Hypothalamic-pituitary axis in adrenal insufficiency of different causes. These panels illustrate hormone secretion in the normal state (upper left), primary adrenal insufficiency (upper right), secondary adrenal insufficiency—ACTH deficiency (lower left), and tertiary adrenal insufficiency—CRH deficiency (lower right). Renin-angiotensin system is also illustrated. In contrast to normal secretion and hormone levels, decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line.
The etiology of primary adrenocortical insufficiency has changed over time. Prior to 1920, tuberculosis was the major cause of adrenocortical insufficiency. Since 1950, autoimmune adrenalitis with adrenal atrophy has accounted for about 80% of cases. It is associated with a high incidence of other immunologic and autoimmune endocrine disorders (see later). Causes of primary adrenal insufficiency are listed in Table 9–3. Primary adrenocortical insufficiency, or Addison disease, is rare, with a reported prevalence of 35 to 140 per million population. When part of the polyglandular system, it is more common in females, with a female-male ratio of approximately 2:1. Addison disease is usually diagnosed in the third to fifth decades.
Table 9–3 Causes of Primary Adrenocortical Insufficiency. ||Download (.pdf)
Table 9–3 Causes of Primary Adrenocortical Insufficiency.
Metastatic malignancy or lymphoma
Tuberculosis, CMV, fungi (histoplasmosis, coccidioidomycosis), HIV
Congenital adrenal hyperplasia
Familial glucocorticoid deficiency and hypoplasia
Ketoconazole, metyrapone, aminoglutethimide, trilostane, mitotane, etomidate
Autoimmune Adrenocortical Insufficiency
Pathologically, the adrenals are small and atrophic, and the capsule is thickened. The adrenal medulla is preserved, although cortical cells are largely absent, show degenerative changes, and are surrounded by a fibrous stroma and the characteristic lymphocytic infiltrates.
Autoimmune Addison disease is frequently accompanied by other immune disorders. There are two different syndromes in which autoimmune adrenal insufficiency may occur. The best characterized one is known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APCED), or autoimmune polyglandular syndrome type 1 (APS-1). This is an autosomal recessive disorder that usually presents in childhood and is accompanied by hypoparathyroidism, adrenal failure, and mucocutaneous candidiasis. APS-1 results in most cases from a mutation of the autoimmune regulator gene (AIRE), which is located on chromosome 21q22.3. These patients have a defect in T-cell–mediated immunity, especially toward the candidal antigens. APS-1 has no relationship to human leukocyte antigen (HLA) and is often associated with hepatitis, dystrophy of dental enamel and nails, alopecia, vitiligo, and keratopathy and may be accompanied by hypofunction of the gonads, thyroid, pancreatic B cell, and gastric parietal cells. Autoantibodies against the cholesterol side chain cleavage enzyme (P450scc, CYP11A1) and others have been described in patients with this disorder.
The more common presentation of autoimmune adrenocortical insufficiency is associated with HLA-related disorders including type 1 diabetes mellitus and autoimmune thyroid disease. Other less common related disorders include alopecia areata, vitiligo, primary hypogonadism, pernicious anemia, and celiac disease. This disorder is often referred to as APS type 2. The genetic susceptibility to this disorder is linked to HLA-DR3 or DR4 (or both). These patients have antiadrenal cytoplasmic antibodies that may be important in the pathogenesis of this disorder, and autoantibodies directed against 21α-hydroxylase (P450c21, CYP21A2) have been identified (see Chapter 2).
Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency. The diagnosis is usually made in critically ill patients in whom a computed tomography (CT) scan of the abdomen is performed. Bilateral adrenal enlargement is found, leading to an assessment of adrenocortical function. Anatomic factors predispose the adrenal glands to hemorrhage. The adrenal glands have a rich arterial blood supply, but they are drained by a single vein. Adrenal vein thrombosis may occur during periods of stasis or turbulence, thereby increasing adrenal vein pressure and resulting in a vascular dam. This causes hemorrhage into the gland and is followed by adrenocortical insufficiency.
