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Describe Cushing syndrome with its causes and investigation. Add notes on adrenal insufficiency, phaeochromocytoma and pituitary disorders.

Pathology · 2nd Professional — Para-Clinical

Cushing Syndrome

Cushing syndrome is the clinical state produced by chronic excess of glucocorticoids, from any cause.

Cause	Share	ACTH	Adrenal morphology
Iatrogenic — exogenous steroids	By far the commonest overall	Suppressed	Bilateral atrophy
Cushing disease — pituitary adenoma	About 70% of endogenous cases	Raised	Bilateral hyperplasia
Adrenal adenoma or carcinoma	About 15–20%	Suppressed	Unilateral tumour with atrophy of the opposite gland
Ectopic ACTH	About 10–15%	Markedly raised	Bilateral hyperplasia; small cell carcinoma of lung is the commonest source

Clinical features — central obesity with moon face and buffalo hump, thin skin with purple striae, easy bruising, proximal myopathy, hypertension, hyperglycaemia, osteoporosis, hirsutism, amenorrhoea, poor wound healing and psychiatric disturbance
The features that best discriminate Cushing syndrome from simple obesity are proximal myopathy, wide purple striae, easy bruising and thin skin — because they reflect protein catabolism, which obesity does not cause
Ectopic ACTH often presents differently — rapid onset with pigmentation, profound hypokalaemic alkalosis and weight loss, because there is no time for the classical body habitus to develop

Investigation of Cushing Syndrome

1. Confirm cortisol excess — 24-hour urinary free cortisol, late-night salivary cortisol, or the overnight low-dose dexamethasone suppression test (failure to suppress confirms it) → 2.
Measure plasma ACTH → ACTH suppressed → the source is adrenal → image the adrenals → ACTH normal or raised → the source is ACTH-dependent → 3.
High-dose dexamethasone suppression — a pituitary adenoma retains some feedback and suppresses
an ectopic source does not → 4.
Imaging — pituitary MRI, chest and abdominal CT
inferior petrosal sinus sampling where the source remains unclear

CLINICAL PEARL

The high-dose test works because a pituitary adenoma is only partly autonomous, not wholly so. It retains enough glucocorticoid receptor feedback to be suppressed by a large dose, while an ectopic tumour has none at all. The whole diagnostic sequence rests on that single difference in degree.

Other Adrenal Cortical Disorders

Disorder	Features
CONN syndrome (primary hyperaldosteronism)	Adrenal adenoma or bilateral hyperplasia; hypertension with hypokalaemia and metabolic alkalosis; raised aldosterone with suppressed renin — the aldosterone:renin ratio is the screening test
Addison disease (primary adrenal insufficiency)	Autoimmune adrenalitis is commonest in the West; tuberculosis is a major cause in INDIA; also metastases, amyloid, haemorrhage, HIV, fungal infection. Fatigue, weight loss, hypotension, hyperpigmentation (from raised ACTH and melanocyte-stimulating hormone), hyponatraemia and hyperkalaemia, and salt craving
Secondary adrenal insufficiency	From pituitary disease or, far more often, abrupt withdrawal of long-term steroids. NO hyperpigmentation (ACTH is low) and mineralocorticoid function is preserved, so hyperkalaemia is absent
Adrenal crisis	Acute insufficiency precipitated by infection, surgery or steroid withdrawal; hypotension, shock, hypoglycaemia and abdominal pain; a medical emergency treated with hydrocortisone and saline before confirmation
Waterhouse–friderichsen syndrome	Bilateral massive adrenal haemorrhage in fulminant meningococcal septicaemia; also with DIC and severe sepsis
Congenital adrenal hyperplasia	21-hydroxylase deficiency in over 90%; cortisol deficiency raises ACTH → adrenal hyperplasia and androgen excess → virilisation and ambiguous genitalia; salt-wasting in the severe form

