Adrenal Gland Disorders

Question 1

Addisons Disease: general characteristics

Answer 1

• Cortisol: major product of fasciculata layer of adrenal cortex, vital for cardiovascular homeostasis
  
  • Deficiency results in decreased cardiac output and vascular tone
  • Patients often develop hypovolemia –> stimulates ADH –> increased free water absorption & hyponatremia
• If primary adrenal cortex dysfunction exists: patients also lack aldosterone –> hyperkalemic
• Divided into primary (adrenal gland) and secondary (pituitary & hypothalamus) dysfunction

Question 2

Primary adrenal insufficiency (adrenal gland dysfunction): causes

Answer 2

• Autoimmune:
  
  • Addisons Disease (70-80%) most common in developed countries
• Tuberculosis:
  
  • 10-20% most common in developing countries
• Other: 10%

Question 3

Secondary adrenal insufficiency: causes

Answer 3

• Pituitary and hypothalamus
• Following exogenous glucocorticoid withdrawal
• Following cure of Cushing’s disease
• Hypothalamic/pituitary lesions

Question 4

Primary adrenal insufficiency: pathophysiology

Answer 4

• Patients with primary adrenal disease: hyperpigmentation due to increased production of POMC (ACTH precursor in the pituitary)
  
  • POMC: also precursor of melanocyte stimulating hormone (MSH) –> hyperpigmentation
• Patients are deficient in cortisol and aldosterone –> develop hyponatremia and hyperkalemia
• 60% of patients with autoimmune adrenal insufficiency have autoimmune dysfunction of another gland (thyroid)
  
  • Hypothyroidism (25%)
  • Graves disease (11%)
  • Premature gonadal failure
  • Type 1 diabetes (10%
• Proposed theory: polyglandular autoimmune syndrome - endocrine cell undergoes normal damage but does not get recognized as self by body (leads to autoimmune attack in susceptible individual - HLA-DR3, -DR4)

Question 5

Secondary adrenal insufficiency: pathophysiology

Answer 5

• Patients have low ACTH levels
• No hyperpigmentation
• Preserved aldosterone synthesis –> normokalemic

Question 6

Addisons Disease: clinical manifestations

Answer 6

• S/S divided into acute and chronic
• Chronic sx:
  
  • Weakness, fatigue, dizziness, anorexia, nausea, abdominal pain, diarrhea
• Acute:
  
  • All of the above + fever, hypotension, confusion
• Other sx: weakness, fatigue, dizziness, anorexia, weight loss, salt craving
• Lab abnormalities: hyponatremia, hyperkalemia (primary), hypoglycemia
  
  • Because cortisol is counter-regulatory hormone
• Identifiable risk factors for adrenal insufficiency: autoimmune disease, trauma, sepsis, HIV/AIDS, malignancy, glucocorticoid treatment, complicated delivery and head injury (pituitary infarct)

Question 7

Addisons Disease: diagnosis

Answer 7

• Best way = Cortrosyn/Cosyntropin stimulation test
  
  • Baseline serum cortisol followed by 250ug of synthetic ACTH
  • Blood drawn at 30 & 60 minutes to check for serum cortisol
  • Stimulated level greater than 20ug/dL indicates adequate adrenal cortisol reserves
  • If < 18 ug/dL: adrenal insufficiency present
• Caveat: in recent (less than 6 month) pituitary or hypothalamic injury - pituitary (adrenal?) may still be able to respond to Cotrosyn test

Question 8

Addisons Disease: imaging considerations

Answer 8

• Two typical abnormal adrenal gland appearances:
  
  • Small atrophic glands with or without dense calcifications indicate autoimmune, ALD, AMN
  • Enlarged glands with hemorrhage or necrosis
• CT identifies both

