Adrenal Disease

Addison Disease

Definition, aetiology and pathophysiology

Addison disease is chronic primary adrenal insufficiency, defined by failure of the adrenal cortex to produce sufficient glucocorticoid and usually mineralocorticoid, with compensatory elevation of ACTH. In the UK and most high-income settings, autoimmune adrenalitis accounts for approximately 80–90% of cases; tuberculosis, metastatic malignancy, bilateral adrenal haemorrhage, infiltrative disease, adrenalectomy, drugs and congenital adrenal hyperplasia are less common but exam-relevant causes.

The autoimmune form is mediated by T-cell destruction of the adrenal cortex and commonly associated with antibodies to 21-hydroxylase. It may occur in autoimmune polyglandular syndrome type 2 with autoimmune thyroid disease and type 1 diabetes; type 1 is AIRE-related and associated with chronic mucocutaneous candidiasis and hypoparathyroidism. Symptoms usually appear only after destruction of >90% of the adrenal cortex. Cortisol deficiency causes fatigue, weight loss, anorexia, nausea, postural hypotension and impaired free-water clearance; aldosterone deficiency causes renal sodium wasting, hypovolaemia, hyperkalaemia and metabolic acidosis. High ACTH and pro-opiomelanocortin-derived melanocyte-stimulating peptides cause hyperpigmentation, particularly palmar creases, buccal mucosa and scars; this distinguishes primary from secondary adrenal insufficiency.

Cause	Clues	Mechanism
Autoimmune adrenalitis	Other autoimmune disease; 21-hydroxylase antibodies	Progressive cortical destruction
Tuberculosis or fungal infection	Calcified/enlarged adrenals; systemic features	Granulomatous adrenal destruction
Bilateral adrenal haemorrhage	Sepsis, antiphospholipid syndrome, anticoagulation	Acute vascular infarction/haemorrhage; Waterhouse–Friderichsen in meningococcaemia
Drugs	Ketoconazole, etomidate, metyrapone, mitotane, rifampicin	Inhibition of steroidogenesis or increased cortisol clearance
Metastases/infiltration	Lung, breast, melanoma, lymphoma; bilateral masses	Replacement of adrenal cortex; usually late

Clinical and biochemical features

The presentation is often insidious: fatigue, proximal weakness, weight loss, abdominal pain, salt craving, low mood, amenorrhoea and reduced libido. Examination may show low BMI, postural hypotension, pigmentation and vitiligo. Typical biochemistry includes hyponatraemia, hyperkalaemia, raised urea, mild non-anion gap metabolic acidosis, hypoglycaemia and normocytic anaemia or eosinophilia. Hypercalcaemia may occur through haemoconcentration and increased renal calcium reabsorption. In secondary adrenal insufficiency, aldosterone is usually preserved because it is mainly renin-angiotensin regulated; potassium and pigmentation are therefore usually normal.

Diagnosis

In a clinically stable patient, an 08:00–09:00 serum cortisol is the screening test. Values <100 nmol/L strongly suggest adrenal insufficiency, whereas >400–500 nmol/L usually exclude it, assay-dependent. Intermediate results require dynamic testing. Simultaneous plasma ACTH is essential: in primary disease ACTH is typically >2-fold the upper limit of normal, often >100 ng/L. Plasma renin is raised and aldosterone low or inappropriately normal.

The standard short Synacthen test uses tetracosactide 250 micrograms IV or IM with cortisol measured at baseline and 30 minutes, sometimes 60 minutes. A normal response is generally peak cortisol >430–550 nmol/L, depending on local assay and binding-globulin status. Modern monoclonal immunoassays and LC-MS/MS often use lower cut-offs than older polyclonal assays. Sensitivity for established primary adrenal insufficiency is high, usually >95%, but early secondary adrenal insufficiency may be missed because the adrenal cortex has not yet atrophied. If adrenal crisis is suspected, treatment must not await testing; draw cortisol and ACTH first if this does not delay hydrocortisone.

