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PA31.8-10 | Adrenal Gland Disorders — SDL Guide

Learning Objectives

Describe the etiology and pathogenesis of adrenal insufficiency (primary and secondary) and explain the mechanism of hyperpigmentation in Addison disease.
Outline the causes, clinical manifestations, laboratory investigations, and morphologic adrenal changes in Cushing syndrome.
Distinguish between primary and secondary hyperaldosteronism (Conn syndrome) in brief.
Classify adrenal neoplasms, differentiate cortical adenoma from adrenocortical carcinoma, and describe the key pathological features of pheochromocytoma and neuroblastoma.

INSTRUCTIONS

The adrenal gland is a high-yield topic in Year-2 pathology and MBBS university exams. Disorders here cut across endocrinology, oncology, and emergency medicine. As you work through this SDL, connect each hormonal pathway to its morphologic consequence — that pairing is the examiner's favourite question format.

References

Robbins & Cotran Pathologic Basis of Disease, 10th ed., Ch. 24 (textbook)

Version 2.0 | NMC CBUC 2024

CLINICAL SCENARIO

A 28-year-old woman is brought to the emergency department with sudden hypotension, vomiting, and altered consciousness. She had been on high-dose prednisolone for rheumatoid arthritis for six months and stopped it abruptly three days ago. Her serum cortisol is critically low. Meanwhile, in the next ward, a 45-year-old man presents with truncal obesity, moon face, striae, hypertension, and a blood glucose of 280 mg/dL.

Same gland, opposite extremes. The adrenal — two grams of tissue above each kidney — governs your blood pressure, stress response, electrolyte balance, and glucose homeostasis simultaneously.

WHY THIS MATTERS

Adrenal pathology is core to the NMC 2024 CBUC PA31 competency group. In clinical practice, Cushing syndrome, Addison disease, and pheochromocytoma are 'great masqueraders' — they present to dermatology, cardiology, and psychiatry before the endocrinologist is called.

For your MBBS exams, expect: (a) a short-answer question on adrenal insufficiency with emphasis on morphology and Waterhouse-Friderichsen syndrome; (b) a structured question on Cushing syndrome causes and the dexamethasone suppression test; (c) a long-answer on pheochromocytoma (rule of 10s, morphology, MEN2). This SDL covers all three competencies — PA31.8, PA31.9, and PA31.10.

RECALL

Before we proceed, anchor the normal adrenal architecture.

Adrenal cortex (mesoderm-derived) — three concentric zones, memorised as GFR:
• Zona glomerulosa (outermost) — secretes mineralocorticoids (aldosterone); regulated by renin-angiotensin system and serum K⁺.
• Zona fasciculata (middle, largest, ~75%) — secretes glucocorticoids (cortisol); regulated by ACTH.
• Zona reticularis (innermost) — secretes adrenal androgens (DHEA, androstenedione); regulated by ACTH.

Adrenal medulla (neural crest-derived) — chromaffin cells secrete catecholamines (epinephrine 80%, norepinephrine 20%); regulated by preganglionic sympathetic fibres.

Pathological changes in each zone are organ-specific: cortical atrophy affects zona fasciculata and reticularis first; aldosteronoma arises from zona glomerulosa.

Low-power histology diagram of the adrenal gland cross-section labeling the fibrous capsule, zona glomerulosa, zona fasciculata, zona reticularis, and medullary chromaffin cells, with a small inset showing the adrenal gland perched on the superior pole of the right kidney for anatomical orientation. — **Panel A:** Fibrous capsule (outer rim), Zona Glomerulosa (cell ball-clusters, mineralocorticoids/aldosterone), Zona Fasciculata (radial columns, foamy vacuolated cytoplasm, glucocorticoids/cortisol), Zona Reticularis (anastomosing compact cords, weak androgens/DHEA), Medulla (chromaffin cells with granular cytoplasm, sinusoids, catecholamines — adrenaline/noradrenaline), proportional scale bar. **Panel B:** Right adrenal (suprarenal) gland, right kidney, diaphragm, IVC, aorta, red star linking to Panel A capsule.

Cushing Syndrome — Etiology and Pathogenesis

Cushing syndrome is the clinical state produced by chronic excess of glucocorticoids, regardless of source.

