Addison’s Disease

Addison’s disease is a rare chronic disorder in which there is deficiency of the corticosteroid hormones hydrocortisone and aldosterone, which are normally produced by the adrenal cortex (the outer parts of the adrenal glands, which are situated on the top of the kidneys).

In addition, excessive amounts of the hormone ACTH are secreted by the pituitary gland (at the base of the brain) in an attempt to increase output of the corticosteroid hormones.

The secretion and activity of another hormone, melanocyte stimulating hormone (MSH), also increase, which leads to increased synthesis of melanin pigment in the skin.

Causes 

Addison’s disease can be caused by any disease that destroys the adrenal cortices. The most common cause is an autoimmune disorder in which the immune system produces antibodies that attack the adrenal glands.

Symptoms 

Symptoms of the disease generally develop gradually over months or years and include tiredness, weakness, abdominal pain, and weight loss. Excess MSH may cause darkening of the skin in the creases of the palms, pressure areas of the body, and the mouth.

Acute episodes, called Addisonian crises, brought on by infection, injury, or other stresses, can also occur. The symptoms of these are mainly due to aldosterone deficiency and include extreme muscle weakness, dehydration, hypotension (low blood pressure), confusion, and coma.

Hypoglycaemia (low blood glucose) also occurs due to a deficiency of hydrocortisone.

Diagnosis and treatment 

Diagnosis of Addison’s disease is generally made if the patient fails to respond to an injection of ACTH, which normally stimulates hydrocortisone secretion.

Lifelong corticosteroid drug treatment is needed to replace the deficient hormones. Treatment of Addisonian crises involves rapid infusion of saline and glucose and supplementary doses of corticosteroid hormones.

Addison's Disease in detail - technical

Essentials

Addison's disease is due to glucocorticoid deficiency from primary hypoadrenalism.

Glucocorticoid deficiency can be due to adrenal disease (primary, in which case mineralocorticoids are also deficient) or because of deficiency of ACTH (secondary, in which case only glucocorticoids are deficient).

Aetiology—primary hypoadrenalism (Addison’s disease) is most commonly caused by autoimmune disease (>70% cases in the Western world, associated with adrenal autoantibodies in many cases, and sometimes with other organ-specific autoimmune diseases) or infection, e.g. tuberculosis (the commonest cause worldwide). The commonest cause of secondary hypoadrenalism is stopping of exogenous glucocorticoid therapy or its inadequacy in stressful situations.

Clinical features—primary adrenal failure may present (1) acutely—with hypotension and acute circulatory failure (Addisonian crisis); or (2) chronically—with vague features of ill health, sometimes including gastrointestinal symptoms, features suggestive of postural hypotension, and salt craving. Skin pigmentation is nearly always present in primary adrenal insufficiency (but not in secondary).

Biochemical diagnosis—this depends on an ACTH stimulation test: plasma cortisol should rise to over 550 nmol/litre in response to injection of tetracosactrin (Synacthen, 250 µg) and failure to do so indicates adrenal insufficiency. In primary adrenal insufficiency the plasma ACTH level is disproportionately elevated in comparison with plasma cortisol.

Management—acute adrenal insufficiency is a medical emergency requiring volume resuscitation and parenteral steroid replacement, e.g. hydrocortisone 100 mg intravenously every 6 h, along with treatment of any precipitating condition, e.g. infection. Long-term treatment requires (1) glucocorticoid replacement—typically hydrocortisone, 20 mg on wakening and 10 mg at 18.00 h, to be doubled in the event of intercurrent stress or illness; (2) mineralocorticoid replacement—fludrocortisone, 0.05 to 0.1 mg/day, is usually required in primary adrenal failure. Every patient should be advised to wear a MedicAlert bracelet or necklace and to carry a ‘steroid card’.

Glucocorticoid deficiency: primary and secondary hypoadrenalism

Primary hypoadrenalism refers to glucocorticoid deficiency occurring in the setting of adrenal disease, whereas secondary hypoadrenalism arises from a deficiency of ACTH, the major trophic hormone controlling cortisol secretion. The principal distinction between these two conditions is that mineralocorticoid deficiency invariably accompanies primary hypoadrenalism, but this does not occur in secondary hypoadrenalism because only ACTH is deficient; the renin–angiotensin–aldosterone axis is intact.

Primary hypoadrenalism

Congenital adrenal hyperplasia

Various inherited enzyme defects have been identified in the synthetic pathway of adrenocortical hormones, which cause a spectrum of glucocorticoid and/or mineralocorticoid deficiency. Adrenal androgens may be increased or decreased, depending upon the underlying enzyme block. This group of conditions is addressed in this article: Congenital adrenal hyperplasia.

