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Adrenal Disorders
Jason Ryan, MD, MPH
Adrenal Disorders
• Excess cortisol
• Insufficient cortisol
• Excess mineralocorticoids
• Tumors
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Cushing’s Syndrome
• Syndrome of clinical features due to excess cortisol
• Most common cause: corticosteroid medication
• Often prescribed for inflammatory conditions
• e.g., daily prednisone for lupus
• Cushing’s disease: Pituitary ACTH-secreting tumor
• One cause of Cushing’s syndrome
Cushing’s Syndrome
Excess Cortisol Effects

• Hypertension
• Hyperglycemia
• Diabetes (insulin resistance)
• Immune suppression
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• Risk of infections, especially opportunistic
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Cushing’s Syndrome
Excess Cortisol Effects

• Cortisol alters GnRH release → ↓ FSH,LH

• Menstrual irregularities in women
• Abnormal cycles (80%)
• Oligomenorrhea (~30%)
• Amenorrhea (~30%)
• Hirsutism of face in women
• Males: Erectile dysfunction
Cushing’s Syndrome
Excess Cortisol Effects

• Stimulation of adipocytes → growth

• Progressive central obesity
• Face, neck, trunk, abdomen
• “Moon face” SherryC1234

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• "Buffalo hump"
• Fat mound at base of back of neck

Homini/Flikr
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Skin Changes
• Thinning of skin
• Easy bruising
• Striae: Stretch marks
• Purple lines on skin
• Fragile skin stretches over trunk, breasts, abdomen
• Thin skin cannot hide venous blood in dermis
• Commonly occur on sides and lower abdomen
Cushing’s Syndrome
Causes

• ACTH-independent (↓ACTH)
• Glucocorticoid therapy
• Adrenal adenoma
• ACTH-dependent (↑ACTH)
• Cushing’s disease (pituitary ACTH secreting tumor)
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• Ectopic ACTH (small cell lung cancer)
• ↑ACTH → adrenal hyperplasia → ↑cortisol
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Cushing’s Syndrome
Causes

• Special note: skin hyperpigmentation

• Can occur in ACTH-dependent Cushing’s syndrome
• Caused by ↑ ACTH not cortisol
• ↑ ACTH → ↑ MSH

Wikipedia/Public Domain
Cushing’s Syndrome
Diagnosis

• Measuring plasma cortisol difficult

• Circadian rhythm → high levels in AM
• Most cortisol bound to CBG
• CBG levels can affect serum measurement
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Cushing’s Syndrome
Diagnosis

• 24-hour urine free cortisol

• Integrates cortisol level over time
• Salivary cortisol
• No cortisol binding globulin in saliva
• Free cortisol level measured at night (should be low)
Cushing’s Syndrome
Diagnosis

• Low dose dexamethasone suppression test

• 1mg dexamethasone (“low dose”) administered at bedtime
• Suppresses normal pituitary ACTH release
• Morning blood test
• Cortisol level should beAfraTafreeh.com
low (suppressed)
• Cortisol remains high in Cushing’s syndrome
• Adenomas, tumors do not suppress cortisol production
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Cushing’s Syndrome
Diagnosis

• Step 1: Establish Cushing’s syndrome

• Step 2: Establish cause
• Key test is serum ACTH level

ACTH-Dependent Causes ACTH-Independent Causes

(High ACTH) (Low ACTH)
Cushing’s disease Steroid therapy
Ectopic ACTH Adrenal adenoma
High Dose Dexamethasone
• Low dose testing (1mg)
• Used to establish diagnosis of Cushing’s syndrome
• High dose dexamethasone test (8mg)
• Differentiate causes of high ACTH Cushing’s syndrome
• Will suppress cortisol in pituitary adenomas (↑ set point)
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• Will not suppress cortisol from ACTH tumors

AM Cortisol After Dexamethasone

Low Dose High Dose
Normal ↓ ↓
Pituitary Adenoma -- ↓
ACTH Tumor -- --
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Cushing’s Syndrome
Treatment

• Surgery
• Removal of adenoma (adrenal gland, pituitary)
• Removal of lung tumor
• Ketoconazole
Ketoconazole
• Antifungal
• Blocks ergosterol synthesis in fungi
• Also blocks 1st step in cortisol synthesis
• Desmolase (side chain cleavage)
• Can be used to treat Cushing’s syndrome
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• Also potent inhibitor androgen synthesis

