Adrenal Insufficiency

Meet the patient

A 38-year-old woman is brought in vague, nauseated, and a stone lighter than her last photograph. Her blood pressure drops when she stands, her sodium is 124, her potassium 5.6 — and the nurse remarks her gums look "stained". She has been told she is depressed for six months.^[1][2]

Three questions decide her next hour, and every endocrinology viva: is this primary or secondary?, is she about to crisi? — and what do you draw before you treat? Hold those three, and the rest of the topic slots into place.^[1][3]

The three levels — and the one physiology fact that runs the whole topic

Three levels of the HPA axis can fail, and the level decides everything downstream. Primary (Addison) is disease of the adrenal cortex itself. Secondary is anterior-pituitary ACTH deficiency. Tertiary is hypothalamic CRH deficiency — and in real life, almost always chronic exogenous glucocorticoid therapy. The clinical task is always two-fold: recognise the syndrome, then localise the level — because primary needs fludrocortisone and a search for the cause, and secondary does neither.^[1][4]

The axis itself is simple. Hypothalamic CRH drives pituitary ACTH (cleaved from POMC, alongside alpha-MSH and beta-endorphin); ACTH binds MC2R on the cortex and drives StAR-mediated cholesterol delivery to the steroidogenic cascade. Circulating cortisol feeds back negatively on both pituitary and hypothalamus — and that feedback is steep and fast, which is exactly why a few weeks of prednisolone can suppress the axis for months.^[2]

One physiology fact runs the entire topic: aldosterone is regulated by angiotensin II and potassium, not by ACTH. The zona glomerulosa answers to the RAAS, with ACTH only permissive. So when the pituitary fails, aldosterone survives — angiotensin II keeps the glomerulosa working — and secondary AI spares the mineralocorticoid axis. When the cortex is destroyed, aldosterone falls too. That single difference generates every discriminator on this page.^[3]

Etymology for viva gold: Addison disease carries Thomas Addison's name — the Guy's Hospital physician who in 1855 described the "bronzed", wasting patients everyone else filed under melancholia. The eponym survived because the bedside picture he drew is unchanged a hundred and seventy years later.^[3]

Primary vs secondary — the three discriminators (pigment, potassium, RAAS)

The level is read off three bedside and biochemical discriminators: pigment, potassium, and the RAAS. Primary destroys all three cortical zones — cortisol, aldosterone and androgens — with high ACTH, high renin, hyperpigmentation, and the signature hyponatraemia with hyperkalaemia. Secondary and tertiary lower ACTH but spare aldosterone — pale skin, hyponatraemia without hyperkalaemia, normal renin.^[1]

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By temporal course — chronic, acute, and the ICU variant

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Who gets it, and why — autoimmune in the West, tuberculosis worldwide

The epidemiology is decided by two words: level and country. Glucocorticoid-induced (tertiary) AI is the commonest form in practice — at least 1 percent of the population uses chronic glucocorticoid therapy and is at risk, and that risk depends on the dose, duration and potency of the glucocorticoid, its route of administration and individual susceptibility. Primary and secondary AI together are rare: an estimated 20 to 50 per 100 000 individuals across Europe.^[13][20]

The cause splits along geography. Autoimmune adrenalitis accounted for 92 percent of primary AI in a recent Italian cohort of 132 patients, most of whom carried additional autoimmune comorbidity — and those with more autoimmune comorbidity, or with premature ovarian insufficiency, were at significantly higher risk of adrenal crisis. Tuberculous Addison's disease remains an important cause where tuberculosis is endemic.^[8][22]

^{[1] [8] [11] [15] [20]}

Host and environmental risk factors are an examiner staple — cluster them, do not list them.^[1][3]

• Autoimmune clustering — personal or family history of autoimmune thyroid disease, type 1 diabetes, vitiligo, premature ovarian failure, pernicious anaemia, coeliac disease (the polyglandular syndromes).
• Chronic glucocorticoid therapy — the dominant tertiary cause; risk worsens with evening dosing, which flattens the early-morning ACTH surge.
• Infection — tuberculosis (especially extrapulmonary), HIV/AIDS with opportunistic adrenalitis (CMV, mycobacteria, cryptococcus, histoplasma), and endemic fungal disease.
• Anticoagulation — heparin (including HIT), warfarin and DOACs risking bilateral adrenal vein thrombosis and haemorrhage; post-surgical and post-cardiac-bypass patients.
• Meningococcaemia — Waterhouse-Friderichsen, bilateral adrenal haemorrhage in children and young adults.
• Critical illness — sepsis with vasopressor-refractory shock may unmask transient CIRCI.
• Drugs — etomidate (11β-hydroxylase — a single dose can precipitate AI), ketoconazole, metyrapone, mitotane, mifepristone, and the enzyme inducers rifampicin and phenytoin (which accelerate cortisol metabolism and precipitate crisis in established Addison).
• Infiltration — haemochromatosis, amyloidosis, sarcoidosis, metastases (lung, breast, melanoma, kidney), lymphoma.
• Pregnancy and postpartum — Sheehan syndrome (postpartum pituitary necrosis after obstetric haemorrhage).^[1]

Why cortisol deficiency causes every symptom

Every symptom traces back to one of six lost cortisol jobs. Cortisol maintains vascular catecholamine tone, drives gluconeogenesis, suppresses vasopressin, limits inflammation, modulates arousal, and feeds back on the pituitary. Lose it and the clinical picture writes itself.^[2]

