Lecture 6 - Adrenal Pathophysiology & Disorders

Cushing Syndrome

• Umbrella term for any cause of hypercortisolism (endogenous or exogenous) • Includes ACTH‑dependent, ACTH‑independent, and steroid‑induced cases

Cushing Disease

• Specific cause of Cushing syndrome • Pituitary corticotroph adenoma producing excess ACTH → elevated cortisol

Cushing‑Like Syndrome

• Hypercortisolism‑like symptoms from long‑term glucocorticoid therapy

Exogenous Steroid Effects on HPA Axis

• External steroids act as cortisol and suppress ACTH and endogenous cortisol production • Causes adrenal atrophy but persistent hypercortisolism

Addison’s Disease – Risk Factors

• Rare disorder • Age 30–50/60 • Consider in patients with autoimmune diseases or immune‑checkpoint inhibitor therapy

Addison’s Disease – Etiologies/Causes

• Autoimmune destruction (MC) • Part of autoimmune polyendocrine syndrome • Infiltrative disease • Cancer • Infections (TB, CMV, histoplasmosis) • Hemorrhage • Congenital causes • Medications

Addison’s Disease – Pathophysiology

• Loss of >90% adrenal cortex → ↓cortisol, ↓aldosterone • Leads to hyponatremia, hyperkalemia, hypoglycemia, dehydration

Addison’s Disease – Clinical Presentation

• Fatigue, weakness, weight loss • N/V/D, orthostatic hypotension • Salt craving • Hyperpigmentation • Abdominal pain • Psychiatric symptoms (anxiety, irritability, depression)

Addison’s Disease – Differential

• Hemochromatosis • Shock • Cancer • Anorexia • Rhabdomyolysis • Cirrhosis • Heart failure

Addison’s Disease – Diagnostic Workup

• Hyponatremia, hyperkalemia, hypoglycemia • AM cortisol <3 mcg/dL with high ACTH • Confirm with cosyntropin test • Anti‑adrenal antibodies • CT adrenal imaging

Addison’s Disease – Management

• Corticosteroid replacement (hydrocortisone) • Mineralocorticoid replacement (fludrocortisone) • Adjust for electrolytes, BP • NaCl tabs for sodium loss

Addison’s Disease – Complications

• Acute adrenal crisis • Dehydration • Shock unresponsive to fluids/pressors • Complications from underlying infections or diseases

Addison’s Disease – Prognosis

• Depends on cause and timeliness of treatment • Crisis is life‑threatening but preventable with proper therapy

Cushing Disease – Risk Factors

• Presence of pituitary corticotroph adenoma • More common in adults of any age

Cushing Syndrome – Risk Factors

• Chronic steroid use • Adrenal tumors • Ectopic ACTH‑producing tumors • Severe obesity, pregnancy, alcohol use, depression, critical illness

Cushing Disease – Etiology/Cause

• ACTH‑dependent hypercortisolism from pituitary adenoma producing excess ACTH

Cushing Syndrome – Etiology/Cause

• Any cause of elevated cortisol: pituitary ACTH, adrenal tumors, ectopic ACTH, exogenous steroids

Cushing Syndrome – Pathophysiology

• Excess cortisol causes insulin resistance, protein catabolism, collagen loss, increased catecholamine sensitivity, electrolyte changes

Cushing Syndrome – Clinical Presentation

• Truncal obesity, moon face, buffalo hump • Hyperglycemia/DM • Muscle wasting/weakness • Osteoporosis • Skin thinning, striae, bruising • Hypertension • Emotional instability

Cushing Syndrome – Differential

• Alcohol use • Pregnancy • Depression • Critical illness • Anorexia • Severe obesity

Cushing Syndrome – Diagnostic Workup

• 24‑hr urinary free cortisol • Serum cortisol • ACTH levels • Dexamethasone suppression test • Late‑evening salivary cortisol • Tumor imaging

Cushing Disease/Syndrome – Management

• Identify cause • Surgery for pituitary tumors, ectopic ACTH tumors, or adrenal tumors • Bilateral adrenalectomy if unresectable • Medical therapy: osilodrostat, ketoconazole, metyrapone, mitotane

Cushing Disease/Syndrome – Complications

• Persistent metabolic dysfunction • Hypertension • Infections • Osteoporosis • Visual field deficits

Cushing Disease/Syndrome – Prognosis

• Symptoms regress over time but residual weakness, bone loss, or cognitive changes may persist • 90–95% surgical survival • 15–20% recurrence after surgery

Primary Adrenal Insufficiency – Risk Factors

• Autoimmune disease • Age 30–60 • History of infection, hemorrhage, infiltrative disease

Primary Adrenal Insufficiency – Etiologies

• Autoimmune destruction (MC) • Infections (TB, CMV, histoplasmosis) • Cancer • Hemorrhage • Congenital adrenal hyperplasia

Primary Adrenal Insufficiency – Pathophysiology

• >90% cortex destruction → ↓cortisol & ↓aldosterone • Electrolyte abnormalities and volume depletion result

