INTRODUCTION — When Thomas Addison described the disease that now bears his name [1], bilateral adrenal destruction by tuberculosis was its most common cause. Now tuberculosis accounts for only 7 to 20 percent of cases; autoimmune disease is responsible for 70 to 90 percent, with the remainder being caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs (table 1) [2-6]. Disseminated tuberculous or fungal infections are still a major cause of adrenal insufficiency in populations with a high prevalence of these diseases, but as tuberculosis has been better controlled, the overall incidence of Addison's disease has decreased [7]. The prevalence of Addison's disease in Western countries has been estimated at 35 to 60 per million, but three studies indicate it may be as high as 144 per million [8-10].
This topic will review the major causes of primary adrenal insufficiency. Rarer causes are discussed separately. The rarer diseases, such as adrenal leukodystrophy/adrenal myeloneuropathy, are mostly inherited disorders that present in infancy or childhood. (See "X-linked adrenoleukodystrophy and adrenomyeloneuropathy".)
AUTOIMMUNE ADRENALITIS
Destruction of adrenal cortex — What long was termed "idiopathic" primary adrenal insufficiency is the result of an autoimmune process that destroys the adrenal cortex. There is evidence of both humoral and cell-mediated immune mechanisms directed at the adrenal cortex, often associated with autoimmune destruction of other endocrine glands (referred to as polyglandular autoimmune syndromes). Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum of up to 86 percent of patients with autoimmune primary adrenal insufficiency (anti-21-hydroxylase [10]), but only rarely in patients with other causes of adrenal insufficiency, or in normal subjects [10,11]. However, up to 10 percent of first-degree relatives of patients with autoimmune primary adrenal insufficiency express these antibodies and have an increased risk of developing adrenal insufficiency [11]. (See "Pathogenesis of autoimmune adrenal insufficiency".)
Sex differences — Patients with autoimmune adrenal insufficiency as part of one of the polyglandular autoimmune syndromes are predominantly female (70 percent). In contrast, patients with isolated autoimmune adrenal insufficiency are predominantly male (71 percent) during the first two decades of life, are equally male and female in the third decade, and are predominantly female (81 percent) thereafter [12]. The explanation for these sex differences is unknown.
Early findings — The first evidence of autoimmune adrenal insufficiency is usually an increase in plasma renin activity in association with a normal or low serum aldosterone concentration, suggesting that the zona glomerulosa is involved initially [13,14]. Several months to years later, zona fasciculata dysfunction becomes evident, first by a decreasing serum cortisol response to adrenocorticotropic hormone (ACTH) stimulation, later by increased basal serum ACTH concentrations, and finally by decreasing basal serum cortisol concentrations and symptoms [13,15].
One study suggests that a rise in serum ACTH is the best predictor of the subsequent development of adrenal insufficiency in patients with 21-hydroxylase autoantibodies. This was illustrated in a report of 87 such individuals (excluding polyglandular autoimmune syndrome type 1 patients), who were followed during the two years preceding the onset of adrenal insufficiency. Seven developed adrenal insufficiency while 80 did not. When compared to nonprogressors, those who progressed to adrenal insufficiency were more likely to have an elevated serum ACTH, but there were no differences in plasma renin activity, or peak cortisol response to exogenous ACTH [16].
Other endocrine disorders — Approximately 50 to 65 percent of patients with autoimmune adrenal insufficiency have one or more other autoimmune endocrine disorders (table 2) [2,3,10,17-20]. On the other hand, patients with the more common autoimmune endocrine disorders, such as type 1 (insulin-dependent) diabetes mellitus, chronic autoimmune thyroiditis, or Graves' disease, rarely develop adrenal insufficiency. In one report, as an example, 11 of 629 patients (1.7 percent) with type 1 diabetes but none of 239 normal subjects had antibodies directed against 21-hydroxylase [21]. Three of the eight patients with anti-21-hydroxylaseantibodies had adrenal insufficiency. In another study, only 1 of 114 children with type 1 diabetes and none of 35 children with autoimmune thyroiditis tested positive for anti-adrenal antibodies measured by immunofluorescence [22].
