History
Patients usually present with features of both glucocorticoid and mineralocorticoid deficiency. The predominant symptoms vary depending on the duration of disease.
Patients may present with clinical features of chronic Addison disease or in acute addisonian crisis precipitated by stress factors such as infection, trauma, surgery, vomiting, diarrhea, or noncompliance with replacement steroids.
Presentation of chronic Addison disease
The onset of symptoms most often is insidious and nonspecific.
Hyperpigmentation of the skin and mucous membranes often precedes all other symptoms by months to years. It is caused by the stimulant effect of excess adrenocorticotrophic hormone (ACTH) on the melanocytes to produce melanin. The hyperpigmentation is caused by high levels of circulating ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes. Other melanocyte-stimulating hormones produced by the pituitary and other tissues include alpha-MSH (contained within the ACTH molecule), beta-MSH, and gamma-MSH. When stimulated, the melanocyte changes the color of pigment to a dark brown or black.
Hyperpigmentation is usually generalized but most often prominent on the sun-exposed areas of the skin, extensor surfaces, knuckles, elbows, knees, and scars formed after the onset of disease. Scars formed before the onset of disease (before the ACTH is elevated) usually are not affected. Palmar creases, nail beds, mucous membranes of the oral cavity (especially the dentogingival margins and buccal areas), and the vaginal and perianal mucosa may be similarly affected.
Hyperpigmentation, however, need not be present in every long-standing case and may not be present in cases of short duration. [15]
Other skin findings include vitiligo, which most often is seen in association with hyperpigmentation in idiopathic autoimmune Addison disease. It is due to the autoimmune destruction of melanocytes.
Almost all patients complain of progressive weakness, fatigue, poor appetite, and weight loss.
Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea. Glucocorticoid-responsive steatorrhea has been reported. [16]
Dizziness with orthostasis due to hypotension occasionally may lead to syncope. This is due to the combined effects of volume depletion, loss of the mineralocorticoid effect of aldosterone, and loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.
Myalgias and flaccid muscle paralysis may occur due to hyperkalemia. [17]
Patients may have a history of using medications known to affect adrenocortical function or to increase cortisol metabolism.
Other reported symptoms include muscle and joint pains; a heightened sense of smell, taste, and hearing; and salt craving.
Patients with diabetes that previously was well-controlled may suddenly develop a marked decrease in insulin requirements and hypoglycemic episodes due to an increase in insulin sensitivity. [18]
Impotence and decreased libido may occur in male patients, especially in those with compromised or borderline testicular function.
Female patients may have a history of amenorrhea due to the combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure. Steroid-responsive hyperprolactinemia may contribute to the impairment of gonadal function and to the amenorrhea.
Presentation of acute Addison disease
Patients in acute adrenal crisis most often have prominent nausea, vomiting, and vascular collapse. They may be in shock and appear cyanotic and confused.
Abdominal symptoms may take on features of an acute abdomen.
Patients may have hyperpyrexia, with temperatures reaching 105° F or higher, and may be comatose.
In acute adrenal hemorrhage, the patient, usually in an acute care setting, deteriorates with sudden collapse, abdominal or flank pain, and nausea with or without hyperpyrexia.
Physical
Physical examination in long-standing cases most often reveals increased pigmentation of the skin and mucous membranes, with or without areas of vitiligo.
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Patients show evidence of dehydration, hypotension, and orthostasis.
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Female patients may show an absence of axillary and pubic hair and decreased body hair. This is due to loss of the adrenal androgens, a major source of androgens in women.
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Addison disease caused by another specific disease may be accompanied by clinical features of that disease.
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Calcification of the ear and costochondral junctions is described but is a rare physical finding.
Causes
The most common cause of Addison disease is idiopathic autoimmune adrenocortical insufficiency resulting from autoimmune atrophy, fibrosis, and lymphocytic infiltration of the adrenal cortex, usually with sparing of the adrenal medulla. This accounts for more than 80% of reported cases. Idiopathic autoimmune adrenocortical atrophy and tuberculosis (TB) account for nearly 90% of cases of Addison disease. [19, 20]
Antibodies against the adrenal tissue are present in a significant number of these patients, and evidence of cell-mediated immunity against the adrenal gland also may be present. The steroidogenic enzyme 21-hydroxylase (21OH) is the main autoantigen, but antibodies against this enzyme are not directly involved in the tissue destruction. [21, 22]
Patients may have a hereditary predisposition to autoimmune Addison disease. [23]
Idiopathic autoimmune Addison disease may occur in isolation or in association with other autoimmune phenomena (eg, Schmidt syndrome, polyglandular autoimmune disease types 1 and 2).