Most patients with adrenal hemorrhage have been taking anticoagulant therapy for an underlying coagulopathy or are predisposed to thrombosis. Heparin-induced thrombocytopenia syndrome may be accompanied by adrenal vein thrombosis and hemorrhage. The primary antiphospholipid antibody syndrome (lupus anticoagulant) has emerged as one of the more common causes of adrenal hemorrhage.
Although tuberculosis is a common cause of primary adrenal insufficiency in the rest of the world, it is a rare cause of this problem in the United States. Clinically significant adrenal insufficiency appears to occur in only about 5% of patients with disseminated tuberculosis. With the use of antituberculous chemotherapy, it may even be reversible if detected in early stages. It is important to recognize that rifampin may accelerate the metabolic clearance of cortisol, thereby increasing the replacement dose needed in these patients. Most if not all systemic fungal infections can involve and destroy the adrenal cortex. Tuberculosis and fungal infections are associated with enlarged adrenals that may show calcifications. Of note, the azole antifungal agents, such as ketoconazole, inhibit adrenal cytochrome P450 steroidogenic enzymes that are essential for cortisol biosynthesis. Thus, azole antifungal treatment, especially with ketoconazole, in patients with marginal adrenocortical reserve due to fungal disease may precipitate adrenal crisis.
HIV/AIDS has been associated with pathologic involvement of the adrenal gland. Although adrenal necrosis is commonly seen in postmortem examination of patients with AIDS, primary adrenal insufficiency appears to complicate only a few patients with this disorder. Primary adrenal insufficiency in AIDS is usually caused by opportunistic infections such as fungal infection, cytomegalovirus, and mycobacterium avium complex. Adrenocortical insufficiency usually occurs as a late manifestation in AIDS patients with very low CD4 counts (see Chapter 25).
X-linked adrenoleukodystrophy is an important cause of adrenal insufficiency in men. This disorder represents two distinct entities that may cause malfunction of the adrenal cortex and demyelination in the central nervous system. These disorders are characterized by abnormally high levels of very long chain fatty acids (VLCFAs) due to their defective beta oxidation within peroxisomes. The abnormal accumulation of VLCFAs in the brain, adrenal cortex, testes, and liver result in the clinical manifestations of this disorder.
Adrenoleukodystrophy has an incidence of approximately one in 25,000 and is an X-linked disorder (chromosome Xq28) with incomplete penetrance. Molecular analysis is available clinically and can be used both in family screening and in prenatal evaluation. Two clinical phenotypes have been described. Cerebral adrenoleukodystrophy usually presents in childhood, and its neurologic symptoms include cognitive dysfunction, behavioral problems, emotional lability, and visual and gait disturbances. It may progress to dementia. Because 30% of these patients develop adrenal insufficiency before the onset of neurologic symptoms, a young man with primary adrenal insufficiency should always be screened for adrenoleukodystrophy. A clinically milder phenotype, adrenomyeloneuropathy, usually presents in the second to fourth decades of life. Spinal cord and peripheral nerve demyelination occur over years and may result in loss of ambulation, cognitive dysfunction, urinary retention, and impotence. Once again, adrenal insufficiency may occur before the onset of neurologic symptoms.
The diagnosis of adrenoleukodystrophy can be confirmed by demonstration of the defect in fatty acid metabolism with the abnormal accumulation of saturated VLCFAs, especially C26:0 fatty acid.
Metastatic Adrenal Disease
The adrenal glands are common sites of metastasis for lung, gastrointestinal, breast, and renal neoplasia. Bilateral adrenal involvement is present in approximately 50% of patients; however, adrenal insufficiency does not occur with unilateral metastatic disease. Even with bilateral involvement adrenal insufficiency appears to be uncommon. Despite being uncommon, patients with bilateral disease should be evaluated for adrenal insufficiency and then followed as adrenal insufficiency is a potentially life threating condition. In addition, non-Hodgkin and Hodgkin lymphoma may present with involvement of the adrenal glands with bilateral adrenal enlargement and primary adrenal insufficiency.