Primary Adrenal Insufficiency – Clinical Presentation

• Fatigue, weight loss • Hyperpigmentation • N/V/D • Orthostatic hypotension • Salt craving • Psychiatric symptoms

Primary Adrenal Insufficiency – Differential

• Hemochromatosis • Cancer • Shock • Anorexia • Rhabdomyolysis • Cirrhosis • Heart failure

Primary Adrenal Insufficiency – Diagnostic Workup

• Hyponatremia, hyperkalemia, hypoglycemia • Low AM cortisol & high ACTH • Cosyntropin test • Adrenal CT

Primary Adrenal Insufficiency – Management

• Hydrocortisone replacement • Fludrocortisone • Adjust based on electrolytes/BP • NaCl tabs

Primary Adrenal Insufficiency – Complications

• Acute adrenal crisis • Severe dehydration • Shock unresponsive to fluids/pressors

Primary Adrenal Insufficiency – Prognosis

• Good with lifelong hormone replacement • Crisis life‑threatening if untreated

Primary Hyperaldosteronism – Risk Factors

• Adrenal adenoma (MC) • Bilateral adrenal hyperplasia • Adrenal carcinoma

Secondary Hyperaldosteronism – Risk Factors

• Dehydration • Shock • Renal artery stenosis • Heart failure

Primary Hyperaldosteronism – Etiology

• Aldosterone‑producing adrenal adenoma • Bilateral hyperplasia

Secondary Hyperaldosteronism – Etiology

• Excess renin from renal hypoperfusion → ↑angiotensin II → ↑aldosterone

Hyperaldosteronism – Pathophysiology

• Sodium/water retention → hypervolemia • Potassium and hydrogen loss → hypokalemia & alkalosis

Hyperaldosteronism – Clinical Presentation

• Hypertension • Hypokalemia • Hypervolemia • Resistant hypertension • LV hypertrophy

Hyperaldosteronism – Differential

• Hypernatremia • Diuretic overuse • Laxative abuse • Renal artery stenosis

Primary Hyperaldosteronism – Diagnostics

• High aldosterone, low renin • Aldosterone suppression tests • Metabolic alkalosis

Secondary Hyperaldosteronism – Diagnostics

• High aldosterone, high renin • Electrolyte abnormalities

Hyperaldosteronism – Management

• Unilateral: adrenalectomy • Bilateral: spironolactone • Eplerenone in pregnancy

Hyperaldosteronism – Complications

• Cardiovascular disease • Post‑op hypoaldosteronism

Hyperaldosteronism – Prognosis

• HTN reversible in two‑thirds after adrenalectomy • Early detection improves outcomes

Pheochromocytoma – Risk Factors

• MEN2A • von Hippel‑Lindau • Neurofibromatosis • 40% hereditary

Pheochromocytoma – Etiology

• Catecholamine‑producing tumor from adrenal medulla chromaffin cells

Pheochromocytoma – Pathophysiology

• Excess epinephrine/norepinephrine → episodic sympathetic surges

Pheochromocytoma – Clinical Presentation

• TRIAD: episodic headache, diaphoresis, tachycardia/HTN • Anxiety • Palpitations • Weight loss

Pheochromocytoma – Differential

• Hyperthyroidism • Panic disorder • Cocaine/amphetamine use • White‑coat HTN • Migraines

Pheochromocytoma – Diagnostic Workup

• Plasma/urine metanephrines • Adrenal CT/MRI • PET for metastasis

Pheochromocytoma – Management

• Alpha‑blocker then beta‑blocker • Surgical adrenalectomy with venous ligation

Pheochromocytoma – Complications

• Hypertensive crisis • Cardiomyopathy • Dysrhythmias • Stroke • Multi‑organ failure

Pheochromocytoma – Prognosis

• Good if removed early • Lifetime surveillance needed • Poorer with metastasis

Sympathetic Paragangliomas – Risk Factors

• Same hereditary syndromes as pheochromocytoma • Extra‑adrenal tumor locations

Sympathetic Paragangliomas – Etiology

• Neuroendocrine tumors outside adrenal glands at sympathetic paraganglia

Sympathetic Paragangliomas – Pathophysiology

• Inconsistent catecholamine release → variable sympathetic symptoms

Sympathetic Paragangliomas – Clinical Presentation

• Similar to pheochromocytoma but less predictable • Head/neck, chest, abdomen tumor sites

Sympathetic Paragangliomas – Differential

• Similar to pheochromocytoma workup • Evaluate secondary HTN causes

Sympathetic Paragangliomas – Diagnostic Workup

• Plasma/urine metanephrines • Imaging for metastatic disease

Sympathetic Paragangliomas – Management

• Surgical resection • Pre‑op alpha and beta blockade (like pheochromocytoma)

Sympathetic Paragangliomas – Complications

• High metastatic potential • Catecholamine complications

Sympathetic Paragangliomas – Prognosis

• Worse than adrenal pheochromocytoma due to metastasis risk

Chronic fatigue, weight loss, salt craving, orthostatic hypotension

Addison’s Disease: adrenal cortex destruction causes cortisol and aldosterone deficiency.

