Medicine chapters
Cushing syndrome, Addison disease, Synacthen test and adrenal crisis
How to recognise and confirm cortisol excess (Cushing syndrome) and cortisol deficiency (Addison disease), how to read the short Synacthen and dexamethasone tests, and how to treat an adrenal crisis.
- Cushing syndrome is too much cortisol, most often from steroid drugs; confirm with a dexamethasone suppression test, then use plasma ACTH to find the source.
- Addison disease is destruction of the whole adrenal cortex (usually autoimmune; TB in our region): low cortisol and aldosterone, pigmentation, low Na, high K; confirm with a short Synacthen test.
- Adrenal crisis is an emergency: take blood, then give hydrocortisone 100 mg IV and 0.9% saline at once; do not wait for results.
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Overview
The adrenal cortex makes cortisol (zona fasciculata), aldosterone (zona glomerulosa) and adrenal androgens. Cortisol is driven by pituitary ACTH, which is driven by hypothalamic CRH; aldosterone is driven mainly by renin–angiotensin, not ACTH.
- Too much cortisol = Cushing syndrome.
- Too little cortisol = adrenal insufficiency: primary (Addison disease, gland destroyed) or secondary (ACTH lack, usually from long-term steroid use).
The general rule: use a suppression test to prove excess and a stimulation test to prove deficiency.
Cushing syndrome
Definition and causes
Cushing syndrome is the clinical picture of excess circulating glucocorticoid. Cushing disease is the special case caused by an ACTH-secreting pituitary adenoma.
| Group | Cause | Approximate share of spontaneous cases | Plasma ACTH |
|---|---|---|---|
| Exogenous | Prednisolone and other steroid drugs | Commonest cause overall | Low |
| ACTH-dependent | Pituitary adenoma (Cushing disease) | About 65% | Normal or high |
| ACTH-dependent | Ectopic ACTH (small cell lung cancer, bronchial carcinoid, medullary thyroid cancer) | About 10% | High, often very high |
| ACTH-independent | Adrenal adenoma or carcinoma, nodular hyperplasia | About 25% | Low or undetectable |
Pseudo-Cushing states (heavy alcohol use, severe depression, obesity) can mimic the look and disturb the tests.
Clinical features
- Appearance: central obesity, moon face, plethora, "buffalo hump", supraclavicular fat pads.
- Skin: thin skin, easy bruising, wide purple striae, acne, hirsutism, poor wound healing, infections.
- Muscle and bone: proximal myopathy, osteoporosis, vertebral fractures, growth arrest in children.
- Metabolic: hypertension, impaired glucose tolerance or diabetes, hypokalaemia (especially ectopic ACTH, because cortisol in huge amounts acts on the mineralocorticoid receptor).
- Mind and periods: depression, psychosis, insomnia; oligo- or amenorrhoea, low libido.
The signs that best separate Cushing syndrome from simple obesity are proximal muscle weakness, thin skin with bruising, and wide purple striae.
Pigmentation occurs only with ACTH-dependent causes and is most marked in ectopic ACTH. A short history, weight loss, pigmentation and hypokalaemic alkalosis suggest an ectopic source such as a lung tumour.
Investigations: step 1, confirm cortisol excess
A random cortisol is useless because cortisol varies through the day. Use one or more of these:
| Test | How it is done | Normal result | Cushing syndrome |
|---|---|---|---|
| Overnight dexamethasone test | 1 mg at 23:00; cortisol at 09:00 | Cortisol suppressed | Not suppressed (simple outpatient screen; some false positives) |
| 48-hour low-dose dexamethasone test | 0.5 mg 6-hourly for 48 hours | Cortisol below about 50 nmol/L | Fails to suppress; very sensitive |
| 24-hour urinary cortisol | Collect all urine for a day | Normal | Raised (repeat; may be normal on some days) |
| Late-night (midnight) cortisol, blood or saliva | Sample near midnight | Low (cortisol is lowest at night) | Loss of the night-time fall |
Investigations: step 2, find the cause
- Plasma ACTH (on more than one occasion).
- Low or undetectable → adrenal cause → CT or MRI of the adrenals. Carcinomas are large and irregular.
- Normal or high → ACTH-dependent → pituitary or ectopic.
- Pituitary MRI (the adenoma is often tiny and may not be seen).
- High-dose dexamethasone test: the pituitary adenoma still obeys feedback partly, so cortisol falls; ectopic and adrenal sources do not.
- CRH test: an exaggerated ACTH and cortisol rise favours the pituitary.
- Inferior petrosal sinus sampling for ACTH when tests disagree.
- CT chest, abdomen and pelvis (and somatostatin-receptor imaging) to look for an ectopic tumour.
The low-dose test answers "is there Cushing syndrome?". The high-dose test and ACTH answer "where is it coming from?". Do not use the high-dose test to make the diagnosis.
