Medical School · Year 2 · Endocrine · includes a quiz and discussion video

Lecture 8: Adrenal Cortex Disorders

Unit 2.3: Endocrine System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the causes, diagnosis, and management of Cushing syndrome
2. Explain primary and secondary adrenal insufficiency
3. Describe acute adrenal crisis and its management
4. Explain primary aldosteronism and its subtypes
5. Describe adrenal incidentalomas and their evaluation
6. Explain rare adrenal disorders including adrenal carcinoma

Lecture Outline

I. Cushing Syndrome - Overview

Cushing syndrome refers to the clinical manifestations of chronic glucocorticoid excess, regardless of the underlying cause. Understanding the distinction between Cushing syndrome (the clinical state) and Cushing disease (specifically pituitary-dependent hypercortisolism) is essential for proper diagnosis and management.

The definition distinguishes between related terms. Cushing syndrome is hypercortisolism from any cause—it is a clinical diagnosis describing the constellation of signs and symptoms from excess glucocorticoid. Cushing disease specifically refers to hypercortisolism caused by an ACTH-secreting pituitary adenoma; it is the most common form of endogenous Cushing syndrome.

The causes of Cushing syndrome are classified as exogenous or endogenous, and endogenous causes are further divided by ACTH dependence. Exogenous Cushing syndrome from iatrogenic glucocorticoid administration is by far the most common cause overall—any patient on chronic prednisone or equivalent is at risk. ACTH is suppressed due to exogenous glucocorticoid feedback. ACTH-dependent causes include pituitary adenoma (Cushing disease), accounting for 70% of endogenous cases; ectopic ACTH secretion from tumors such as small cell lung cancer, bronchial carcinoid, or other neuroendocrine tumors; and rare ectopic CRH secretion. In all ACTH-dependent forms, ACTH is elevated or inappropriately normal. ACTH-independent causes include adrenal adenoma (unilateral cortisol-secreting tumor), adrenal carcinoma (often secreting androgens as well as cortisol), and bilateral adrenal hyperplasia (including primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia). In ACTH-independent forms, ACTH is suppressed.

Epidemiologically, endogenous Cushing syndrome is relatively rare, with an incidence of 2-3 per million population per year. Women are affected approximately three times more frequently than men. Of endogenous cases, Cushing disease (pituitary) accounts for about 70% of ACTH-dependent cases. Ectopic ACTH accounts for 10-15% of ACTH-dependent cases. Adrenal tumors account for 15-20% of all endogenous cases.

<image>Panel A: Primary classification dividing Cushing syndrome into exogenous (iatrogenic glucocorticoids, most common cause overall) and endogenous causes as the first branch point. Panel B: Endogenous ACTH-dependent causes showing pituitary adenoma (Cushing disease, 70%), ectopic ACTH secretion (SCLC, carcinoid, 10-15%), and ectopic CRH (rare) with pie chart of relative frequencies. Panel C: Endogenous ACTH-independent causes showing adrenal adenoma, adrenal carcinoma, and bilateral adrenal hyperplasia with suppressed ACTH levels indicated. Panel D: Summary pie chart of all endogenous Cushing syndrome causes with relative frequency percentages and ACTH status (elevated versus suppressed) for each category.</image>

II. Cushing Syndrome - Clinical Features

The clinical manifestations of Cushing syndrome reflect the widespread effects of cortisol excess on metabolism, connective tissue, the immune system, and other organ systems. Recognizing the classic features enables clinical suspicion, though many features are nonspecific and common in the general population.

Classic manifestations of Cushing syndrome result from specific pathophysiologic effects of cortisol. Central obesity with fat redistribution to the abdomen, face, and dorsocervical area occurs while the extremities may actually lose fat. Moon facies describes the rounded, plethoric facial appearance from facial fat deposition. Buffalo hump (dorsocervical fat pad) reflects supraclavicular and posterior neck fat accumulation. Purple striae, typically wider than 1 cm, appear on the abdomen, flanks, thighs, and arms, resulting from skin thinning combined with rapid stretching of weakened connective tissue. Easy bruising reflects capillary fragility from loss of connective tissue support. Proximal myopathy causes difficulty rising from a chair or climbing stairs, reflecting protein catabolism in muscle. Thin, fragile skin with poor wound healing results from collagen breakdown.

Metabolic effects of cortisol excess affect multiple systems. Hyperglycemia and frank diabetes mellitus occur from increased gluconeogenesis and insulin resistance. Hypertension develops from multiple mechanisms including mineralocorticoid effects of cortisol and enhanced vascular sensitivity to catecholamines. Dyslipidemia with elevated LDL and triglycerides increases cardiovascular risk. Osteoporosis with increased fracture risk results from decreased bone formation and increased resorption. Hypokalemia may occur, particularly when cortisol is markedly elevated and overwhelms 11β-HSD2, allowing cortisol to activate mineralocorticoid receptors.