Question 9

Addisons Disease: treatment

Answer 9

• Glucocorticoids replacement: oral glucocorticoids given on chronic basis
  
  • Hydrocortisone, prednisone, dexamethasone
• In acute crisis: saline infusion and stress dose steroids given
• Fludrocortisone to replace aldosterone in primary gland failure
• Sex steroid replacement necessary in women: give DHEA

Question 10

Pheochromocytoma: general characteristics

Answer 10

• Chromaffin cells: adrenal medulla cells that appear dark due to oxidized catecholamines
• Chromaffin cell tumors secrete excess epinephrine and norepinephrine
• Most arise from adrenal medullary cells
• Pheochromocytomas: rare
  
  • 2-8 cases/million people
  • Represents the most common adrenal tumor in adults

Question 11

Pheochromocytoma: pathophysiology

Answer 11

• Neuroendocrine cells contain surface receptor (ret) –> binds glial-derived neurotrophic growth factor (GDNF) causing cell signaling –> initiates production of NE and epi
• Mutation to ret receptor –> increased activation and hormone secretion
• Germline mutations in ret implicated in Multiple Endocrine Syndrome:
  
  • MEN 2a: pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism
  • MEN 2b: pheochromocytoma, medullary thyroid caricinoma, mucosal neuromas
• Other germline mutations discovered that indicate familial forms of pheochromocytomas - may account for 25-30% of cases
  
  • VHL, NF1, familial carotid body tumors, familial paragangliomas

Question 12

Pheochromocytoma: clinical manifestations

Answer 12

• Headache, sweating, palpitations (clinical triad)
  
  • +/- hypertension
• No flushing - pallor instead because of vasoconstriction
• Other sx: anxiety, epigastric pain, orthostatic hypotension (hypovolemia), and chest pain
• Pheochromocytomas (<1%), hyperaldosteronism (5-10%), and Cushing’s (<0.5%) can all cause HTN, should be included in DDX for secondary HTN
  
  • Primary HTN accounts for 85% of the cases
• Signs and symptoms
  
  • Revolve principally around excess catecholamines
    
    • α1 receptors mediate vasoconstriction and thus activation can lead to HTN
    • β1 receptors mediate positive inotropy, chronotropy, increase sweating
    • β2 receptors mediate muscle bed vasodilation
• Epinephrine works principally through β receptors to cause tachycardia, sweating, but not significant HTN (mostly due to β2 vasodilation)
• Norepinephrine works through a & β receptors causing similar set of signs, but with added a1 related hypertension
• Secretion from tumor can fluctuate - symptoms can be episodic

Question 13

Possible risk of patient with pheochromocytoma being on beta blocker

Answer 13

• Unopposed a1 vasoconstrition and HTN —> dramatic increase in blood pressure
• Start on a-blocker first
• Then β-blocker after adequate blockade pre-operatively

Question 14

Pheochromocytoma: differential diagnosis

Answer 14

• Anxiety/panic attacks
• Alcoholism
• Drugs (cocaine/PCP)
• Thyrotoxicosis
• Menopausal syndrome
• Hypoglycemia
• Withdrawal of adrenergic inhibitor

Question 15

Pheochromocytoma: diagnosis

Answer 15

• Can be tough - pheo called “great mimic”
• Endocrine principle: biochemical diagnosis must be established prior to anatomic localization - 5-10% of people with adrenal mass on CT have non-functioning masses
• Great deal of variety in what product a tumor creates - standard workup includes 24 hour urine for catecholamines (Epi & NE), metabolites (metanephrine, normetanephrine, VMA, HVA)
• Plasma metanephrines if high risk patient with family hx and adrenal mass
• Plasma catecholamine measurement is difficult
• Certain drugs can interfere with testing, should be avoided for two weeks:
  
  • TCA, beta-blockers, alpha-blockers, alpha-2-agonists (clonidine), decongestants, benzos, amphetamines, ETOH withdrawal
• Once diagnosis is made - localization is relatively easy
  