Management
- Iatrogenic: reduce the steroid to the lowest dose that controls the disease; never stop long-term steroids suddenly.
- Control cortisol first (before surgery or while waiting): metyrapone (blocks 11β-hydroxylase) or ketoconazole; etomidate infusion in severe cases.
- Cushing disease: trans-sphenoidal removal of the adenoma is the treatment of choice (remission in roughly three-quarters). Pituitary radiotherapy if surgery fails. Pasireotide (somatostatin analogue) is an option. Bilateral adrenalectomy is the last resort.
- Adrenal adenoma: laparoscopic adrenalectomy. The other adrenal is suppressed and may take a year or more to recover, so steroid cover is needed after surgery.
- Adrenal carcinoma: surgery where possible plus mitotane; poor outlook.
- Ectopic ACTH: remove the tumour if possible; otherwise block cortisol medically or by adrenalectomy.
Untreated Cushing syndrome is often fatal; patients die of clots (VTE), heart attack, high blood pressure, heart failure or sepsis.
Nelson syndrome: after bilateral adrenalectomy for Cushing disease, loss of cortisol feedback lets the pituitary adenoma enlarge; very high ACTH causes marked pigmentation. It follows in about one in five cases.
Addison disease (primary adrenal insufficiency)
Pathophysiology
The whole cortex is destroyed, so cortisol, aldosterone and adrenal androgens all fall. Low cortisol removes feedback, so ACTH rises and causes pigmentation (ACTH shares a precursor with MSH).
In secondary adrenal failure (pituitary disease or long-term steroids), ACTH is low, aldosterone is preserved (it depends on renin), so there is no pigmentation and no hyperkalaemia.
Causes
- Autoimmune adrenalitis: the commonest cause in the UK (antibodies to 21-hydroxylase); may come with other autoimmune diseases (polyglandular syndromes: type 1 diabetes, thyroid disease, pernicious anaemia, vitiligo, premature ovarian failure).
- Tuberculosis: important where TB is common, including Pakistan; adrenals may be calcified on imaging.
- Adrenal haemorrhage: meningococcal septicaemia (Waterhouse–Friderichsen syndrome), anticoagulation.
- Metastases, amyloid, HIV-related infections, surgical removal, adrenoleukodystrophy (young men with neurological signs).
- In children, the commonest cause is congenital adrenal hyperplasia.
Clinical features
- Vague onset: tiredness, weakness, weight loss, anorexia, nausea, vomiting, abdominal pain, salt craving.
- Pigmentation (over 90%): buccal mucosa, palmar creases, knuckles, pressure areas and new scars.
- Postural hypotension (most patients), from salt and water loss; dizziness on standing.
- Vitiligo in autoimmune cases; loss of body hair in women.
Investigations
| Finding | Explanation |
|---|---|
| Hyponatraemia, hyperkalaemia, raised urea | Aldosterone lack; volume depletion (can be normal) |
| Mild metabolic acidosis | Aldosterone lack (reduced H+ excretion) |
| Hypoglycaemia | Cortisol lack |
| Mild hypercalcaemia, eosinophilia, anaemia (after rehydration) | Cortisol lack |
| Low 09:00 cortisol with high ACTH | Primary failure |
| High plasma renin | Low aldosterone |
| Adrenal antibodies | Present in most autoimmune cases |
| CT adrenals, chest X-ray | Calcification or TB |
A random daytime cortisol below about 100 nmol/L strongly suggests deficiency; one above about 550 nmol/L makes it unlikely. In between, a dynamic test is needed.
The short Synacthen (ACTH stimulation) test
Synacthen (tetracosactide) is synthetic ACTH, the first 24 amino acids of the natural hormone.
- Dose: 250 μg IV or IM at time 0, any time of day (morning best), no fasting.
- Samples: serum cortisol at 0 and 30 minutes.
- Normal: 30-minute cortisol rises above the laboratory cut-off (Kumar quotes above 600 nmol/L, with 400–600 borderline; cut-offs vary with the assay).
- Abnormal: a poor rise means the adrenal cannot respond, i.e. adrenal insufficiency.
Baseline cortisol 110 nmol/L; 30-minute cortisol 180 nmol/L; ACTH very high; Na 128, K 5.9
Poor cortisol rise → adrenal insufficiency
High ACTH + high K → primary (Addison disease), not pituitary
A failed Synacthen test proves hypoadrenalism but does not say whether it is primary or secondary (in long-standing ACTH lack the adrenals shrink and also respond poorly). The 09:00 ACTH makes the distinction: high in Addison, low in secondary.
Within about 6 weeks of a sudden pituitary insult (surgery, apoplexy) the adrenals have not yet shrunk, so the Synacthen test can be falsely normal. The insulin tolerance test is the reference test for the whole axis in specialist units.