Other features span multiple organ systems. Psychiatric manifestations including depression, anxiety, irritability, cognitive impairment, and psychosis are common. Immune suppression leads to increased susceptibility to infections and impaired wound healing. Reproductive effects include menstrual irregularity and amenorrhea in women and decreased libido in both sexes. Skin manifestations include hirsutism and acne, particularly in ACTH-dependent forms where adrenal androgens are also elevated. Cardiovascular risk is substantially increased, with elevated rates of myocardial infarction, stroke, and venous thromboembolism.

Certain features suggest malignancy or ectopic ACTH production. Rapid onset of symptoms over weeks to months suggests aggressive disease. Severe hypokalemia suggests very high cortisol levels. Markedly elevated ACTH favors ectopic source. Virilization in women (deepening voice, male-pattern baldness, clitoromegaly) suggests adrenal carcinoma co-secreting androgens.

<image>Panel A: Central figure of a patient with characteristic Cushing syndrome body habitus showing moon facies, buffalo hump, central obesity, thin extremities, and purple abdominal striae wider than 1 cm with labeled annotation boxes. Panel B: Metabolic and cardiovascular manifestations organized as diabetes and hyperglycemia, hypertension, dyslipidemia, and osteoporosis with pathophysiologic mechanisms for each. Panel C: Additional system manifestations including psychiatric (depression, cognitive impairment), skin (thin skin, bruising, hirsutism), musculoskeletal (proximal myopathy), and immune (infections, poor wound healing) categories. Panel D: Warning box highlighting features suggesting malignancy or ectopic ACTH including rapid symptom onset, severe hypokalemia, markedly elevated ACTH, and virilization in women suggesting adrenal carcinoma.</image>

III. Cushing Syndrome - Diagnosis

The diagnosis of Cushing syndrome proceeds through three steps: confirming hypercortisolism, determining ACTH dependence, and localizing the source. This systematic approach prevents misdiagnosis and ensures appropriate treatment.

Step 1 involves confirming hypercortisolism through biochemical testing. At least two positive first-line tests are typically required for diagnosis. The 24-hour urine free cortisol (UFC) measures integrated cortisol excretion; values greater than three times the upper limit of normal are highly specific. Late-night salivary cortisol detects loss of the normal circadian rhythm (cortisol should be at its nadir around midnight); two elevated samples are required. The 1 mg overnight dexamethasone suppression test (DST) evaluates whether a small dose of exogenous glucocorticoid appropriately suppresses morning cortisol; failure to suppress cortisol below 1.8 μg/dL suggests autonomous cortisol production. The 2-day low-dose DST (0.5 mg every 6 hours for 48 hours) is an alternative with similar interpretation. Pseudo-Cushing states (depression, alcoholism, obesity, poorly controlled diabetes) can cause mild biochemical abnormalities, and clinical correlation is essential.

Step 2 determines ACTH dependence by measuring plasma ACTH level. A suppressed ACTH (less than 5 pg/mL) indicates ACTH-independent Cushing syndrome, and the source is in the adrenal gland. An elevated ACTH (greater than 20 pg/mL) indicates ACTH-dependent Cushing syndrome from either pituitary or ectopic source. Intermediate ACTH (5-20 pg/mL) may require additional testing.

Step 3 localizes the source of hypercortisolism. For ACTH-independent disease, adrenal CT or MRI reveals unilateral adenoma, carcinoma, or bilateral disease. For ACTH-dependent disease, distinguishing pituitary from ectopic source requires additional testing. Pituitary MRI may visualize an adenoma (often a microadenoma less than 1 cm). The high-dose dexamethasone suppression test (2 mg every 6 hours for 48 hours or 8 mg overnight) is based on the principle that pituitary tumors retain some feedback sensitivity, while ectopic tumors do not; greater than 50% suppression of cortisol or UFC suggests pituitary source. The CRH stimulation test provokes ACTH and cortisol release in pituitary Cushing disease but not in ectopic ACTH. Inferior petrosal sinus sampling (IPSS) is the gold standard when non-invasive tests are inconclusive; a central-to-peripheral ACTH gradient (ratio greater than 2 at baseline or greater than 3 after CRH) confirms pituitary source.