• Loss of vascular catecholamine permissiveness — reduced arteriolar tone and cardiac output; postural hypotension, and in crisis a vasodilatory shock refractory to catecholamines until cortisol is replaced.
• Loss of hepatic gluconeogenesis — fasting hypoglycaemia, especially in children.
• Loss of ADH suppression — free-water retention and dilutional hyponatraemia in both primary and secondary AI.
• Loss of aldosterone (primary only) — renal sodium wasting with potassium and hydrogen retention: hyponatraemia with hyperkalaemia and metabolic acidosis, volume depletion, secondary hyper-reninaemia.
• Loss of negative feedback (primary only) — ACTH rises, MSH from POMC cleavage drives melanocytes, and hyperpigmentation appears.
• Loss of adrenal androgens (primary only) — in women, loss of axillary and pubic hair and reduced libido; men are protected by testicular androgens.^[1]

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Autoimmune Addison — the prototype

Autoimmune Addison is an organ-specific T-cell destruction of the cortex, and 21-hydroxylase is the autoantigen. Anti-21-hydroxylase antibodies are the diagnostic serological marker (sensitivity over 90 percent in recent-onset disease); CD4 and CD8 T-cells infiltrate the fasciculata and reticularis, the glands become small and atrophic, and the association with HLA-DR3/DR4, CTLA-4 and PTPN22 marks the autoimmune diathesis.^[2][3]

Two polyglandular syndromes travel with Addison — name them both.^[2]

• APS-1 (Whitaker syndrome) — autosomal recessive, AIRE gene on chromosome 21; the classic triad is chronic mucocutaneous candidiasis (often first, in childhood), hypoparathyroidism and Addison disease. Diagnose with two of the triad or by AIRE sequencing.
• APS-2 (Schmidt syndrome) — polygenic, HLA-associated, commoner in adult women; Addison plus autoimmune thyroid disease (Hashimoto or Graves) plus or minus type 1 diabetes. Far commoner than APS-1.^[2]

Etymology for viva gold: Schmidt syndrome (APS-2) is named for the pathologist who described Addison with thyroiditis; Whitaker for the kindred that defined APS-1. Examiners reward the eponym and the gene — AIRE, "autoimmune regulator".^[2]

Tuberculous Addison — the worldwide cause

TB Addison is a late, destructive complication — more than 90 percent of the cortex must be destroyed before symptoms appear. Haematogenous spread seeds caseating granulomata in both glands; early they are enlarged with necrotic centres, late they are atrophic and calcified (the CT clue). The lesson: tuberculous Addison often declares itself years after the primary infection.^[4]

Congenital adrenal hyperplasia — the neonatal crisis

21-hydroxylase deficiency is over 90 percent of classic CAH, and the neonate presents in salt-wasting crisis. The block shunts steroidogenesis into androgens, producing cortisol and aldosterone deficiency with virilisation — so a 46,XX neonate may present with ambiguous genitalia, and a 46,XY neonate appears normal externally and presents with vomiting, dehydration, hyponatraemia and hyperkalaemia at one to two weeks. 17-hydroxyprogesterone is markedly raised; the newborn heel-prick screen catches it. 11β-hydroxylase deficiency, by contrast, causes hypertension (excess 11-deoxycorticosterone) and virilisation.^[1][2]

What you see at the bedside

The chronic syndrome is cortisol deficiency with or without mineralocorticoid deficiency — read it system by system.^[2][3]

General (almost universal):

• Fatigue and profound weakness, anorexia and weight loss (typically 5 to 10 kg over months), lethargy and malaise.
• Salt craving — a key historical clue in primary AI; patients salt everything.
• Nausea, vomiting, abdominal pain, diarrhoea — GI symptoms can be so prominent they mimic a surgical abdomen.^[1]

Cardiovascular:

• Postural dizziness and syncope, with a near-universal postural drop in primary AI from volume depletion.
• In crisis, shock — vasodilatory and refractory to catecholamines until hydrocortisone is given (the bedside clue that should make you think of the diagnosis).^[1]

Skin and pigmentation (the distinguishing feature of PRIMARY AI):

• Hyperpigmentation — diffuse dusky, bronzelike darkening of palmar creases, buccal mucosa, gums, lips, recent scars, extensor surfaces, pressure points, areolae and sun-exposed skin. Pathognomonic for primary AI and absent in secondary AI; it may precede other symptoms by months.
• Vitiligo — in autoimmune Addison, coexisting with the pigmentation in striking contrast.
• Loss of axillary and pubic hair in women — a feature of primary AI only.^[1]

Neuropsychiatric and reproductive:

• Depression, apathy, irritability, decreased libido, cognitive slowing — often misattributed to depression; psychosis in severe disease.
• Amenorrhoea, reduced libido, infertility in women; secondary AI adds the flavour of other pituitary deficits (hypothyroidism, hypogonadism, bitemporal hemianopia).^[1]

The named trap: the bedside combination that should make you reach for a cortisol is hyperpigmentation with weight loss and a postural drop, hyponatraemia with or without hyperkalaemia, unexplained postural syncope, or refractory vasodilatory shock. Check a morning cortisol and ACTH.^[1]