• Key side effect: gynecomastia

Desmolase
Cholesterol Pregnenolone
Cortisol
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Adrenal Insufficiency
• Insufficient cortisol production
• Primary adrenal insufficiency (Addison’s disease)
• Failure of adrenal gland
• Cortisol and aldosterone will be low
• ACTH will be high
• Secondary adrenal insufficiency
• Failure of pituitary ACTH release
• Only cortisol will be low
Adrenal Insufficiency
Symptoms
• Loss of cortisol
• Weakness, fatigue
• Weight loss
• Postural hypotension
• Nausea, abdominal pain, diarrhea
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• Hypoglycemia
• Loss of aldosterone
• Potassium retention → hyperkalemia
• H+ retention → acidosis
• Sodium loss in urine → hypovolemia
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ACTH Effects
• ACTH is high in primary adrenal insufficiency
• This leads to skin hyperpigmentation
• Melanocyte stimulating hormone (MSH) shares
common precursor protein in pituitary with ACTH
• ↑ melanin synthesis

Proopiomelanocortin

ACTH MSH
Addison’s Hyperpigmentation
• Generalized hyperpigmentation
• Most obvious in sun-exposed areas
• Face, neck, backs of hands
• Also areas of friction/pressure
• Elbows, knees, knuckles,
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• May occur is palmar creases

• Classic scenario:
• GI symptoms (nausea, pain)
• Darkening skin

Wikipedia/Public Domain
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Adrenal Crisis
• Acute adrenal insufficiency
• Abrupt loss of cortisol and aldosterone
• Main manifestation is shock
• Hypoglycemia
• Other symptoms: nausea, vomiting, fatigue, confusion
• Often when acute ↑ adrenal function cannot be met
• Infection, surgery, trauma in patient with adrenal insufficiency
• Patients on chronic steroids
• “Stress dose steroids” for prevention
Addison’s Disease
Common Causes

• Autoimmune adrenalitis
• Antibody and cell-mediated disorder
• Antibodies to 21-hydroxylase commonly seen
• Atrophy of adrenal gland
• Loss of cortex AfraTafreeh.com
• Medulla is spared
• Infections
• Tuberculosis
• Fungal (histoplasmosis, cryptococcus)
• CMV
• Rare: tumor metastasis especially lung
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Metastasis from Lung Cancer

• Adrenals
• Usually found on imaging without symptoms
• Brain
• Headache, neuro deficits, seizures
• Bone
• Pathologic fractures
• Liver
• Hepatomegaly, jaundice
Waterhouse-Friderichsen
Syndrome
• Rare cause of acute adrenal insufficiency
• Caused by acute hemorrhage into adrenal glands
• Associated with meningococcemia
• Clinical scenario
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• Patient with bacterial meningitis
• Acute onset of shock

Xishan01/Wikipedia
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2o Adrenal Insufficiency
• Most common cause: glucocorticoid therapy
• Chronic suppression ACTH release
• Leads to adrenal atrophy over time
• Sudden discontinuation → hypoadrenalism
2o Adrenal Insufficiency
• Basis for “weaning” off steroids
• Slow discontinuation over time
• Basis for “stress dose steroids”
• Patients on chronic steroids with infection, trauma, surgery
• Risk of adrenal crisis AfraTafreeh.com
• High dose of glucocorticoids administered
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2 Adrenal Insufficiency
o
Important Points

• No skin findings
• ACTH is not elevated
• No hyperkalemia
• Aldosterone not effected
Adrenal Insufficiency
Diagnostic Tests

• 8 AM serum cortisol
• Levels should be highest at this time
• Low level indicates disease
• Serum ACTH
• High ACTH with low cortisol = primary disease
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• Low ACTH with low cortisol = secondary disease
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Adrenal Insufficiency
Diagnostic Tests

• ACTH stimulation test (“cosyntropin stim test”)

• Exogenous ACTH administered
• Cortisol should rise 30-60 minutes later
• Failure to rise = primary adrenal insufficiency
• Normal rise = secondary disorder
Primary Aldosteronism
Mineralocorticoid Excess

• Hypertension, classically at a young age

• Hypokalemia
• Weakness, muscle cramps
• Unreliable finding → many cases with normal K+
• Metabolic alkalosis AfraTafreeh.com
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Primary Aldosteronism
Most common causes

• Bilateral idiopathic hyperaldosteronism (~60%)

• Aldosterone-producing adenoma (~30%)
• Sometimes called Conn’s syndrome
Primary Aldosteronism
Diagnosis

• Plasma aldosterone concentration (PAC)

• Plasma renin activity (PRA)
• Plasma incubated
• Renin cleaves angiotensinogen in plasma
• Angiotensin I producedAfraTafreeh.com
→ measured by assay
• ↓ PRA and ↑ PAC = Primary aldosteronism
• ↑ PRA and ↑ PAC = Secondary aldosteronism
• Renal artery stenosis, CHF, low volume
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Primary Aldosteronism
Diagnosis