<image>Panel A: Step 1 confirming hypercortisolism with three first-line tests (24-hour urine free cortisol, late-night salivary cortisol, 1 mg overnight dexamethasone suppression test) showing interpretation criteria and threshold values for each. Panel B: Step 2 determining ACTH dependence with plasma ACTH measurement thresholds showing suppressed (less than 5 pg/mL) pointing to adrenal imaging and elevated (greater than 20 pg/mL) proceeding to source localization. Panel C: Step 3 localizing the source for ACTH-dependent disease showing testing cascade of pituitary MRI, high-dose DST, and CRH stimulation test with expected results for pituitary versus ectopic source. Panel D: Inferior petrosal sinus sampling (IPSS) as gold standard showing catheter placement in bilateral petrosal sinuses with central-to-peripheral ACTH gradient interpretation (ratio greater than 2 at baseline or greater than 3 after CRH confirms pituitary source).</image>

IV. Cushing Syndrome - Treatment

Treatment of Cushing syndrome aims to normalize cortisol levels and address the underlying cause. The approach depends on the etiology, with surgery as first-line treatment for most causes and medical therapy playing supportive or temporizing roles.

Treatment of pituitary Cushing disease (the most common endogenous cause) centers on transsphenoidal surgery. Selective adenomectomy preserves normal pituitary tissue while removing the tumor. Initial remission rates are 70-90% for microadenomas and lower for macroadenomas. Postoperative hypocortisolism is expected and actually indicates successful removal; patients require glucocorticoid replacement during HPA axis recovery, which can take months to over a year. Recurrence occurs in 15-25% of patients. For failed surgery or recurrence, options include repeat surgery, radiation therapy (conventional or stereotactic radiosurgery, with effect developing over years), medical therapy to control hypercortisolism, or bilateral adrenalectomy as a last resort.

Treatment of ectopic ACTH syndrome involves resection of the causative tumor when possible. Localization requires comprehensive imaging, and some occult tumors cannot be found. Medical therapy controls hypercortisolism when the source cannot be resected. Bilateral adrenalectomy provides definitive control when the tumor is unresectable.

Treatment of adrenal tumors involves surgical resection. For adrenal adenoma, unilateral adrenalectomy (laparoscopic if possible) is curative, with excellent prognosis. For adrenal carcinoma, radical resection with lymphadenectomy is performed when feasible; mitotane (an adrenolytic drug) is used as adjuvant therapy or for unresectable disease; chemotherapy may be added for advanced disease; prognosis is poor for advanced cases.

Medical therapy serves several roles. Steroidogenesis inhibitors block cortisol synthesis in the adrenal. Ketoconazole inhibits multiple cytochrome P450 enzymes; side effects include hepatotoxicity and drug interactions. Metyrapone inhibits 11β-hydroxylase. Osilodrostat is a newer, potent 11β-hydroxylase inhibitor. These drugs are used as a bridge to surgery, for unresectable disease, or when surgery is contraindicated. Mitotane is adrenolytic (destroys adrenal cortex) and is used for adrenal carcinoma and severe Cushing syndrome. Mifepristone is a glucocorticoid receptor antagonist that blocks cortisol action at the receptor; cortisol levels remain elevated, so it cannot be monitored; useful for hyperglycemia in Cushing syndrome. Pituitary-directed therapy includes pasireotide (a somatostatin analog) and cabergoline (a dopamine agonist), which may reduce ACTH secretion from pituitary adenomas.

<image>Panel A: Pituitary Cushing disease treatment showing transsphenoidal surgery as first-line with 70-90% remission for microadenomas, and second-line options including repeat surgery, radiation therapy, and medical therapy for failure or recurrence. Panel B: Ectopic ACTH treatment showing tumor resection if localizable, medical therapy for hypercortisolism control when source is unresectable, and bilateral adrenalectomy as definitive option. Panel C: Adrenal tumor treatment showing laparoscopic adrenalectomy for adenoma (curative) and radical resection with mitotane adjuvant therapy for adrenal carcinoma with post-operative adrenal insufficiency management notes. Panel D: Medical therapy options organized by mechanism showing steroidogenesis inhibitors (ketoconazole, metyrapone, osilodrostat), adrenolytic (mitotane), glucocorticoid receptor antagonist (mifepristone), and pituitary-directed agents (pasireotide, cabergoline) with their sites of action.</image>

V. Adrenal Insufficiency - Overview

Adrenal insufficiency is the clinical syndrome resulting from deficient cortisol production or action. Classification by anatomic level guides diagnosis and management, as primary and secondary forms have distinct clinical features and treatment requirements.

The classification of adrenal insufficiency depends on the level of the defect. Primary adrenal insufficiency (Addison's disease) results from destruction or dysfunction of the adrenal cortex itself; ACTH is elevated due to loss of negative feedback. Secondary adrenal insufficiency results from pituitary ACTH deficiency; ACTH is low or inappropriately normal. Tertiary adrenal insufficiency results from hypothalamic CRH deficiency; ACTH is similarly low. Secondary and tertiary forms are often grouped as "central" adrenal insufficiency.