Adrenal crisis — the decompensated extreme

Adrenal crisis is acute decompensation under a stressor the failing axis cannot meet. Cortisol demand rises several-fold in illness, surgery or trauma; in AI that rise is impossible. The patient develops vasodilatory shock refractory to fluids and catecholamines, volume depletion from vomiting (which also blocks absorption of oral hydrocortisone — a vicious cycle), hypoglycaemia from failed gluconeogenesis, hyponatraemia worsened by ADH excess, and abdominal pain severe enough to mimic a surgical abdomen. Historically, patients were occasionally laparotomised before the diagnosis was recognised.^[8]

The classic tetrad, plus the electrolyte signature.^[1]

• Hypotension and shock — vasodilatory, often refractory to fluids and vasopressors.
• Abdominal pain, nausea, vomiting, diarrhoea — may mimic an acute surgical abdomen; do not operate first.
• Hypoglycaemia — especially in children and in fasting secondary AI; can cause seizures and coma.
• Hyponatraemia with hyperkalaemia (primary) or hyponatraemia alone (secondary), with metabolic acidosis, occasional hypercalcaemia, and eosinophilia.
• Fever (infection is the common precipitant) or hypothermia.^[1]

Almost always a crisis is precipitated — in a prospective cohort of 206 crises, vomiting and/or diarrhoea (65 percent), infection (38 percent) and emotional stress (29 percent) were the commonest triggers; a significant number occurred in patients already taking glucocorticoids.^[8][9]

The differential — three lists for three questions

The differential depends on which question you are answering: the cause of primary AI, the syndrome before cortisol returns, or the hyperpigmentation.^[1]

Differential of the cause of PRIMARY AI

^[1]

Differential of the syndrome (when cortisol is not yet back)

• Chronic fatigue or depression — but normal cortisol, no pigmentation, no electrolyte shift.
• Occult malignancy — weight loss and anorexia, but no pigmentation and imaging finds a primary.
• Gastroenteritis or acute abdomen — but no chronic weight loss or pigmentation; always check cortisol in shock with abdominal pain.
• Septic shock or CIRCI — baseline cortisol often normal; a dynamic SST defines CIRCI.
• SIADH — the dangerous one: hyponatraemia with low osmolality and inappropriately concentrated urine. Check cortisol and ACTH before labelling SIADH, because the hyponatraemia of AI is partly dilutional but the patient is also volume-depleted.^[1][7]

Differential of hyperpigmentation

Distinguish ACTH-driven Addison pigmentation — diffuse, in palmar creases and mucosa and recent scars, with systemic features and hyponatraemia — from sun exposure and racial pigmentation (which spares the mucosa), haemochromatosis (bronze diabetes with cirrhosis and raised iron studies), porphyria cutanea tarda, Peutz-Jeghers (perioral macules with GI polyps), Cushing disease and Nelson syndrome (ACTH-driven but with central obesity, striae, or a growing pituitary tumour after bilateral adrenalectomy), chronic renal failure, and drug-induced pigmentation (amiodarone, minocycline, chlorpromazine, heavy metals).^[3]

The bedside round — pigment, pallor, postural drop

Examination rarely makes the diagnosis, but it localises the level and catches the crisis. Aim for four things: recognise the chronic syndrome, split primary from secondary at the bedside, detect crisis, and seek the cause.^[1]

Vital signs and general: postural blood pressure (a systolic drop over 20 mmHg on standing suggests volume depletion in primary AI), weight loss, fever as a precipitant, shock in crisis.^[1]

Named bedside signs of primary AI (examiner favourites):

• Hyperpigmentation in palmar creases, knuckles, buccal mucosa, gums, lips, recent scars, extensor surfaces and sun-exposed areas — generalised and including mucosa, which distinguishes it from racial pigmentation (racial spares mucosa).
• Vitiligo in autoimmune Addison.
• Loss of axillary and pubic hair in women.
• Postural hypotension, salt craving by history, and in crisis, cachexia and abdominal tenderness.^[1]

Distinguishing secondary or tertiary AI at the bedside: pale skin (no ACTH, no MSH, no pigment), fine periocular wrinkling, loss of axillary and pubic hair in both sexes if panhypopituitarism, and signs of other pituitary deficits — pale cool dry skin, loss of secondary sexual characteristics, bitemporal hemianopia from a pituitary mass, headache with ophthalmoplegia in apoplexy, and failure of postpartum lactation with amenorrhoea in Sheehan syndrome.^[1]

Bedside clues to the cause: lymphadenopathy, pleural effusion or spinal gibbus (TB, Pott disease); chronic mucocutaneous candidiasis with hypocalcaemia (APS-1); vitiligo, goitre and type 1 diabetes features (APS-2); a purpuric rash in a febrile shocked child or young adult (Waterhouse-Friderichsen); sudden severe headache with ophthalmoplegia (pituitary apoplexy).^[1]

Investigation — confirm, localise, then find the cause

Investigation has three goals: confirm AI biochemically, localise the level, and find the cause. Run them in that order, and the patient is never left untreated while you wait.^[1][2]

Step 1 — Screen with a morning cortisol and ACTH when the stimulation test is not possible

The guideline's gold standard is the stimulation test; the morning plasma ACTH and cortisol is the initial screening procedure when a short corticotropin test is not possible in the first instance. With modern, more specific cortisol assays, a morning cortisol below 348 nmol/L (12.6 mcg/dL) was 100 percent sensitive for adrenal insufficiency in a large retrospective cohort — while a very low morning cortisol alone did not reliably predict the stimulation response in hospitalised patients, so screening values must always be confirmed with stimulation testing.^[1][15]