Causes (memorise in frequency order):

Cause	ACTH level	Adrenal morphology
Exogenous steroids (iatrogenic, commonest overall)	Suppressed (↓↓)	Bilateral cortical atrophy
Cushing disease — pituitary ACTH-secreting adenoma	Elevated (↑)	Bilateral cortical hyperplasia
Ectopic ACTH — small-cell lung carcinoma, carcinoid, others	Very elevated (↑↑↑)	Bilateral cortical hyperplasia
Adrenal adenoma	Suppressed (↓↓)	Contralateral atrophy
Adrenocortical carcinoma	Suppressed (↓↓)	Contralateral atrophy

Pathogenesis: Excess cortisol drives a cascade:
1. Gluconeogenesis ↑ → hyperglycaemia / steroid diabetes.
2. Protein catabolism ↑ → muscle wasting (proximal myopathy), skin thinning, purple striae, poor wound healing.
3. Fat redistribution → truncal obesity, moon face, buffalo hump (dorsal fat pad).
4. Mineralocorticoid receptor activation at high cortisol levels → hypertension, hypokalaemia.
5. Immunosuppression → opportunistic infections.
6. Bone collagen loss → osteoporosis, vertebral fractures.

Two-row diagram: top panel shows the complete HPA axis cascade (hypothalamus CRH → anterior pituitary ACTH → adrenal cortex cortisol) with dashed negative feedback arrows; bottom row shows four mini-axis panels annotating the site and ACTH level for each Cushing syndrome cause — pituitary adenoma, ectopic ACTH, adrenal adenoma, and exogenous steroids. — **Panel A:** Complete HPA axis: Hypothalamus (CRH) → Anterior Pituitary (ACTH) → Adrenal Cortex (Cortisol); dashed negative feedback arrows from cortisol back to pituitary and hypothalamus; numbered disruption markers at each level. **Panel B:** Cushing Disease (Pituitary): pituitary adenoma highlighted at pituitary level; ACTH HIGH; High-dose DST suppresses >50%. **Panel C:** Ectopic ACTH Syndrome: external ectopic ACTH source bypasses hypothalamic control; ACTH HIGH; High-dose DST does not suppress. **Panel D:** Adrenal Adenoma/Carcinoma: autonomous cortisol from adrenal; upstream hypothalamus and pituitary suppressed (grey); ACTH LOW. **Panel E:** Exogenous Corticosteroids: external cortisol (pill/syringe icon) suppresses both hypothalamus and pituitary; ACTH LOW; iatrogenic cause.

Cushing Syndrome — Clinical Manifestations and Laboratory Diagnosis

Clinical features (know the classic triad for MCQs: truncal obesity + moon face + purple striae):
• Central (truncal) obesity with thin limbs
• Moon face (rounded face due to facial fat deposition)
• Buffalo hump (dorsocervical fat pad)
• Purple/violaceous striae (skin thinning + dermal collagen rupture)
• Hypertension (common, renin-independent)
• Proximal muscle weakness
• Hirsutism and menstrual irregularities (androgen excess from zona reticularis stimulation)
• Psychiatric disturbances (depression, psychosis)
• Osteoporosis, pathological fractures
• Impaired glucose tolerance or frank diabetes

Laboratory investigations:

24-hour urinary free cortisol (UFC) — screening; elevated in Cushing syndrome.
Overnight 1-mg dexamethasone suppression test (DST) — screening; normal persons suppress cortisol below 1.8 µg/dL; Cushing syndrome patients fail to suppress.
Low-dose DST (2 mg/48 h) — confirms Cushing syndrome if cortisol unsuppressed.
High-dose DST (8 mg/48 h) — differentiates pituitary Cushing disease (suppresses >50%) from ectopic ACTH or adrenal tumour (does NOT suppress).
Plasma ACTH — low/undetectable in adrenal tumours and exogenous; high in pituitary and ectopic ACTH.
Hypokalaemic metabolic alkalosis — especially prominent in ectopic ACTH (very high cortisol activating mineralocorticoid receptors).

Imaging: MRI pituitary (Cushing disease); CT chest/abdomen (ectopic ACTH, adrenal tumour).