Primary adrenal insufficiency (Addison's disease) has multiple etiologies. Autoimmune adrenalitis is the most common cause in developed countries, accounting for approximately 80% of cases; it may occur in isolation or as part of autoimmune polyglandular syndromes. Infectious causes include tuberculosis (the most common cause worldwide), HIV/AIDS, fungal infections (histoplasmosis, coccidioidomycosis), and cytomegalovirus. Infiltrative diseases include metastatic cancer (lung, breast, melanoma), lymphoma, and amyloidosis. Adrenal hemorrhage (Waterhouse-Friderichsen syndrome associated with meningococcemia, or hemorrhage in anticoagulated patients) causes acute adrenal destruction. Drug-induced causes include ketoconazole, etomidate, and mitotane. Genetic causes include congenital adrenal hyperplasia, adrenoleukodystrophy (X-linked, with neurologic manifestations), and rare enzymatic defects.

Secondary and tertiary adrenal insufficiency causes relate to pituitary or hypothalamic dysfunction. Exogenous glucocorticoid therapy is the most common cause overall—chronic supraphysiologic doses suppress the HPA axis. Pituitary tumors, either through compression of normal corticotrophs or following surgical removal. Pituitary surgery or radiation causes hypopituitarism. Infiltrative diseases (sarcoidosis, hemochromatosis, Langerhans cell histiocytosis) may affect the pituitary. Sheehan syndrome (postpartum pituitary necrosis following obstetric hemorrhage) causes panhypopituitarism. Traumatic brain injury can damage the pituitary.

A critical difference between primary and secondary adrenal insufficiency is that mineralocorticoid function is preserved in secondary/tertiary disease. Aldosterone production is primarily regulated by the RAAS and potassium, not ACTH, so the zona glomerulosa remains functional when ACTH is deficient.

<image>Panel A: Three anatomic levels of adrenal insufficiency showing primary (adrenal gland destruction, high ACTH), secondary (pituitary ACTH deficiency, low ACTH), and tertiary (hypothalamic CRH deficiency, low ACTH) with corresponding organ highlighted at each level. Panel B: Primary adrenal insufficiency causes listed as autoimmune adrenalitis (80% in developed countries), infections (tuberculosis most common worldwide), infiltrative disease, adrenal hemorrhage, drug-induced, and genetic causes. Panel C: Secondary and tertiary causes listed as exogenous glucocorticoids (most common overall), pituitary tumor, surgery or radiation, Sheehan syndrome, and traumatic brain injury. Panel D: Key distinction diagram showing mineralocorticoid deficiency present only in primary adrenal insufficiency (both cortisol and aldosterone affected) versus preserved mineralocorticoid function in secondary and tertiary forms (only cortisol affected, aldosterone regulated by RAAS independently).</image>

VI. Adrenal Insufficiency - Clinical Features

The clinical manifestations of adrenal insufficiency result from deficiency of cortisol (in all forms) and aldosterone (in primary adrenal insufficiency only). Understanding these features enables recognition of this potentially life-threatening condition.

Cortisol deficiency produces symptoms common to all forms of adrenal insufficiency. Fatigue and weakness are nearly universal and often the most prominent complaints. Anorexia with nausea and vomiting leads to weight loss. Hypotension, particularly orthostatic hypotension, results from loss of cortisol's permissive effects on catecholamine action. Hypoglycemia reflects loss of cortisol's gluconeogenic effects, particularly during fasting or stress.

Mineralocorticoid deficiency (primary adrenal insufficiency only) produces additional distinctive features. Salt craving is a common symptom as patients attempt to compensate for sodium losses. Hyponatremia results from renal sodium wasting; this is more severe than the dilutional hyponatremia of secondary adrenal insufficiency. Hyperkalemia results from impaired renal potassium excretion. Volume depletion and dehydration compound the hypotension. Metabolic acidosis from impaired renal hydrogen ion excretion may occur.

ACTH excess (primary adrenal insufficiency only) causes characteristic features. Hyperpigmentation is pathognomonic for primary adrenal insufficiency and results from elevated POMC-derived peptides including melanocyte-stimulating hormone (MSH). Pigmentation is accentuated in sun-exposed areas, pressure points (knuckles, elbows, knees), palmar creases, oral mucosa (buccal mucosa, gingival margin), scars, and areolae. Secondary/tertiary adrenal insufficiency causes pallor rather than hyperpigmentation because ACTH is low.

Associated findings may suggest the underlying cause. Autoimmune associations including thyroid disease (Hashimoto's or Graves'), type 1 diabetes, vitiligo, and pernicious anemia suggest autoimmune polyglandular syndrome. Eosinophilia and lymphocytosis may be present, reflecting loss of cortisol's suppressive effects on these cell populations.