Step 2 — Confirm with the corticotropin stimulation test

The 250 mcg short corticotropin test is the guideline gold standard for diagnosing primary adrenal insufficiency. The classical protocol injects 0.25 mg (250 mcg) of tetracosactrin intravenously with cortisol sampled immediately before, and 30 and 60 minutes after, the injection. A peak cortisol below 500 nmol/L (18.1 mcg/dL) is the traditional guideline-recommended cutoff for a subnormal response; with newer, more specific assays a cutoff of 405 nmol/L (14.7 mcg/dL) has been proposed, and nearly one in six patients is reclassified as having AI depending on which cutoff is applied.^[1][6][15]

The classic trap: the ACTH stimulation test is not one uniform test. In secondary AI its diagnostic accuracy varies greatly with the dose, route of administration, timing and cortisol assay used, so results must be read against the clinical background and pretest probability — a normal response does not by itself exclude secondary AI.^[14]

The insulin tolerance test remains the gold standard for assessing the whole HPA axis, but it is not widely used because of safety issues; the ACTH stimulation test is the safer, well-tolerated alternative for diagnosing secondary AI.^[14]

Step 3 — Localise the level with ACTH

Plasma ACTH does the localisation. Secondary AI is defined by inappropriately low ACTH secretion due to hypothalamic or pituitary disease; primary AI is adrenal failure, in which deficiency of all adrenocortical hormones (including mineralocorticoid) points to the gland.^[1][14]

Reading the stimulation result at the viva

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Step 4 — Find the cause

A validated assay of autoantibodies against 21-hydroxylase settles autoimmune Addison; in autoantibody-negative individuals, other causes should be sought. 17-hydroxyprogesterone excludes classic CAH in children and young adults; TB testing (Quantiferon, chest X-ray, AFB) and adrenal CT (small and atrophic in autoimmune, enlarged with calcification in TB, hyperdense acutely in haemorrhage, bilateral masses in metastasis or infiltration) complete the primary workup. For secondary AI, MRI pituitary looks for adenoma, empty sella, apoplexy or infiltration. If autoimmune Addison is confirmed, follow-up should screen for associated autoimmune disease, particularly autoimmune thyroid disease.^[1][2]

Associated laboratory abnormalities (examiner favourites): in a cohort of 132 patients with primary AI, hyponatraemia accompanied 77 percent of adrenal crises and gastrointestinal symptoms 85 percent; hypoglycaemia is prominent especially in children and the fasting; look also for mild normocytic anaemia, eosinophilia and lymphocytosis, mild metabolic acidosis in primary AI, occasional hypercalcaemia, and raised urea from volume depletion.^[1][8]

Parenteral hydrocortisone — the crisis dose

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Adrenal crisis is a fatal endocrine emergency, and treatment must not await cortisol or ACTH confirmation. Draw the cortisol and ACTH before the first hydrocortisone — they remain diagnostic in crisis — but treat empirically, immediately, and in parallel.^[1][8]

1. ABCDE, high-flow oxygen if hypoxic, cardiac monitoring, two large-bore cannulae, and bloods including cortisol and ACTH before the first hydrocortisone.
2. Parenteral hydrocortisone — an initial intravenous bolus of 50 to 100 mg, followed by a continuous intravenous infusion of 200 mg per 24 hours; pharmacokinetic modelling in adrenal insufficiency identified exactly this regimen as best suited to maintaining cortisol concentrations in the range observed during major stress, and continuous infusion should be favoured over intermittent bolus administration.
3. Fluid resuscitation with isotonic (0.9 percent) saline, with dextrose-containing fluid if hypoglycaemic, especially in children.
4. Treat the precipitant — vomiting and/or diarrhoea (65 percent) and infection (38 percent) are the commonest triggers: take cultures and start empirical antimicrobials where sepsis is suspected.
5. Monitor and correct glucose and electrolytes — hyponatraemia accompanied 77 percent of crises in one cohort; correct gently as the axis is restored.
6. Intensive care for the shocked or comatose, with vasopressors for refractory shock.
7. Taper to the usual oral maintenance regimen once stable — hydrocortisone 15 to 25 mg per day in divided doses, plus fludrocortisone for primary AI.^[1][8][11]

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Three pillars of long-term replacement

Chronic management stands on three pillars: hormone replacement, patient education with sick-day rules, and crisis prevention. Get all three right and life expectancy approaches normal; neglect any one and the patient keeps coming back in crisis.^[1][9]

Pillar 1 — Hydrocortisone, fludrocortisone, and the diurnal rhythm

Hydrocortisone is the standard glucocorticoid replacement: 15 to 25 mg per day in two to three daily doses, or cortisone acetate 20 to 35 mg per day in two to three doses. Monitoring of glucocorticoid replacement quality is hampered by the lack of objective methods of assessment and is therefore largely based on clinical grounds — wellbeing, weight, blood pressure and electrolytes — aiming for the lowest dose that keeps the patient well.^[1][3]

Fludrocortisone is for primary AI only. The guideline recommends once-daily fludrocortisone (median 0.1 mg), and standard replacement is multiple daily doses of hydrocortisone (or cortisone acetate) combined with fludrocortisone.^[1][20]

Adrenal androgen replacement is selective, not routine. A meta-analysis of ten randomised placebo-controlled trials found DHEA produced only a small — perhaps trivial — improvement in health-related quality of life and depression in women with adrenal insufficiency, with no significant effect on anxiety or sexual well-being; the authors concluded the evidence is insufficient to support routine use.^[21]