Test	Primary adrenal insufficiency	Secondary/tertiary adrenal insufficiency
ACTH	High	Low or inappropriately normal
Renin/aldosterone	Renin high; aldosterone low	Usually preserved
Potassium	Often high	Usually normal
Skin pigmentation	Common	Absent

Management

Guidance from the Endocrine Society Clinical Practice Guideline supports physiologic glucocorticoid replacement with hydrocortisone 15–25 mg/day orally in 2–3 divided doses, for example 10 mg on waking, 5 mg at lunchtime and 5 mg early evening; prednisolone 3–5 mg once daily is an alternative. Hydrocortisone has a short biological half-life of approximately 8–12 hours despite a plasma half-life of about 90 minutes. Avoid chronic over-replacement, which causes weight gain, hypertension, osteoporosis and impaired glucose tolerance. Monitoring is clinical: weight, blood pressure, postural symptoms, energy, intercurrent illness and features of Cushingoid excess; routine cortisol day curves are not generally required.

Mineralocorticoid replacement is with fludrocortisone 50–200 micrograms once daily, titrated to postural blood pressure, oedema, serum sodium/potassium and plasma renin in the upper reference range or mildly raised. Higher doses may be required in hot climates, heavy exercise or pregnancy; lower doses are needed if hypertension or oedema develops. Patients should not restrict salt unless specifically indicated.

Adrenal crisis and prevention

Adrenal crisis presents with shock, severe weakness, vomiting, abdominal pain, fever, confusion, hypoglycaemia, hyponatraemia and hyperkalaemia. Immediate treatment is hydrocortisone 100 mg IV or IM, followed by 200 mg/24 h by continuous IV infusion or 50 mg IV/IM every 6 hours, plus rapid isotonic saline; use dextrose-containing fluids if hypoglycaemic. Once clinically stable and eating, taper to oral replacement over 24–72 hours and restart fludrocortisone when total hydrocortisone is below approximately 50 mg/day, because higher hydrocortisone doses provide mineralocorticoid activity.

All patients require education, steroid emergency card, medical alert identification and injectable hydrocortisone. During febrile illness they should usually double oral hydrocortisone; for vomiting, trauma, surgery or inability to absorb oral medication they require parenteral hydrocortisone. Peri-operative cover is typically 100 mg IV at induction for major surgery followed by 200 mg/24 h, then step down according to clinical status.

Cushing Syndrome

Definition, mechanisms and classification

Cushing syndrome is the clinical state resulting from chronic glucocorticoid excess; Cushing disease refers specifically to an ACTH-secreting pituitary corticotroph adenoma. The commonest cause is iatrogenic glucocorticoid exposure, including oral, inhaled, topical, intra-articular and “herbal” preparations. Endogenous disease is classified biochemically by ACTH dependence.

Category	Typical ACTH	Mechanism	Key examples
ACTH-dependent, pituitary	Normal/high	Autonomous corticotroph ACTH secretion with retained partial feedback sensitivity	Pituitary microadenoma; accounts for approximately 60–70% of endogenous cases
ACTH-dependent, ectopic	High, often markedly	Non-pituitary ACTH or rarely CRH secretion	Small-cell lung carcinoma, bronchial carcinoid, thymic/pancreatic NET, medullary thyroid carcinoma
ACTH-independent	Suppressed, usually <1.1 pmol/L or <5 pg/mL	Primary adrenal cortisol secretion suppressing pituitary ACTH	Adrenal adenoma, carcinoma, bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenocortical disease

Excess cortisol activates glucocorticoid receptors, increases hepatic gluconeogenesis, antagonises insulin signalling, promotes proteolysis and lipolysis with centripetal fat redistribution, suppresses osteoblast function and gonadotrophins, and potentiates catecholamine-mediated vasoconstriction. Mineralocorticoid effects become clinically relevant when 11β-HSD2 is saturated, particularly in ectopic ACTH, producing hypokalaemic metabolic alkalosis.

