Endocrinology: Adrenal Disease (Complete)

• Basics: What Is Adrenal Disease? | Anatomy and Physiology | Cortisol and the HPA Axis | Aldosterone and the RAAS | Principles of Testing
• Adrenal insufficiency: Adrenal Insufficiency: Causes | Addison's Disease | Secondary Adrenal Insufficiency | Glucocorticoid-induced Adrenal Insufficiency | Adrenal Insufficiency: Clinical Features | Adrenal Insufficiency: Diagnosis | Long-term Steroid Replacement | Sick Day Rules and Steroid Emergency Card | Adrenal Crisis | Steroid Cover for Surgery and Procedures | Adrenal Haemorrhage
• Cortisol excess: Cushing's Syndrome: Causes | Cushing's Syndrome: Clinical Features | Cushing's Syndrome: Investigations | Cushing's Disease | Ectopic ACTH Syndrome | Adrenal Cushing's | Cushing's Syndrome: Treatment
• Aldosterone disorders: Primary Aldosteronism | Primary Aldosteronism: Diagnosis | Primary Aldosteronism: Treatment | Renin and Aldosterone Patterns | Hypoaldosteronism
• Adrenal medulla: Phaeochromocytoma and Paraganglioma | Phaeochromocytoma: Diagnosis | Phaeochromocytoma: Treatment
• Masses and congenital: Adrenal Incidentaloma | Adrenocortical Carcinoma | Congenital Adrenal Hyperplasia
• Special situations: Critical Illness and Septic Shock | Pregnancy | Older Adults | Immunotherapy and Other Drugs
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧂 Adrenal disease means too much or too little of the hormones made by the adrenal glands: cortisol, aldosterone, adrenal androgens and catecholamines. Adrenal disease is uncommon, but it is often missed and it can kill quickly - an adrenal crisis or a phaeochromocytoma crisis can be fatal within hours. It is also eminently treatable.
Your four questions for every patient: Which hormone is wrong - too much or too little? Is the problem in the adrenal or the pituitary? Is this an emergency (adrenal crisis, phaeochromocytoma crisis)? Is the patient on steroids, and are they at risk of adrenal crisis?

What Is Adrenal Disease?

The adrenal disorders fall into a few groups:

• Too little cortisol (adrenal insufficiency): Addison's disease, pituitary failure, and - by far the commonest - suppression by prescribed steroids. Untreated, it leads to adrenal crisis.
• Too much cortisol (Cushing's syndrome): Most often caused by prescribed steroids; otherwise a pituitary, adrenal or ectopic tumour.
• Too much aldosterone (primary aldosteronism): The commonest curable cause of hypertension, and badly under-diagnosed.
• Too much catecholamine (phaeochromocytoma): Rare, dangerous and curable.
• Adrenal masses: Incidental lumps found on scans, and rarely cancer.
• Congenital adrenal hyperplasia: An inherited enzyme defect.

💡 Clinical Pearl: The adrenal problem you will meet most often as a junior doctor is adrenal suppression from prescribed steroids. Every patient on long-term steroids needs sick-day rules and a Steroid Emergency Card.

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Anatomy and Physiology

Each adrenal gland sits on top of a kidney and is really two organs in one:

• The adrenal cortex (outer part) makes steroid hormones from cholesterol, in three layers. Remember "GFR - salt, sugar, sex":
  • Zona Glomerulosa → aldosterone ("salt"). Controlled mainly by the renin–angiotensin system and by potassium, not by ACTH.
  • Zona Fasciculata → cortisol ("sugar"). Controlled by ACTH from the pituitary.
  • Zona Reticularis → androgens (DHEA, androstenedione - "sex"). Also ACTH-driven.
• The adrenal medulla (inner part) is modified nervous tissue that releases adrenaline and noradrenaline into the blood in response to sympathetic stimulation ("fight or flight").

Why this layout matters clinically:

• In pituitary (secondary) adrenal insufficiency, ACTH is lost, so cortisol falls - but aldosterone is preserved, because it does not depend on ACTH. These patients do not become hyperkalaemic and do not need fludrocortisone.
• In adrenal (primary) failure, the whole cortex is destroyed, so both cortisol and aldosterone are lost.

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Cortisol and the HPA Axis

The control loop (hypothalamic–pituitary–adrenal axis):

• The hypothalamus releases CRH.
• CRH stimulates the pituitary to release ACTH.
• ACTH stimulates the adrenal cortex to release cortisol.
• Cortisol switches off CRH and ACTH (negative feedback).

