euthyroid

Go to Next Step

Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Primary Hypothyroidism Diagnosis Algorithm

TSH >4.0 IU/mL
Test FT4 FT4 High Consult Endocrinologist for Possible TSH-Secreting Pituitary Tumor or Thyroid Hormone Resistance
*Free T4 estimate

FT4 Normal Patient Subclinical Hypothyroid Consult Hypothyroidism Management Algorithm

FT4 Low Patient Hypothyroid Consult Hypothyroidism Management Algorithm

Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003. Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320. Ayala AR, et al. The Endocrinologist. 1997;7:44-50. Endocr Pract. 2002;8:457-469.

Hypothyroidism Treatment
Levothyroxine sodium is the treatment of choice for the routine management of hypothyroidism
Adults: about 1.7 g/kg of body weight/d Children up to 4.0 g/kg of body weight/d Elderly <1.0 g/kg of body weight/d

Clinical and biochemical evaluations at 6- to 8-week intervals until the serum TSH concentration is normalized Given the narrow and precise treatment range for levothyroxine therapy, it is preferable to maintain the patient on the same brand throughout treatment
Singer PA, et al. JAMA. 1995;273:808-812. Endocr Pract. 2002;8:457-469.

Primary Hypothyroidism Treatment Algorithm

Initial Levothyroxine Dose

6-8 Weeks
TSH >4 IU/mL Repeat TSH Test TSH <0.5 IU/mL

TSH 0.5- 2.0 IU/mL Symptoms Resolved Increase Levothyroxine Dose by 12.5 to 25 g/d Continue Dose Measure TSH at 6 Months, Then Annually or When Symptomatic Decrease Levothyroxine Dose by 12.5 to 25 g/d
Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Therapy Initiation and Titration

Therapy with levothyroxine sodium products

requires individualized patient dosing

Careful titration: use a formulation with consistent doses Clinical evaluation: symptoms resolve more slowly than

TSH response Laboratory monitoring: need consistent, sensitive TSH measurements

Individualized patient dosing is influenced by

Age and weight Cardiovascular health Severity and duration of hypothyroidism Concomitant disease states and treatment
Endocr Pract. 2002;8:457-469. Singer PA, et al. JAMA. 1995;273:808-812.

Therapy Monitoring
Clinical and laboratory monitoring enable
Evaluation of the clinical response Assessment of patient compliance Assessment of drug interactions, if applicable Adjustment of dosage, as needed

Clinical and laboratory evaluations should be performed

At 6- to 8-week intervals while titrating Annually once a euthyroid state is established
Singer PA, et al. JAMA. 1995;273:808-812. Demers LM, Spencer CA, eds.
Demers LM, Spencer CA, eds. The National Academy of Clinical Biochemistry Web site. Available at: http://www.nacb.org/lmpg/thyroid_lmpg.stm. Accessed July 1, 2003.

Special Considerations Elderly Patients

Higher prevalence of hypothyroidism compared with younger persons Appropriate dose selection and monitoring critical for elderly patients with cardiac abnormalities Poor patient compliance, adherence, and persistence may be an issue
Felicetta JV. Consultant. 2002;1597-1606. Available at: www.consultantlive.com. Accessed July 1, 2003.

Caution in Patients With Underlying Cardiac Disease

Using LT4 in those with ischemic heart disease increases the risk of MI, aggravation of angina, or cardiac arrhythmias For patients <50 years of age with underlying cardiac disease, initiate LT4 at 25-50 g/d with gradual dose increments at 6- to 8-week intervals For elderly patients with cardiac disease, start LT4 at 12.5-25 g/d, with gradual dose increments at 4- to 6-week intervals The LT4 dose is generally adjusted in 12.5-25 g increments
Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Kohno A, et al. Endocr J. 2001;48:565-572. Synthroid [package insert]. Abbott Laboratories; 2003.

Impact of Maternal Hypothyroidism on Subsequent Neuropsychological Development of Offspring

Undiagnosed hypothyroidism in pregnant women may adversely affect fetuses Treating maternal hypothyroidism during pregnancy appears to be beneficial, even when treatment falls short of euthyroid status Screening for hypothyroidism before or very early in pregnancy may be warranted

Haddow JE, et al. N Engl J Med. 1999;341:549-555.

