c Cushing's Syndrome

c Thyroid
c Parathyroid
c Caused by prolonged exposure to elevated levels of either endogenous
glucocorticoids or exogenous glucocorticoids.
c Normal cortisol metabolism

In response to stress or a to low level of blood glucocorticoids.

Hypothalamus secretes corticotropin-releasing hormone (CRH) which triggers

pituitary secretion of adrenal corticotrophic hormone (ACTH)

ACTH is then carried by the blood to the adrenal cortex where it triggers Cortisol
secretion.
  
 
þ
 
Pituitary adenoma secreting ACTH (this is know as Cushing͛s
Disease)
 þ
  
Iatrogenic (chronic glucocorticoid therapy eg for asthma)
Adrenal Adenoma
Adrenal Carcinoma
  Alcoholism
 
  
 Major depressive illness

 Primary obesity
c 

c Patients with Cushing syndrome may complain of weight gain, especially in the face,
supraclavicular region, upper back, and torso.

c Patients notice changes in their skin, including purple stretch marks, easy bruising, and other
signs of skin thinning.

c Patients may have difficulty climbing stairs, getting out of a low chair, and raising their arms
because of progressive proximal muscle weakness.

c Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in women

c Men may complain of decreased libido and impotence.

c Psychological problems such as depression, cognitive dysfunction, and emotional lability

may develop.

c Difficulty with wound healing, increased infections, and osteoporotic fractures may occur.

c Patients may complain of developing headaches, polyuria and nocturia, visual problems, or
galactorrhea usually due to an ACTH-producing pituitary tumour (Cushing disease)
c  
c ãbesity
£ Patients may have increased adipose tissue in the face (moon face), upper back at the
base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).
£ Central obesity with increased adipose tissue in the mediastinum and peritoneum
Increased waist-to-hip ratio greater than 1 in men and 0.8 in women

c Skin
£ Flushed face may be present, especially over the cheeks.
£ Striae are observed most commonly over the abdomen, buttocks, lower back, upper
thighs, upper arms, and breasts.
£ Skin bruising may be present.
£ Cutaneous atrophy with exposure of subcutaneous vasculature tissue and dehydration
may be evident.
£ If glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocortical
carcinomas, hirsutism and male pattern balding may be present in women.
£ Steroid acne, consisting of papular or pustular lesions over the face, chest, and back,
may be present.
£ Hyperpigmentation of the skin (Acanthosis nigricans), which is associated with insulin
resistance and hyperinsulinism, may be present. The most common sites are axilla and
areas of frequent rubbing, such as over elbows, around the neck, and under the breasts.

c Cardiovascular and renal

£ Hypertension and possibly oedema may be present due to cortisol activation of the
mineralocorticoid receptor leading to sodium and water retention.
c -I
£ Peptic ulceration may occur with or without symptoms.

c Endocrine
£ -alactorrhea may occur when anterior pituitary tumours compress the pituitary stalk,
leading to elevated prolactin levels.
£ Low testosterone levels in men may lead to decreased testicular volume from inhibition
of LHRH and LH/FSH function.

c Skeletal/muscular
£ Proximal muscle weakness may be evident.
£ ãsteoporosis may lead to fractures and increased kyphosis, height loss, and axial
skeletal bone pain.
£ Avascular necrosis of the hip is also possible from glucocorticoid excess.

c Neuropsychological
£ Patients may experience emotional liability, fatigue, and depression.
£ Visual-field defects and blurred vision may occur in individuals with large ACTH-
producing pituitary tumours that impinge on the optic chiasma.
c Adrenal crisis
£ Patients with Cushing͛s features may present to the emergency department in adrenal
crisis.
£ Adrenal crisis may occur in patients on steroids who stop taking their glucocorticoids or
neglect to increase their steroids during an acute illness.
£ It also may occur in patients who have recently undergone resection of an ACTH-
producing or cortisol-producing tumours or who are taking adrenal steroid inhibitors.
£ Physical findings that occur in a patient in adrenal crisis include:
c hypotension
c abdominal pain
c vomiting
c mental confusion
c hypoglycaemia
c hyperkalemia
c hyponatremia
c metabolic acidosis.
c Investigations



 



!
 Î -hr timed collection (some centres use Normal range depends on assay
overnight collections corrected for creatinine)

"
 
 

1 mg orally at midnight; measure plasma Plasma cortisol < 60 nmol/l (< Î.Î ʅg/dl)
cortisol at 0800-0900 hrs excludes Cushing's

 
  
 Sample for cortisol at 0900 hrs and at Î
00 Evening level > 75% of morning level in
hrs (requires acclimatisation to ward for at Cushing's
least 8 hrs)