In contrast, about 80 percent of patients with diabetes mellitus associated with the DQ8 HLA allele who also have the DRB*0404 HLA allele and autoantibodies against 21-hydroxylase develop adrenal insufficiency [23,24]. In another report of 38 patients with type 1 diabetes who also had antibodies directed against 21-hydroxylase, those who were homozygous for MICA5.1 (an MHC class I-related molecule located between tumor necrosis factor-alpha and HLA-B) were at higher risk for developing adrenal insufficiency than those without homozygosity [24,25].
Adrenal insufficiency is easily diagnosed and treated and is potentially lethal if unrecognized; this has led some investigators to recommend screening for this disorder in all patients with type 1 diabetes. Nevertheless, we do not believe that testing this large patient population is warranted, given the approximately 1 percent prevalence of subnormal responses to ACTH in these patients.
Patients with celiac disease had an 11-fold increased risk for adrenal insufficiency in a Swedish study, and 6 of 76 patients with adrenal insufficiency had celiac disease in a Norwegian study, suggesting that patients with either disorder should be evaluated for the other as well [26,27].
The combination of autoimmune adrenal insufficiency with other autoimmune endocrine disorders is referred to as the polyglandular autoimmune syndromes types 1 and 2 [28-31]. The genetics and pathogenesis of these disorders are discussed separately. (See "Pathogenesis of autoimmune adrenal insufficiency".)
Polyglandular autoimmune syndrome type 1 — Polyglandular autoimmune syndrome type 1, also referred to as the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, is a rare autosomal recessive disorder in which females are affected slightly more frequently than males [28-30]. It is most common among Finns, Sardinians, and Iranian Jews; sporadic cases also have been identified elsewhere, including most European countries [32,33]. (See "Pathogenesis of autoimmune adrenal insufficiency".)
Genetics — APECED appears to be due to mutations in the so-called autoimmune regulator (AIRE) gene on chromosome 21q22.3 [34-36]. The AIRE gene product is expressed in the thymus, lymph nodes, pancreas, adrenal cortex, and fetal liver; it appears to be a nuclear transcription factor, but its exact mechanism in causing the syndrome is unclear. One theory is that it is important in the selection and generation of regulatory T cells [35-40]. The predominant gene mutation differs in different patient populations [36,37,41,42]. There is no apparent correlation between specific gene mutations and phenotype.
Clinical manifestations
●Hypoparathyroidism or chronic mucocutaneous candidiasis is usually the first manifestation, characteristically appearing during childhood or early adolescence, always by the early twenties (table 3) [12,28-30]. The hypoparathyroidism may [43,44] or may not [45] occur in association with anti-parathyroid gland antibodies that are directed against the calcium-sensing receptor. (See "Etiology of hypocalcemia in adults", section on 'Autoimmune'.)
The candidiasis almost always involves the mouth, although it may involve just the nail beds or be more extensive (picture 1) [28]. It is chronic or recurrent, and is resistant to conventional therapy (see "Overview of Candida infections", section on 'Chronic mucocutaneous candidiasis'). Oral mucous squamous cell carcinoma has been rarely reported in association with the candidiasis of APECED [46].
●Adrenal insufficiency usually develops later, at age 10 to 15 years. The antigen targets are adrenal enzymes including P450scc (side-chain cleavage enzyme), P450c17 (17-alpha-hydroxylase), and P450c21 (21-hydroxylase) [47]. The presence of adrenal autoantibodies has a high (92 percent) positive predictive value for development of adrenal insufficiency [15,39]. (See "Pathogenesis of autoimmune adrenal insufficiency", section on 'Prediction of adrenal insufficiency'.)
●Primary hypogonadism occurs in about 60 percent of patients. (See "Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)".)