Special Considerations
Levothyroxine Therapy With Other Populations
Pregnant women
Thyroid failure may impede the intellectual development of the child Increased LT4 doses may be necessary TSH levels should be monitored each trimester

Postpartum thyroiditis
Can lead to symptomatic thyrotoxicosis and/or hypothyroidism Reported prevalence varies from 2% to 21% Has been associated with postpartum depression Can lead to chronic hypothyroidism
Synthroid [package insert]. Abbott Laboratories; 2003. Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Treating Hypothyroidism Before and During Pregnancy

Encourage adherence with levothyroxine replacement therapy before conception Monitor TSH levels before conception and during first trimester Increase the levothyroxine dosage in athyreotic patients by 25%-50% when pregnancy is confirmed Monitor TSH levels every 6 to 8 weeks throughout pregnancy Reinstate prepregnancy levothyroxine dosage immediately following delivery
Gharib H, et al. Endocr Pract. 1999;5:367-368. Mandel SJ, et al. N Engl J Med. 1990;323:91-96.

Subclinical Hypothyroidism Treatments

Subclinical Hypothyroidism Prevalence

Worldwide prevalence between 1% and 10% Highest rates are in women older than 60 years of age Over the age of 74, 16% of men and 21% of women have the disorder

Cooper DS. N Engl J Med. 2001;345:260-264.

Prevalence and Incidence of Subclinical Hypothyroidism

Prevalence
4% to 10% in large population screening surveys Increases with increasing age Is more common in women than in men

Incidence
2.1% to 3.8% per year in thyroid antibody-positive patients 0.3% per year in thyroid antibody-negative patients

McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Caraccio N, et al. J Clin Endocrinol Metab. 2002;87:1533-1538. Biondi B, et al. Ann Intern Med. 2002;137:904-914.

Definition of Subclinical Hypothyroidism

Elevated TSH level (>4.0 IU/mL) Normal total or free serum T4 and T3 levels Few or no signs or symptoms of hypothyroidism

McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000;1001.

Many Patients With Hypothyroidism Report No Symptoms

50 Participants, % 40
>35% >25%

Euthyroid Mild Thyroid Failure Hypothyroid

30
20 10 0 0

2 Number of Symptoms

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Ladenson PW, et al. Arch Intern Med. 2000;160:1573-1575.

Causes of Subclinical Hypothyroidism

Exogenous factors
Levothyroxine underreplacement Medications, such as lithium, cytokines, or iodine-containing agents (eg, amiodarone) Antithyroid medications 131I therapy or thyroidectomy

Endogenous factors
Previous subacute or silent thyroiditis Hashimoto thyroiditis

Biondi B, et al. Ann Intern Med. 2002;137:904-914.

Subclinical Hypothyroidism and Cardiovascular Disease

Cardiac manifestations
Left ventricular systolic and diastolic dysfunction Increased systolic time interval Myocardial infarction

Coronary artery disease

Elevated total cholesterol levels, LDL-C levels, and triglyceride levels Aortic atherosclerosis Hyperhomocysteinemia
Biondi B, et al. Ann Intern Med. 2002;137:904-914. Ayala AR, et al. Cleve Clin J Med. 2002;69:313-320. Aldin V, et al. Am Fam Physician. 1998;57:776-780.

Subclinical Hypothyroidism and Aortic Atherosclerosis in Women

100

Presence of Aortic Atherosclerosis

Condition Present Condition Absent

Patients, %

50

Women With Mild Thyroid Failure

Euthyroid Women

Women With Mild Thyroid Failure and Antibodies to Thyroid Peroxidase

Euthyroid Women Without Antibodies to Thyroid Peroxidase

Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Subclinical Hypothyroidism Affects Cardiac Function

Cardiac function is subtly impaired in patients with mild thyroid failure Abnormalities can include
Subtle abnormalities in systolic time intervals and myocardial contractility Diastolic dysfunction at rest or with exercise Reduction of exercise-related stroke volume, cardiac index, and maximal aortic flow velocity

The clinical significance of the changes is unclear

McDermott MT, et al. J Clin Endocrinol Metab. 2001;86:4585-4590. Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:1004.

Subclinical Hypothyroidism May Increase Cardiovascular Disease Risk

Mild thyroid failure has been evaluated as a cardiovascular risk factor associated with
Increased serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels Reduced high-density lipoprotein cholesterol (HDL-C) levels Increased prevalence of aortic atherosclerosis

Increased incidence of myocardial infarction

The Rotterdam Study Design and Objectives

A population-based cross-sectional cohort study conducted in a district of Rotterdam, the Netherlands
Cohort included 3105 men and 4878 women aged 55 and older Thyroid status was determined from a random sample of 1149 elderly women (mean age 69 7.5 years) selected from the study

The study's objective was to investigate whether mild thyroid failure and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction

Subclinical Hypothyroidism Increases Risk of Myocardial Infarction (MI)

Findings from the Rotterdam Study
Subclinical Hypothyroidism contributed to 60% of MI cases in patients with diagnosed subclinical hypothyroidism, and 14% of all MI instances in the study population Subclinical Hypothyroidism appeared to be a strong indicator of risk for aortic atherosclerosis and MI in older women Thyroid autoimmunity by itself was not associated with aortic atherosclerosis or MI
Hak AE, et al. Ann Intern Med. 2000;132:270-278.