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Idiopathic hypoparathyroidism
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Mucocutaneous candidiasis
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Type 1 diabetes mellitus [18]
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Hashimoto thyroiditis
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Graves disease
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Vitiligo
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Alopecia areata, totalis and universalis
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Premature ovarian or testicular failure
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Pernicious anemia
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Myasthenia gravis
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Idiopathic hypophysitis
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Chronic active hepatitis
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Primary biliary cirrhosis
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The association of Addison disease and Hashimoto thyroiditis is known as Schmidt syndrome.
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The association of Addison disease with hypoparathyroidism and mucocutaneous candidiasis is described as polyglandular autoimmune syndrome type 1. It may have an autosomal recessive mode of inheritance. It has no human leukocyte antigen (HLA) associations. [27] . It is also termed autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). It is caused by mutations in the autoimmune regulator gene (AIRE).
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Other autoimmune phenomena, as outlined above, can occur in either of the 2 polyglandular syndromes.
Additional causes of chronic Addison disease:
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Chronic granulomatous diseases [19]
TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis could involve the adrenal glands.
In the preantibiotic era, TB was the most common cause and still may be a major consideration in areas where TB is common. It tends to involve both the adrenal cortex and the medulla; however, medullary involvement may not have any major consequences.
TB of the adrenal glands usually is a tertiary disease due to the hematogenous spread of infection to the adrenal glands, but clinical evidence of the primary infection is not always present.
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Hematologic malignancies
Malignant infiltration of the adrenal cortices, as with Hodgkin and non-Hodgkin lymphoma and leukemia, may cause Addison disease.
Hodgkin and non-Hodgkin lymphoma initially could present with adrenal gland involvement and features of adrenocortical insufficiency.
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Metastatic malignant disease - Bilateral involvement of the adrenal glands could occur in the setting of metastatic cancer of the lung, breast, or colon or renal cell carcinoma.
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Infiltrative metabolic disorders - Amyloidosis and hemochromatosis could involve the adrenal glands and lead to primary adrenocortical insufficiency.
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Acquired immunodeficiency syndrome (AIDS) [30, 31, 32]
The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the setting of a low CD4 cell count.
It is caused by opportunistic infections such as cytomegalovirus, Mycobacterium avium intracellulare, cryptococci, or Kaposi sarcoma.
Adrenocortical hypofunction in patients with HIV may be due to glucocorticoid resistance syndrome. These patients tend to present with features of adrenocortical insufficiency and mucocutaneous hyperpigmentation but also with increased plasma and urinary cortisol levels and a slight elevation in ACTH levels. Hyperpigmentation in patients with HIV is thought to be due to elevated alpha-interferon levels.
Another possible cause of adrenocortical insufficiency in patients with AIDS is the use of megestrol acetate (Megace) as an appetite stimulant to stem HIV wasting disease. However, this causes secondary adrenocortical insufficiency and not Addison disease. The glucocorticoid effect of megestrol acetate suppresses pituitary ACTH production and leads to secondary adrenocortical insufficiency.
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Although patients with congenital adrenocortical unresponsiveness to ACTH (Allgrove syndrome) may present with features of glucocorticoid deficiency and skin hyperpigmentation, the aldosterone production and function in these patients is normal and responds appropriately to low sodium intake.
This typically presents in childhood with failure to thrive, features of adrenocortical insufficiency, and hypoglycemia.
Some patients may have components of alacrima and achalasia. [35] It is also sometimes called triple A syndrome.
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Abnormalities of beta oxidation of very-long-chain fatty acids
These patients (usually men) present with adrenocortical insufficiency and features of progressive demyelination of the CNS. It is caused by mutation in the ABCD1 gene. it is the most common cause of adrenal insufficiency in a male child less than 7 years of age.
This is caused by the accumulation of very-long-chain fatty acids (VLCFA) in various organs, including the adrenal cortex, brain, testis, and liver.
These disorders are X-linked recessive, with poor penetrance.
Other symptoms include cognitive dysfunction, behavioral problems, disturbance of gait, and emotional lability.