Addison’s disease

Thomas Addison described this condition in his classic monograph published in 1855. Addison worked with Bateman, a dermatologist who produced one of the first classifications of skin disease. It seems likely that this stimulated Addison’s interest in the skin pigmentation that is so characteristic of this disease.

Aetiology

This is a rare condition, with an estimated incidence in the developed world of 0.8 cases per 100 000 population. The causes of Addison’s disease are listed in Table 1.

Worldwide, infectious diseases are the most common cause of primary adrenal insufficiency. Leading causes include tuberculosis, fungal infections (histoplasmosis, cryptococcosis), and cytomegalovirus. Adrenal failure may occur in AIDS. In tuberculous Addison’s disease the adrenals are initially enlarged, with extensive epithelioid granulomas and caseation. Calcification eventually ensues in most cases. Both the cortex and the medulla are affected.

In the Western world, autoimmune adrenalitis accounts for over 70% of all cases of Addison’s disease. Pathologically, the adrenal glands are atrophic, with loss of most of the cortical cells, but the medulla is usually intact. Adrenal autoantibodies can be detected in up to 75% of newly diagnosed cases, and have helped elucidate the cause of the disease. Fifty per cent of patients with Addison’s disease have an associated autoimmune disease, and these polyglandular autoimmune syndromes have been classified into two distinct variants:

  • Type I (OMIM 240300) is inherited as an autosomal recessive condition and comprises Addison’s disease, chronic mucocutaneous candidiasis, and hypoparathyroidism. The condition is rare and usually presents in childhood with either candidiasis or hypoparathyroidism. Other autoimmune conditions, such as pernicious anaemia, thyroid disease, chronic active hepatitis, and gondal failure may occur, but are rare. Autoantibodies to the cholesterol side-chain cleavage enzyme and 17α-hydroxylase may be detected, but not to 21-hydroxylase. The condition occurs because of mutations in the autoimmune regulator gene, AIRE.
  • Type II polyglandular autoimmune syndrome (OMIM 269200) is more common, comprising Addison’s disease, autoimmune thyroid disease, diabetes mellitus, and hypogonadism. The condition has an inherited basis, with linkage to the HLA major histocompatibility complex, notably HLA DR3 and DR4. Autoantibodies to 21-hydroxylase are usually present, and are predictive for the development of adrenal destruction.
Table 1 Aetiology of adrenocortical insufficiency
Primary: Addison’s disease
Tuberculosis
Autoimmune:
 Sporadic
 Polyglandular deficiency type I (Addison’s disease, chronic mucocutaneous candidiasis hypoparathyroidism, dental enamel hypoplasia, alopecia, primary gonadal failure)
 Polyglandular deficiency type II (Schmidt’s syndrome) (Addison’s disease, primary hypothyroidism, primary hypogonadism, insulin-dependent diabetes, pernicious anaemia, vitiligo)
Metastatic tumour
Lymphoma
Amyloid
Intra-adrenal haemorrhage (Waterhouse–Friderichsen syndrome) following meningococcal septicaemia
Haemochromatosis
Adrenal infarction or infection other than tuberculosis (especially AIDS)
Adrenoleucodystrophies
Congenital adrenal hypoplasia (DAX-1 mutations)
Hereditary adrenocortical unresponsiveness to ACTH
Bilateral adrenalectomy
Secondary
Exogenous glucocorticoid therapy
Hypopituitarism:
 Selective removal of ACTH-secreting pituitary adenoma
 Pituitary tumours and pituitary surgery, craniopharyngiomas
 Pituitary apoplexy
 Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma)
 Secondary tumour deposits (breast, bronchus)
 Postpartum pituitary infarction (Sheehan’s syndrome)
 Pituitary irradiation (effect usually delayed for several years)
 Isolated ACTH deficiency

X-linked adrenoleukodystrophy causes adrenal insufficiency in association with demyelination within the nervous system, and results from a failure of β-oxidation of fatty acids within peroxisomes. Increased accumulation of very long-chain fatty acids (VLCFA) occurs in many tissues, and serum assays can be used diagnostically. Only male patients have the fully expressed condition, and female carriers are usually normal. Two forms are recognized, adrenoleukodystrophy and adrenomyeloneuropathy. Adrenoleukodystrophy (OMIM 300371) presents at 5 to 10 years of age, with progression eventually to a blind, mute, and severely spastic tetraplegic state. Adrenal insufficiency is usually present, but does not appear to correlate with the neurological deficit. X-linked adrenoleucodystrophy accounts for about 10% of cases of adrenocortical failure in boys and men.