Pillar 2 — Sick-day rules and crisis prevention

Sick-day rules stand on patient education and proactive dose adjustment. Adrenal crisis frequency is inversely correlated with how often patients self-adjust their glucocorticoid dose, and proactive dose adjustment shows a protective effect against crises regardless of biological vulnerability.^[19]

• Febrile or intercurrent illness — the patient increases ("stress-doses") the oral glucocorticoid for the duration of the illness; the guideline requires that every patient is educated about stress dosing.
• Severe illness, vomiting, diarrhoea, trauma or surgery — parenteral hydrocortisone, ideally as an initial 50 to 100 mg IV bolus followed by a 200 mg per 24 hour continuous infusion for major stress.
• Vomiting or inability to absorb oral hydrocortisone is an emergency — use the emergency parenteral preparation and seek medical review.^[1][11][19]

The classic trap: telling a steroid-dependent patient to "skip the dose if vomiting". Every patient should be equipped with an emergency card and an emergency set and trained in self-injection of hydrocortisone — after a standardised multicentre education programme, 91 percent of patients said they would dare to self-inject, up from 68 percent before training.^[9]

Steroid-stress dosing for surgery

Surgical stress scales with the operation — and the evidence favours less, not more.^[16]

• All patients take their usual daily glucocorticoid preoperatively, regardless of the dose or chronicity of prior treatment.
• Continuing the daily dose perioperatively is not associated with a higher risk of adrenal crisis in glucocorticoid-induced AI — but oral intake may be unreliable in the early postoperative period.
• Add a short course of IV hydrocortisone 25 to 100 mg per day, scaled to the degree of surgical stress — lower doses and shorter durations are sufficient to maintain homeostasis.
• Labour and delivery are a major stress: cover with parenteral hydrocortisone as for major stress — an initial 50 to 100 mg IV bolus followed by a 200 mg per 24 hour continuous infusion.^[11][16]

Pillar 3 — Prevent the next crisis

Prevention is education, emergency preparation and tapering discipline. Every patient is educated about stress dosing and equipped with a steroid card and a glucocorticoid preparation for parenteral emergency administration. Never withdraw chronic glucocorticoids abruptly: taper more rapidly while the dose is supraphysiological, and more slowly once in the physiological range, because the degree and persistence of HPA suppression after cessation depend on overall exposure and recovery varies greatly between individuals.^[1][13]

CIRCI — the cortisol deficiency of critical illness

CIRCI is a transient, reversible HPA dysfunction of severe sepsis, ARDS and major trauma — distinct from chronic AI, and managed by a single rule. The 2017 SCCM and ESICM guideline does not recommend routine testing; the diagnosis is clinical, on vasopressor-dependent shock.^[7]

The recommendation, reproduced exactly: intravenous hydrocortisone under 400 mg per day for at least 3 days in adults with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy. The evidence base sits behind it — Annane 2002 and CORTICUS 2008 — and the disagreement between them is exactly what examiners probe.^[5][7]

• Annane 2000 (JAMA) — a 3-level prognostic classification in septic shock, based on baseline cortisol and the cortisol response to 0.25 mg intravenous tetracosactrin sampled immediately before and 30 and 60 minutes after injection; non-responders (delta max no more than 9 mcg/dL) defined the poor-prognosis group (28-day mortality 82 percent when baseline cortisol exceeded 34 mcg/dL and delta max was 9 mcg/dL or less).^[6]
• Annane 2002 (JAMA) — hydrocortisone 50 mg IV bolus every 6 hours plus fludrocortisone 50 mcg once daily for 7 days reduced 28-day mortality in non-responders to the corticotropin test (hazard ratio 0.67, 95% CI 0.47 to 0.95); there was no significant difference between groups in responders.^[5]
• 2017 CIRCI guideline — suggests IV hydrocortisone under 400 mg per day for at least 3 days only for septic shock not responsive to fluid and moderate- to high-dose vasopressors, and suggests against corticosteroids in adult sepsis without shock.^[7]

Drug-induced adrenal insufficiency — etomidate, rifampicin, mitotane

Three drugs come up in every exam, and each works differently.^[1][7]

• Etomidate — even a single induction dose inhibits 11β-hydroxylase and can precipitate AI in the critically ill; avoid in septic shock or use with corticosteroid cover.
• Ketoconazole (and less so fluconazole, itraconazole) — inhibits multiple steroidogenic CYP enzymes and can cause primary AI.
• Metyrapone — 11β-hydroxylase inhibitor used in Cushing syndrome; monitor the axis.
• Mitotane (for adrenocortical carcinoma) — adrenolytic; double or triple the hydrocortisone replacement dose, because mitotane raises cortisol-binding globulin and accelerates cortisol metabolism.
• Mifepristone — glucocorticoid receptor antagonist; causes clinical cortisol deficiency with normal cortisol levels.
• Rifampicin, phenytoin, barbiturates — hepatic enzyme inducers that accelerate cortisol metabolism: in a reported case of tuberculous Addison's disease, the hydrocortisone requirement increased after rifampicin was started, and cortisol measured two hours after the dose guided the optimal replacement.^[7][22]

Secondary and tertiary AI — hydrocortisone only

Secondary and tertiary AI take hydrocortisone alone — no fludrocortisone, because the RAAS is intact. Investigate and treat the underlying cause (transsphenoidal surgery for an adenoma, urgent steroids and possible surgery for apoplexy), and screen for and replace other pituitary hormones.^[1]