<image>Panel A: Symptoms organized by cortisol deficiency (fatigue, weakness, anorexia, weight loss, hypotension, hypoglycemia) common to all forms of adrenal insufficiency. Panel B: Mineralocorticoid deficiency symptoms exclusive to primary adrenal insufficiency including salt craving, hyponatremia, hyperkalemia, volume depletion, and metabolic acidosis. Panel C: Hyperpigmentation distribution figure showing ACTH excess effects with darkened palmar creases, oral mucosa (buccal and gingival), sun-exposed areas, pressure points, scars, and areolae. Panel D: Comparison table contrasting primary adrenal insufficiency (hyperpigmentation, hyponatremia with hyperkalemia, autoimmune associations) versus secondary adrenal insufficiency (pallor, milder dilutional hyponatremia, no hyperkalemia, other pituitary hormone deficiencies).</image>

VII. Adrenal Insufficiency - Diagnosis

The diagnosis of adrenal insufficiency requires biochemical confirmation followed by determination of whether the process is primary or secondary. Prompt diagnosis is essential given the life-threatening nature of adrenal crisis.

Screening tests suggest adrenal insufficiency but are not definitive. Morning cortisol (8 AM) of less than 3 μg/dL strongly suggests adrenal insufficiency, while levels greater than 15-18 μg/dL make the diagnosis unlikely. Intermediate values require dynamic testing. Random cortisol during acute illness should be elevated; a low level in a critically ill patient raises concern for adrenal insufficiency.

The ACTH stimulation test (cosyntropin test) is the definitive diagnostic test for adrenal insufficiency. The standard protocol administers 250 μg of cosyntropin (synthetic ACTH 1-24) intravenously or intramuscularly. Cortisol is measured at baseline and at 30 and 60 minutes. A normal response is peak cortisol of 18-20 μg/dL or greater, indicating adequate adrenal reserve. A subnormal response (peak cortisol less than 18 μg/dL) confirms adrenal insufficiency. The standard-dose test reliably detects primary adrenal insufficiency but may be falsely normal in recent or partial secondary adrenal insufficiency before adrenal atrophy has occurred. A low-dose (1 μg) test may be more sensitive for secondary adrenal insufficiency but is technically more difficult.

Differentiating primary from secondary adrenal insufficiency uses additional testing. Baseline ACTH measurement distinguishes primary (elevated, often greater than two times normal) from secondary (low or inappropriately normal) adrenal insufficiency. Aldosterone and renin levels are abnormal only in primary adrenal insufficiency: aldosterone is low, and renin activity is elevated. Potassium is elevated in primary adrenal insufficiency (from aldosterone deficiency) but typically normal in secondary.

Additional testing helps determine the cause. Adrenal antibodies (21-hydroxylase antibodies) are positive in autoimmune adrenal insufficiency. Adrenal CT evaluates structure: small, atrophic adrenals suggest autoimmune destruction; enlarged adrenals suggest infiltrative disease, infection, or hemorrhage; calcifications suggest prior tuberculosis or histoplasmosis. Pituitary MRI is indicated for secondary adrenal insufficiency to evaluate for pituitary pathology. Very long-chain fatty acids (VLCFA) screening in young men diagnoses adrenoleukodystrophy.

<image>Panel A: Morning cortisol screening showing interpretation thresholds with less than 3 mcg/dL indicating likely adrenal insufficiency, greater than 15 mcg/dL making diagnosis unlikely, and 3-15 mcg/dL requiring dynamic testing. Panel B: ACTH stimulation test timeline showing cosyntropin 250 mcg injection with cortisol measurements at 0, 30, and 60 minutes, normal response threshold at 18 mcg/dL or greater, and subnormal response confirming adrenal insufficiency. Panel C: Differentiation between primary and secondary adrenal insufficiency with parallel diagnostic pathways comparing ACTH level (elevated versus low), aldosterone and renin (abnormal versus normal), and potassium (elevated versus normal). Panel D: Further workup boxes showing adrenal antibodies and adrenal CT for primary adrenal insufficiency versus pituitary MRI for secondary adrenal insufficiency with additional tests including VLCFA screening for adrenoleukodystrophy.</image>

VIII. Adrenal Insufficiency - Treatment

Treatment of adrenal insufficiency involves hormone replacement therapy tailored to the type of insufficiency, with particular attention to stress dosing during illness or surgery. Patient education is critical for prevention of adrenal crisis.

Glucocorticoid replacement is required for all forms of adrenal insufficiency. Hydrocortisone (cortisol) is the most commonly used replacement, given in divided doses to mimic the physiologic circadian rhythm: typically 15-25 mg per day, with approximately two-thirds given in the morning and one-third in the afternoon. Alternatively, prednisone 3-5 mg daily (usually as a single morning dose) may be used. Cortisone acetate 25-37.5 mg daily (converted to cortisol in the liver) is another option. Monitoring is clinical rather than laboratory-based, aiming to avoid over-replacement (which causes Cushingoid features, osteoporosis, and weight gain) while preventing under-replacement (fatigue, weight loss, hypotension).