Adrenomyeloneuropathy by contrast presents later in life, with the gradual development of spastic paresis and peripheral neuropathy. Both the childhood and adult conditions result from mutations in the ABCD1 gene on chromosome Xq28, which encodes an ATP-binding cassette peroxisomal membrane protein involved in the import of VLCFA into the peroxisome.

Monounsaturated fatty acids that block the synthesis of saturated VLCFA have been used for treatment. A combination of erucic acid and oleic acid (Lorenzo’s oil) has led to normal levels of VLCFA, but this has not altered the rate of neurological deterioration. Bone marrow transplantation appears to be more effective if undertaken in the early stages of the disease.With the exception of tuberculosis and autoimmune adrenal failure, other causes of Addison’s disease are rare (Table 1).

Adrenal metastases (most commonly from primary lung and breast tumours) are often found at postmortem examinations, but adrenal insufficiency from these is uncommon. Necrosis of the adrenals following intra-adrenal haemorrhage should be considered in any severely ill patient, and may result from infection, trauma, or hypercoagulability. Intra-adrenal bleeding may be found in severe septicaemia of any cause, particularly in children. When this is caused by meningococci, the association with adrenal insufficiency is known as Waterhouse–Friderichsen syndrome. Adrenal replacement leading to glandular failure may also occur with amyloidosis and haemochromatosis.

Congenital adrenal hypoplasia (OMIM 300200) is an X-linked disorder comprising congenital adrenal insufficiency and hypogonadotropic hypogonadism. The condition is caused by mutations in the DAX1 (NR0B1) gene, a known member of the nuclear receptor family that is expressed in the adrenal cortex, gonads, and hypothalamus.

Familial glucocorticoid deficiency is a rare autosomal recessive cause of hypoadrenalism that usually presents in childhood. The renin–angiotensin–aldosterone axis is intact, and children usually present either with neonatal hypoglycaemia, or later with increasing pigmentation, often with enhanced growth velocity. Patients have glucocorticoid deficiency with very high plasma ACTH levels; this occurs because of mutations in the melanocortin 2 receptor (MC2R; ACTH receptor; OMIM 607397) or an accessory protein involved in the cellular trafficking of MC2R (OMIM 60916).

A variant syndrome is called the triple A or Allgrove’s syndrome (OMIM 231550), and refers to a triad of adrenal insufficiency, namely ACTH resistance, achalasia, and alacrima. Mutations have not been found in the ACTH receptor and the molecular basis for this inherited syndrome is unknown.

Secondary hypoadrenalism (ACTH deficiency)

This is a common clinical problem and most often results from a sudden cessation of exogenous glucocorticoid therapy, or a failure to give glucocorticoid cover for intercurrent stress in a patient who has been on long-term glucocorticoid therapy. Such therapy suppresses the hypothalamic–pituitary–adrenal axis, with consequent adrenal atrophy that may last for months after stopping glucocorticoid treatment. Adrenal atrophy and subsequent deficiency should be anticipated in any subject who has taken more than the equivalent of 30 mg of oral hydrocortisone per day (approximately 7.5 mg/day prednisolone or 0.75 mg/day dexamethasone) for longer than 1 month. In addition to the magnitude of the dose of glucocorticoid, the timing of administration may affect the degree of adrenal suppression. Thus prednisolone in a dose of 5 mg at night and 2.5 mg in the morning will produce more marked suppression of the hypothalamic–pituitary–adrenal axis than 2.5 mg at night and 5 mg in the morning because the larger evening dose blocks the early morning surge of ACTH.

Other causes of secondary adrenal insufficiency are rare (Table 1), and reflect inadequate ACTH production from the anterior pituitary gland. In many of these, other pituitary hormones are deficient in addition to ACTH, so that the patient presents with partial or complete hypopituitarism. The clinical features of hypopituitarism make this a relatively easy diagnosis to make (see Chapter 13.4). However, if there is isolated ACTH deficiency this diagnosis may be readily missed. Lymphocytic hypophysitis and mutations in a transcription factor gene, Tpit (TBX19), involved in dictating the corticotroph lineage within the anterior pituitary, are rare diseases that may cause isolated ACTH deficiency (OMIM 604614).

Hypoadrenalism may also complicate critical illness, even in individuals with a previously intact hypothalamic–pituitary–adrenal axis. This functional adrenal insufficiency is usually transient and not caused by a structural lesion. Debate continues regarding its diagnosis and aetiology, but an inability to mount an adequate cortisol response to overwhelming stress and/or sepsis encountered in intensive care units substantially increases the risk of death during acute illness. This can be reversed with supplementary corticosteroids.