#$  
 

0.5 mg 6-hourly for 8 hrs; sample Î -hr urine Urine cortisol < 100 nmol/day (
6 ʅg/day) or
cortisol during second day and 0900-hr plasma cortisol < 60 nmol/l (< Î.Î ʅg/dl)
plasma cortisol after 8 hrs excludes Cushing's


 

Peak plasma cortisol > 1Î0% of baseline
excludes Cushing's

  
 

Î mg 6-hourly for 8 hrs; sample Î -hr urine Urine cortisol < 50% of basal suggests
cortisol at baseline and during second day pituitary-dependent disease; > 50% of basal
suggests ectopic ACTH syndrome



  

100 ʅg ovine CRH i.v. and monitor plasma Peak plasma cortisol > 1Î0% and/or ACTH >
ACTH and cortisol for Î hrs 150% of basal values suggests pituitary-
dependent disease; lesser responses suggest
ectopic ACTH syndrome


  
Catheters placed in both inferior petrosal ACTH concentration in either petrosal sinus >
sinuses and simultaneous sampling from Î00% peripheral ACTH suggests pituitary-
these and peripheral blood for ACTH; may be dependent disease; < 150% suggests ectopic
repeated 10 minutes after peripheral CRH ACTH syndrome
injection
c Management
c Treatment of Cushing syndrome is directed by the primary cause of the syndrome.
c In general, therapy should reduce the cortisol secretion to normal levels.
c The treatment of choice for endogenous Cushing syndrome is surgical resection of
the causative tumour.
c The primary therapy for Cushing disease is transsphenoidal surgery, and the
primary therapy for adrenal tumours is adrenalectomy.
c When surgery is not successful or cannot be used, as often occurs with ectopic
ACTH or metastatic adrenal carcinoma, control of hypercortisolism may be
attempted with medication. However, medication failures are common, and
adrenalectomy may be indicated in ACTH-mediated Cushing syndrome.
c Pituitary radiation may be useful if surgery fails for Cushing disease.
c The treatment for exogenous Cushing syndrome is gradual withdrawal of
glucocorticoid.
c Drug agents that inhibit steroidogenesis, such as mitotane, ketoconazole,
metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to
cause medical adrenalectomy.
c These medications are used rarely and often are toxic at the doses required to
reduce cortisol secretion.
c Management
c Hormone replacement:
£ Patients with endogenous Cushing syndrome who undergo resection of pituitary,
adrenal, or ectopic tumours should receive stress doses of glucocorticoid in the
intraoperative and immediate postoperative period.
£ Hydrocortisone is infused intravenously, continuously (10 mg/h) starting prior to surgery
and for the first Î hours afterward.
£ If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-
Î days and replaced with an oral formulation.
£ The rate of steroid taper may be slowed if severe preoperative hypercortisolism was
present.
£ In the event of pituitary destruction or bilateral adrenalectomy, lifelong glucocorticoid
replacement is necessary.
  

 
   
% -raves͛ Disease Pituitary TSHoma
Multinodular -oitre
Adenoma
Subacute Thyroiditis
 Hashimoto͛s Thyroiditis Hypopituitarism
Atrophic Hypothyroidism
&
 Thyroid Hormone
Resistance Syndrome 5͛-
monodeiodinase deficiency

'

 Differentiated Carcinoma
Medullary Carcinoma
Lymphoma
c 


£ Hyperthyroidism is a hypermetabolic condition (excess synthesis

and secretion of thyroid hormone by the thyroid) associated with
elevated levels of free thyroxine (T ) and/or free triiodothyronine
(T
) and decreased/undetectable serum TSH.
c - " 

c The most common cause of thyrotoxicosis is -raves disease (76%)

c -raves disease is an organ-specific autoimmune disorder characterized by a variety
of circulating antibodies, including common autoimmune antibodies, as well as
anti-thyroid peroxidase (anti-TPã) and antithyroglobulin (anti-T-) antibodies and
the most important autoantibody is thyroid-stimulating immunoglobulin (TSI).
c TSI acts as a TSH-receptor agonist. Similar to TSH, TSI binds to the TSH receptor on
the thyroid follicular cells to activate thyroid hormone synthesis and release and
thyroid growth (hypertrophy).
c The characteristic picture of -raves disease is:
£ diffusely enlarged thyroid
£ very high radioactive iodine uptake
£ excessive thyroid hormone levels
c
(
 -


c ãccurs in 15-Î0% of patients with thyrotoxicosis.