Daily rhythm: Cortisol peaks on waking (around 6–8 am) and is lowest around midnight. This is why:

• 9 am cortisol is used to look for deficiency.
• Late-night cortisol is used to look for excess (in Cushing's, the normal night-time fall is lost).

What cortisol does:

• Raises blood glucose.
• Maintains blood pressure and vascular responsiveness to adrenaline.
• Allows the kidney to excrete free water.
• Suppresses inflammation and immunity.
• Breaks down protein and bone.

Stress: During illness or surgery, cortisol output rises several-fold. A patient who cannot mount this response - adrenal insufficiency - collapses with shock when unwell.

Why ACTH causes pigmentation: ACTH is cut from a larger precursor, POMC, which also produces melanocyte-stimulating hormone. Very high ACTH levels (primary adrenal failure, ectopic ACTH) therefore darken the skin.

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Aldosterone and the RAAS

The renin–angiotensin–aldosterone system:

• When the kidney senses low blood pressure, low sodium delivery or sympathetic stimulation, it releases renin.
• Renin converts angiotensinogen to angiotensin I.
• ACE converts angiotensin I to angiotensin II, which constricts blood vessels and stimulates aldosterone release.
• High potassium also directly stimulates aldosterone.

What aldosterone does: It acts on the collecting duct of the kidney to retain sodium (and therefore water) and excrete potassium and hydrogen ions.

• Too much: Hypertension, hypokalaemia and metabolic alkalosis.
• Too little: Salt loss, low blood pressure and hyperkalaemia.

💡 Key concept: Always interpret aldosterone alongside renin. High aldosterone with suppressed renin means the adrenal is making aldosterone autonomously (primary aldosteronism). High aldosterone with high renin means the kidney is driving it (secondary hyperaldosteronism).

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Principles of Testing

Adrenal hormones fluctuate, so a single random level is often unhelpful. Two rules guide dynamic testing:

• Suspect too little hormone → try to stimulate it. Example: the short Synacthen test (synthetic ACTH) for adrenal insufficiency. A normal adrenal responds; a failed one cannot.
• Suspect too much hormone → try to suppress it. Examples:
  • The dexamethasone suppression test for Cushing's - normal cortisol is switched off by dexamethasone; autonomous cortisol is not.
  • The saline infusion test for primary aldosteronism - a salt load normally suppresses aldosterone.
• Measure the controlling hormone to locate the problem:
  • ACTH separates adrenal from pituitary causes of cortisol disorders.
  • Renin separates primary from secondary aldosterone disorders.
• Do biochemistry before imaging. Adrenal lumps are common and usually irrelevant, so prove the hormone abnormality first, then image.

💡 Clinical Pearl: Oral oestrogens (the combined pill, HRT) raise cortisol-binding globulin and therefore total cortisol, which can falsely reassure. Interpret results with this in mind, and stop oral oestrogen for about 6 weeks before testing where possible.

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Adrenal Insufficiency: Causes

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Addison's Disease

Mechanism: Primary adrenal failure, usually autoimmune destruction of the adrenal cortex (antibodies against the enzyme 21-hydroxylase). Symptoms appear only once about 90% of the cortex is destroyed, so onset is gradual. A stress such as an infection then tips the patient into crisis. It affects about 1 in 10,000 people in the UK, most often women aged 30–50.

What is lost: Both cortisol and aldosterone (and adrenal androgens). ACTH rises steeply, causing pigmentation.

Associations - autoimmune polyglandular syndromes:

• Type 2 (commonest): Addison's plus autoimmune thyroid disease and/or type 1 diabetes.
• Type 1: Rare, childhood onset. Addison's, hypoparathyroidism and chronic mucocutaneous candidiasis (an AIRE mutation).
• Also vitiligo, pernicious anaemia, coeliac disease and premature ovarian insufficiency.

Distinctive features compared with secondary adrenal insufficiency:

• Hyperpigmentation, especially of palmar creases, knuckles, scars, gums, the inside of the cheeks and pressure areas.
• Hyperkalaemia and salt craving.
• Postural hypotension.

Management: Lifelong hydrocortisone plus fludrocortisone, sick-day rules and an emergency hydrocortisone injection kit. Screen periodically for associated autoimmune disease (TFTs, HbA1c, B12, coeliac serology).