  • 90% of tumors are in adrenal gland
  • 10% are extra-adrenal in sympathetic chain
  • 98% of tumors in abdomen - CT and MRI are helpful

Question 16

Pheochromocytoma: 10% rule

Answer 16

• 10% extra-adrenal
• 10% bilateral
• 10% malignant (dopamine secretion) - most likely extra-adrenal
• 10% recurrence after removal
• 10% calcify
• 10% kids
• 10% familial (now thought to be more like 20-30%)

Question 17

Pheochromocytomas: imaging considerations

Answer 17

• AKA paraganglioma or ganglioneuroma
• Usually appear spherical and well-circumscribed on imaging > 4cm in size - easy to see
• CT: variable
• MRI: hyperintense on T2WI
  
  • Heterogeneous enhancement

Question 18

Pheochromocytomas: treatment

Answer 18

• Surgical removal after a-blockade with labetolol or phenoxybenzamine to avoid hypertensive crisis
• Need a-blockers because they will vasodilate once removed, become very hypotensive

Question 19

Adrenal insufficiency: familial syndromes

Answer 19

• MEN 2A/2B
• VHL
• NF1
• Familial carotid body tumors
• Familial paragangliomas
• Can test for all with genetic testing

Question 20

Cushing’s Syndrome: causes

Answer 20

• Most commonly iatrogenic (due to chronic administration of glucocorticoids in tx of autoimmune/inflammatory disorders)
• Otherwise, ACTH-dependent or ACTH-independent
  
  • ACTH-independent: caused by excess function of adrenal cortex
• Most common cause of endogenous Cushing’s: pituitary tumor (80%)

Question 21

Cushing’s Syndrome: clinical signs and symptoms

Answer 21

• Obesity: central adiposity, supraclavicular fat pad, dorsoclavicular fat pad (buffalo hump), facial fat pads
• Skin changes: facial plethora, easy bruisability, “onion paper skin” (very thin), purplish-red striae
  
  • Purple striae seldom seen in other diseases
• Insulin resistance and hyperglycemia
• Hirsutism
• Hypertension
• Gonadal dysfunction: amenorrhea, infertility, decreased libido
• Proximal muscle weakness
• Osteoporosis
• Depression
• Routine lab findings: hypokalemic alkalosis in syndromes of marked hypersecretion of cortisol - ectopic ACTH or adrenal carcinoma
  
  • Due to increased cross-reactivity with mineralocorticoid receptor

Question 22

Cushing’s Syndrome: diagnosis

Answer 22

• Defined by inappropriate elevation of cortisol
• Examine sequential photographs: look for clinical signs and symptoms
• If clinical s/s are present & chronic administration of glucocorticoids not thought to be the cause - proceed with 2 diagnostic tests
  
  • Bedtime salivary cortisol - positive result is elevated
  • Overnight 1mg dexamethasone suppression test (DST)
    
    • Administer 1mg dexamethasone at 11pm night before
    • Positive test = 8am plasma cortisol > 1.8ug/dL
  • 24-hour urinary free cortisol (UFC)
    
    • Positive test = > 90-100 ug/day

Question 23

Situations that can cause false-positives in Cushing’s screening DST

Answer 23

• Acute and chronic illness
• Obesity
• Sleep apnea
• PCOS
• High estrogen states
• Drugs (dilantin, phenobarbital)
• Alcoholism
• Anorexia
• Renal failure
• Depression

But most of these situations will have normal 24-hour UFC

Question 24

Cushing’s Syndrome: how to distinguish ACTH-dependent from ACTH-independent

Answer 24

• High/normal ACTH = ACTH dependent
  
  • = Cushings Disease or ectopic ACTH syndrome
• Low ACTH = ACTH independent
  
  • = Cortisol producing adrenal adenoma, cortisol producing adrenal carcinoma, or nodular adrenal hyperplasia
• Also use 8mg dexamethasone suppression test (DST)
  
