Adrenal Insufficiency: Addison's Disease and Adrenal Crisis

Introduction

Adrenal insufficiency is deficient production of adrenocortical hormones. It is uncommon, easily missed because the symptoms are so non-specific, and lethal when missed - a patient in adrenal crisis who is not recognised will die of a condition that responds within hours to a cheap and readily available drug.

Causes

Primary adrenal insufficiency

• Autoimmune adrenalitis - 80 to 90% of UK cases, with positive 21-hydroxylase antibodies. It clusters as autoimmune polyglandular syndrome type 2 (Schmidt syndrome) with autoimmune thyroid disease and type 1 diabetes, or type 1 (APECED) with hypoparathyroidism and chronic mucocutaneous candidiasis.
• Tuberculosis - the commonest cause worldwide, and still seen in the UK; adrenal calcification may be visible on imaging
• Adrenal haemorrhage or infarction - Waterhouse-Friderichsen syndrome in meningococcal sepsis, and also with anticoagulation, antiphospholipid syndrome and trauma
• Metastatic malignancy - lung, breast, kidney, melanoma and lymphoma. Bilateral involvement is needed before insufficiency develops.
• Infection in immunosuppression - CMV adrenalitis and disseminated fungal infection in advanced HIV
• Infiltration - amyloidosis, haemochromatosis, sarcoidosis
• Congenital adrenal hyperplasia - most often 21-hydroxylase deficiency
• Adrenoleukodystrophy - X-linked; consider in a young male with adrenal insufficiency and neurological signs, and measure very long chain fatty acids
• Bilateral adrenalectomy
• Drugs - ketoconazole, metyrapone, etomidate, mitotane, and immune checkpoint inhibitors

Secondary and tertiary

• Exogenous glucocorticoids - the commonest cause of adrenal insufficiency overall. Suppression can follow oral, inhaled, topical, intranasal, intra-articular or epidural steroid, and may persist for months after withdrawal.
• Pituitary tumour, and its treatment by surgery or radiotherapy
• Pituitary apoplexy - sudden haemorrhage or infarction, with headache, visual loss and ophthalmoplegia
• Sheehan's syndrome - postpartum pituitary infarction after major obstetric haemorrhage, classically presenting with failure of lactation and amenorrhoea
• Hypophysitis - lymphocytic, IgG4-related, or induced by immune checkpoint inhibitors, which is now an increasingly common cause
• Craniopharyngioma, infiltration and head injury

Clinical features

The onset is insidious and the symptoms are individually unremarkable, which is why the average patient sees several clinicians before the diagnosis is made and why a substantial proportion present in crisis.

Symptoms

• Fatigue and profound weakness - the dominant complaint
• Anorexia and weight loss
• Nausea, vomiting and abdominal pain - which can be severe enough to mimic an acute abdomen
• Dizziness and postural symptoms
• Myalgia and arthralgia
• Salt craving - specific to primary disease, from aldosterone deficiency, and worth asking about directly
• Low mood, irritability and poor concentration - frequently misattributed to depression
• Loss of axillary and pubic hair and reduced libido in women - from loss of adrenal androgens, which are the main androgen source in women

Signs

• Hyperpigmentation - in primary disease only. Look at palmar creases, buccal mucosa and gums, recent scars, pressure areas, nipples and the vermilion border of the lips.
• Postural hypotension - a drop in systolic blood pressure on standing, present in most
• Weight loss and cachexia
• Vitiligo - reflecting the autoimmune association, and a useful clue
• Signs of other autoimmune disease - goitre, alopecia areata
• Signs of hypopituitarism in secondary disease - pallor, fine wrinkling, loss of body hair, small testes, and features of other axis deficiencies

Investigations

Establishing cortisol deficiency

• 9 am serum cortisol - the screening test, taken at the physiological peak. A value below 100 nmol/L strongly suggests adrenal insufficiency; a value above around 400 to 500 nmol/L makes it very unlikely. Intermediate values require dynamic testing. Thresholds vary between assays, so check the local laboratory range.
• Short Synacthen test (SST) - the definitive test. 250 micrograms of tetracosactide is given intramuscularly or intravenously, and serum cortisol measured at 0 and 30 minutes (some protocols add 60 minutes). A normal response is a peak cortisol above around 450 to 500 nmol/L; failure to reach this confirms adrenal insufficiency.
• A caveat: in recent-onset secondary insufficiency - for example within a few weeks of pituitary surgery - the adrenals have not yet atrophied and may still respond to Synacthen, giving a false negative. Specialist testing with an insulin tolerance test or glucagon stimulation test may be needed.
• Do not delay treatment for testing in a sick patient. Take blood for cortisol and ACTH if it can be done immediately, then treat; the diagnosis can be established once the patient is stable.