💡 Clinical Pearl: A young man with Addison's should have very-long-chain fatty acids checked for adrenoleukodystrophy, an X-linked condition that can also cause progressive neurological disease.

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Secondary Adrenal Insufficiency

Mechanism: The pituitary fails to produce ACTH, so the adrenals are understimulated and cortisol falls. Aldosterone is preserved because it is controlled by renin, not ACTH.

Differences from Addison's:

• No pigmentation - ACTH is low; patients may look pale.
• No hyperkalaemia, and fludrocortisone is not needed.
• Hyponatraemia still occurs, because cortisol is needed to excrete free water. It looks just like SIADH.
• Usually other pituitary hormones are also deficient: gonadotrophins (amenorrhoea, low libido), TSH (central hypothyroidism) and growth hormone. A pituitary tumour may cause headache or visual field loss.

Investigations: Low or inappropriately normal ACTH with a low cortisol; check the other pituitary hormones; pituitary MRI.

Management: Hydrocortisone alone. Replace cortisol before starting levothyroxine for any coexisting central hypothyroidism - otherwise thyroxine can precipitate an adrenal crisis.

💡 Clinical Pearl: Never diagnose SIADH until adrenal insufficiency and hypothyroidism have been excluded. Check a 9 am cortisol in every patient with unexplained hyponatraemia.

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Glucocorticoid-induced Adrenal Insufficiency

Mechanism: Prescribed steroids feed back to suppress CRH and ACTH. After a few weeks the adrenal glands shrink from lack of stimulation. If the steroid is stopped suddenly, or the body needs more during illness, the adrenals cannot respond. It is by far the commonest cause of adrenal insufficiency.

Who is at risk? NHS and Society for Endocrinology guidance identifies risk in patients taking:

• Prednisolone 5 mg or more daily (or equivalent) for 4 weeks or longer.
• 40 mg or more of prednisolone for more than 1 week, or repeated courses.
• High-dose inhaled steroids, or potent topical, intra-articular or other injected steroids, particularly in combination.
• Any steroid combined with a CYP3A4 inhibitor (e.g. ritonavir, cobicistat, itraconazole, clarithromycin). These block steroid breakdown - even inhaled fluticasone or injected triamcinolone can then cause Cushing's syndrome and adrenal suppression.

Glucocorticoid equivalent doses (approximate anti-inflammatory equivalence):

Management:

• Never stop long-term steroids abruptly. Taper gradually once the dose reaches physiological levels (about prednisolone 5 mg daily); the axis may take months to recover.
• A 9 am cortisol (taken before the morning dose, ideally 24 hours after the last hydrocortisone dose or a longer gap for prednisolone) or a short Synacthen test can show whether the axis has recovered.
• Patients at risk need sick-day rules and a Steroid Emergency Card, and need steroid cover for surgery.

⚠️ Safety Pearl: A patient on long-term prednisolone who is vomiting, or "nil by mouth" before surgery, is at risk of adrenal crisis. Give parenteral hydrocortisone - do not simply omit the steroid.

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Adrenal Insufficiency: Clinical Features

Symptoms are vague and develop slowly, so the diagnosis is often delayed for months, until a crisis.

Symptoms:

• Fatigue and weakness.
• Weight loss and anorexia.
• Nausea, vomiting and abdominal pain (sometimes mistaken for a surgical abdomen).
• Dizziness on standing.
• Muscle and joint aches.
• Low mood.
• Salt craving (primary only).
• Loss of axillary and pubic hair and low libido in women (loss of adrenal androgens).

Signs:

• Postural hypotension.
• Hyperpigmentation (primary only).
• Vitiligo (autoimmune).
• Dehydration.

Blood tests:

• Hyponatraemia (in about 80%).
• Hyperkalaemia (primary only).
• Raised urea (dehydration).
• Hypoglycaemia (especially in children).
• Eosinophilia.
• Mild hypercalcaemia.
• Normocytic anaemia.
• Raised TSH (which corrects with steroid replacement).

💡 MRCP Pearl: Hyponatraemia + hyperkalaemia + postural hypotension + pigmentation = Addison's disease. Hyponatraemia with normal potassium and no pigmentation = consider pituitary disease.

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Adrenal Insufficiency: Diagnosis

If the patient is unwell, treat first. Take blood for cortisol and ACTH, then give hydrocortisone immediately without waiting for results.