The classic trap: giving thyroxine before hydrocortisone in panhypopituitarism. Thyroxine accelerates cortisol clearance and precipitates crisis — always replace hydrocortisone first. For chronic steroid withdrawal, taper slowly and test the axis before declaring recovery.^[1]

The classic traps that cost marks — and patients

These are the recurring, preventable errors. Name them at every viva.^[1]

• Treating SIADH with fluid restriction before excluding AI — the hyponatraemia is partly dilutional but the patient is volume-depleted; restriction worsens shock. Check cortisol and ACTH in any unexplained hyponatraemia.
• Giving thyroxine before hydrocortisone in panhypopituitarism — accelerates cortisol clearance, precipitates crisis.
• Misdiagnosing adrenal crisis as an acute abdomen and laparotomising a patient in shock. Check cortisol in any shocked patient with abdominal pain and electrolyte disturbance.
• Forgetting stress-dose steroids in a known Addison patient undergoing surgery or in labour.
• Telling a steroid-dependent patient to skip the dose if vomiting — vomiting is the trigger for parenteral hydrocortisone.
• Missing the diagnosis in chronic steroid withdrawal — the axis can take months to recover; taper slowly and test before stopping.
• Withholding cortisol while waiting for the stimulation test in a patient in crisis — the test can wait; treat empirically, after drawing cortisol and ACTH.
• Forgetting rifampicin accelerates cortisol metabolism — increase the hydrocortisone dose in Addison on anti-TB therapy.^[1]

How patients with AI come to harm — the preventable list

• Death from an unrecognised adrenal crisis treated as sepsis or an acute abdomen — the preventable death.^[8]
• Recurrent crisis in a poorly educated or non-adherent patient — the risk that education and proactive dose adjustment reduce.^[9][19]
• Hyponatraemic encephalopathy from severe untreated hyponatraemia.
• Hypoglycaemic brain injury in children and fasting adults.
• Hyperkalaemic arrhythmia (primary AI) from severe hyperkalaemia.
• Septic shock refractory to catecholamines — the vascular unresponsiveness that should prompt empiric hydrocortisone.
• Iatrogenic Cushing from over-replacement — osteoporosis, diabetes, hypertension; use the lowest dose that restores wellbeing and watch bone density.^[1]

Prognosis and disposition

With adequate replacement, education and emergency preparedness, life expectancy in treated AI approaches normal. The residual risk is crisis: a contemporary cohort measured 10.5 adrenal crises per 100 patient-years in primary AI, with 65.9 percent of patients experiencing at least one crisis; in adolescents and young adults the estimated incidence is 6 to 8 crises per 100 patient-years. Patients with additional autoimmune comorbidity or premature ovarian insufficiency are at higher risk, and proactive dose adjustment is protective.^[8][10][19]

Adrenal crisis remains life-threatening — it is the most severe manifestation of primary AI and is associated with high mortality; a significant number of crises occur in patients already on glucocorticoid therapy, so vigilance is required even in treated patients. Survivors return to chronic management with intensified education.^[8]

Secondary and tertiary prognosis depends on the cause — pituitary adenoma biology and surgery for secondary; recovery of the suppressed axis after chronic steroid withdrawal varies greatly between individuals and can take years. The lethal event in unrecognised secondary AI is crisis when another illness raises the steroid requirement. Annual follow-up by an endocrinologist should focus on optimisation of replacement therapy and detection of new autoimmune diseases, particularly autoimmune thyroid disease.^[1]

Special populations — the scenarios examiners love

Children. The guideline recommends hydrocortisone at approximately 8 mg per square metre per day in children; the same rules apply — stress-dosing education, a steroid card and a glucocorticoid preparation for parenteral emergency administration, with follow-up aimed at appropriate dosing and detection of associated autoimmune disease.^[1]

Pregnancy. Adrenal insufficiency in pregnancy is managed medically, with adjustments of doses based on clinical signs and symptoms; the guideline advises a low diagnostic threshold in pregnant women with unexplained persistent nausea, fatigue and hypotension. Labour is a major stress — cover it with parenteral hydrocortisone as for any major stress (initial 50 to 100 mg IV bolus, then 200 mg per 24 hours by continuous infusion).^[1][11][23]

The elderly. Atypical presentation — fatigue, weight loss, depression, falls, hyponatraemia — with hyperpigmentation subtle or attributed to age. Keep a low threshold for a cortisol in any older patient with unexplained weight loss, fatigue or hyponatraemia; co-medications raise drug-induced AI; start at lower hydrocortisone doses and titrate to wellbeing to avoid worsening osteoporosis, diabetes and hypertension.^[1]

Immunocompromised (HIV/AIDS). Opportunistic adrenalitis (CMV, mycobacteria — TB and MAC, cryptococcus, histoplasma, toxoplasma); clinical AI is uncommon unless over 90 percent of the cortex is destroyed. Kaposi sarcoma and lymphoma can also infiltrate the adrenals; evaluate and treat the underlying infection alongside cortisol replacement.^[1]

Anticoagulated and post-surgical. Bilateral adrenal haemorrhage complicates therapeutic anticoagulation (especially heparin-induced thrombocytopenia), post-cardiac-surgery states, severe trauma and the postpartum period — presenting with abdominal or flank pain, dropping haemoglobin, shock and biochemical AI. Treat with corticosteroid replacement and fluid resuscitation and address the underlying coagulopathy.^[1][18]