Mineralocorticoid replacement is required only for primary adrenal insufficiency. Fludrocortisone 0.05-0.2 mg daily replaces aldosterone. Monitoring includes blood pressure (avoiding supine hypertension), serum potassium (should normalize), and plasma renin activity (target the upper normal range; elevated renin suggests inadequate dosing, suppressed renin suggests excessive dosing).

DHEA replacement may be considered in women with primary adrenal insufficiency who have low energy, decreased libido, or depression despite adequate glucocorticoid and mineralocorticoid replacement. Typical dose is 25-50 mg daily. Evidence of benefit is mixed, and this remains optional.

Stress dosing is essential to prevent adrenal crisis during physiologic stress. For minor febrile illness, double the oral glucocorticoid dose for 2-3 days. For moderate stress (outpatient surgery, gastroenteritis with vomiting), give hydrocortisone 50 mg every 8 hours. For major stress (major surgery, critical illness, trauma), give hydrocortisone 100 mg IV bolus followed by 50 mg IV every 6-8 hours. As stress resolves, rapidly taper back to maintenance replacement over 1-3 days.

Patient education is critical. Patients must understand that they cannot stop glucocorticoids abruptly and must increase doses during stress. Medical alert identification (bracelet or necklace) ensures appropriate treatment if the patient is incapacitated. Emergency injection kit with injectable hydrocortisone allows self-administration or administration by a family member during vomiting or loss of consciousness. Sick day rules with clear instructions should be provided in writing.

<image>Panel A: Glucocorticoid replacement options showing hydrocortisone 15-25 mg per day with circadian dosing (two-thirds morning, one-third afternoon) and alternative prednisone 3-5 mg as single morning dose with monitoring guidance. Panel B: Mineralocorticoid replacement for primary adrenal insufficiency showing fludrocortisone 0.05-0.2 mg daily with monitoring parameters including blood pressure, serum potassium, and plasma renin activity targets. Panel C: Stress dosing protocol displayed as stepped diagram showing minor illness (double oral dose for 2-3 days), moderate stress (hydrocortisone 50 mg every 8 hours), and major stress (100 mg IV bolus followed by 50 mg every 6-8 hours) with rapid taper back to baseline. Panel D: Patient education essentials highlighted showing medical alert identification bracelet, emergency injectable hydrocortisone kit, written sick day rules, and instructions about never stopping glucocorticoids abruptly.</image>

IX. Adrenal Crisis

Adrenal crisis is a life-threatening emergency resulting from acute cortisol deficiency. Prompt recognition and treatment are essential, as untreated adrenal crisis is rapidly fatal.

Precipitants of adrenal crisis trigger acute cortisol insufficiency in patients with limited adrenal reserve. Infection is the most common precipitant. Surgery or trauma without adequate stress dosing overwhelms insufficient cortisol production. Abrupt discontinuation of chronic glucocorticoids prevents the suppressed HPA axis from responding. Adrenal hemorrhage (in anticoagulated patients, meningococcemia, or spontaneously) destroys adrenal tissue. Undiagnosed adrenal insufficiency may present as adrenal crisis during the first major illness.

Clinical features of adrenal crisis reflect severe cortisol and mineralocorticoid deficiency. Hypotension progressing to shock is the hallmark; characteristically refractory to volume resuscitation and vasopressors until glucocorticoids are given. Severe nausea, vomiting, and abdominal pain may mimic an acute abdomen. Fever is often present (from the underlying infection or from cortisol deficiency itself). Altered mental status ranges from confusion to obtundation to coma. Severe hypoglycemia may occur.

Laboratory findings in adrenal crisis include characteristic electrolyte abnormalities. Hyponatremia results from both mineralocorticoid and cortisol deficiency (the latter impairing free water excretion). Hyperkalemia occurs from mineralocorticoid deficiency (in primary adrenal insufficiency). Hypoglycemia reflects impaired gluconeogenesis. Eosinophilia and lymphocytosis result from loss of cortisol's suppressive effects. Azotemia occurs from hypovolemia.

Treatment of adrenal crisis is urgent and should not be delayed for diagnostic testing. Intravenous fluid resuscitation with normal saline (1-2 liters or more as needed) addresses hypovolemia. Hydrocortisone 100 mg IV bolus is given immediately; this provides both glucocorticoid and mineralocorticoid effects (high-dose hydrocortisone has significant mineralocorticoid activity). Continue hydrocortisone 50-100 mg IV every 6-8 hours until stable. Treat the precipitating illness (usually infection). Do not wait for diagnostic test results before treating—empiric treatment should begin immediately if adrenal crisis is suspected.