In stable patients:

• 9 am serum cortisol: Thresholds are assay-dependent.
  • Very low (e.g. below about 100 nmol/L): Strongly suggests adrenal insufficiency.
  • Clearly adequate (e.g. above about 400–450 nmol/L): Makes it unlikely.
  • In between: Needs a short Synacthen test.
• Short Synacthen test (SST):
  • Method: Tetracosactide 250 micrograms IV or IM, with cortisol measured at 0 and 30 minutes (some centres also at 60 minutes).
  • Normal response: A peak cortisol above the laboratory threshold - typically about 430–450 nmol/L on modern specific assays (older assays used 550 nmol/L).
  • Pitfall: The SST can be falsely normal in recent-onset pituitary failure (within about 4–6 weeks of pituitary surgery or apoplexy), because the adrenals have not yet shrunk.
  • Not useful in critical illness.
• Plasma ACTH (taken at 9 am, before steroids):
  • High → primary (adrenal).
  • Low or normal → secondary (pituitary) or steroid-induced.
• Renin and aldosterone: High renin with low aldosterone confirms mineralocorticoid deficiency in primary disease.
• Finding the cause:
  • 21-hydroxylase antibodies (autoimmune).
  • CT adrenals if antibody-negative (TB, haemorrhage, metastases).
  • Very-long-chain fatty acids in young men.
  • Pituitary MRI and other pituitary hormones in secondary disease.

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Long-term Steroid Replacement

Glucocorticoid replacement:

• Hydrocortisone 15–25 mg daily in 2–3 divided doses, mimicking the natural rhythm. The largest dose goes on waking - e.g. 10 mg on waking, 5 mg at midday and 5 mg in the early afternoon.
• Alternative: Prednisolone 3–5 mg once daily.
• Dose adjustment is guided by symptoms, weight and blood pressure. Cortisol levels are of limited use.
• Avoid over-replacement: It causes weight gain, diabetes, hypertension and osteoporosis.

Mineralocorticoid replacement (primary adrenal insufficiency only):

• Fludrocortisone 50–200 micrograms daily (usually 100 micrograms).
• Titrate to postural blood pressure, potassium and renin. Too little causes postural hypotension and salt craving; too much causes hypertension, oedema and hypokalaemia.
• Patients should not restrict salt.

Patient education is essential:

• Sick-day rules.
• A Steroid Emergency Card and a medical alert bracelet.
• An emergency hydrocortisone injection kit (100 mg IM), with training for the patient and family.
• Enough tablets when travelling.

Drug interactions:

• Enzyme inducers (rifampicin, carbamazepine, phenytoin) increase steroid requirements.
• CYP3A4 inhibitors reduce requirements.
• Starting levothyroxine increases cortisol clearance.

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Sick Day Rules and Steroid Emergency Card

Patients with adrenal insufficiency cannot raise their own cortisol during illness, so they must increase their steroid dose themselves. These rules prevent adrenal crises and deaths.

• Sick Day Rule 1: For fever above 37.5 °C, an illness needing bed rest, or an infection needing antibiotics, double the usual daily glucocorticoid dose, keeping the same timing. Continue until recovered, usually 2–3 days. Fludrocortisone does not need changing.
• Sick Day Rule 2: For vomiting or diarrhoea preventing the tablets being kept down, or severe illness, injury or collapse, inject hydrocortisone 100 mg IM and seek urgent medical help (call 999). Show the Steroid Emergency Card.
• Other situations:
  • Strenuous exercise: an extra small dose (e.g. 5 mg hydrocortisone) beforehand.
  • Dental work and minor procedures: double the dose on the day.
  • Surgery and labour: see Steroid Cover for Surgery.
• NHS Steroid Emergency Card: Introduced nationally in 2020 after deaths from missed adrenal crises. It should be issued to everyone with adrenal insufficiency and to anyone on long-term steroids at risk of adrenal suppression. Clinicians who see the card must give hydrocortisone without delay if the patient is unwell.

⚠️ Safety Pearl: If a patient shows you a Steroid Emergency Card and is vomiting or unwell, give hydrocortisone 100 mg IV or IM immediately - do not wait for blood results.

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Adrenal Crisis

Mechanism: An acute, life-threatening cortisol deficiency. Without cortisol, blood vessels cannot respond to adrenaline, and shock follows. It occurs in about 6–8 per 100 patient-years in people with known adrenal insufficiency, and carries a significant mortality.