●Malabsorption and other gastrointestinal disorders occur in about 25 percent of patients [48,49], of whom 90 percent have autoantibodies to tryptophan hydroxylase, an intestinal antigen. Only one-third of patients without gastrointestinal disorders have these autoantibodies. One report described a patient with severe malabsorption syndrome due to a deficiency of cholecystokinin-producing enteroendocrine cells in the mucosa of the proximal small bowel [50].
In one series of 68 Finnish patients, approximately 50 percent of patients developed the triad of candidiasis, hypoparathyroidism, and adrenal failure [28]. Diabetes mellitus and chronic autoimmune thyroiditis are uncommon. Graves' disease is not associated with this disorder (table 3).
In the patient series noted [28], the incidence of various manifestations was different from that reported in other smaller series and reviews of the literature [28]. These differences from previous reports may reflect a variant form of the disorder or more thorough examination of affected patients. As an example, diabetes mellitus was 12 times more prevalent, and manifestations of ectodermal dysplasia, including dental enamel hypoplasia, pitted dystrophy of the nails, keratopathy, and calcified plaques on the tympanic membranes, were present in one-third to two-thirds of the patients. In a report of 62 Finnish and seven Swedish patients, 17 percent had autoimmune chronic active hepatitis in association with antibodies directed against aromatic l-amino acid decarboxylase [51]. The use of autoantibodies to predict disease manifestations is reviewed elsewhere. (See "Pathogenesis of autoimmune adrenal insufficiency", section on 'Humoral immunity'.)
The variable clinical presentation and progression are presumably due to environmental factors and genetic factors other than AIRE gene mutations [36].
Polyglandular autoimmune syndrome type 2 — The type 2 syndrome is much more prevalent than the type I syndrome and primary adrenal insufficiency is its principal manifestation [29,30,52]. Antibodies to steroidogenic enzymes also are present in this disorder [47]. Autoimmune thyroid disease, usually chronic autoimmune thyroiditis but occasionally Graves' disease, and type 1 diabetes mellitus are also common (table 2 and table 3). The type 2 syndrome with primary adrenal insufficiency and autoimmune thyroid disease was formerly referred to as "Schmidt's syndrome." Patients with autoimmune thyroid disease or diabetes mellitus who have adrenal autoantibodies but do not yet have adrenal insufficiency and relatives who have one or more components of the syndrome should also be considered to have the disorder.
Approximately one-half of cases are familial and several modes of inheritance (autosomal recessive, autosomal dominant, and polygenic) have been reported [12,29,30]. Women are affected up to three times more often than men [52]. The age of onset ranges from childhood to late adulthood, with most cases occurring between age 20 and 40 years [12,19,29,52].
Affected endocrine organs
●Adrenal insufficiency is the initial manifestation in about 50 percent of patients, occurs simultaneously with autoimmune thyroid disease or diabetes mellitus in about 20 percent, and follows them in about 30 percent [12,19,29]. In one series, however, adrenal insufficiency was the initial manifestation in only 19 percent of patients [52].
●Primary hypogonadism can occur first and, as in polyglandular autoimmune syndrome type 1, ovarian failure is more frequent than testicular failure [19,29,30]. (See "Clinical features and diagnosis of autoimmune primary ovarian insufficiency (premature ovarian failure)".)
●Hypoparathyroidism does not occur in this disorder, and alopecia and pernicious anemia are much less frequent than in the type I syndrome.
●Hypopituitarism due to autoimmune hypophysitis, preferentially causing ACTH deficiency, can occur alone or in combination with thyrotropin or, rarely, growth hormone deficiency [53]. (See "Causes of hypopituitarism".)
●Other nonendocrine autoimmune disorders, such as vitiligo, myasthenia gravis, thrombocytopenic purpura, Sjögren's syndrome, rheumatoid arthritis, and primary antiphospholipid syndrome, occur occasionally [29,30,54], as does serositis with pericardial and/or pleural involvement [55]. Patients with vitiligo, as an example, can have autoantibodies to tyrosinase, an enzyme involved in the synthesis of melanin, tyrosinase-related proteins, or to a melanocyte-specific protein called Pmel17 [56]. (See "Clinical manifestations of antiphospholipid syndrome".)