Subclinical Hypothyroidism Elevates Serum Lipid Levels

300 250 200 150 Hypothyroid

Lipid Levels, mg/dL

Subclinical Hypothyroid
Euthyroid Subclinical Hyperthyroid Hyperthyroid Total-C* LDL-C* HDL-C* Triglycerides

100
50

*Total-C indicates total cholesterol; LDL-C, LDL-Cholesterol; HDL-C, HDL-Cholesterol

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Rationale for Treating Mild Thyroid Failure

Potential benefits from treatment
Prevent progression to overt hypothyroidism Improve serum lipid profile, which may reduce the risk of death from cardiovascular causes Reduce symptoms, including psychiatric and cognitive abnormalities

Cooper DS. N Engl J Med. 2001;345:260-264.

Mild Thyroid Failure Treated With Levothyroxine Therapy: Effects on Total Cholesterol
Gorman et al, 1979 Change in Total Cholesterol (mg/dL), % 0 -5 -10 -15 -20 Elder et al, Wiseman et al, 1990 1993

-25
-30 -35 -40
Tanis BC, et al. Clin Endocrinol. 1996;44:643-649.

Levothyroxine Therapy Reduces Cholesterol in Subclinical Hypothyroidism

Basel Thyroid Study (N=63)
TSH
14 TSH (IU/mL) LDL-C (mg/dL) 12 TC (mg/dL) 10 8 6 4 240 150

250

Total Cholesterol 155

LDL-C

145

2
0
LT4 Placebo

230
LT4 Placebo

140
LT4 Placebo

Before

After

Meier C, et al. J Clin Endocrinol Metab. 2001;86:4860-4866.

The Rate of Progression of Subclinical Hypothyroidism to Overt Hypothyroidism

Subclinical Hypothyroidism is a common disorder that frequently progresses to overt hypothyroidism
Progression has been reported in about 3% to 18% of affected patients per year Progression may take years or may rapidly occur The rate is greater if TSH is higher or if there are positive antithyroid antibodies The rate may also be greater in patients who were previously treated with radioiodine or surgery

Treatment of subclinical hypothyroidism

Whether to treat subclinical hypothyroidism remains a dilemma. Most clinicians treat subclinical hypothyroidism who have a serum TSH > 10 mIU/L. Whereas opinions differ about the management of mild disease in which TSH ranges between 4.5 10 mIU/L especially in elderly asymptomatic patients
Biondi and Cooper Endocrine Reviews. 2008 ; 29:76-131

Factors That May Reduce Levothyroxine Effectiveness

Malabsorption Syndromes
Postjejunoileal bypass

Drugs That Increase Clearance

Rifampin Carbamazepine Phenytoin

surgery Short bowel syndrome Celiac disease

Reduced Absorption

Colestipol hydrochloride to T3 Clearance Sucralfate Amiodarone Ferrous sulfate Selenium deficiency Food (eg, soybean formula) Other Mechanisms Aluminum hydroxide Lovastatin Cholestyramine Sertraline Sodium polystyrene sulfonate

Factors That Reduced T4

Braverman LE, Utiger RD, eds. The Thyroid: A Fundamental and Clinical Text. 8th ed. 2000. Synthroid [package insert]. Abbott Laboratories; 2003.

Thyroid Status of Treated Patients

Colorado Thyroid Disease Prevalence Study
100 Participants, %
80 60 40 20 20.7 0.9
Hyperthyroid Subclinical Hyperthyroid Euthyroid Subclinical Hypothyroid

Overtreated >20%
60.1

Undertreated >18%

17.6 0.7
Hypothyroid

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Under-Replacement Risks
Switching between different levothyroxine

formulations can lead to under-replacement Under-replacement risk (TSH >5.0 IU/mL)

Continued hypothyroid state Hyperlipidemia Decreased heart rate and ventricular contractility Increased peripheral vascular resistance and

diastolic pressure Memory loss, fatigue, and weight gain Depression

Over-Replacement Risks
Switching a narrow therapeutic index drug, such as LT4,

without retesting and retitrating can cause inconsistent TSH control, resulting in over-replacement Over-replacement risks (TSH <0.5 IU/mL) Iatrogenic thyrotoxic state Increased heart rate and myocardial contractility For cardiac patients, increased risk of angina and MI Reduced bone density/osteoporosis Psychiatric symptoms, such as anxiety, sleep disturbance, irritability, and fatigue

Synthroid [package insert]. Abbott Laboratories; 2003.