• Abdominal imaging for adrenal nodules/tumors

• Adrenal vein sampling
• Differentiates unilateral vs. bilateral disease
• Measure PAC and PRA in each vein
Primary Aldosteronism
Treatment

• Surgical adrenalectomy
• Adenomas
• Unilateral hyperplasia
• Spironolactone
• Drug of choice AfraTafreeh.com
• Potassium-sparing diuretic
• Blocks aldosterone effects
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Licorice
• Contains glycyrrhetinic acid (a steroid)
• Weak mineralocorticoid effect Pikaluk/Flikr
• Inhibits renal 11-beta-hydroxysteroid dehydrogenase
• Large amounts → Hypertension, hypokalemia
• Plasma aldosterone level low

11-beta-hydroxysteroid
Cortisol dehydrogenase Cortisone
Pheochromocytoma
• Catecholamine-secreting tumor
• Secrete epinephrine, norepinephrine, dopamine
• Chromaffin cells of adrenal medulla
• Derivatives of neural crest
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Pheochromocytoma
• Clinical presentation
• Classically episodic symptoms
• Hypertension
• Headaches
• Palpitations
• Sweating
• Pallor (pale skin)
Pheochromocytoma
Diagnosis

• Serum catecholamine levels not routinely used

• Levels fluctuate
• Some metabolism intratumoral
• Breakdown products of catecholamines measured
• Usually via 24 hour urine collection
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Pheochromocytoma
Diagnosis

COMT
MAO

COMT
MAO
Dopamine
Homovanillic
Acid
(HVA)

Monoamine Oxidase (MAO)

Catechol-O-methyltransferase (COMT)
Pheochromocytoma
Diagnosis

COMT
Norepinephrine Normetanephrine

MAO
MAO AfraTafreeh.com
Dihydroxymandelic COMT Vanillylmandelic
Acid acid (VMA)
MAO
MAO
COMT
Epinephrine Metanephrine
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Pheochromocytoma
Diagnosis

• Metanephrines often measured for diagnosis

• Metanephrine and normetanephrine
• 24hour urine collection or plasma
• Older test: 24 hour collection of VMA
Pheochromocytoma
Treatment

• Definitive therapy: Surgery

• Pre-operative management:
• Phenoxybenzamine (irreversible α blocker)
• Non-selective beta blockers (propranolol)
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Paraganglioma
• Catecholamine-secreting tumor
• Arise from sympathetic ganglia (extraadrenal)
• Similar clinical presentation to pheochromocytoma
Neuroblastoma
• Tumor of primitive sympathetic ganglion cells
• Also derived from neural crest cells
• Can arise anywhere in sympathetic nervous system
• Adrenal gland most common (40 percent)
• Abdominal (25 percent)AfraTafreeh.com
• Thoracic (15 percent)
• Almost always occurs in children
• 3rd most common childhood cancer (leukemia, brain tumors)
• Most common extracranial tumor
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Neuroblastoma
• Symptoms related to tumor mass effect
• Commonly present as abdominal pain
• Can synthesize catecholamines
• Rarely cause symptoms like pheochromocytoma
• Urinary HVA/VMA levels used for diagnosis
• Rare feature: Opsoclonus-myoclonus-ataxia (OMA)
• Rare paraneoplastic syndrome
• Rapid eye movements, rhythmic jerking, ataxia
• Half of OMA patients have a neuroblastoma
Neuroblastoma
• Diverse range of disease progression
• Key risk factor: Age at diagnosis
• Infants with disseminated disease often cured
• Children over 18 months often die despite therapy
• Younger age = better prognosis
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• N-myc
• Proto-oncogene
• Amplified/overexpressed in some tumors
• Associated with poor prognosis
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MIBG 131

Metaiodobenzylguanidine
MIBG
• Chemical analog of norepinephrine
• Diagnosis of pheochromocytoma & neuroblastoma
• Concentrated in sympathetic tissues
• Labeled with radioactive iodine (I131)
• Will concentrate in tumors → emit radiation
• Special note: thyroid gland must be protected
• Simultaneous administration of potassium iodide
• Non-radioactive iodine
• Will be taken up by thyroid instead

Norepinephrine
Adrenal Adenomas
• Often discovered on abdominal imaging
• “Adrenal incidentaloma”
• Concern for malignancy and/or functioning adenoma

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Adrenal Adenomas
• May secrete cortisol or aldosterone
• Common functional tests
• 24 hour urine metanephrines (pheochromocytoma)
• 24 hour urine free cortisol (Cushing’s)
• Low dose dexamethasone suppression (Cushing’s)
• Serum PRA/aldosterone (aldosteronism)
• Often followed for growth over time (non-functional)
• Large (>5cm) often removed