Triggers:

• Gastroenteritis (the commonest - tablets cannot be absorbed).
• Other infection.
• Surgery, trauma, pregnancy and labour.
• Missed or stopped steroids.
• Starting levothyroxine in untreated adrenal insufficiency.
• Adrenal haemorrhage.
• First presentation of undiagnosed Addison's.

Clinical pattern:

• Hypotension and shock that respond poorly to fluids and vasopressors.
• Vomiting and abdominal pain (can mimic an acute abdomen).
• Fever.
• Confusion, drowsiness or coma.
• Severe weakness.

Blood tests:

• Hyponatraemia.
• Hyperkalaemia (in primary disease).
• Hypoglycaemia.
• Raised urea.

Immediate management:

• Hydrocortisone 100 mg IV (or IM) immediately. If undiagnosed and time allows, take blood for cortisol and ACTH first - but never delay treatment.
• Continuing hydrocortisone: 200 mg over 24 hours by continuous IV infusion, or 50 mg IV/IM 6-hourly.
• Fluids: 0.9% sodium chloride, 1 litre over the first hour, then guided by response; cardiac monitoring.
• Glucose: IV glucose for hypoglycaemia.
• Treat the trigger (e.g. antibiotics).
• Monitor sodium to avoid correcting it too fast (risk of osmotic demyelination, especially if chronic and severe).
• Recovery: Taper to double the oral dose over 1–3 days, then the usual dose. Fludrocortisone is not needed while hydrocortisone is above 50 mg daily (high-dose hydrocortisone has mineralocorticoid action).
• Before discharge: Review education, sick-day rules, the emergency kit and the Steroid Emergency Card.

⚠️ Safety Pearl: Unexplained shock in a patient on long-term steroids, or with hyponatraemia and hyperkalaemia, is adrenal crisis until proven otherwise. Hydrocortisone first, tests later.

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Steroid Cover for Surgery and Procedures

Surgery is a major physical stress. Patients with adrenal insufficiency, or on steroids at doses that suppress the adrenals, need extra steroid. This is based on 2020 UK guidance (Association of Anaesthetists, Royal College of Physicians and Society for Endocrinology):

• Major surgery (general or regional anaesthesia):
  • Hydrocortisone 100 mg IV at induction.
  • Then 200 mg over 24 hours by continuous infusion (or 50 mg IV/IM 6-hourly) while nil by mouth or unwell.
  • Then double the usual oral dose for 48 hours (longer after major surgery or complications), then back to normal.
• Labour and delivery: Hydrocortisone 100 mg IM or IV at the onset of active labour, then 200 mg over 24 hours until delivery. Double the oral dose for 48 hours afterwards.
• Minor procedures and investigations (e.g. endoscopy, colonoscopy with bowel preparation, dental surgery): Usually double the oral dose on the day. Bowel preparation causing diarrhoea may need parenteral cover.
• Practical: Flag steroid dependence in the pre-operative assessment, record it on the anaesthetic chart and drug chart, and continue the regular dose up to surgery.

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Adrenal Haemorrhage

Mechanism: Bleeding into both adrenal glands destroys the cortex suddenly, causing acute primary adrenal insufficiency.

Causes:

• Anticoagulation.
• Sepsis - classically meningococcal (Waterhouse–Friderichsen syndrome), also Pseudomonas and others.
• Antiphospholipid syndrome.
• Heparin-induced thrombocytopenia.
• Trauma.
• After surgery.
• Pregnancy.

Clinical pattern:

• Abdominal, flank or back pain.
• Fever.
• Falling haemoglobin.
• Hypotension progressing to adrenal crisis, often in an already sick inpatient.
• In meningococcal sepsis: a purpuric rash and rapid shock.

Diagnosis: CT shows enlarged adrenals with haemorrhage; cortisol is low.

Management: Treat as adrenal crisis, with hydrocortisone immediately; treat the underlying cause; review anticoagulation. Many patients need lifelong replacement.

💡 Clinical Pearl: An anticoagulated inpatient who develops flank pain, a falling haemoglobin and then refractory hypotension may have bilateral adrenal haemorrhage. Give hydrocortisone.

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Cushing's Syndrome: Causes

Cushing's syndrome is the clinical state of chronic cortisol excess from any cause. Cushing's disease specifically means a pituitary ACTH-secreting adenoma.

💡 Clinical Pearl: Always take a full drug history - including inhalers, creams, joint injections and HIV medication - before investigating for endogenous Cushing's.