Two-panel diagram: Panel A shows a top-down dexamethasone suppression test diagnostic flowchart starting from elevated UFC, branching through low-dose and high-dose DST and ACTH level measurement to identify pituitary, ectopic, or adrenal causes of Cushing syndrome with expected cortisol and ACTH values at each branch; Panel B shows a color-coded comparison table of the three etiologies with a clinical pearl about ectopic ACTH syndrome. — **Panel A:** Diagnostic flowchart nodes: Elevated 24-h UFC (entry); Low-Dose DST decision diamond with suppressed (excluded) and non-suppressed branches; ACTH Level decision diamond with three arms (< 10, 20–200, > 200 pg/mL); High-Dose DST decision diamond for intermediate ACTH; Terminal boxes for Adrenal Cause (ACTH ↓, no DST suppression), Pituitary Cushing Disease (ACTH ↑, suppresses on high-dose DST), and Ectopic ACTH Syndrome (ACTH ↑↑↑, no suppression). **Panel B:** 4-column comparison table rows: ACTH Level, High-Dose DST response, 24-h UFC magnitude, and Typical Cause — columns for Pituitary (purple), Ectopic (dark red), Adrenal (red); Clinical Pearl callout box about ectopic ACTH presenting without classic Cushingoid features in smokers.

CLINICAL PEARL

The ectopic ACTH syndrome is a clinical pitfall: small-cell lung carcinoma can secrete ACTH so massively that Cushingoid fat redistribution does not have time to develop — patients present with rapid-onset hypertension, hypokalaemia, oedema, and profound weakness without the classic moon face. The very high cortisol activates mineralocorticoid receptors massively. Always check ACTH and do high-dose DST when Cushing syndrome presents acutely in a smoker.

Cushing Syndrome — Adrenal Morphology

The adrenal morphology in Cushing syndrome depends on the underlying cause:

Bilateral cortical hyperplasia (pituitary Cushing disease or ectopic ACTH):
• Both adrenals enlarged (combined weight up to 25–30 g; normal ~8–10 g).
• Cut section shows diffuse or nodular yellow-orange thickening of the cortex.
• Histology: expansion of the clear-cell zona fasciculata; all three zones preserved but hypertrophied.

Cortical atrophy (exogenous steroids — most important to know):
• Exogenous steroids suppress ACTH → zona fasciculata and reticularis undergo disuse atrophy.
• Zona glomerulosa (ACTH-independent) is spared.
• This is the morphologic correlate of adrenal crisis on abrupt steroid withdrawal.

Adrenal cortical adenoma (ACTH-independent):
• Usually unilateral, small (<5 cm), well-encapsulated, golden-yellow (lipid-rich).
• Contralateral adrenal and uninvolved ipsilateral cortex show atrophy (suppressed ACTH).

Adrenocortical carcinoma: described in the neoplasms section.

Three-panel diagram comparing bilateral adrenal cortical hyperplasia cut sections (Panel A) with a normal adrenal gland at the same scale (Panel B), and a color-coded cortical zone map annotating ACTH-dependent versus ACTH-independent layers (Panel C). — **Panel A:** Both hyperplastic adrenal glands cut-face up; labels: diffusely thickened yellow-orange cortex, compressed dark-brown medulla, combined weight callout (20–30 g). **Panel B:** Single normal adrenal gland cut-face up at matched scale; labels: thin pale-yellow cortex, normal-proportion medulla. **Panel C:** Concentric cortical zone cross-section; labels: zona glomerulosa (light blue, ACTH-independent / RAAS-regulated, spared), zona fasciculata (yellow, ACTH-dependent, atrophies), zona reticularis (orange, ACTH-dependent, atrophies), medulla (brown).

SELF-CHECK

A patient on long-term prednisolone for nephrotic syndrome stops the drug abruptly. Which adrenal zone is MOST affected by the resulting atrophy?

A. Zona glomerulosa only

B. Zona fasciculata and zona reticularis

C. Adrenal medulla only

D. All three cortical zones equally

Reveal Answer

Answer: B. Zona fasciculata and zona reticularis

Exogenous glucocorticoids suppress pituitary ACTH via negative feedback. Zona fasciculata and zona reticularis are ACTH-dependent and undergo disuse atrophy. Zona glomerulosa is regulated primarily by the renin-angiotensin-aldosterone system and is therefore ACTH-independent, so it is relatively spared.