<image>Panel A: Common precipitants of adrenal crisis with icons showing infection (most common), surgery or trauma without stress dosing, abrupt discontinuation of glucocorticoids, adrenal hemorrhage, and undiagnosed adrenal insufficiency with new illness. Panel B: Clinical features showing hypotension and shock refractory to vasopressors (hallmark finding), severe nausea and vomiting mimicking acute abdomen, fever, altered mental status ranging to coma, and hypoglycemia. Panel C: Laboratory findings showing hyponatremia, hyperkalemia (in primary AI), hypoglycemia, eosinophilia, lymphocytosis, and azotemia from hypovolemia. Panel D: Emergency treatment protocol with numbered steps showing IV normal saline 1-2 liters bolus, hydrocortisone 100 mg IV immediately, continue hydrocortisone 50-100 mg IV every 6-8 hours, treat precipitating illness, and bold warning to not delay treatment for diagnostic test results.</image>

X. Primary Aldosteronism

Primary aldosteronism (PA) is autonomous aldosterone production independent of the renin-angiotensin system. It is now recognized as a common and underdiagnosed cause of hypertension, with specific treatment implications.

Overview of primary aldosteronism reveals its importance in hypertension. PA is defined as aldosterone production that is inappropriately high for sodium status and is not suppressible by salt loading. Prevalence is estimated at 5-10% of all patients with hypertension, and much higher (15-20%) among those with resistant hypertension. Recognition is important because PA causes more cardiovascular damage than essential hypertension at the same blood pressure level, and specific treatment (surgery or mineralocorticoid antagonists) can be curative or highly effective.

Causes of primary aldosteronism are predominantly two subtypes. Bilateral adrenal hyperplasia (idiopathic hyperaldosteronism) accounts for 60-70% of cases; both adrenals have autonomous function, and treatment is medical. Aldosterone-producing adenoma (Conn syndrome) accounts for 30-40% of cases; a unilateral adenoma is the source, and treatment is surgical (adrenalectomy is potentially curative). Rare causes include unilateral hyperplasia, adrenal carcinoma, and familial forms (glucocorticoid-remediable aldosteronism).

Clinical features of primary aldosteronism relate to aldosterone excess. Hypertension is typically moderate to severe and may be resistant to multiple antihypertensives. Hypokalemia is the classic finding but is present in only 30-50% of cases. Symptoms of hypokalemia include muscle weakness, cramping, and polyuria (from nephrogenic diabetes insipidus). Metabolic alkalosis results from renal hydrogen ion excretion. Notably, edema is typically absent despite sodium retention due to "aldosterone escape" in the proximal tubule.

Diagnosis of primary aldosteronism proceeds through screening, confirmation, and subtype differentiation. Screening uses the aldosterone-to-renin ratio (ARR): a ratio greater than 30 (with aldosterone greater than 15 ng/dL) is suggestive; certain medications (beta-blockers, diuretics, ACE inhibitors, ARBs, spironolactone) interfere with interpretation and should ideally be held. Confirmatory testing demonstrates that aldosterone fails to suppress appropriately; oral sodium loading (high sodium diet for 3 days followed by urine aldosterone measurement) or intravenous saline infusion (2L over 4 hours with post-infusion aldosterone measurement) are options. Subtype differentiation distinguishes unilateral from bilateral disease. Adrenal CT evaluates anatomy but can be misleading (may miss small adenomas, may show non-functioning incidentalomas). Adrenal vein sampling (AVS) is the gold standard for lateralization, measuring aldosterone and cortisol in both adrenal veins and comparing to peripheral levels.

Treatment of primary aldosteronism depends on the subtype. For unilateral disease (adenoma or unilateral hyperplasia), laparoscopic adrenalectomy is recommended; cure of hypertension occurs in 50-60%, with improvement in most others. For bilateral hyperplasia, medical therapy with mineralocorticoid receptor antagonists is the treatment of choice. Spironolactone is effective but has anti-androgen side effects (gynecomastia, erectile dysfunction, menstrual irregularities). Eplerenone is more selective with fewer anti-androgen effects but may be less potent.

<image>Panel A: Two main subtypes of primary aldosteronism showing bilateral adrenal hyperplasia (idiopathic hyperaldosteronism, 60-70%, treated medically) and aldosterone-producing adenoma (Conn syndrome, 30-40%, treated surgically) with relative frequency pie chart. Panel B: Diagnostic algorithm showing screening with aldosterone-to-renin ratio greater than 30 with aldosterone greater than 15 ng/dL, confirmatory salt loading test demonstrating non-suppressible aldosterone, and clinical features (hypertension, hypokalemia in 30-50%, metabolic alkalosis). Panel C: Subtype differentiation showing adrenal CT for anatomic assessment followed by adrenal vein sampling (gold standard) illustrated with catheter positions in both adrenal veins measuring aldosterone and cortisol for lateralization. Panel D: Treatment by subtype showing laparoscopic adrenalectomy for unilateral disease (50-60% hypertension cure rate) and mineralocorticoid receptor antagonists (spironolactone or eplerenone) for bilateral hyperplasia with side effect profiles listed.</image>

XI. Adrenal Incidentaloma

An adrenal incidentaloma is an adrenal mass discovered incidentally on imaging performed for unrelated reasons. With increased use of cross-sectional imaging, incidentalomas are increasingly common and require systematic evaluation to identify the small percentage that require intervention.