Clinical features of adrenal insufficiency

The most obvious feature differentiating primary from secondary hypoadrenalism is skin pigmentation, which is nearly always present in primary adrenal insufficiency (unless of short duration) and absent in secondary. The pigmentation is seen in sun-exposed areas, recent rather than old scars, axillae, nipples, palmar creases, pressure points, and in mucous membranes (buccal, vaginal, vulval, anal). The pigmentation reflects increased melanocyte activity induced by POMC-related peptides acting via the melanocortin 1 receptor (MC1R). In autoimmune Addison’s disease there may be associated vitiligo.

Patients with primary adrenal failure usually have both glucocorticoid and mineralocorticoid deficiency. By contrast, those with secondary adrenal insufficiency have an intact renin–angiotensin–aldosterone system. This accounts for differences in salt and water balance in the two groups of patients, which in turn result in different clinical presentations.

Primary adrenal failure may present with hypotension and acute circulatory failure (addisonian crisis). Anorexia may be an early feature that progresses to nausea, vomiting, diarrhoea, and sometimes, abdominal pain. These crises may be precipitated by intercurrent infection or by stress, such as surgery. Alternatively, the patient may present with vague features of chronic adrenal insufficiency—weakness, tiredness, weight loss, nausea, intermittent vomiting, abdominal pain, diarrhoea or constipation, general malaise, muscle cramps, and symptoms suggestive of postural hypotension. Salt craving may be a feature, and there may be a low-grade fever. The lying blood pressure is usually normal, but almost invariably there is a fall in blood pressure on standing.

In adrenal insufficiency secondary to hypopituitarism, the presentation may relate to deficiency of hormones other than ACTH, notably luteinizing hormone/follicle-stimulating hormone (infertility, oligo-/amenorrhoea, poor libido), thyroid-stimulating hormone (weight gain, cold intolerance), and growth hormone (hypoglycaemia). Patients with isolated ACTH deficiency present with malaise, weight loss, and other features of chronic adrenal insufficiency. By contrast with primary adrenal failure, patients are usually pale.

Laboratory investigation of hypoadrenalism
Routine biochemical profile

In established primary adrenal insufficiency, hyponatraemia is present in about 90% of cases and hyperkalaemia in 65%. The blood urea concentration is usually elevated. In secondary adrenal failure there may be dilutional hyponatraemia, with normal or low blood urea, because glucocorticoids are required to maintain the glomerular filtration rate and excrete a water load. Hypoglycaemia has been found in up to 50% of patients with chronic adrenal insufficiency.

Plasma cortisol/ACTH

Clinical suspicion of the diagnosis should be confirmed with definitive diagnostic tests. Basal plasma cortisol and urinary free cortisol levels are often in the low normal range and cannot be used to exclude the diagnosis. In primary adrenal insufficiency the simultaneous measurement of plasma cortisol and plasma ACTH reveals an ACTH level that is disproportionately elevated in comparison with plasma cortisol.

Mineralocorticoid status

In primary hypoadrenalism there is usually mineralocorticoid deficiency, with elevated plasma renin activity and either low or low-normal plasma aldosterone. This aspect of investigation is all too frequently ignored in patients with Addison’s disease. By contrast, in secondary adrenal failure, only ACTH drive to the adrenal cortex is lacking; the renin–angiotensin–aldosterone axis is intact.

Stimulation tests

In practice, all patients suspected of having adrenal insufficiency should have an ACTH stimulation test. This involves the intramuscular or intravenous administration of 250 µg of tetracosactrin (Synacthen), a peptide comprising the first 24 amino acids of normally secreted 1–39 ACTH. Plasma cortisol levels are measured at 0 and 30 min after tetracosactrin administration, and a normal response is defined by a peak plasma cortisol of more than 550 nmol/litre. Levels of less than 550 nmol/litre in response to tetracosactrin are found in both primary and secondary adrenal insufficiency, although false-positive results have occasionally been reported, particularly in cases of sudden-onset secondary hypoadrenalism. A low-dose ACTH stimulation test giving only 1 µg ACTH has been proposed to screen for adequate function of the hypothalamo–pituitary–adrenal axis, with the suggestion that it may be more sensitive than the conventional 250 µg test. At present there are insufficient data to support such a concept.

A prolonged ACTH stimulation test, involving the administration of depot tetracosactrin in a dose of 1 mg by intramuscular injection, with measurement of plasma cortisol at 0, 4, and 24 h will differentiate primary from secondary hypoadrenalism. However, the test is now rarely required if plasma ACTH has been appropriately measured at baseline.