INFECTIOUS ADRENALITIS — A variety of infectious agents can infect the adrenal gland and lead to adrenal insufficiency.
Tuberculosis — Tuberculosis can destroy the adrenal glands. Tuberculous adrenalitis results from hematogenous spread from active infection elsewhere in the body [57]. Extraadrenal tuberculosis is usually evident, but may be clinically latent [57,58]. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Clinical manifestations'.)
Adrenal destruction is gradual, with the medulla being destroyed more often than the cortex, for unknown reasons [57]. Antiadrenal autoantibodies are not present in serum [59]. The adrenal glands are usually enlarged by inflammatory cell infiltration of the cortex and granulomas early in the disease; the increase in size can be detected by computed tomography (CT) or magnetic resonance imaging (MRI) [58,60,61]. Caseous nodules and fibrosis then gradually replace the adrenal gland tissue [58], so that after about two years the adrenals become normal or small in size [58,60-62].
●Adrenal calcifications can be seen radiographically in 50 percent of patients [58,60,62]. However, the absence of enlarged or calcified adrenal glands does not rule out tuberculosis as the cause of adrenal insufficiency.
●Recovery of normal adrenal function may occur after effective antituberculous therapy [63], but usually does not [64].
The adrenal glands may be enlarged in patients with pulmonary tuberculosis even when adrenal function is normal. Adrenal size becomes smaller after successful treatment of the tuberculosis [65].
Disseminated fungal infections — Several species of fungi can involve the adrenal glands and cause adrenal insufficiency. Histoplasmosis [66,67] and paracoccidioidomycosis (South American blastomycosis) [5,68] are important causes of adrenal insufficiency in endemic areas. In contrast, adrenal insufficiency is rare in patients with cryptococcosis, coccidioidomycosis, and North American blastomycosis [69-71]. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Adrenal involvement'.)
●The adrenal glands are enlarged and may become calcified in all of these disorders.
●Recovery of adrenal function after prolonged anti-fungal treatment can occur [67].
HIV infection — In the early acquired immunodeficiency syndrome (AIDS) epidemic, the diverse endocrine manifestations of human immunodeficiency virus (HIV) infection, including adrenal insufficiency, were more often a consequence of opportunistic infections (OIs), neoplasms, or concomitant systemic illness. The widespread use of potent antiretroviral therapy (ART) has led to a decline in the incidence of endocrine complications. (See "Pituitary and adrenal gland dysfunction in patients with HIV", section on 'Alterations in adrenal function'.)
Other infections — A few other infections are rare causes of primary adrenal insufficiency. These include:
●Syphilis, in which gumma formation and demonstrable spirochetes may be seen [57].
●African trypanosomiasis, unrelated to its treatment with suramin, which can impair adrenal function when given in higher than the usual therapeutic doses [72]. In another study of 60 patients, five had insufficient cortisol responses to ACTH stimulation on admission, and another five had an abnormal response on discharge; all improved during follow-up evaluation [73].
HEMORRHAGIC INFARCTION — Acute adrenal insufficiency may occur as a result of bilateral adrenal infarction caused by hemorrhage or adrenal vein thrombosis [74-76]. Adrenal hemorrhage has been associated with meningococcemia (Waterhouse-Friderichsen syndrome) [77], but Pseudomonas aeruginosa was the most common pathogen in one report of 51 children dying of sepsis and bilateral adrenal hemorrhage [78]. Waterhouse-Friderichsen syndrome has also been reported with sepsis from Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, and Staphylococcus aureus. (See "Clinical manifestations of Staphylococcus aureus infection in adults".)
Bilateral adrenal hemorrhages are present in about 1 percent of routine autopsies and, before the availability of computed tomography (CT) scanning (image 1) and magnetic resonance imaging, the diagnosis was usually made at autopsy [74,76]. The symptoms and signs include hypotension or shock (>90 percent of patients); abdominal, back, flank, or lower chest pain (86 percent); fever (66 percent); anorexia, nausea, or vomiting (47 percent); confusion or disorientation (42 percent); and abdominal rigidity or rebound (22 percent) [75].