Definition and epidemiology reflect the growing clinical importance of incidentalomas. An incidentaloma is an adrenal mass 1 cm or larger discovered on imaging not performed to evaluate adrenal disease. Prevalence on CT scans is approximately 4-5% and increases with age, reaching 10% in elderly populations. The vast majority are benign and non-functioning.

Differential diagnosis spans benign and malignant, functioning and non-functioning lesions. Adenoma is the most common diagnosis (70-80% of incidentalomas) and is benign. Metastases from lung, breast, renal, and melanoma primaries are common in patients with known malignancy; bilateral involvement is typical. Pheochromocytoma (approximately 5% of incidentalomas) must be excluded because of perioperative risk. Adrenocortical carcinoma (less than 5%) has concerning imaging features. Myelolipoma is a benign fat-containing tumor easily recognized on CT. Simple or complex cysts are generally benign.

Evaluation of an adrenal incidentaloma addresses two questions: is it functioning, and is it malignant? Hormonal evaluation should be performed in all patients. Cortisol excess is assessed with a 1 mg overnight dexamethasone suppression test (the most commonly identified hormone excess from incidentalomas). Pheochromocytoma is excluded by plasma or 24-hour urine metanephrines. Aldosterone excess is assessed with aldosterone-to-renin ratio in hypertensive patients. Imaging characteristics help distinguish benign from malignant. Size greater than 4-6 cm raises concern for malignancy. Hounsfield units (HU) on unenhanced CT less than 10 indicates lipid-rich tissue (adenoma). Contrast washout greater than 50% at 15 minutes is characteristic of adenoma. Heterogeneity, irregular margins, and invasion suggest malignancy.

Management depends on functionality and malignancy risk. Non-functioning masses smaller than 4 cm with benign imaging features can be observed with repeat imaging (typically at 6-12 months initially) and biochemical testing. Functioning tumors (secreting cortisol, aldosterone, or catecholamines) should generally be resected, regardless of size. Masses greater than 4-6 cm or with concerning imaging features should be resected due to malignancy risk. Biopsy should be performed only after pheochromocytoma is excluded (due to hypertensive crisis risk); biopsy is most useful when metastasis from a known malignancy is suspected.

<image>Panel A: Definition and epidemiology of adrenal incidentaloma showing mass 1 cm or larger found incidentally on imaging, 4-5% prevalence on CT increasing with age, and differential diagnosis (adenoma 70-80%, metastasis, pheochromocytoma, carcinoma, myelolipoma). Panel B: Hormonal assessment showing 1 mg overnight dexamethasone suppression test for cortisol excess, plasma or urine metanephrines to exclude pheochromocytoma, and aldosterone-to-renin ratio if hypertensive. Panel C: Imaging assessment showing size evaluation (greater than 4-6 cm raises malignancy concern), Hounsfield units on unenhanced CT (less than 10 HU indicates lipid-rich adenoma), contrast washout characteristics (greater than 50% at 15 minutes favors adenoma), and heterogeneity or irregular margins suggesting malignancy. Panel D: Management pathways showing observation with follow-up imaging for non-functioning benign masses less than 4 cm, surgical resection for functioning tumors or masses greater than 4-6 cm, and biopsy only after pheochromocytoma exclusion when metastasis is suspected.</image>

Summary

Cushing syndrome results from chronic glucocorticoid excess, manifesting with central obesity, purple striae, proximal myopathy, hypertension, and diabetes. Diagnosis involves confirming hypercortisolism (UFC, late-night salivary cortisol, DST), determining ACTH dependence, and localizing the source. Cushing disease (pituitary ACTH adenoma) is treated with transsphenoidal surgery.

Adrenal insufficiency is classified as primary (adrenal, high ACTH, hyperpigmentation, hyperkalemia) or secondary/tertiary (pituitary/hypothalamus, low ACTH, preserved mineralocorticoid function). Treatment requires glucocorticoid replacement, mineralocorticoid replacement for primary AI, and stress dosing during illness.

Adrenal crisis is a life-threatening emergency requiring immediate IV fluids and hydrocortisone 100 mg IV without waiting for diagnostic confirmation.

Primary aldosteronism causes resistant hypertension and should be screened with ARR. Subtype differentiation with adrenal vein sampling distinguishes adenoma (surgical treatment) from bilateral hyperplasia (medical treatment with mineralocorticoid antagonists).

Adrenal incidentalomas require evaluation for hormone secretion (especially cortisol and pheochromocytoma) and malignancy risk (size, imaging features). Most are benign non-functioning adenomas that can be observed.

Key Terms

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