Hyperpigmentation

Addison’s Disease: high ACTH stimulates melanocytes causing darkened skin.

N/V/D, dehydration, hypotension

Addison’s Disease: progressive hormone deficiency leads to volume loss and GI symptoms.

Shock unresponsive to fluids/pressors

Addison’s Disease: acute adrenal crisis causing life‑threatening circulatory collapse.

Truncal obesity, moon face, buffalo hump

Cushing Syndrome: hypercortisolism redistributes adipose tissue.

Hyperglycemia, polyuria

Cushing Syndrome: cortisol causes insulin resistance and glucose elevation.

Muscle weakness, thin extremities

Cushing Syndrome: protein catabolism from excess cortisol.

Purple striae, easy bruising, skin thinning

Cushing Syndrome: collagen loss causes fragile skin.

Hypertension, emotional instability

Cushing Syndrome: cortisol increases vascular sensitivity and affects mood.

Chronic steroid use

Cushing‑Like Syndrome: exogenous glucocorticoids cause hypercortisolism features.

Hyperpigmentation

Primary Adrenal Insufficiency: high ACTH increases melanin production.

Abrupt steroid withdrawal

Secondary Adrenal Insufficiency: pituitary suppression from prolonged steroid use.

Hyponatremia + hyperkalemia

Primary Adrenal Insufficiency: aldosterone deficiency alters electrolytes.

Low cortisol with normal/low ACTH

Secondary Adrenal Insufficiency: impaired pituitary ACTH output.

Hypertension + hypokalemia

Hyperaldosteronism: aldosterone excess increases sodium retention and potassium loss.

Resistant hypertension

Primary Hyperaldosteronism: adrenal overproduction of aldosterone.

Hypervolemia without edema

Primary Hyperaldosteronism: water retention without significant edema.

Dehydration, renal artery stenosis, heart failure

Secondary Hyperaldosteronism: renin‑driven increase in aldosterone.

Episodic headache + diaphoresis + tachycardia/HTN

Pheochromocytoma: classic catecholamine‑release triad.

Sudden anxiety, palpitations, weight loss

Pheochromocytoma: episodic catecholamine surges.

Extreme BP fluctuations

Pheochromocytoma: unstable sympathetic activation.

Pheochromocytoma‑like symptoms but inconsistent

Sympathetic Paraganglioma: catecholamine secretion varies.

Tumor in neck, chest, abdomen

Sympathetic Paraganglioma: extra‑adrenal sympathetic origin.

Evidence of metastasis

Sympathetic Paraganglioma: higher metastatic potential than pheochromocytoma.

Addison’s Disease

Diagnosis: morning cortisol <3 with high ACTH; cosyntropin test; electrolyte abnormalities; CT adrenals. Management: hydrocortisone + fludrocortisone; NaCl tablets; treat adrenal crisis immediately with steroids and fluids.

Primary Adrenal Insufficiency

Diagnosis: hyponatremia, hyperkalemia, hypoglycemia; low cortisol, high ACTH; positive cosyntropin test. Management: corticosteroid and mineralocorticoid replacement with dose titration to BP/electrolytes.

Cushing Syndrome

Diagnosis: 24‑hr urinary cortisol, ACTH levels, dexamethasone suppression, salivary cortisol, imaging. Management: treat cause; adrenal or ectopic tumor resection; medical therapy (osilodrostat, ketoconazole).

Cushing Disease

Diagnosis: ACTH‑dependent hypercortisolism with pituitary adenoma on imaging. Management: transsphenoidal surgery; radiosurgery; craniotomy for large tumor; bilateral adrenalectomy if unresectable.

Hyperaldosteronism (Primary)

Diagnosis: high aldosterone, low renin; suppression testing; metabolic alkalosis. Management: unilateral adrenalectomy or spironolactone for hyperplasia.

Hyperaldosteronism (Secondary)

Diagnosis: high aldosterone AND high renin; underlying renal‑perfusion trigger. Management: treat cause (renal artery stenosis, dehydration, HF); mineralocorticoid antagonists as needed.

Pheochromocytoma

Diagnosis: plasma/urine metanephrines; adrenal CT/MRI; possible PET for metastasis. Management: alpha‑blocker then beta‑blocker; surgical adrenalectomy with venous ligation.

Sympathetic Paraganglioma

Diagnosis: metanephrines; CT/MRI for extra‑adrenal mass; evaluate for metastasis. Management: alpha‑blocker then beta‑blocker; surgical removal; monitor long‑term due to metastasis risk.

Adrenal Pathophysiology & Disorders

• Study of adrenal gland function and related disorders involving cortisol, aldosterone, and catecholamines.

Cushing Syndrome

• Hypercortisolism from any cause. • Includes endogenous and exogenous cortisol excess.

Cushing Disease

• Pituitary corticotroph adenoma producing excess ACTH. • A specific cause of Cushing syndrome.

Cushing‑like Syndrome

• Hypercortisolism caused by chronic glucocorticoid therapy mimicking Cushing syndrome.

ACTH‑Dependent Hypercortisolism

• Excess ACTH from pituitary or ectopic tumor stimulates cortisol overproduction.