Braverman LE, et al. Werner & Ingbars The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000. Felicetta JV. Consultant. 2002;1597-1606. Available at: www.consultantlive.com. Accessed July 1, 2003.

Summary
Hypothyroidism increases in prevalence and incidence among the elderly. Autoimmune thyroiditis is the most common cause of hypothyroidism Levothyroxine sodium is the treatment of choice for the routine management of hypothyroidism Treatment and management of subclinical hypothyroidism and population screening are still controversial Special considerations may apply in planning treatment due to changes in the metabolic clearance of thyroid hormone, drug interactions and potential adverse reaction

Parathyroid Hormone (PTH)

Is an 84 aminoacid chain, but its biologically activity resides in the first 34 residues. In the parathyroid gland, a Pre-Pro-PTH are synthesized Pre-Pro-PTH is converted to Pro-PTH and Pro-PTH converted to PTH. When serum Calcium level falls, signal is transduced through calcium sensing receptors, and secretion of PTH increased.

PARATHYROID GLANDS
The parathyroid glands are embedded on the posterior surfaces of the lateral lobes of the thyroid principal cells produce parathyroid hormone oxyphil cells function is unknown Parathyroid hormone (PTH) regulates the homeostasis of calcium and phosphate increase blood calcium level decrease blood phosphate level increases the number and activity of osteoclasts increases the rate of Ca+2 and Mg+2 from reabsorption from urine and inhibits the reabsorption of HPO4-2 so more is secreted in the urine promotes formation of calcitriol, which increases the absorption of Ca+2, Mg+2,and HPO4-2 from the GI tract
Principles of Human Anatomy and Physiology, 11e 58

Histology of Parathyroid Gland

Principal cells produce parathyroid hormone (PTH) Oxyphil cell function is unknown

Principles of Human Anatomy and Physiology, 11e

59

Biologic Effects of PTH

The central function of PTH is to regulate ionized ( Ca2+) levels by concerted effects on three principal target organ : Bone Intestinal mucosa Kidney The effect of PTH on intestinal calcium absorpsion is indirect, resulting from increased renal production of the intestinally active vitamin D metabolite 1,25(OH)2D. By its integrated effects on kidney, gut and bone PTH acts to increased the flow of calcium into the extracellular fluid and thus defend against hypocalcemia. Removal of the parathyroid glands results in profound hypocalcemia and ultimately in tetani and death
Principles of Human Anatomy and Physiology, 11e 60

Figure 1813

Regulation of Calcium Blood Levels

High or low blood levels of Ca+2 stimulate the release of different hormones --- PTH or Calcitonin
Principles of Human Anatomy and Physiology, 11e 62

Biosynthesis, Storage & Secretion of PTH PTH is synthesized as the preprohormone (Preproparathyroid Hormone) by parathyroid gland chief cells The active form of PTH is cleaved from the preprohormone before release from the gland PTH is synthesized continously (it is either released from the gland or degraded) PTH is released by exocytosis in response to reduced plasma calcium Vitamin D feeds back to reduce PTH secretion as a secondary mechanism

Biological Activity of PTH

BONE PTH stimulates bone osteoblasts to increase growth & metabolic activity PTH stimulated bone resorption releases calcium & phosphate into blood KIDNEY PTH increases reabsorption of calcium & reduces reabsorption of phosphate Net effect of its action is increased calcium & reduced phosphate in plasma INTESTINE Increases calcium reabsorption via vitamin D

Calcitonin
Calcitonin is a peptide hormone secreted by the parafollicular or C cells of the thyroid gland It is synthesized as the preprohormone & released in response to high plasma calcium Calcitonin acts on bone osteoclasts to reduce bone resorption. Net result of its action is a decline in plasma calcium & phosphate

Synthesis, Release & Activity of Active Vitamin D

Vitamin D3 is may be obtained from the diet or made in the skin It is converted to the active form (1,25-OHD3 by sequential enzymatic reactions in the liver and kidney (stimulated by PTH) Vitamin D3 stimulates intestinal calcium uptake, increased bone calcium resorption & increased kidney phosphate uptake