Determining the level

Establishing the cause

• 21-hydroxylase adrenal antibodies - positive in the great majority of UK cases of Addison's disease and, if positive, no further imaging is needed
• CT of the adrenals - if antibodies are negative, looking for tuberculosis (with calcification), haemorrhage, metastases, lymphoma or infiltration
• MRI pituitary and assessment of the other pituitary axes - in secondary insufficiency. Check thyroid function, gonadotrophins with testosterone or oestradiol, prolactin, IGF-1 and, where relevant, growth hormone.
• Very long chain fatty acids - in young males, for adrenoleukodystrophy
• Screen for associated autoimmune disease - thyroid function and antibodies, coeliac serology, vitamin B12 and HbA1c
• Consider HIV testing and tuberculosis screening where the clinical context suggests them

Management

Hormone replacement

Monitoring is largely clinical - weight, energy, blood pressure lying and standing, pigmentation (which fades with adequate replacement), and features of over-replacement such as weight gain, oedema and Cushingoid change. Check U&Es and renin in primary disease. Cortisol levels are not used to titrate the dose.

Situations that need particular attention

• Starting levothyroxine - thyroid hormone accelerates cortisol metabolism and can precipitate an adrenal crisis in someone with unrecognised adrenal insufficiency. Always give glucocorticoid first where both are deficient, as in autoimmune polyglandular syndrome or hypopituitarism.
• Withdrawing long-term corticosteroids - taper slowly, and consider testing the axis before final withdrawal after prolonged courses. Patients remain at risk for months.
• Pregnancy - hydrocortisone requirements rise in the third trimester, typically by 20 to 40%. Give intravenous hydrocortisone during labour and delivery.
• Drugs that induce CYP3A4 - phenytoin, carbamazepine, rifampicin - accelerate hydrocortisone metabolism and the dose must be increased
• Enteral feeding interruptions and nil by mouth periods - a common cause of inadvertent omission in hospital; prescribe parenteral steroid
• Immune checkpoint inhibitor therapy - can cause both hypophysitis and primary adrenalitis; have a low threshold for testing

Adrenal crisis

An acute, life-threatening deficiency of cortisol, and a genuine medical emergency. It may be the first presentation of Addison's disease, or occur in a known patient under stress.

Complications

• Adrenal crisis and death - the principal risk, and the reason for the emphasis on education and emergency injection kits
• Over-replacement - producing iatrogenic Cushing syndrome with weight gain, osteoporosis, diabetes and hypertension. Under-replacement causes fatigue, nausea and postural symptoms - the balance is genuinely difficult.
• Impaired quality of life - persistent fatigue and reduced work capacity are reported by a large proportion of patients even on apparently optimal replacement, and this should be acknowledged rather than dismissed
• Osteoporosis - from long-term glucocorticoid exposure
• Associated autoimmune disease - thyroid disease, type 1 diabetes, pernicious anaemia, coeliac disease, premature ovarian insufficiency and vitiligo
• Hypertension, oedema and hypokalaemia from fludrocortisone over-replacement
• Complications of the underlying cause - tuberculosis, malignancy or pituitary disease

Red flags

Prognosis

With appropriate replacement, patients with adrenal insufficiency can expect a normal or near-normal life expectancy - a remarkable transformation, since before the availability of cortisone in the 1950s Addison's disease was uniformly fatal within a few years.

Two important caveats qualify that optimism. First, excess mortality persists, and the excess is attributable largely to adrenal crisis - which occurs at a rate of roughly 6 to 8 episodes per 100 patient-years and remains fatal in a small but real proportion. The great majority of these events are preventable, and prevention depends almost entirely on patient education, an emergency injection kit and clinicians who prescribe steroid cover reliably. This is one of the few conditions in which patient education is more important than any adjustment of the prescription.

Second, quality of life is often impaired even on good replacement. Patients consistently report fatigue, reduced work capacity and impaired wellbeing compared with matched controls, because no oral regimen truly reproduces the physiological cortisol rhythm. Acknowledging this - rather than assuming that normal electrolytes mean a well patient - matters a great deal to people living with the condition.

Secondary adrenal insufficiency from exogenous steroids usually recovers, though it may take 6 to 12 months or longer after prolonged high-dose treatment, and patients must be treated as adrenally insufficient throughout that period. Prognosis in other secondary causes is determined by the underlying pituitary pathology and by whether the other axes are also affected.