Addison's Disease

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Contents

Introduction

Addison's disease is primary failure of the adrenal cortex and is therefore characterised by a deficiency of endogenous corticoids and mineralocorticoids. The incidence is around 3 to 6 per 100,000 per year and the disease is more common in women. The causes are as follows.

Failure of the adrenal cortex can also occur as a secondary phenomenon if the supply of ACTH to the adrenal cortex is inadequate, due either to diseases of the pituitary gland or the hypothalamus. Secondary adrenocortical failure also occurs if withdrawal of exogenous corticosteroid treatment is too abrupt. Pituitary and hypothalamic disorders can also be associated with the failure of other endocrine organs that are regulated by the hypothalamus and pituitary gland. Mineralocorticoid function tends to be preserved in secondary adrenocortical failure.

Rightly or wrongly, the term Addison's disease may also be applied to secondary failure of the adrenal gland.


Pathology

The commonest cause of primary adrenal failure is autoimmune disease, which accounts for around 70% of cases. The glands are atrophic and demonstrate a chronic inflammatory cell infiltrate. Almost all patients possess antibodies to the 21-hydroxylase enzyme that is present in the adrenal cortex and allows progestagens to be converted into glucocorticoids.

The caseating granulomas and fibrosis of tuberculosis can damage the adrenal cortex.

Spontaneous haemorrhage into the adrenal glands can be a complication of septicaemia (particularly menigococcal septicaemia) or less commonly hypothermia, burns or cardiac failure. The haemorrhage is accompanied by necrosis of the adrenal glands.

Adrenoleukodystrophy is a rare X-linked recessive disorder of fatty acid metabolism which leads to the accumulation of cholesterol and gangliosides in the brain and adrenal glands. The neurological effects are severe.

Polyglandular deficiency type 1 is an autosomal recessive condition that comprises Addison's disease, hypoparathyroidism, mucocutaneous candidiasis, alopecia, primary gonadal failure and dental enamel hypoplasia. Although it is an inherited disease it is also an autoimmune condition.

Type 2 polyglandular deficiency is also an inherited autoimmune disease but is autosomal dominant. There is Addison's disease, hypothyroidism, type 1 diabetes mellitus, primary hypogonadism, vitiligo and pernicious anaemia.


Clinical Features

The clinical features of adrenocortical insufficiency centre around the role of glucocorticoids in the stress response and supporting the cardiovascular system. The loss of aldosterone in primary adrenocortical failure exacerbates the cardiovascular features.

Lethargy and weakness occur. Patients suffer from fatigue easily. Nausea and vomiting can be present. There may be anorexia and weight loss.

The loss of mineralocorticoid drive for salt and water retention leads to hypotension, which may be particularly marked on standing up. The hypotension is exacerbated by the loss of glucocorticoid support for the cardiovascular system. The increased renal loss of sodium can produce salt cravings. The impaired excretion of potassium can result in hyperkalaemia. The electrolyte disturbances may exacerbate the weakness.

There may be alterations in personality such as irritability and restlessness.

Hypoglycaemia can contribute to the lethargy, weakness and irritability.

Diarrhoea and/or abdominal pain may develop.

Menstrual disorders can occur.

In primary adrenocortical insufficiency the pituitary gland responds by elevating levels of ACTH in order to try to stimulate the adrenal cortex. The generation of ACTH is accompanied by an increase in the levels of melanocyte stimulating hormones. This results in pigmentation of sun-exposed areas, the creases of the palm, recent scars, pressure points, the axillae and nipples.

An Addisonian crisis is a severe, acute form of hypoadrenalism that can be precipitated by a stressful event such as infection. There can be marked hypotension / hypovolaemic shock, lethargy, vomiting, confusion, convulsions and coma.


Investigations

The utility of demonstration of a low level of cortisol is curtailed by the natural variations in cortisol that occur in normal individuals. A single measurement of cortisol can be performed but has to be interpreted with caution. Additional information can be obtained by determining the quantity of cortisol in a 24 hour urinary collection but in most cases the mainstay investigation is the synacthen test. Synacthen is a synthetic form of ACTH. If a person who has normal adrenal cortical function is given a dose of synacthen there will be a considerable increase in their level of blood cortisol 4 hours later and little further elevation by 24 hours. In primary adrenocortical insufficiency there will be no increase either at 4 hours or 24 hours because the adrenal glands are incapable of responding to the ACTH. There is no 4 hour increase in secondary adrenocortical insufficiency but there may be an elevation by 24 hours once the adrenal cortex has had a chance to start to pump itself back up after the re-exposure to ACTH.

The presence of autoantibodies directed against the adrenal cortex can be detected.

Adrenocortical insufficiency can have assorted metabolic disturbances and these can be assessed by various blood tests.

FBC Eosinophilia can occur
U+E Around 90% of patients have hyponatraemia and there is hyperkalaemia in 65%
Glucose Hypoglycaemia is common
Calcium Hypercalcaemia is encountered in 10 to 20%

It is often prudent to check the thyroid function tests because patients who have autoimmune Addison's disease are at an increased risk of having autoimmune thyroid disease (including in the absence of polyglandular insufficiency).


Treatment

Replacement of glucocorticoids and mineralocorticoids is required. The glucocorticoid role is filled by hydrocortisone while fludrocortisone is a synthetic analogue of aldosterone. The doses of hydrocortisone need to be increased if an infection occurs or the patient faces a stressful challenge such as surgery.

An Addisonian crisis requires volume replacement with normal saline and 5% dextrose, together with correction of any hypoglycaemia. Large doses of hydrocortisone should be given. In the acute stage fludrocortisone is not necessary because the high doses of glucocorticoids offer some mineralocorticoid function and the use of normal saline addresses the hypovolaemia in a direct fashion. Determination of the cause of the crisis is also important.