Phaeochromocytoma

A tumour of chromaffin cells of the adrenal medulla secreting catecholamines
The "rule of 10s" — about 10% are extra-adrenal (paraganglioma, commonly at the organ of Zuckerkandl), 10% bilateral, 10% malignant, 10% occur in children, and about 25% are familial (men 2A and 2B, von Hippel–Lindau, neurofibromatosis 1)
Clinically — episodic hypertension with the classical triad of headache, palpitations and sweating; also pallor, anxiety, tremor and hyperglycaemia. Sustained hypertension occurs in about half
Diagnosis — plasma free or urinary fractionated metanephrines (more reliable than catecholamines, since secretion is episodic but metabolism is continuous); then CT or MRI and MIBG scanning
Malignancy is defined by metastasis, not by histology — there is no reliable microscopic criterion
Treatment — surgical excision, but only after alpha-blockade (phenoxybenzamine) is established, with beta-blockade added afterwards. Giving a beta-blocker first is dangerous, as unopposed alpha stimulation precipitates a hypertensive crisis

Comparison of Adrenal Insufficiency

Feature	Primary (Addison)	Secondary
Lesion	The adrenal gland itself	Pituitary or hypothalamus; usually steroid withdrawal
ACTH	High	Low
Pigmentation	Present — buccal mucosa, palmar creases, scars; from high ACTH	Absent — the single most useful clinical discriminator
Aldosterone	Deficient — the zona glomerulosa is destroyed	Preserved — it is regulated by renin, not ACTH
Potassium	High	Normal
Sodium	Low	May be low (from ADH excess) but less marked
Other pituitary hormones	Normal	Often also deficient
Short Synacthen test	No cortisol response	Blunted response, but may be normal early

Aldosterone is the key — it is under renin control, so it is preserved in secondary insufficiency. That is why hyperkalaemia and salt craving belong to Addison disease alone

Pituitary Disorders and Applied Aspects

Disorder	Features
Prolactinoma	The commonest functioning pituitary adenoma; amenorrhoea, galactorrhoea and infertility in women; impotence and visual failure in men, who present later. Treated medically with dopamine agonists (cabergoline, bromocriptine), not surgically
Acromegaly / gigantism	Growth hormone excess; gigantism if before epiphyseal fusion, acromegaly after. Coarse features, prognathism, large hands and feet, carpal tunnel syndrome, diabetes, hypertension and cardiomyopathy. Diagnosed by failure of growth hormone to suppress during an oral glucose tolerance test, and by raised IGF-1
Mass effects of any adenoma	Bitemporal hemianopia from compression of the optic chiasm; headache; hypopituitarism from compression of normal gland
Sheehan syndrome	Post-partum pituitary necrosis after obstetric haemorrhage; the enlarged pregnant pituitary outgrows its blood supply. Failure of lactation is the earliest sign, then amenorrhoea and panhypopituitarism. Still seen in India
Diabetes insipidus	ADH deficiency (cranial) or renal resistance (nephrogenic); polyuria with dilute urine and a high plasma osmolality

Never stop long-term corticosteroids abruptly — the suppressed axis cannot respond, and adrenal crisis follows; the dose must be tapered and increased during intercurrent illness
In India, always consider tuberculosis in adrenal insufficiency, and look for adrenal calcification on imaging
Exclude phaeochromocytoma before operating on any adrenal mass, since unprepared surgery can be fatal
The adrenal incidentaloma — a mass found on imaging done for another reason; it must be assessed for function (cortisol, aldosterone, metanephrines) and for malignancy (size over 4 cm and irregular features are concerning)
Adrenocortical carcinoma is rare, usually large at diagnosis, often functional with rapid virilisation or Cushing syndrome, and carries a poor prognosis
Steroid-treated patients need a "sick day" plan and a medical alert card, doubling the dose during intercurrent illness and taking parenteral hydrocortisone if vomiting
Postural blood pressure and electrolytes are the cheapest screening tests for adrenal insufficiency, and hyponatraemia with hyperkalaemia in an unwell patient should always raise the possibility
Prolactin should be checked in any patient on antipsychotics before attributing a raised level to a tumour, since dopamine antagonists raise it commonly
A "stalk effect" — any large pituitary mass compressing the stalk raises prolactin modestly by blocking dopamine, which must not be mistaken for a prolactinoma; the level is the discriminator
Pituitary apoplexy — sudden haemorrhage into an adenoma causing severe headache, visual loss and collapse; a neurosurgical emergency requiring immediate steroids

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