Calcium Metabolism:

Figure 23-20: Calcium balance in the body

Hormonal Regulation of Calcium and Phosphate Balance

Decreased Plasma Calcium Causes: Increased PTH Resulting in mobilization of bone Ca & phosphate, increased renal phosphate excretion & Ca retention and increased Vitamin D3 synthesis The outcome is a rise in plasma Ca levels & maintenance of normal phosphate levels

Alterations of Parathyroid Function

Hyperparathyroidism
Primary hyperparathyroidism Excess secretion of PTH from one or more parathyroid glands Secondary hyperparathyroidism Increase in PTH secondary to a chronic disease

Hypoparathyroidism
Abnormally low PTH levels Usually caused by parathyroid damage in thyroid surgery

69

Hyperparathyroidism
The incidence of the disease increases dramatically after the age of 50 and it is 24 folds more common in women. A single adenoma occurs in about 80% of patients with primary hyperparathyroidism. Four glands hyprplasia account for 1520% of cases. A parathyroid carcinoma could be the etiology in a rare incidence of less then 1%.

Clinical Feature of Hyperparathyroidism

In skeleton a condition called osteitis fibrosa cystica could occur with subperiosteal resorption of the distal phalanges, distal tappering of the clavicles, a salt and pepper appearance of the skull as well as bone cysts and brown tumors of the long bones. Such overt bone disease even though typical of primary hyperparathyroidism is very rarely encountered.

Clinical Feature of Hyperparathyroidism

Clinical Features:
The two major sites of potential complications are the bones and the kidneys. The kidneys may have renal stones (nephrolithiasis) or diffuse deposition of calciumphosphate complexes in the parachyma (nephrocalcinosis). Now a days such complications are seen less commonly and around 20% of patients or less show such complications.

Hypoparathyroidism
Diagnosis:
In the absence of renal failure the presence of hypocalcaemia with hyperphosphataemia is virtually diagnostic of hypoparathyroidism. Undetectable serum iPTH confirms the diagnosis or it can be detectable if the assay is very sensitive.

Hypoparathyroidism Clinical Features:

A. Neuromuscular
Parathesia Tetany Hyperventilation Adrenergic symptoms Convulsion (More common in young people and it can take the form of either generalized tetany followed by prolonged tonic spasms or the typical epileptiform seizures. Signs of latent tetany Chvostek sign,Trousseau sign and extrapyramidal signs (due to basal ganglia calcification)

Hypoparathyroidism Clinical Features:

B. Other clinical manifestation 1. Posterio lenticular cataract 2. Cardiac manifestation: Prolonged QT interval in the ECG Resistance to digitalis Hypotension Refractory heart failure with cardiomegally can occur.

Hypoparathyroidism Clinical Features:

B. Other clinical manifestation 3. Dental Manifestation Abnormal enamel formation with delayed or absent dental eruption and defective dental root formation. 4. Malabsorption syndrome Presumably secondary to decreased calcium level and may lead to steatorrhoea with long standing untreated disease.

Treating Hypoparathyroidism
It seems logical that PTH would be beneficial in treating hypoparathyroidism. However few studies are available that have looked at this traetment possibility. Study among patients with hypoparathyroidism to PTH twice a day or calcium and calcitriol to attain normal calcium concentration. Calcium, phosphorus and magnesium levels did not differ between the group. No significant BMD between the group. PTH however does not have the FDA indication for hypoparathyroidism (Painter and Camacho,2007)

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Hypoparathyroidism Treatment:
The mainstay of treatment is a combination of oral calcium with pharmacological doses of vitamin D or its potent analogues. Phosphate restriction in diet may also be useful with or without aluminum hydroxide gel to lower serum phosphate level.

Emergency Treatment for Hypocalcaemic Tetany:

Calcium should be given parenterally till adequate serum calcium level is obtained and then vitamin D supplementation with oral calcium should be initiated.

Osteoporosis: Disease of Bone Growth & Calcium Metabolism

Bone reabsorption exceeds deposition Osteoclasts mobilize Ca++ to plasma Factors: inadequate Ca++ intake, genes, hormones, smoking

Figure 23-21: Osteoclasts are responsible for bone resorption

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Definition of osteoporosis
a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk.

World Health Organization (WHO), 1994

World Health Organization (WHO) guidelines for osteoporosis

Peak Bone Mass

Normal

Osteoporosis

Osteopenia

T-Score

-2.5

-1

Mosby items and derived items 2006 by Mosby, Inc.