The insulin-induced hypoglycaemia or insulin tolerance test remains one of the most useful in assessing ACTH and growth hormone reserves. It should not be performed in patients with ischaemic heart disease (check ECG before test), epilepsy, or severe hypopituitarism (i.e. plasma cortisol at 09.00 <180 nmol/litre). The test involves the intravenous administration of soluble insulin in a dose of 0.1 to 0.15 U/kg body weight, with measurement of plasma cortisol at 0, 30, 45, 60, 90, and 120 min. Adequate hypoglycaemia (blood glucose <2.2 mmol/litre, with signs of neuroglycopenia—sweating and tachycardia) is essential. In normal subjects the peak plasma cortisol exceeds 500 nmol/litre. However, the response to hypoglycaemia can be reliably predicted by the response to acute ACTH stimulation (see above); a safer, cheaper, and quicker test. If the ACTH test is normal, insulin-induced hypoglycaemia testing is not necessary in the vast majority of cases, unless there is a need to document endogenous growth hormone reserve in a patient with pituitary disease.

Other tests

Radioimmunoassays to detect autoantibodies, such as those against the 21-hydroxylase antigen, are available and should be undertaken in patients with primary adrenal failure. In autoimmune Addison’s disease it is also important to look for evidence of other organ-specific autoimmune disease. In long-standing tuberculous adrenal disease there may be adrenal atrophy with calcification on plain radiographs or CT scanning. Early morning urine samples should be cultured for mycobacteria if tuberculosis is suspected.

Treatment of acute adrenal insufficiency

This is an emergency, and treatment should not be delayed while waiting for definitive proof of diagnosis. However, in addition to the measurement of plasma electrolytes and blood glucose, appropriate samples for ACTH and cortisol determination should be taken before giving corticosteroid therapy. If the patient is not critically ill, an acute ACTH stimulation test can be performed. However, if necessary, this can be delayed and carried out with the patient on corticosteroid therapy; provided the drug used does not interfere with the plasma cortisol assay (e.g. change from hydrocortisone to dexamethasone).

Intravenous hydrocortisone should be given at a dose of 100 mg every 6 h. If this is not possible then the intramuscular route should be used. In the patient with shock, 1 litre of normal saline should be given intravenously over the first hour. Because of possible hypoglycaemia, it is usual to give 5% dextrose saline. Subsequent intravenous fluid replacement will depend on biochemical monitoring and the patient’s condition. Clinical improvement, especially in blood pressure, should be seen within 4 to 6 h if the diagnosis is correct. It is important to recognize and treat any associated condition, such as an infection, that may have precipitated the acute adrenal crisis.

After the first 24 h the dose of hydrocortisone can be reduced, usually to 50 mg intramuscularly every 6 h for the second 24 h and then, if the patient can take by mouth, to oral hydrocortisone, 40 mg in the morning and 20 mg at 18.00. This can then be rapidly reduced to the normal replacement dose of 20 mg on waking and 10 mg at 18.00. Some patients will require more than 30 mg/day, but most patients can cope with less than this (usually 15–25 mg/day in divided doses). In primary adrenal failure, cortisol day curves with simultaneous ACTH measurements may provide some insight into the adequacy of replacement therapy, but unfortunately there are no good objective tests in secondary adrenal failure. Nevertheless, crude objectives such as weight and body mass index, well-being, and blood pressure are important in this regard.

In primary adrenal failure, mineralocorticoid replacement is usually also required in the form of fludrocortisone at a dose of 0.05 to 0.1 mg/day. This has mineralocorticoid activity about 125 times that of hydrocortisone. After the acute phase has passed, the adequacy of mineralocorticoid replacement can be assessed by measuring electrolytes, supine and erect blood pressure, and plasma renin activity; too little fludrocortisone may cause postural hypotension with elevated plasma renin activity, and too much causes the converse.

Patients receiving glucocorticoid replacement therapy should be advised to double the dose in the event of an intercurrent febrile illness, accident, or mental stress such as an important examination. If the patient is vomiting and cannot take by mouth, parenteral hydrocortisone must be given urgently, as indicated above. For minor surgery, 50 to 100 mg of hydrocortisone hemisuccinate is given with the premedication. For major procedures this is then followed by the same regimen as for acute adrenal insufficiency.

Every patient on glucocorticoid therapy should be advised to register for a MedicAlert bracelet or necklace and must carry a steroid card giving information on the treatment being given.

For patients with both primary and secondary adrenal failure, beneficial effects have been reported for adrenal androgen replacement therapy with 25 to 50 mg/day DHEA. Benefit is principally confined to female patients and includes improvement in sexual function and well-being.