Adrenal crisis (acute adrenal insufficiency)
Triggers: infection, surgery, trauma, vomiting in a known patient, sudden withdrawal of long-term steroids, adrenal haemorrhage.
Features: shock that does not respond to fluids alone, vomiting, abdominal pain, confusion, fever, hyponatraemia, hyperkalaemia, hypoglycaemia.
Emergency management
- Take blood for cortisol (and ACTH), urea and electrolytes and glucose, but do not wait for results.
- Hydrocortisone 100 mg IV (or IM) bolus.
- 0.9% saline 1 L over 30–60 minutes, then several litres over the first 24 hours, guided by haemodynamics.
- Glucose IV if hypoglycaemic.
- Continue hydrocortisone 100 mg 6-hourly until stable; treat the trigger (e.g. antibiotics).
- Switch to oral hydrocortisone as the patient recovers and taper to maintenance.
- Fludrocortisone is not needed acutely: large hydrocortisone doses have enough mineralocorticoid effect. Start it before discharge in primary disease.
If adrenal crisis is suspected, treat first and test later. A Synacthen test can be done once the patient is stable.
Long-term replacement and patient advice
| Drug | Typical adult dose | Monitor by |
|---|---|---|
| Hydrocortisone | About 15–25 mg a day in 2–3 doses, largest on waking (e.g. 10 mg, 5 mg, 5 mg) | Wellbeing, weight; avoid over-replacement |
| Fludrocortisone (primary only) | 50–300 μg a day | Blood pressure lying and standing, electrolytes, renin |
Every patient on replacement should:
- Double the dose during a febrile illness ("sick day rules").
- Carry a steroid card and wear a medical alert bracelet.
- Keep an injectable hydrocortisone kit at home for vomiting or collapse.
- Receive steroid cover for surgery: for major surgery, hydrocortisone 100 mg IM at induction then 50–100 mg 6-hourly until eating and well.
In hypopituitarism, always start hydrocortisone before thyroxine. Thyroxine speeds up cortisol breakdown and can precipitate a crisis.
Addison = "salt out, potassium in, skin darkens". Cushing = "moon face, buffalo hump, purple striae, weak thighs".
Prognosis
With proper replacement and sick-day education, people with Addison disease can expect a near-normal life. Most deaths come from missed or under-treated crises.
Expect: the commonest cause of Cushing syndrome (steroid drugs) and of endogenous Cushing (pituitary adenoma); low-dose versus high-dose dexamethasone tests and what an undetectable ACTH means; ectopic ACTH with pigmentation and hypokalaemia in a smoker; metyrapone and trans-sphenoidal surgery; Nelson syndrome; Addison disease presenting as postural dizziness with low sodium, high potassium and acidosis; pigmentation of buccal mucosa and palmar creases; TB and autoimmune causes; the short Synacthen test dose and timing; ACTH to separate primary from secondary failure; immediate IV hydrocortisone and saline in crisis; sick day rules and the danger of stopping long-term steroids.
Quick revision
- Cushing: iatrogenic > pituitary (65%) > adrenal (25%) > ectopic (10%) among spontaneous cases.
- Confirm: overnight or 48-hour low-dose dexamethasone, 24-hour urine cortisol, late-night cortisol.
- ACTH low → adrenal CT; ACTH high → pituitary MRI, high-dose test, CRH test, petrosal sampling.
- Treat: metyrapone or ketoconazole; trans-sphenoidal surgery; adrenalectomy; Nelson syndrome afterwards.
- Addison: autoimmune (UK), TB (our region); pigmentation, postural hypotension, low Na, high K, low glucose.
- Short Synacthen: 250 μg, cortisol at 0 and 30 minutes; poor rise = insufficiency; ACTH separates primary and secondary.
- Crisis: blood test, then hydrocortisone 100 mg IV + 0.9% saline; glucose if needed; no fludrocortisone acutely.
- Replacement: hydrocortisone in divided doses + fludrocortisone; double dose when ill; steroid card.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
What is the difference between Cushing syndrome and Cushing disease?
Cushing syndrome means any state of cortisol excess; Cushing disease is the particular form caused by an ACTH-secreting pituitary adenoma.
Why is there pigmentation in Addison disease but not in secondary adrenal failure?
In Addison disease low cortisol switches off feedback and ACTH rises to high levels, which darkens the skin; in secondary failure ACTH itself is low.
Does a normal short Synacthen test always exclude adrenal insufficiency?
No. Soon after a sudden pituitary insult the adrenals can still respond to Synacthen, so a normal result in the first weeks can be misleading.
Should fludrocortisone be given in an adrenal crisis?
Not at first. High-dose hydrocortisone has enough salt-retaining action; fludrocortisone is added later for long-term care of primary disease.
Why must long-term steroids not be stopped suddenly?
They suppress CRH and ACTH so the adrenals shrink; stopping abruptly leaves the body without cortisol and can cause an adrenal crisis.