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Cushing's Syndrome: Clinical Features

Cortisol excess breaks down protein (muscle, skin, bone), raises glucose, redistributes fat, and has some mineralocorticoid effect.

Features that best discriminate Cushing's from simple obesity:

• Easy bruising.
• Wide (over 1 cm) purple striae on the abdomen, thighs and breasts.
• Proximal myopathy (difficulty rising from a chair).
• Thin skin (in younger patients).
• Facial plethora.
• Osteoporosis or fractures in young people.

Other features:

• Central obesity, round "moon" face, dorsocervical fat pad ("buffalo hump"), supraclavicular fat pads.
• Hypertension.
• Diabetes.
• Recurrent infections and poor wound healing.
• Hirsutism and acne; irregular periods; low libido.
• Depression, anxiety, insomnia or psychosis.
• Kidney stones.
• Growth failure with weight gain in children.

Blood clues:

• Hyperglycaemia.
• Hypokalaemic metabolic alkalosis - especially marked in ectopic ACTH.
• Neutrophilia with low lymphocytes and eosinophils.

Complications: Cardiovascular disease, venous thromboembolism, opportunistic infection (including PJP in severe disease), osteoporosis, and an increased mortality if untreated.

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Cushing's Syndrome: Investigations

Investigation has two stages: first prove cortisol excess, then find the source. Always exclude exogenous steroids first.

Stage 1 - Confirm cortisol excess: Use at least one test (ideally two), repeating any abnormal result.

• Overnight dexamethasone suppression test: Dexamethasone 1 mg at 11 pm; serum cortisol at 9 am. A normal person suppresses cortisol to below 50 nmol/L; failure to suppress suggests Cushing's.
• 24-hour urinary free cortisol: Collected on at least 2 occasions.
• Late-night salivary cortisol: Taken on at least 2 nights. It detects the loss of the normal night-time fall.
• Low-dose 48-hour dexamethasone suppression test: 0.5 mg every 6 hours for 48 hours. Used in specialist centres.
• Interpretation pitfalls: Oral oestrogen, enzyme-inducing drugs (which speed up dexamethasone breakdown), pseudo-Cushing's states, shift work and acute illness.

Stage 2 - Find the source:

• Plasma ACTH:
  • Suppressed → ACTH-independent (adrenal) → CT adrenals.
  • Normal or raised → ACTH-dependent (pituitary or ectopic).
• Pituitary or ectopic?
  • Pituitary MRI. Many Cushing's adenomas are tiny and invisible on MRI, and incidental pituitary lumps are common.
  • High-dose dexamethasone suppression or CRH test: Pituitary tumours usually still respond partly to feedback; ectopic tumours do not.
  • Bilateral inferior petrosal sinus sampling: The gold standard. ACTH is measured in the veins draining the pituitary and compared with peripheral blood after CRH or desmopressin stimulation.
• Looking for an ectopic source: CT chest, abdomen and pelvis, and functional imaging (e.g. gallium-68 DOTATATE PET) for neuroendocrine tumours.

💡 Clinical Pearl: Never image first. Adrenal and pituitary "incidentalomas" are common, and imaging before biochemistry leads to the wrong operation.

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Cushing's Disease

Mechanism: A pituitary adenoma (usually a microadenoma under 1 cm) secretes ACTH, driving both adrenals to make excess cortisol. It is the commonest endogenous cause, most often in women aged 25–45.

Clinical pattern: Gradual onset of the classic Cushingoid features over months to years. Pigmentation is mild or absent (ACTH is only modestly raised).

Investigations:

• Normal or mildly raised ACTH.
• Usually suppresses partly on high-dose dexamethasone.
• Pituitary MRI may show the adenoma.
• Inferior petrosal sinus sampling confirms a pituitary source when imaging is unclear.

Management:

• Transsphenoidal surgery by an expert pituitary surgeon - the first-line treatment. Remission rates are about 70–90% for microadenomas.
• After successful surgery, cortisol falls very low, because the normal corticotroph cells have been suppressed. Patients need hydrocortisone replacement for months to years until the axis recovers.
• Persistent or recurrent disease: Repeat surgery, pituitary radiotherapy, medical therapy or bilateral adrenalectomy.
• Nelson's syndrome: After bilateral adrenalectomy, loss of cortisol feedback can allow the pituitary tumour to grow aggressively, causing intense pigmentation and local mass effects. Patients need MRI surveillance.