c ãccurs more commonly in elderly individuals.
c Thyroid hormone excess develops very slowly over time and often is only mildly
elevated at the time of diagnosis.
c Sign and symptoms of thyrotoxicosis are mild, often because only a slight elevation
of thyroid hormone levels is present.
c ) 




c The next most common cause of thyrotoxicosis is subacute thyroiditis (
%)

c Virus induced (e.g. Coxsackie) transient inflammation of the thyroid gland
c Thyroid hormone levels can be extremely elevated in this condition.
c  

c The presentation of thyrotoxicosis is variable among patients.
c Common symptoms of thyrotoxicosis include the following:
£ Nervousness
£ Anxiety
£ Increased perspiration
£ Heat intolerance
£ Tremor
£ Hyperactivity
£ Palpitations
£ Weight loss despite increased appetite
£ Reduction in menstrual flow or oligomenorrhea
c Common signs of thyrotoxicosis include the following:
£ Hyperactivity
£ Tachycardia or atrial arrhythmia
£ Systolic hypertension
£ Warm, moist, and smooth skin
£ Lid lag
£ Stare
£ Tremor
£ Muscle weakness
c Younger patients tend to exhibit symptoms of more sympathetic activation, such as anxiety,
hyperactivity, and tremor
c ãlder patients have more cardiovascular symptoms, including dyspnea and atrial fibrillation
with unexplained weight loss.
c "



c 'lood Tests
£ Serum TSH
£ Serum T
£ Serum T

c Thyroid autoantibodies
£ The most specific autoantibody for autoimmune thyroiditis is an enzyme-linked
immunosorbent assay (ELISA) for anti-TPã antibody.
c Nuclear thyroid scintigraphy iodine 1Î
uptake and scan
c Hyperthyroidism in older patients often presents with atrial arrhythmias or CHF.
EC- is recommended if an irregular heart rate or CHF is noted upon examination.
c



c Symptomatic relief
£ Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are
relieved by beta-blocker therapy.
£ Calcium-channel blockers can be used for the same purposes when beta
blockers are contraindicated or poorly tolerated.
c Antithyroid drugs
£ methimazole inhibit multiple steps in the synthesis of T and T
, leading to a
gradual reduction in thyroid hormone levels over Î-8 weeks or longer.
c Surgical Care
£ Subtotal thyroidectomy or total thyroidectomy
c 


c Hypothyroidism is an endocrine disorder resulting from deficiency of

thyroid hormone with normal T and raised TSH levels.
c 
c Iodine deficiency remains the foremost cause of hypothyroidism.
c The prevalence of antibodies is higher in women, and increases with age.
c  




c The most frequent cause of acquired hypothyroidism is autoimmune thyroiditis.

c The body recognizes the thyroid antigens as foreign, and a chronic immune
reaction ensues, resulting in lymphocytic infiltration of the gland and progressive
destruction of functional thyroid tissue.
c 


c Fatigue, loss of energy, lethargy
c Weight gain
c Decreased appetite
c Cold intolerance
c Dry skin
c Hair loss
c Sleepiness
c Muscle pain, joint pain, weakness in the extremities
c Depression
c Emotional lability, mental impairment
c Forgetfulness, impaired memory, inability to concentrate
c Constipation
c Menstrual disturbances, impaired fertility
c Decreased perspiration
c Paresthesia and nerve entrapment syndromes
c 'lurred vision
c Decreased hearing
c Fullness in the throat, hoarseness

c
$ 


 


*

c Painless thyroid enlargement

c Feeling of fullness in the throat
c Exhaustion
c Neck pain, sore throat, or both
c Low-grade fever
c  % 


c Hypothermia
c Weight gain
c Slowed speech and movements
c Dry skin
c Jaundice
c Pallor
c Coarse, brittle, strawlike hair
c Loss of scalp hair, axillary hair, pubic hair, or a combination
c Dull facial expression
c Coarse facial features
c Periorbital puffiness
c -oitre
c Hoarseness
c Decreased systolic blood pressure and increased diastolic blood pressure
c 'radycardia
c Pericardial effusion
c Abdominal distension, ascites (uncommon)
c Nonpitting oedema (myxedema)
c Pitting oedema of lower extremities
c Hyporeflexia with delayed relaxation, ataxia, or both
c "


c 'lood Tests
£ Serum TSH
£ Serum T
£ Serum T

c Evaluation of the presence of thyroid autoantibodies (anti-TPã antibodies)
c



c The treatment goals for hypothyroidism are the reversal of clinical progression and
the corrections of metabolic derangements as evidenced by normal blood levels of
TSH and free T .
c Thyroid hormone is administered to supplement or replace endogenous
production.
c In general, hypothyroidism can be adequately treated with a constant daily dose of
levothyroxine (LT ).
c ' +
c The parathyroid glands regulate serum calcium and phosphorus levels through the
secretion of parathyroid hormone (PTH), which raises serum calcium levels while
lowering the serum phosphorus concentration.
c The regulation of PTH secretion occurs through a negative feedback loop in which
calcium-sensing receptors on the membranes of parathyroid cells trigger decreased
PTH production as serum calcium concentrations rise.
  
