Adrenal Insufficiency and Addison's Disease

Adrenal insufficiency leads to a reduction in the output of adrenal hormones i.e. glucocorticoids and/or mineralocorticoids. There are two types of adrenal insufficiency:¹

1. Primary insufficiency - there is an inability of the adrenal glands to produce enough steroid hormones (Addison's disease is the name given to the autoimmune cause of this insufficiency). Glucocorticoid and often mineralocorticoid hormones are lost.
2. Secondary insufficiency - there is inadequate pituitary or hypothalamic stimulation of the adrenal glands.

• Primary insufficiency - rare 0.8 per 100,000; affects both sexes equally and can occur at any age.²
• Secondary insufficiency - relatively common compared to the primary type as exogenous steroid use is frequent leading to suppression of the hypothalamic-pituitary axis.

80% of the cases of adult adrenal insufficiency have an autoimmune basis.²

• Adrenal insufficiency is rare in children
• Presentation is nonspecific and thus often there is a delay in diagnosis
• The commonest causes are congenital adrenal hyperplasia (72% of cases), adrenoleukodystrophy (15% of cases) and autoimmune adrenalitis (13% of cases)³

• Patients who are critically ill are increasingly recognised to be at risk of adrenal dysfunction
• Furthermore nonsurvivors are more likely to have higher baseline cortisol levels which does not respond to ACTH stimulation⁴
• It should be considered in patients who are pressor dependent or have biochemical clues
• ACTH testing may be unhelpful⁵
• Etomidate influences ACTH results⁴
• A trial of steroids may be indicated

• Can have CMV necrotizing adrenalitis, also Mycobacterium avium intracellulare and Cryptococcus infection
• Adrenal tests are commonly abnormal in patients with HIV
• These abnormalities may be due to drug interactions e.g. phenytoin, ketoconazole

Note: Advanced adrenal insufficiency is more easier to diagnose but recognition of early cases is more difficult.

Presentation in part depends on the rapidity of adrenal hypofunction

• Acute - e.g. Waterhouse-Friderichsen syndrome (infarction secondary to septicaemia e.g. meningococcal); presents with collapse and shock²
• Chronic - symptoms develop insidiously and may be mild

Symptoms

• Fatigue and weakness
• Anorexia
• Nausea
• Vomiting
• Weight loss
• Abdominal pain
• Diarrhoea
• Constipation
• Syncope
• Dizziness
• Confusion
• Personality change
• Irritability
• Amenorrhoea

Signs

• Cutaneous and mucosal pigmentation - look at mucosa and in new scars
• Hypotension
• Postural hypotension

Addisons disease is characterised by progressive destruction of the adrenal glands. This is usually autoimmune based and most likely the result of cytotoxic T lymphocytes, although 50% of patients have circulating adrenal antibodies.² Clinical and biochemical insufficiency only occurs once >90% of the gland is destructed.

In the early period of adrenal insufficiency investigations may be normal however, patients have no reserve when faced with stress.

Other investigations

• Insulin tolerance test¹ - hypoglycaemia is induced by an insulin infusion and the cortisol response is monitored; this is not regularly performed due to safety issues
• Adrenal autoantibodies - if negative consider investigating for other causes e.g. tuberculosis
• ECG - PR and QT interval prolongation
• CXR - lung neoplasm
• AXR - any adrenal calcification which may indicate previous TB infection
• Specific investigations - e.g. CT scan of adrenals
• May be appropriate to test other hormones of the hypothalamic-pituitary axis e.g. TSH, prolactin, FSH/LH

Hormonal abnormalities

• Low baseline (09:00am) cortisol (<100nmol/L) is strongly suggestive; >220 nmol/L excludes diagnosis
• Plasma renin and aldosterone levels - will give an indication of mineralocorticoid activity
• Diagnosis requires ACTH stimulation to assess adrenal reserves

Short synACTHen test

• 0 min - baseline blood for cortisol; follow by 250mcg synacthen IV/IM
• 30-60 min - cortisol level
• 95% sensitivity and 97% specificity
• Less useful alone in secondary adrenal insufficiency⁶

Interpreting results of the short synacthen test

If initial cortisol >140nmol/L and second cortisol >400 - 500nmol/L this excludes Addisons.

