Adrenal Insufficiency (PA 31.8)

Overview

Types: Primary, Secondary, and Tertiary

Etiology

Primary Adrenal Insufficiency

• Autoimmune adrenalitis - most common in industrialized countries; may occur in isolation or as part of Autoimmune Polyglandular Syndrome type 1 (with hypoparathyroidism + mucocutaneous candidiasis) or type 2 (with type 1 DM, autoimmune thyroid disease, vitiligo)
• Infections - tuberculosis is classic; also histoplasmosis, coccidioidomycosis, blastomycosis; CMV or MAI in AIDS
• Bilateral metastases - lung, breast, kidney, gut primaries; primary lymphoma
• Adrenoleukodystrophy - X-linked; deficiency of peroxisomal membrane protein leads to accumulation of very long chain fatty acids (VLCFA), which impair ACTH signal transduction in the adrenal cortex
• Congenital adrenal hyperplasia (CAH) - enzyme deficiency (CYP21A2, CYP11B1) prevents cortisol synthesis
• Drugs - ketoconazole, etomidate, rifampicin
• Sarcoidosis, amyloidosis, hemochromatosis (infiltrative)

• Adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia; also anticoagulation, antiphospholipid syndrome, trauma)

Secondary Adrenal Insufficiency

• Pituitary tumor, surgery, or irradiation
• Sheehan syndrome (postpartum pituitary necrosis)
• Pituitary apoplexy
• Lymphocytic hypophysitis
• Most common overall cause: exogenous glucocorticoid use - suppresses the HPA axis (tertiary mechanism)
• Traumatic brain injury, empty sella syndrome, sarcoidosis

Pathogenesis

• Cortisol (zona fasciculata) - glucocorticoid; regulates carbohydrate, protein, and lipid metabolism
• Aldosterone (zona glomerulosa) - mineralocorticoid; regulates Na/K and fluid balance
• DHEA (zona reticularis) - androgen

Clinical Manifestations

Chronic Adrenal Insufficiency

• Fatigue, weakness, lack of energy
• Weight loss, anorexia
• Nausea, vomiting, abdominal pain
• Myalgia, arthralgia
• Hypoglycemia (especially in children)
• Low blood pressure, postural hypotension
• Hyponatremia (loss of cortisol inhibition of AVP -> water retention)
• Mild fever
• Normochromic anemia, lymphocytosis, eosinophilia

• Salt craving
• Orthostatic hypotension, syncope
• Hyperkalemia
• Hyperchloremia and metabolic acidosis
• Elevated serum creatinine (volume depletion)

• Loss of axillary and pubic hair (especially in women)
• Loss of libido (in women)
• Dry, itchy skin (in women)

• Hyperpigmentation - sun-exposed areas, areas of friction/pressure, buccal mucosa (due to excess POMC-derived MSH)
• Vitiligo (autoimmune association)

• Pale "alabaster" skin (low POMC peptides)
• Amenorrhea
• Decreased libido, impotence
• Loss of axillary and pubic hair

Acute Adrenal Crisis

• Refractory hypotension and shock - hallmark; does not respond to fluids or vasopressors
• Fever
• Abdominal pain (can mimic acute abdomen)
• Severe nausea, vomiting
• Hypoglycemia

Laboratory Features

• Anti-21-hydroxylase antibodies - positive in most autoimmune cases
• Plasma VLCFA (C26:0) in males with negative antibodies - to exclude adrenoleukodystrophy
• Adrenal CT - to look for hemorrhage, granulomas, metastases, or masses
• Screen for other autoimmune endocrinopathies (thyroid, diabetes)

Morphologic Features

• Autoimmune AI: Atrophic adrenal glands with lymphocytic infiltration; normal architecture replaced by fibrosis
• TB/granulomatous: Caseating granulomas replacing adrenal tissue; often calcified on imaging
• Hemorrhagic: Blood-filled or necrotic adrenal glands (bilateral); classic Waterhouse-Friderichsen syndrome shows massive bilateral hemorrhage
• Metastatic: Bilateral adrenal enlargement with tumor replacement
• Adrenoleukodystrophy: VLCFA accumulation in adrenal cortex cells; also demyelination in CNS

Complications

• Adrenal crisis - life-threatening acute decompensation; triggers include infection, surgery, trauma, vomiting/diarrhea (inability to take oral steroids)
• Cardiovascular collapse and death if untreated
• Chronic morbidity: reduced quality of life, fatigue, impaired stress response
• Hypoglycemia (especially in children)
• Increased susceptibility to infections

Treatment

Acute Adrenal Crisis (Emergency)

• Hydrocortisone 100 mg IV immediately (has both glucocorticoid and mineralocorticoid activity)
• IV normal saline for volume expansion
• IV dextrose for hypoglycemia
• Vasopressors if needed
• Alternative: Dexamethasone 4 mg IV (does not interfere with serum cortisol assays - useful if diagnosis not yet confirmed)

Chronic Replacement

• Glucocorticoid: Hydrocortisone 10-12 mg/m²/day orally in 1-3 divided doses (mimicking diurnal cortisol rhythm - two-thirds in morning, one-third in afternoon). Prednisone 4-7 mg/day is an alternative
• Mineralocorticoid (primary AI only): Fludrocortisone 50-300 mcg/day; dose adjusted to normalize plasma renin activity; encourage salt intake
• Sick-day rules: Double or triple the glucocorticoid dose during fever, illness, or minor procedures; 100 mg hydrocortisone IV for surgery or major stress

Key Distinguishing Points

Recent evidence (2026): A systematic review on glucocorticoid-induced AI (PMID 41521083) confirmed that systemic glucocorticoid therapy is a major cause of adrenal insufficiency. A 2025 meta-analysis (PMID 40587340) specifically addressed evaluation and management of glucocorticoid-induced AI in IBD patients. These do not alter the classic framework above but reinforce the importance of iatrogenic AI in clinical practice.