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Ectopic ACTH Syndrome

Mechanism: A non-pituitary tumour secretes ACTH, often in very large amounts and with no feedback control.

Causes:

• Small cell lung cancer.
• Bronchial and thymic carcinoid tumours.
• Pancreatic neuroendocrine tumours.
• Medullary thyroid cancer.
• Phaeochromocytoma.

Clinical pattern: Usually differs from classic Cushing's because onset is rapid and cortisol levels are extreme:

• Rapid onset of severe hypokalaemia and metabolic alkalosis.
• Muscle weakness and oedema.
• Hypertension.
• Diabetes.
• Psychosis.
• Pigmentation (very high ACTH).
• Weight loss rather than obesity in malignant cases.
• Severe infections.

The classic Cushingoid appearance may be absent. Slow-growing carcinoids can cause classic features that mimic Cushing's disease.

Investigations: Very high ACTH and cortisol; no suppression with high-dose dexamethasone; inferior petrosal sinus sampling shows no central gradient; CT chest, abdomen and pelvis and functional imaging to find the tumour.

Management:

• Remove the tumour if possible.
• Urgent medical control of cortisol: Metyrapone, osilodrostat or ketoconazole; IV etomidate in severe cases.
• Correct hypokalaemia.
• Thromboprophylaxis and PJP prophylaxis.
• Bilateral adrenalectomy if the source cannot be found or controlled.

💡 MRCP Pearl: A smoker with weight loss, severe hypokalaemic alkalosis, oedema, hypertension and pigmentation = ectopic ACTH from small cell lung cancer.

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Adrenal Cushing's

Mechanism: An adrenal tumour makes cortisol autonomously. ACTH is suppressed, so the other adrenal shrinks.

Types:

• Benign adrenal adenoma: Pure cortisol excess, gradual onset.
• Adrenocortical carcinoma: Rapid onset, often with androgen excess (virilisation in women) and a large mass.
• Mild autonomous cortisol secretion (from adrenal incidentalomas): No overt Cushing's features, but an increased risk of hypertension, diabetes, osteoporosis and cardiovascular disease.

Investigations: Cortisol excess with a suppressed ACTH; CT adrenals.

Management:

• Laparoscopic adrenalectomy for an adenoma.
• After surgery: The remaining adrenal has been suppressed, so the patient needs hydrocortisone (often for months) until it recovers. Steroid cover from the time of surgery is essential.
• Carcinoma: See Adrenocortical Carcinoma.

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Cushing's Syndrome: Treatment

• Exogenous: Reduce the steroid to the lowest effective dose, use steroid-sparing agents, and taper slowly (the axis is suppressed). Review interacting drugs.
• Treat the source:
  • Pituitary surgery for Cushing's disease.
  • Adrenalectomy for an adrenal adenoma or carcinoma.
  • Tumour resection for ectopic ACTH.
• Medical therapy (to control cortisol before surgery, while awaiting radiotherapy effect, or when surgery fails):
  • Steroidogenesis inhibitors: Metyrapone, osilodrostat, ketoconazole (liver monitoring), IV etomidate in critical cases.
  • Pituitary-directed: Pasireotide, cabergoline.
  • Glucocorticoid receptor blocker: Mifepristone (limited UK use).
  • All risk causing adrenal insufficiency, so a "block-and-replace" approach or careful monitoring is needed.
• Bilateral adrenalectomy: A definitive option for refractory disease. Patients then need lifelong hydrocortisone and fludrocortisone, and pituitary surveillance for Nelson's syndrome.
• Treat the complications:
  • Hypertension and diabetes.
  • Hypokalaemia.
  • Bone protection.
  • VTE prophylaxis, especially around surgery.
  • PJP prophylaxis when cortisol is very high.
  • Psychological support.
• After cure: Patients often feel worse for months (steroid withdrawal), with fatigue, aches and low mood, and need hydrocortisone and support during recovery.

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Primary Aldosteronism

Mechanism: The adrenal cortex makes aldosterone autonomously, independent of renin. The kidneys retain sodium and water, raising blood pressure, and waste potassium. The expanded blood volume suppresses renin. Aldosterone also directly damages the heart, blood vessels and kidneys, so patients have more strokes, AF and heart failure than people with essential hypertension at the same blood pressure.

How common: The commonest cause of secondary hypertension - about 5–10% of all hypertensive patients and about 20% of those with resistant hypertension. Most cases are never diagnosed.

