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PA31.8-10 | Adrenal Gland Disorders — SDL Guide (Part 2)

Hyperaldosteronism — Conn Syndrome (Brief Overview)

Primary hyperaldosteronism (Conn syndrome) results from autonomous aldosterone excess independent of the renin-angiotensin system.

Causes:
• Aldosterone-producing adenoma (APA) — ~65% of primary cases; small (<2 cm), bright-yellow, zona glomerulosa–derived.
• Idiopathic bilateral adrenal hyperplasia (BAH) — ~30%; both glands show zona glomerulosa hyperplasia.
• Adrenocortical carcinoma producing aldosterone — rare.

Pathophysiology: Excess aldosterone → Na⁺ retention + K⁺ excretion → hypertension + hypokalaemia + suppressed plasma renin (key lab finding that distinguishes primary from secondary).

Secondary hyperaldosteronism: Renin is elevated (e.g., renal artery stenosis, congestive heart failure, cirrhosis). Both renin and aldosterone are elevated; adrenal morphology shows bilateral hyperplasia secondary to angiotensin II drive.

Key lab: Elevated aldosterone-to-renin ratio (ARR >30) with suppressed renin is diagnostic of primary hyperaldosteronism.

Conn Adenoma (Zona Glomerulosa Adenoma) — Gross Specimen and Normal Adrenal Cortex

Primary Adrenal Insufficiency — Addison Disease

Adrenal insufficiency is the failure to produce adequate cortisol and/or aldosterone. Primary adrenal insufficiency (Addison disease) involves destruction or dysfunction of the adrenal cortex itself.

Etiology (causes of Addison disease):

1. Autoimmune adrenalitis — commonest cause in developed countries (~70–80%). Autoantibodies against 21-hydroxylase (key enzyme in steroid synthesis). Often part of autoimmune polyendocrine syndrome (APS) types 1 or 2.
2. Tuberculosis — historically important; still commonest cause in developing countries including India. Haematogenous spread → bilateral caseating granulomas → adrenal destruction. Glands are enlarged initially, then fibrotic and calcified.
3. Metastatic carcinoma — lung, breast, melanoma can destroy >90% of both glands; functional insufficiency usually requires >90% destruction.
4. Histoplasmosis, CMV (HIV patients) — opportunistic infections.
5. Waterhouse-Friderichsen syndrome (acute adrenal insufficiency) — bilateral adrenal haemorrhage in overwhelming sepsis, classically Neisseria meningitidis (also DIC, Pseudomonas). Endotoxin-driven vascular injury + DIC → haemorrhagic infarction of both glands → adrenal crisis.

Morphology:
• Autoimmune: bilateral adrenal atrophy; cortex replaced by lymphocytic infiltrate and fibrosis; medulla spared.
• TB: bilateral enlargement → caseating granulomas → eventual calcification.
• Waterhouse-Friderichsen: massively enlarged, haemorrhagic adrenals — cortex appears as a blood-soaked rim.

Waterhouse-Friderichsen Syndrome: Gross Pathology and Pathogenesis

Adrenal Insufficiency — Clinical Manifestations, Lab, and Mechanism of Hyperpigmentation

Manifestations of primary adrenal insufficiency (Addison disease):

Feature	Mechanism
Weakness, fatigue	Reduced cortisol (impaired gluconeogenesis, metabolic effects)
Hypotension, postural dizziness	Aldosterone deficiency → Na⁺ loss, K⁺ retention, volume depletion
Hyponatraemia, hyperkalaemia	Aldosterone deficiency
Hypoglycaemia	Cortisol deficiency — reduced gluconeogenesis
Hyperpigmentation (skin + buccal mucosa)	See below
Nausea, vomiting, weight loss	Non-specific, cortisol deficiency
Salt craving	Aldosterone deficiency

Mechanism of hyperpigmentation (frequently asked in exams):
• Cortisol deficiency disinhibits the pituitary → ↑ ACTH secretion.
• ACTH is derived from pro-opiomelanocortin (POMC) by cleavage. The same POMC molecule also gives rise to melanocyte-stimulating hormone (α-MSH).
• Elevated POMC processing → elevated α-MSH → stimulates MC1R (melanocortin-1 receptor) on melanocytes → increased melanin synthesis.
• Hyperpigmentation is therefore a feature of primary insufficiency (elevated ACTH) and is ABSENT in secondary insufficiency (pituitary disease → ACTH is low).

Secondary adrenal insufficiency: Pituitary disease (tumor, infarction, Sheehan syndrome) → ↓ ACTH → ↓ cortisol. Aldosterone is preserved (RAAS intact). No hyperpigmentation. No hyperkalaemia. Hypoglycaemia and hyponatraemia (via SIADH) predominate.

Laboratory: Low serum cortisol (AM); Low 24-h urinary cortisol; ACTH stimulation test (Synacthen test) — in primary, adrenals fail to respond; in secondary, adrenals respond sluggishly (functional atrophy) but eventually respond with prolonged ACTH stimulation.

POMC Cleavage Pathway and Skin Pigmentation in Adrenal Insufficiency