Distinguish between primary and secondary insufficiency by measuring the ACTH level

• Primary insufficiency - ACTH increased
• Secondary insufficiency - ACTH decreased

Other autoimmune illnesses may also be present e.g. thyroid disorders, pernicious anaemia, vitiligo and premature ovarian failure. In these patients it is important to consider the possibility of polyglandular autoimmune syndrome.

Patient education

• Information about condition
• Medicalert bracelet
• Steroid card⁹
• Importance of not missing steroids
• Intercurrent illness - if tolerating oral medication then dose should be doubled until better. If so unwell that are unable to take orally then need to take parenterally - thus need to be given IM hydrocortisone and to be taught how to administer it.
• Seek medical help if require parenteral therapy

Hormone replacement

• Glucocorticoid replacement - Hydrocortisone is the mainstay of treatment; dose divided so that 2/3s in morning and 1/3 in the late afternoon (thus stimulating the normal diurnal adrenal rhythm).
• If there is coexistent thyroid deficiency then thyroid hormones should not be replaced before glucocorticoids as a crises may be precipitated.¹
• Mineralocorticoid replacement - this is usually required in primary adrenal insufficiency.
• Fludrocortisone is used and adequacy of therapy involves measuring blood pressure and looking for postural hypotension and normalising of serum electrolytes (Na and K).

• This may selectively effect ACTH or may involve multiple deficiencies i.e. panhypopituitarism.
• Other causes include ACTH suppression by sodium valproate, metastases, craniopharyngioma, tuberculosis, post partum pituitary necrosis (Sheehan's syndrome), trauma and post radiotherapy or surgery.
• Presentation is similar to primary insufficiency although there is usually no hyperpigmentation as ACTH is low (hyperpigmentation results from metabolites of ACTH).
• Management involves hormone replacement and may also require more definitive treatment e.g. surgical removal of a pituitary tumour.

NB. Acute adrenal insufficiency occurs rapidly and can be fatal if not promptly recognised and treated

Patient mortality is reduced by prevention of adrenal crises.

Causes include

• Adrenal crises on top of chronic insufficiency e.g. sepsis, gastroenteritis or stress
• Sepsis with Pseudomonas spp. or meningococcaemia (Waterhouse-Friderichsen syndrome)
• Haemorrhage e.g. pregnancy, complication of venography
• Drugs e.g. phenytoin

Presentation includes

• Sudden severe back and abdominal pain
• Diarrhoea and vomiting
• Tachycardia
• Hypotension
• Fever
• Shock
• Coma

Management

• This begins with adequate resuscitation e.g. intravenous fluids, intravenous glucose.
• Intravenous hydrocortisone 100mg which should be continued four times daily afterwards until the patient can take oral medication. IM may be better as IV dose is rapidly removed from the circulation (but initial dose should be IV).
• Adrenal insufficiency should be considered in any patient who presents with a collapse or hypotension.
• In such cases a baseline cortisol should be sent and intravenous hydrocortisone given without awaiting the results.

The prognosis for any patient with adrenal insufficiency will depend on the underlying cause. In those patients in whom the prognosis is not affected by the underlying pathology, replacement therapy should result in a return to health with a normal life expectancy. However, a retrospective observational study in Sweden reported the risk of death for patients with Addison's disease was two-fold higher.¹⁰ The cause of this extra mortality was cardiovascular, malignant and infectious disease related.

Thomas Addison (1793-1860) first described the syndrome in 1855. He was a student of Medicine in Edinburgh (1812-15) and went on to be one of the three "Giants of Guys Hospital" - (together with Richard Bright (1789-1858) and Thomas Hodgkin (1798-1866)). Life-saving replacement therapy only became available following the synthesis of cortisone (Kendall, Sarett, and Reichstein in 1949).