   
- 
   
% Primary Hyperparathyroidism Secondary
Tertiary Hyperparathyroidism hyperparathyroidism
 Post Surgical
Autoimmune
Autosomal dominant
hypoparathyroidism
&
 Pseudohypoparathyroisism
Familial hypocalciuric
hypercalcaemia
 '

 Parathyroid carcinoma
c   

c Accounts for most hyperparathyroidism cases, results from excessive release of
PTH and manifests as hypercalcaemia.
c Patients with hypercalcaemia who have normal renal function and no malignancy
must be suspected of having primary hyperparathyroidism and must be
subsequently tested for elevated PTH levels.
c Usually the result of a single benign adenoma - a minority of patients have
hyperplasia in all parathyroid glands.
c Parathyroid carcinoma accounts for an insignificant minority (<0.5% of patients
with hyperparathyroidism).
c   

c ãccurs when the parathyroid glands become hyperplastic after long-term
hyperstimulation and release of PTH.
c In secondary hyperparathyroidism, elevated PTH levels do not result in
hypercalcaemia.

c

  

c Tertiary hyperparathyroidism refers to hypercalcaemia caused by autonomous
parathyroid function after long-term hyperstimulation.
c With long-term hyperstimulation, the glands function autonomously and produce
high levels of PTH even after correction of chronic hypocalcemia.
c 


c Symptomatic hyperparathyroidism is characterized by vague, nonspecific symptoms

including
£ generalized weakness
£ Fatigue
£ poor concentration
£ depression.

c Mnemonic ͞Painful bones, renal stones, abdominal groans, and psychic moans͟
disease can be used to recall the typical symptoms of hypercalcaemia.
£ Painful bones are the result of abnormal bone remodeling due to
overproduction of parathyroid hormone (PTH).
£ Nephrolithiasis occurs secondary to hyperparathyroid diseaseʹinduced
hypercalcaemia and resultant hypercalciuria.
£ Abdominal groans refers to hypercalcaemia-induced ileus.
£ Psychic moans or depression may occur in the presence of persistently elevated
serum calcium levels.
c  % 

c Central nervous system
£ Neuropsychiatric illness: Patients frequently display clinical signs of mental depression, poor general
health, low energy levels, decreased ability to complete daily tasks at home or at work, decreased social
interaction, and pain, particularly in the legs.
£ Altered mental status

c Cardiovascular system
£ Hypertension, left ventricular hypertrophy, vascular calcification and stiffness

c Musculoskeletal system
£ low bone density, osteopenia/osteoporosis
£ Vertebral collapse
£ Chondrocalcinosis and pseudogout
£ Easily fatigued muscle (particularly proximal muscle groups)

c -I system
£ Pancreatitis and pancreatic calcification
£ Peptic ulcer disease

c Renal system
£ Nephrolithiasis
£ Nephrocalcinosis
£ impaired renal function.
c "


c PTH levels
c U&E
c Calcium and phosphate levels
c X-ray:
£ subperiosteal resorption that is best seen at the radial sides of the phalanges,
distal phalangeal tufts, and distal clavicles.
£ Salt and pepper skull/ground glass appearance on lateral view of skull
£ 'rown tumour
c 'one-density measurements based on dual energy x-ray absorptiometry (DEXA)
c technetium-99m imaging, ultrasonography, CT scanning, and MRI.
c Management

c


"   *

£ &
$
  
c To replace as much as a -6 l deficit
c May need monitoring with central venous pressure in old age or renal
impairment
£ '

c disodium pamidronate 90 mg i.v. over hours
c Causes a fall in calcium which is maximal at Î-
days and lasts a few weeks
c Unless the cause is removed, follow up with an oral bisphosphonate

£ þ
  
 
c May be required in very ill patients
c Forced diuresis with saline and furosemide
c -lucocorticoids, e.g. prednisolone 0 mg daily
c Calcitonin
c Haemodialysis
c &

c http://emedicine.medscape.com/article/1Î1865-overview accessed
Î7.07.Î010

c http://emedicine.medscape.com/article/117
65-overview accessed
Î7.07.Î010

c http://emedicine.medscape.com/article/1ÎÎ
9
-overview accessed
Î7.07.Î010

c http://emedicine.medscape.com/article/766906-overview accessed
Î7.07.Î010

c Davidson͛s principals and practice of medicine. Î0th ed. Î006. Philadelphia:

Churchill Livingston Elsevier

c Longmore, M., Wilkinson, I.'., Davidson, E.H., Foulkes, A. and Mafi, R.M.
Î010. ãxford handbook of clinical medicine. New York: ãxford University
press