Clinical phenotype and examination priorities

High-discriminatory features for examination purposes are proximal myopathy, wide violaceous striae >1 cm, easy bruising, facial plethora, unexplained osteoporosis/fracture, thin skin and progressive metabolic syndrome in a younger patient. Common but less specific features include obesity, hypertension, diabetes, depression, menstrual disturbance, hirsutism/acne, infection susceptibility and poor wound healing. Ectopic ACTH often presents abruptly with severe hypertension, oedema, hyperpigmentation, hypokalaemia and weight loss rather than classic cushingoid habitus. Pseudo-Cushing states include alcohol excess, severe depression, uncontrolled diabetes, obesity and obstructive sleep apnoea; pregnancy and oral oestrogens increase cortisol-binding globulin and confound serum cortisol interpretation.

Biochemical diagnosis

Current Endocrine Society guidance recommends testing only patients with multiple progressive features or adrenal incidentaloma suspicious for cortisol excess. Do not use random serum cortisol. Establish hypercortisolism with at least two abnormal first-line tests, preferably repeated because secretion may be cyclical.

Test	Positive threshold	Comments and performance
1 mg overnight dexamethasone suppression test	08:00–09:00 serum cortisol >50 nmol/L after dexamethasone 1 mg at 23:00	Sensitivity approximately >95% at 50 nmol/L; specificity lower. False positives with enzyme inducers such as phenytoin, carbamazepine, rifampicin; oral oestrogens increase CBG.
Late-night salivary cortisol	Above assay-specific upper limit, commonly >3–4 nmol/L	Detects loss of circadian nadir; sensitivity/specificity often 90–95%. Avoid shift work, smoking, liquorice, topical hydrocortisone contamination.
24-hour urinary free cortisol	>Upper limit of normal; values >3 times ULN strongly supportive	Collect at least two samples with creatinine adequacy. False low in eGFR <60 mL/min/1.73 m²; false high with high fluid intake or stress.

Localising the source

Once endogenous Cushing syndrome is confirmed, measure plasma ACTH. Suppressed ACTH indicates adrenal disease and should prompt adrenal CT. Detectable or elevated ACTH requires pituitary MRI and evaluation for ectopic ACTH. MRI identifies many pituitary microadenomas but incidentalomas are common; lesions <6 mm may be non-diagnostic.

The high-dose dexamethasone suppression test is less definitive than historically taught: pituitary disease may suppress cortisol by >50%, whereas ectopic ACTH usually does not, but overlap is substantial. CRH stimulation supports pituitary disease if ACTH rises >35% or cortisol >20%. The reference standard when imaging is equivocal is bilateral inferior petrosal sinus sampling after CRH or desmopressin: a central-to-peripheral ACTH ratio >2 basally or >3 after stimulation indicates pituitary source; reported sensitivity and specificity are approximately 95% and 90–100% in expert centres.

Management principles

Treatment is directed at the cause while controlling cortisol toxicity, thromboembolic risk, sepsis risk, diabetes, hypertension and osteoporosis. Untreated severe Cushing syndrome carries high cardiovascular and infective mortality. Peri-operative glucocorticoid cover is required after curative surgery because the contralateral adrenal axis is suppressed.

Situation	Preferred therapy	Important details
Cushing disease	Trans-sphenoidal adenomectomy	Initial remission roughly 70–90% for microadenomas in expert hands; recurrence 10–20% over long-term follow-up. Post-operative cortisol <50 nmol/L suggests remission.
Adrenal adenoma/carcinoma	Unilateral adrenalectomy; oncological resection for carcinoma	Adrenocortical carcinoma may require mitotane and oncology input; assess androgen excess and tumour size/invasion.
Ectopic ACTH	Resect source if localised	If occult or metastatic, use steroidogenesis blockade; bilateral adrenalectomy may be lifesaving in refractory severe hypercortisolism.

Medical therapy

Medical treatment is used as a bridge to surgery, for persistent/recurrent disease, or when surgery is not feasible. Monitor cortisol response, liver tests, QT interval where relevant, potassium and adrenal insufficiency symptoms.