Chronic steroid withdrawal. Glucocorticoid-induced AI is the commonest form of AI: a systematic review of 73 studies found adrenal insufficiency in a median 37 percent of glucocorticoid-exposed patients (interquartile range 13 to 63), demonstrable even at prednisolone-equivalent doses under 5 mg per day, under 4 weeks of exposure and after tapered withdrawal — and persisting in 15 percent of patients retested three years after withdrawal. Taper rather than stop — more rapidly within the supraphysiological range, more slowly once on physiological dosing — and test the axis before declaring recovery.^[12][13]

Waterhouse-Friderichsen — the bleeding adrenal

Waterhouse-Friderichsen syndrome is bilateral adrenal haemorrhage, classically resulting from meningococcal sepsis. It is rare but potentially fatal, and presents acutely with shock, petechial rashes, abdominal pain and non-specific symptoms such as headache, fatigue and vomiting. Treatment consists of fluid resuscitation, corticosteroid replacement and possibly surgery, and the prognosis is poor despite treatment. Consider bilateral adrenal haemorrhage in any shocked patient with abdominal or flank pain and a dropping haemoglobin.^[18]

Regional deltas

^{[1] [1] [22]}

The evidence behind the numbers

Endocrine Society Clinical Practice Guideline 2016 (Bornstein et al) is the landmark for primary AI. Recommend diagnostic testing in every patient with indicative clinical symptoms or signs, with a low diagnostic (and therapeutic) threshold in acutely ill patients and in pregnant women with unexplained persistent nausea, fatigue and hypotension. The 250 mcg short corticotropin test is the gold standard; if it is not possible in the first instance, screen with morning plasma ACTH and cortisol. Diagnose the cause with a validated assay of autoantibodies against 21-hydroxylase, seeking other causes if negative. Replace with hydrocortisone 15 to 25 mg per day (or cortisone acetate 20 to 35 mg per day) in two to three daily doses, once-daily fludrocortisone (median 0.1 mg) and, in children, hydrocortisone at approximately 8 mg per square metre per day; educate about stress dosing and equip every patient with a steroid card and a glucocorticoid preparation for parenteral emergency administration.^[1]

Lancet 2014 (Charmandari), Lancet 2003 (Arlt and Allolio) and NEJM 1996 (Oelkers) established the modern classification and work-up — primary adrenal failure versus secondary impairment of the hypothalamic–pituitary axis, glucocorticoid deficiency alone in secondary and tertiary AI, the diagnostic pitfalls of secondary AI, and DHEA replacement as an addition that may help restore quality of life.^[2][3][4]

Annane and the CIRCI evidence (JAMA 2000, JAMA 2002, NEJM 2008, Crit Care Med 2017) set the septic-shock story. JAMA 2000 showed a short corticotropin test (0.25 mg IV, sampled at 0, 30 and 60 minutes) has good prognostic value and defined non-responders (delta max 9 mcg/dL or less) as the high-risk group; JAMA 2002 showed hydrocortisone 50 mg IV every 6 hours plus fludrocortisone 50 mcg once daily for 7 days reduced 28-day mortality in non-responders (hazard ratio 0.67); CORTICUS 2008 (50 mg IV every 6 hours for 5 days, then tapered) found no significant difference in mortality even in non-responders, faster reversal of shock, and more episodes of superinfection including new sepsis and septic shock; the 2017 guideline restricts IV hydrocortisone to under 400 mg per day for at least 3 days, and only for septic shock unresponsive to fluid and moderate- to high-dose vasopressors.^{[5][6][7][17]}

Endocrine 2009 to 2025 — crisis incidence, education and androgens. Alkatib (2009) meta-analysed DHEA and found only small, possibly trivial quality-of-life benefit. Burger-Stritt (2020) showed a standardised education programme significantly and durably improves patient knowledge and self-injection confidence (91 percent willing to self-inject after training); Chifu (2023) showed proactive dose adjustment protects against crises; Scala (2025) measured 10.5 crises per 100 patient-years and Rushworth (2022) an estimated 6 to 8 per 100 patient-years in adolescents and young adults.^{[8][9][10][19][21]}

Controversies to name calmly. Multiple glucocorticoid formulations now exist — short-acting, intermediate and long-acting agents, novel modified-release hydrocortisone and subcutaneous formulations — but availability varies widely across Europe. DHEA shows only small and possibly trivial quality-of-life benefit and is not recommended for routine use. The diagnostic accuracy of the ACTH stimulation test in secondary AI depends on dose, route, timing and assay. Hydrocortisone in septic shock is confined to shock unresponsive to fluids and moderate- to high-dose vasopressors, at under 400 mg per day.^{[7][14][20][21]}

The memory bank — the devices that earn the marks

^{[1] [2] [8] [9]}

The mantra

The mantra: Pigment points to the gland, potassium points to the mineralocorticoid, and parenteral hydrocortisone is the one dose that cannot wait.^[1][8]