Major risk factors for adrenal hemorrhage include anticoagulant drug or heparin therapy (heparin-induced thrombocytopenia resulting in bilateral adrenal hemorrhage) [79], thromboembolic disease, hypercoagulable states such as antiphospholipid syndrome [80,81], physical trauma, the postoperative state, sepsis, and any cause of severe stress [76,82]. In patients treated with anticoagulants, clotting test results are usually within the therapeutic range, and spontaneous bleeding elsewhere is not evident [75].
Evidence of occult hemorrhage, such as a sudden fall in hemoglobin and hematocrit, and progressive hyperkalemia, hyponatremia, and volume contraction should suggest the diagnosis. However, the condition is difficult to recognize clinically and, despite the often dramatic symptoms, the diagnosis is often missed. Without appropriate therapy, shock progresses to coma and death.
The pathogenesis of adrenal hemorrhage is unclear. Increased adrenal blood flow stimulated by adrenocorticotropic hormone (ACTH) secreted in response to stress may play a contributory role [76]. Anticoagulation therapy is implicated in about one-third of patients, but adrenal hemorrhage occurs very rarely in patients who are anticoagulated; when it does, it is usually within the first 2 to 12 days of therapy [74,76,79]. A case-control study (23 patients with bilateral massive adrenal hemorrhage and 92 control patients) reported that thrombocytopenia, heparin use, and sepsis were the variables that were most strongly and independently associated with adrenal hemorrhage risk [82].
METASTATIC DISEASE — Infiltration of the adrenal glands by metastatic cancer is common, probably because of their rich sinusoidal blood supply. At autopsy, adrenal metastases are found in 40 to 60 percent of patients with disseminated lung or breast cancer, 30 percent of patients with melanoma, and 14 to 20 percent of patients with stomach or colon cancer, but clinically evident adrenal insufficiency is uncommon [83-85]. Similar findings occur with lymphoma [86,87].
The apparent low incidence of clinical adrenal insufficiency in patients with malignant disease is due to the fact that most of the adrenal cortex must be destroyed before hypofunction becomes evident [88,89]. In addition, some of the symptoms of adrenal insufficiency may mistakenly be attributed to cancer. Two small studies have suggested that 20 to 35 percent of patients with bilateral adrenal metastases have at least partial adrenal insufficiency and benefit from glucocorticoid replacement therapy [84,85].
DRUGS — Several drugs may cause adrenal insufficiency by inhibiting cortisol biosynthesis. They include the anesthetic-sedative drug etomidate [90], the antimycotic drugs ketoconazole and fluconazole [91,92], metyrapone [93], and the antiparasitic drug suramin, which is also being tested for use in treating prostate cancer [94-96]. These drugs usually do not cause clinically important adrenal insufficiency in patients with normal hypothalamic-pituitary-adrenal function because enzyme inhibition is incomplete and increased adrenocorticotropic hormone (ACTH) secretion overrides the pharmacologic blockade. However, patients with limited pituitary or adrenal reserve may develop symptomatic adrenal insufficiency.
Other drugs accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes. They include phenytoin [97,98], barbiturates [97], and rifampin [97,99,100]. These drugs, therefore, can cause adrenal insufficiency in patients with limited pituitary or adrenal reserve and those with adrenal insufficiency who are receiving glucocorticoid therapy.
The adrenocorticolytic drug mitotane is used to treat adrenal tumors and to diminish cortisol synthesis in refractory Cushing's syndrome. It also accelerates the metabolism of halogenated synthetic steroids such as dexamethasone and fludrocortisone [101], and can provoke adrenal insufficiency in patients with adrenal carcinoma who are receiving steroids of this type. (See "Treatment of adrenocortical carcinoma", section on 'Adrenal insufficiency'.)