• Metyrapone: 250 mg three times daily, titrated rapidly up to 1–2 g three to four times daily; inhibits 11β-hydroxylase. Adverse effects include hypertension, hypokalaemia, acne and hirsutism from steroid precursors.
• Ketoconazole: 200 mg twice daily, titrated to 400 mg two or three times daily; inhibits multiple CYP steroidogenic enzymes. Risk of hepatotoxicity and drug interactions; avoid in significant liver disease.
• Osilodrostat: 1–2 mg twice daily, titrated; potent 11β-hydroxylase inhibitor. Phase III data showed normalisation of mean urinary free cortisol in a majority of patients by 24 weeks; monitor QT prolongation and adrenal insufficiency.
• Pasireotide: somatostatin analogue targeting pituitary corticotrophs; useful in Cushing disease but frequently worsens hyperglycaemia.
• Mifepristone: glucocorticoid receptor antagonist, typically 300 mg daily titrated upward; cortisol cannot be used to monitor efficacy and hypokalaemia may occur.
• Etomidate: intravenous ICU option for life-threatening hypercortisolism, e.g. infusion 0.03–0.1 mg/kg/hour, with cortisol monitoring.

After remission, patients require surveillance for recurrence, adrenal insufficiency education, cardiovascular risk reduction and bone protection. Persistent hypertension or diabetes does not exclude biochemical cure, because chronic cortisol exposure may leave residual cardiometabolic disease.

Primary Hyperaldosteronism

Primary hyperaldosteronism (PA) is autonomous aldosterone excess causing sodium retention, potassium and hydrogen ion loss, extracellular volume expansion and renin suppression. It is the commonest endocrine cause of secondary hypertension, present in approximately 5–10% of unselected hypertensive patients and up to 20% of resistant hypertension. Hypokalaemia is absent in most cases; normokalaemic PA is common and should not be dismissed in examinations.

Pathophysiology and classification

Aldosterone acts via the mineralocorticoid receptor in the distal nephron, increasing epithelial sodium channel activity and Na⁺/K⁺-ATPase expression. The result is sodium retention, potassium wasting, metabolic alkalosis and suppressed plasma renin. “Aldosterone escape” limits oedema through pressure natriuresis and natriuretic peptides; therefore peripheral oedema is not typical.

Subtype	Approximate frequency	Key features	Treatment implication
Bilateral adrenal hyperplasia	60–70%	Often older patients; bilateral aldosterone secretion	Medical mineralocorticoid receptor antagonism
Aldosterone-producing adenoma	30–40%	Unilateral Conn adenoma; often more severe hypokalaemia	Laparoscopic adrenalectomy if lateralised
Unilateral adrenal hyperplasia	Uncommon	Unilateral hypersecretion without discrete adenoma	Surgery if proven by adrenal venous sampling
Familial hyperaldosteronism	<5%	Type I glucocorticoid-remediable aldosteronism due to CYP11B1/CYP11B2 chimeric gene; type II often CLCN2; type III KCNJ5	Genetic testing in young onset, family history, stroke <40 years
Adrenocortical carcinoma/ectopic aldosterone	Very rare	Large adrenal mass, mixed steroid excess	Oncological management

When to screen

Endocrine Society guidance recommends screening hypertensive patients with: resistant hypertension; sustained BP >150/100 mmHg on repeated measurements; hypertension with spontaneous or diuretic-induced hypokalaemia; adrenal incidentaloma; sleep apnoea; family history of early-onset hypertension or cerebrovascular accident before age 40; or a first-degree relative with PA.

Biochemical diagnosis

The screening test is the aldosterone-to-renin ratio (ARR), interpreted with the absolute aldosterone concentration. A typical positive screen is plasma aldosterone concentration >10–15 ng/dL (>280–420 pmol/L) with suppressed renin and ARR >20–30 ng/dL per ng/mL/hour, though assay-specific thresholds are mandatory. In SI units, local laboratory cut-offs vary substantially; exam questions usually emphasise high aldosterone with undetectable renin.