Ward-round test — four stems, thirty seconds each

Stem 1 — the woman with the stained gums (answer)ShowHide

The 38-year-old with sodium 124, potassium 5.6, a postural drop and pigmented gums. Name the first two investigations and the discriminator that settles the level. Model: Draw a morning cortisol and plasma ACTH together, then a 250 mcg short corticotropin test — a peak cortisol below 500 nmol/L (18.1 mcg/dL) is the traditional cutoff for a subnormal response (405 nmol/L with modern assays). The level is settled by ACTH: secondary AI means inappropriately low ACTH from hypothalamic or pituitary disease, primary means adrenal failure with deficiency of all adrenocortical hormones. This is primary Addison until the 21-hydroxylase autoantibody assay and imaging tell you which cause.^[1][14][15]

Stem 2 — the post-operative patient on long-term prednisolone in shock (answer)ShowHide

A 64-year-old on prednisolone 10 mg for rheumatoid arthritis collapses hypotensive on day 2 after a hip replacement. What do you do in the next 15 minutes, and what must you draw first? Model: This is acute glucocorticoid-induced (secondary) adrenal crisis under surgical stress. Draw cortisol and ACTH before the first dose, then treat empirically: an intravenous hydrocortisone bolus of 50 to 100 mg followed by a continuous infusion of 200 mg per 24 hours, isotonic saline, treat any precipitant, and escalate to ICU. Do not wait for results — the cortisol drawn in crisis is diagnostic, and the empiric dose is the stress requirement. Taper to the usual oral maintenance dose once stable.^[1][11]

Stem 3 — the septic patient on two vasopressors (answer)ShowHide

A 56-year-old in septic shock is on noradrenaline and vasopressin despite adequate fluids. The registrar wants to start hydrocortisone. What does the evidence support, and who benefits? Model: This is the CIRCI scenario. The 2017 SCCM and ESICM guideline suggests intravenous hydrocortisone under 400 mg per day for at least 3 days for adults with septic shock not responsive to fluid and moderate- to high-dose vasopressor therapy; it does not recommend routine testing, although a delta cortisol under 9 mcg/dL at 60 minutes after 250 mcg cosyntropin, or a random plasma cortisol under 10 mcg/dL, may be used. The benefit tracks the Annane non-responder subgroup (cortisol rise of 9 mcg/dL or less); CORTICUS 2008 (50 mg IV every 6 hours for 5 days) showed no significant mortality difference even in non-responders, faster shock reversal, and more superinfections.^{[5][6][7][17]}

Stem 4 — the Addison patient who is vomiting (answer)ShowHide

A known Addison patient calls — she has been vomiting for 12 hours and could not keep her morning hydrocortisone down. What is the single instruction that prevents crisis? Model: Vomiting is the trigger for parenteral hydrocortisone, never omission. She uses her emergency parenteral hydrocortisone preparation — she was trained in self-injection and carries an emergency card and set — and seeks medical review immediately. The classic trap is telling a steroid-dependent patient to "skip the dose if vomiting"; vomiting and diarrhoea are the commonest crisis triggers.^[1][8][9]

References23ShowHide

1. [1]Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab, 2016.PMID 26760044
2. [2]Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency Lancet, 2014.PMID 24503135
3. [3]Arlt W, Allolio B. Adrenal insufficiency Lancet, 2003.PMID 12788587
4. [4]Oelkers W. Adrenal insufficiency N Engl J Med, 1996.PMID 8815944
5. [5]Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA, 2002.PMID 12186604
6. [6]Annane D, Sébille V, Troché G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin JAMA, 2000.PMID 10697064
7. [7]Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 Crit Care Med, 2017.PMID 28938253
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9. [9]Burger-Stritt S, Eff A, Quinkler M, et al. Standardised patient education in adrenal insufficiency: a prospective multi-centre evaluation Eur J Endocrinol, 2020.PMID 32580144
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12. [12]Joseph RM, Hunter AL, Ray DW, et al. Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review Semin Arthritis Rheum, 2016.PMID 27105755
13. [13]Beuschlein F, Else T, Bancos I, et al. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency J Clin Endocrinol Metab, 2024.PMID 38724043
14. [14]Birtolo MF, Antonini S, Saladino A, et al. ACTH Stimulation Test for the Diagnosis of Secondary Adrenal Insufficiency: Light and Shadow Biomedicines, 2023.PMID 36979883
15. [15]Colling C, Nachtigall L, Biller BMK, et al. The biochemical diagnosis of adrenal insufficiency with modern cortisol assays: Reappraisal in the setting of opioid exposure and hospitalization Clin Endocrinol (Oxf), 2022.PMID 34498295
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17. [17]Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock N Engl J Med, 2008.PMID 18184957
18. [18]Rijal R, Kandel K, Aryal BB, et al. Waterhouse-Friderichsen syndrome, septic adrenal apoplexy Vitam Horm, 2024.PMID 38408808
19. [19]Chifu I, Burger-Stritt S, Schrader A, et al. Predisposing factors for adrenal crisis in chronic adrenal insufficiency: a case-control study Eur J Endocrinol, 2023.PMID 38006230
20. [20]Nowotny H, Ahmed SF, Bensing S, et al. Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis Endocrine, 2021.PMID 33661460
21. [21]Alkatib AA, Cosma M, Elamin MB, et al. A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency J Clin Endocrinol Metab, 2009.PMID 19773400
22. [22]Kusuki K, Watanabe S, Mizuno Y. Tuberculous Addison's disease with increased hydrocortisone requirements due to administration of rifampicin BMJ Case Rep, 2019.PMID 30872343
23. [23]Mathew J, Yeung A. Adrenal Disorders in Pregnancy Endocrinol Metab Clin North Am, 2026.PMID 42067275