Two subtypes are described. The first subtype is adrenoleukodystrophy (ALD). This usually presents in childhood. Thirty percent of cases may present with adrenal insufficiency before the onset of neurologic symptoms. Other features include severe hypotonia, seizure disorder, retinitis pigmentosa, and optic atrophy. The second subtype is adrenomyeloneuropathy (AMN). [36] This usually is mild. It tends to present in the 20- to 40-year age group with features of adrenal insufficiency and progressive CNS demyelination.
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Congenital adrenal hyperplasia
Primary adrenocortical insufficiency may occur in patients with the StAR [37] or 20,22-desmolase enzyme deficiency, 3-beta hydroxysteroid dehydrogenase enzyme deficiency, and the severe form of the 21-hydroxylase enzyme deficiency (virilizing and salt wasting).
Infants usually present in shock, with hypoglycemia and adrenal insufficiency.
In 3-beta hydroxysteroid dehydrogenase enzyme deficiency, female infants appear virilized, whereas male infants may have pseudohermaphroditism from insufficient androgen activity.
Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis. Male infants usually have features of pseudohermaphroditism due to an associated deficiency of gonadal steroids. [37, 38]
The rapid ACTH test usually helps to establish the diagnosis. Patients with CAH respond with a marked increase in 17-OH progesterone levels, an increase in other precursors preceding the enzyme block, and a subnormal cortisol response.
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Drug-related causes
Ketoconazole inhibits the adrenal cytochrome P450 steroidogenic enzymes.
Aminoglutethimide blocks the early conversion of cholesterol to pregnenolone by inhibiting the 20,22-desmolase enzyme.
Mitotane (O,P'-DDD) blocks adrenal mitochondrial steroid biosynthesis.
Busulphan, etomidate, and trilostane inhibit or interfere with adrenal steroid biosynthesis.
Methadone, perhaps by depleting pituitary ACTH, may cause secondary adrenocortical insufficiency in some patients. [39]
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Abdominal irradiation
Addison disease could result from situations where a radiation field involves the adrenal glands.
The lag time to onset of disease usually is 2-7 years, but the disease could occur earlier depending on the dose of the radiation.
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Hypogandotropic Hypogonadism and DAX-1 gene mutation [40]
Causes of acute Addison disease:
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Stress - Acute adrenal crisis precipitated by infection, trauma, surgery, emotional turmoil, or other stress factors may be the initial presentation of Addison disease in as many as 25% of cases.
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Failure to increase steroids
Failure to appropriately increase daily replacement steroid doses in patients with adrenocortical insufficiency in times of stress could precipitate an adrenal crisis.
Failure to adjust the replacement steroid dose in patients on cytochrome P450 enzyme-inducing medications such as rifampin and Dilantin also could precipitate an adrenal crisis. [41, 42]
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Bilateral adrenal hemorrhage
This may be the cause of an acute adrenal crisis, and it may occur as a complication of bacterial infection with Meningococcus or Pseudomonas species, as in Waterhouse-Friderichsen syndrome.
It also may occur as a complication of pregnancy, anticoagulant therapy with heparin or warfarin, and as a complication of coagulopathies such as antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE).
The mechanism of action of adrenal hemorrhage is not fully understood. Diagnosis usually is made in the setting of a critically ill patient on anticoagulants (or with any of the causes mentioned above) who becomes acutely hypotensive with tachycardia, nausea, vomiting, fever, and confusion or disorientation. Abdominal or flank pain with associated tenderness may develop.
A rapid ACTH test usually should be performed in this setting, and the patient should be started on hydrocortisone without waiting for the results. When time is critical, a random cortisol should be drawn and the patient started on hydrocortisone in stress doses. An abdominal computed tomography (CT) scan often reveals bilateral adrenal gland enlargement.
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Bilateral adrenal artery emboli and bilateral vein thrombosis
This is a very rare cause of Addison disease but may occur in critically ill patients on heparin as a complication of heparin-induced thrombosis (HIT) or as a complication of other states that predispose to thrombosis.
It also may occur as a complication of radiographic contrast studies involving the adrenal glands.
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Bilateral adrenalectomy for any reason
The surgical removal of a unilateral cortisol-producing adrenal adenoma in a patient with Cushing syndrome can cause an acute adrenal crisis from secondary adrenocortical insufficiency.
This is due to the atrophy of the normal adrenal cortex from lack of the stimulant effect of pituitary ACTH.