Drugs that primarily suppress the corticotropin-releasing hormone (CRH) or ACTH production, such as glucocorticoids, megestrol acetate or opioids, or drugs that potentiate glucocorticoid effects by decreasing its metabolism (eg, ritonavir), are discussed under causes of secondary or tertiary adrenal insufficiency. (See "Causes of secondary and tertiary adrenal insufficiency in adults".)
As noted above, heparin-induced thrombocytopenia is a risk factor for acute adrenal insufficiency due to bilateral adrenal hemorrhage. (See 'Hemorrhagic infarction' above.)
Ipilimumab, an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody used for advanced melanoma, has been associated with endocrinopathies, most commonly secondary adrenal insufficiency (16 out of 19), hypogonadism, and hypothyroidism [102,103]. However, primary adrenal insufficiency has also been rarely described. These are thought to represent autoimmune/autoinflammatory adverse events. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Endocrinopathies'.)
SEVERE INFLAMMATORY DISEASE — Seriously ill patients may have lower serum cortisol concentrations during severe inflammatory disease than when there is less inflammation. In one series of six patients with critical illness, the mean basal serum cortisol was 13 mcg/dL (359 nmol/L) during the inflammatory stage and 30 mcg/dL (828 nmol/L) after the inflammation had subsided [104]. The mechanism by which this occurs and whether supplemental glucocorticoid therapy is of benefit are not clear. One possibility is that albumin levels reduced total cortisol levels. In one study, 21 of 36 critically ill patients with low albumin concentration (2.5 g per deciliter or less) had basal cortisol levels less than 15 mcg per deciliter (413.8 nmol per liter) but normal free levels [105].
SUMMARY — Adrenal insufficiency is a rare disorder, occurring in up to 144 people per million population. Autoimmune adrenalitis is responsible for 70 to 90 percent, with the remainder being caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs.
Autoimmune adrenalitis involves destruction of the cortex by both humoral and cell-mediated immune mechanisms.
●Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum in up to 86 percent of patients.
●Up to 50 percent of patients with autoimmune adrenalitis have additional autoimmune disorders; however, adrenal insufficiency is rarely found in patients who present with other autoimmune diseases.
●Polyglandular autoimmune syndrome type 1 is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene, which may be important in the selection and generation of regulatory T cells. Hypoparathyroidism or chronic mucocutaneous candidiasis appears by the mid-twenties, followed by adrenal insufficiency and potentially by other autoimmune diseases.
●Polyglandular autoimmune syndrome type 2 is much more prevalent than type 1 syndrome. Primary adrenal insufficiency is its principal manifestation, but autoimmune thyroid disease and type 1 diabetes mellitus are also common. About half of the cases are familial, with polygenic modes of inheritance. It occurs later than type 1, usually presenting by age 40 years.
Infectious causes of adrenal insufficiency include tuberculosis, fungal infections, cytomegalovirus and Mycobacterium avium-intracellulare (usually in the context of human immunodeficiency virus [HIV] infection), syphilis, and African trypanosomiasis.
Bilateral adrenal hemorrhage can inhibit adrenal function. This usually occurs in specific settings:
●Disseminated infection (meningococcus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Haemophilus influenzae, and Staphylococcus aureus).
●Clotting abnormalities (anticoagulant drug or heparin therapy or coagulopathy, thromboembolic disease, hypercoagulable states such as antiphospholipid syndrome).
●Other associations include physical trauma, the postoperative state, sepsis, and severe stress.
Metastatic disease with replacement of the cortex of both adrenal glands can cause adrenal insufficiency. This is most commonly associated with lung, breast, stomach, or colon cancer, melanoma, and lymphoma.
Drugs are an important cause of primary adrenal insufficiency in patients with limited reserves who cannot overcome their effects.
●These include drugs that inhibit cortisol biosynthesis, such as etomidate, ketoconazole, fluconazole, metyrapone, mitotane, and suramin.
●Other drugs accelerate the metabolism of cortisol and most synthetic glucocorticoids by inducing hepatic mixed-function oxygenase enzymes (eg, phenytoin, barbiturates, mitotane, and rifampin).
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