  • Suppression happens = pituitary
  • No suppression = ectopic/adrenal

Question 25

Cushing’s Disease: imaging considerations used to distinguish different types of adrenal hypersecretion of cortisol

Answer 25

• Try to localize it: pituitary MRI, chest CT, abdominal CT, inferior petrosal sinus sampling
  
  • Tx with pituitary surgery, chest surgery, abdominal surgery, cortisol synthesis inhibitors
• CT, MRI, ultrasonography, isotope scanning with iodocholesterol - used to define adrenal lesions
  
  • In ACTH hypersecretion: used to exclude presence of solitary adrenal adenoma/carcinoma & confirm bilateral adrenal hyperplasia/nodular adrenal hyperplasia
  • Effectively localize adrenal tumors (usually > 1.5cm)
  • 10% incidence of silent adrenal nodules - biochemical testing performed in conjunction with localization studies (ensure identified lesion is biologically significant)

Question 26

Cushing’s Disease/primary adrenal disease: treatment

Answer 26

• Surgical removal of:
  
  • Isolated adenoma OR
  • Adrenal affected with macronodular hyperplasia OR
  • Adrenal gland containing carcinoma
• Bilateral adrenalectomy
  
  • May be required to adequately treat macronodular hyperplasia with bilateral involvement
• Medical therapy
  
  • Usually adjunctive/temporizing/not curative
  • Involves use of drugs that inhibit adrenal cortisol production
    
    • Ketoconazole, metyrapone, aminoglutethimide, mitotane
    • Mitotaine: only adrenolytic agent, used palliatively in carcinoma patients

Question 27

Hyperaldosteronism: causes

Answer 27

• Aldosterone-producing adenoma (APA) = 34% of patients
  
  • Treat with surgery
• Idiopathic hyperaldosteronism (IHA) = 66% of patients
  
  • Treat medically

Question 28

Hyperaldosteronism: features suggestive of primary disease (in patient with hypertension)

Answer 28

• High likelihood of APA
• Young age at onset (< 40 years old)
• Resistance to multiple antihypertensive medications
• Stage 2 ( > 160-179 / 100-109) or more severe hypertension
• Presence of hypertension with adrenal adenoma found incidentally on body imaging
• Hypertension in patient who has first-degree relative with primary hyperaldosteronism

Question 29

Primary hyperaldosteronism: diagnosis

Answer 29

• Clinical triad: hypertension, hypokalemia, metabolic alkalosis
• Aldosterone/plasma renin activity (PRA) ratio > 20-30
  
  • with PRA < 2 ng/mL/hr
• Biochemical dx confirmed with suppression test prior to anatomic localization
  
  • Challenged with IV saline load - should suppress aldosterone levels in patient with essential hypertension, has little effect on patient with primary hyperaldosteronism

Question 30

Antihypertensive medications that interfere with diagnosis of primary hyperaldosteronism

Answer 30

• Beta-blockers
• Diuretics
• Spironolactone
• ACE inhibitors

Patient should also be euvolemic and normokalemic (avoid confounding stimuli to renin/aldosterone)

Question 31

Hyperaldosteronism: imaging considerations and treatment

Answer 31

• CT scan of adrenal gland performed
• Unilateral lesion > 1 cm seen: aldosterone-producing adenoma diagnosed
  
  • Surgery is therapeutic choice
• No lesion, bilateral lesions, or very small lesions seen: confirm diagnosis with adrenal vein sampling
  
  • Unilateral elevation of aldosterone: small adenoma, requires surgery
  • Bilateral elevation of aldosterone: either idiopathic hyperaldosteronism (IHA) or glucocorticoid-remedial hyperaldosteronism (GRA)
    
    • GRA diagnosed by direct genetic testing, elevated levels of 18-hydroxycortisol; treated with glucocorticoid replacement
    • IHA treated with aldosterone antagonist (spironolactone, eplerenone)