• Pre-analytical points: correct hypokalaemia before testing, as hypokalaemia suppresses aldosterone and may cause false negatives. Liberalise sodium intake. Sample in the morning after the patient has been ambulant for at least 2 hours and seated for 5–15 minutes.
• Drug effects: spironolactone, eplerenone and amiloride should ideally be stopped for 4–6 weeks. ACE inhibitors, ARBs, diuretics and dihydropyridine calcium-channel blockers tend to raise renin and may cause false negatives. Beta-blockers suppress renin and may cause false positives. Verapamil SR, hydralazine and alpha-blockers are preferred bridging agents.
• No confirmatory test may be needed when there is spontaneous hypokalaemia, undetectable renin and plasma aldosterone >20 ng/dL (>550 pmol/L), a high-specificity phenotype.

Confirmatory test	Protocol	Positive result	Cautions
Saline infusion test	2 L 0.9% saline IV over 4 hours	Post-infusion aldosterone >10 ng/dL supports PA; <5 ng/dL excludes	Avoid in severe uncontrolled hypertension, heart failure, advanced CKD
Oral sodium loading	High salt intake for 3 days, 24-hour urinary aldosterone	Urine aldosterone >12 µg/24 h with urine sodium >200 mmol/24 h	Requires adherence and safe renal/cardiac status
Captopril challenge	25–50 mg captopril orally, measure aldosterone/renin at 1–2 h	Failure of aldosterone suppression	Less standardised; useful when volume loading unsafe
Fludrocortisone suppression	Fludrocortisone 0.1 mg 6-hourly for 4 days plus salt/K+	Persistent elevated aldosterone	Most sensitive but labour-intensive and higher risk

Subtype classification

All confirmed cases should undergo adrenal CT to exclude carcinoma and define anatomy, but CT cannot reliably lateralise secretion: non-functioning incidentalomas increase with age and small microadenomas may be missed. Adrenal venous sampling (AVS) is the gold standard for distinguishing unilateral from bilateral disease, particularly in patients over 35 years or when imaging is discordant. Cosyntropin-stimulated AVS improves cannulation success. Selectivity is confirmed by adrenal vein to peripheral cortisol ratio, commonly >5 with ACTH stimulation; lateralisation is suggested by aldosterone/cortisol ratio at least 4-fold higher on one side than the other. AVS may be omitted in selected patients younger than 35 years with marked PA, hypokalaemia and a solitary unilateral adenoma on CT.

Management

Unilateral PA is treated with laparoscopic adrenalectomy, which normalises hypokalaemia in most patients and cures hypertension in approximately 30–60%; persistent hypertension reflects age, duration of hypertension, renal impairment and vascular remodelling. The PASO study standardised outcomes after adrenalectomy, distinguishing complete biochemical success from complete, partial or absent clinical success.

Drug	Typical dose	Key adverse effects and notes
Spironolactone	Start 12.5–25 mg once daily; titrate every 4–8 weeks, commonly 50–100 mg/day	Gynaecomastia, erectile dysfunction, menstrual irregularity due anti-androgen/progestogenic effects; hyperkalaemia and fall in eGFR require monitoring
Eplerenone	25 mg twice daily, titrate to 50 mg twice daily	More selective, fewer sex-steroid effects; shorter half-life about 4–6 h; less potent and more expensive
Amiloride	5–10 mg/day, up to 20 mg/day	ENaC blocker; useful if mineralocorticoid receptor antagonists not tolerated, including gynaecomastia

For bilateral disease or non-surgical patients, mineralocorticoid receptor blockade is titrated to normokalaemia, BP control and ideally unsuppressed renin, as persistently suppressed renin may indicate inadequate blockade and ongoing cardiovascular risk. PA confers excess atrial fibrillation, stroke, myocardial infarction, left ventricular hypertrophy, albuminuria and CKD compared with essential hypertension at similar BP; targeted treatment reduces but may not fully abolish this risk. Follow-up requires BP, U&E/eGFR within 1–2 weeks after dose changes, then periodically, with dietary sodium restriction and conventional antihypertensives as required.