Causes:

• Bilateral adrenal hyperplasia (about 60–65%): Treated with drugs.
• Aldosterone-producing adenoma (Conn's syndrome, about 30–35%): Curable with surgery.
• Rare: Unilateral hyperplasia, adrenocortical carcinoma, familial hyperaldosteronism. The familial forms include glucocorticoid-remediable aldosteronism, which is suppressed by dexamethasone.

Clinical pattern:

• Hypertension, often resistant or presenting young.
• Hypokalaemia in only about a quarter to a half - a normal potassium does not exclude it.
• Muscle weakness, cramps, polyuria and nocturia (from hypokalaemia).
• Metabolic alkalosis; sodium high-normal.

Who to screen:

• Resistant hypertension (uncontrolled on three drugs including a diuretic).
• Hypertension with hypokalaemia, including diuretic-induced.
• Hypertension in people under 40.
• Hypertension with an adrenal incidentaloma.
• Hypertension with AF or obstructive sleep apnoea.
• A family history of early hypertension or stroke.

💡 Clinical Pearl: Hypertension + hypokalaemia (especially if it worsens on a thiazide) = check the aldosterone:renin ratio. Many patients with primary aldosteronism have a normal potassium.

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Primary Aldosteronism: Diagnosis

Step 1 - Screening: aldosterone:renin ratio (ARR)

• Interpretation: A high ratio (high aldosterone with suppressed renin) is a positive screen.
• Before testing: Correct hypokalaemia (low potassium suppresses aldosterone and causes false negatives).
• How to sample: Take the sample mid-morning, after the patient has been up for at least 2 hours and seated for 5–15 minutes.
• Interfering drugs:
  • Stop for 4–6 weeks: Spironolactone, eplerenone, amiloride and high-dose loop diuretics.
  • Cause false negatives (raise renin): ACE inhibitors, ARBs, diuretics and dihydropyridine calcium channel blockers.
  • Cause false positives (suppress renin): Beta blockers and NSAIDs.
  • Where safe, switch temporarily to drugs with little effect: doxazosin, verapamil (modified release) and hydralazine.
  • If drugs cannot be changed, interpret with care.

Step 2 - Confirmation (in most patients; not needed if the result is unequivocal with spontaneous hypokalaemia):

• Saline infusion test: 2 litres of 0.9% saline over 4 hours. Aldosterone fails to suppress in primary aldosteronism. Avoid in heart failure or uncontrolled hypertension.
• Alternatives: oral salt loading, the fludrocortisone suppression test, the captopril challenge test.

Step 3 - Subtype: is it one adrenal or both?

• CT adrenals: Looks for an adenoma and excludes carcinoma. CT cannot reliably tell which gland is responsible - non-functioning lumps are common, especially over 35–40.
• Adrenal vein sampling: Measures aldosterone (corrected for cortisol) in each adrenal vein. It is the standard way to confirm unilateral disease before surgery in patients who would want an operation.

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Primary Aldosteronism: Treatment

• Unilateral disease (adenoma or unilateral hyperplasia): laparoscopic adrenalectomy.
  • Hypokalaemia is cured in almost all patients.
  • Blood pressure improves in most, and is fully cured in about 30–50% (less often with long-standing hypertension).
  • Watch for hyperkalaemia after surgery, because the other adrenal has been suppressed. Stop potassium supplements and MRAs.
• Bilateral disease, or patients unsuitable for or not wanting surgery: mineralocorticoid receptor antagonists.
  • Spironolactone, e.g. 25–100 mg daily. Side effects include gynaecomastia, breast tenderness, erectile dysfunction and menstrual upset.
  • Eplerenone, e.g. 25–50 mg twice daily. Fewer sex-hormone side effects, but less potent.
  • Amiloride is an alternative.
  • Aim for renin to become unsuppressed - a sign of adequate blockade - and monitor potassium and creatinine.
• Glucocorticoid-remediable aldosteronism: Low-dose glucocorticoid suppresses ACTH-driven aldosterone.
• All patients: Additional antihypertensives as needed, and cardiovascular risk reduction.

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Renin and Aldosterone Patterns

In a patient with hypertension and hypokalaemia, renin and aldosterone sort the causes:

💡 MRCP Pearl: Hypertension, hypokalaemia, low renin and low aldosterone → think liquorice, Liddle's syndrome or Cushing's - not primary aldosteronism.