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- auto-immune atrophy (cmst)
- TB
- metastatic CA (lung, breast, kidney) or lymphoma
- systemic fungal infections (eg histoplasmosis, cryptococcosis, blastomycosis)
- amyloid
- granulomatous disease
- late stage of AIDS (CMV, bacterial or protozoal infection or Kaposi’s)
- Schilder's disease (hereditary leucodystrophy and adrenocortical atrophy)
- Wolman's disease (adrenal insufficiency, hepatosplenomegaly,steatorrhoea with lipid-filled lysosymes)

• meningococcal or other sepsis
• coagulation disorders
• as a result of warfarin therapy
• anti-phospholipid syndrome

• exogenous glucocorticoids
• pituitary lesions (in approx. order of freq.)
  - pituitary surgery
  - pituitary irradiation (usual, but often delayed for yrs)
  - large pituitary adenoma (usually non-functioning as lack of endocrine excess synthesis allows tumour to grow undetected)
  - pituitary apoplexy
  - granulomatous disease
  - secondaries
  - idiopathic isolated ACTH deficiency
• hypothalamic and midbrain lesions
  - craniopharyngioma
  - cranial irradiation
  - third ventricle tumours and cysts
  - other tumours (eg glioma, meningioma)
  - granulomatous disease (eg sarcoid, TB, eosinophilic granuloma, Wegener's)

• Sheehan's syndrome
• necrosis or bleeding into pituitary macroadenoma
• head trauma, lesions of pituitary stalk
• surgery for lesions in region of hypothalamus, pituitary or midbrain

Cortisol deficiency due to hypothalamic or midbrain lesions is more likely to be asociated with diabetes insipidus than cortisol deficiency due to pituitary lesions.

• Only features which distinguish primary from secondary form are associated features of failure of pituitary function other than ACTH in the secondary type and endocrine pigmentation and features of associated diseases in the primary type.
• Addisonian pigmentation useful when present but often absent in auto-immune cases - characteristically seen in palmar creases, other skin creases, exposed areas, scars and buccal mucosa. May be associated vitiligo
• Weight loss - cmst symptom of cortisol insufficiency
• Vomiting and diarrhoea
• Non-specific abdo pain, often severe and colicky
• Malaise and loss of energy
• Shock and hypotension (Addisonian crisis - may be ppt. by intercurrent disease or infection)
• Spont. hypoglycaemia
• Postural hypotension
• Acute cortisol deficiency results in muscle cramps, myalgia with unexplained fever, shock and hypotension.
• Loss of hair in women.
• Secondary hypoadrenalism results in reproductive failure, +/- skin thickening, accentuation of tendency to hypoglycaemia (GH deficiency). Secondary hypothyroidism is a late feature.

Other autoimmune endocrinopathies:

- hypo and hyperthyroidism
- type I DM
- premature ovarian failure with ovarian auto-antibodies
- primary hypoparathyroidism
- pernicious anaemia
- alopecia
- mucocutaneous candidiasis

- consider diagnosis in presence of unexplained catecholamine-resistant hypotension, especially if the patient has hyperpigmentation, vitiligo, pallor, scanty axillary and pubic hair, hyponatraemia, or hyperkalaemia
- possibility of spontaneous adrenal insufficiency due to adrenal haemorrhage or adrenal vein thrombosis must be considered in patients with upper abdominal or loin pain, abdominal rigidity, vomiting, confusion, and arterial hypotension

- raised urea - most consistent biochemical abnormality
- raised K (primary hypoadrenalism), decreased Na, Cl, HCO₃. Although hyponatraemia occurs in both primary and secondary forms the pathophysiology is different. In primary form it is mainly due to aldosterone deficiency and sodium wasting while in secondary form it is due to cortisol deficiency, increased ADH and water retention.
- anaemia
- eosinophilia, lymphocytosis
- raised ESR
- plasma cortisol: >700 nmol/l probably excludes diagnosis. Useful in acutely ill patient in whom Addison's suspected - take blood before giving IV hydrocortisone.
- (raised ACTH - disproportionately high compared with cortisol level)
- short Synacthen test: 250 mcg IM/IV. Measure cortisol before and 30 or preferably 60 min after. Adrenal function normal if basal or post synacthen plasma cortisol >500 nmol/l or preferably >550. Most use the highest plasma cortisol as the criterion for normality not the absolute increase after injection. In patients with primary or severe secondary adrenal insufficiency plasma cortisol rises little (2° ) or not at all (1° or 2° ). In mild or recent onset secondary test may be normal even though results of insulin or metyrapone tests are abnormal. Can be carried out on patients who are already on steroids provided that treatment is of < 2/52 duration and patient changed on to dexamethasone 24 hrs beforehand.
- insulin stress test, corticotrophin releasing hormone test and metyrapone test can be used to diagnose secondary adrenal insufficiency
- +/- auto-antibodies
- +/- adrenal calcification (tuberculous)
- ST segment flattening / low voltage on ECG in acute form
- CT/MRI

- CA
- TB
- salt-losing nephropathy
- anorexia
- malnutrition
- severe GI disease
- malabsorption
- congenital adrenal hyperplasia - usually results in cortisol deficiency in infancy when Addison's is rare.

- resuscitate with saline. May require large volumes. Should be supplemented with glucose
- IV hydrocortisone 100mg followed by 100-200 mg by infusion over 24 h - in combination with saline should increase BP within 4 - 6 hours if diagnosis is correct.

- primary: gluco- and mineralocorticoid. Dose determined mainly by clin. assessment and adjustment. Right dose of hydrocortisone for adults is the lowest dose that maintains well-being and weight. Usually 20-40 mg daily. Measurement of cortisol seldom helpful. Plasma t_1/2 of cortisol is short (100 mins) and levels fluctuate widely during the day depending on the times of doses. Occasionally may be helpful in order to confirm absorption (eg in intestinal disease) - measure 1-2 hrs after morning dose. Fludrocortisone doses should be enough to abolish postural hypotension, return Na and K to normal, maintain plasma renin in upper normal range and sustain well being. Usually 50 - 200 mcg daily. Excessive doses of fludrocortisone or hydrocortisone may result in unacceptable weight gain, oedema and hypertension ( NB coincidental essential hypertension may be unmasked by treatment). Latter is usually due to excess fludrocortisone. Conventionally 2/3 of total daily dose of hydrocortisone given in the morning. Fludrocortisone given as a single daily dose.
- secondary: glucocorticoid only
- stress: - double or triple dose of hydrocortisone whenever patient has febrile illness or injury. Operations - see below.

- resuscitate if necessary
- steroid cover:100mg of hydrocortisone IM with premed. Post-op: IV infusion of 100 - 150 mg/day or 50 mg IM 6 hourly. No need to tail off gradually - resume normal dose when patient free of pain, afebrile and eating normally.

© Charles Gomersall December 1999

©Charles Gomersall, June, 2013 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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