Familial Glucocorticoid Deficiency and Congenital Adrenal Hypoplasia
Familial glucocorticoid deficiency is a rare disorder in which there is hereditary adrenocortical unresponsiveness to ACTH. This leads to adrenal insufficiency with subnormal glucocorticoid and adrenal androgen secretion as well as elevated plasma ACTH levels. As a rule, aldosterone secretion is preserved. At least two distinct types of this disorder have been described. One type is associated with mutations in the ACTH receptor on the cells of the adrenal cortex. Another type is often associated with achalasia and alacrima (Allgrove syndrome; triple A syndrome) and progressive neurologic impairment, but no mutations in the ACTH receptor have been seen in these patients. The responsible gene is on chromosome 12 (12q13) and encodes a protein belonging to the WD repeat proteins. Its function remains unknown. Congenital adrenal hypoplasia is a developmental abnormality usually presenting in the neonatal period. X-linked forms associated with mutations of DAX1 and autosomal recessive forms have been reported.
Primary cortisol resistance is an unusual disorder representing target cell resistance to cortisol due to either qualitative or quantitative abnormalities of the glucocorticoid receptor. This disorder is characterized by hypercortisolism without clinical manifestations of glucocorticoid excess. Pituitary resistance to cortisol results in hypersecretion of ACTH, which stimulates the adrenal gland to produce excessive amounts of cortisol, mineralocorticoids, and adrenal androgens. The increased production of cortisol and these nonglucocorticoid adrenal steroids may cause hypertension, hypokalemia, virilization, and sexual precocity. Because cortisol is essential for life, this disorder actually represents partial rather than complete resistance.
Drug-Induced Adrenal Insufficiency
Drugs associated with primary adrenal insufficiency include the azole antifungal agents, the anesthetic agent etomidate, the antiparasitic agent suramin as well as the steroid synthesis inhibitors aminoglutethimide, metyrapone, and mitotane. Mifepristone is a progesterone antagonist that also antagonizes the glucocorticoid receptor and may cause adrenal insufficiency if given in a sufficient dose. Megestrol acetate, a synthetic progesterone derivative used to stimulate appetite, binds to the glucocorticoid receptor and suppresses the HPA axis leading to adrenal insufficiency after withdrawal of therapy. Opioid narcotics cause a transient suppression of the HPA axis and can lead to suppression of plasma cortisol levels. Additionally, the use of protease inhibitors with exogenous glucocorticoids (from oral, injectable, inhaled, or even optic routes) can cause secondary adrenal insufficiency after cessation of glucocorticoid use.
Cortisol in Critical Illness
In 2002 it was reported that 77% of 299 patients with severe sepsis had plasma cortisol increments of less than 9 μ g/dL to standard ACTH-stimulation testing. These patients were classified as having relative adrenal insufficiency (also termed partial adrenal insufficiency or decreased adrenal reserve) and randomized to therapy with hydrocortisone and fludrocortisones with a modest survival benefit. The study led to a widespread recommendation that all severely ill patients with sepsis be tested with ACTH and treated with corticosteroids. However, the study was compromised by two major issues. First, 30% of the patients classified as relatively adrenal insufficient had received etomidate (a drug which causes adrenal insufficiency) within 12 hours of enrollment. Second, the authors did not recognize that total plasma cortisol levels and their response to ACTH are lowered in severely ill patients who frequently have hypoalbuminemia and low corticosteroid-binding globulin levels. Subsequent studies have shown that both plasma free cortisol and salivary cortisol are appropriately elevated and respond normally to ACTH in patients with sepsis. In addition, several studies have shown no survival benefit following corticosteroid therapy. Thus, there is no convincing evidence that adrenal insufficiency is frequent in critically ill patients.
Loss of more than 90% of both adrenal cortices results in the clinical manifestations of adrenocortical insufficiency. Gradual destruction, such as occurs in the idiopathic and invasive forms of the disease, leads to chronic adrenocortical insufficiency. However, more rapid destruction occurs in many cases; about 25% of patients are in crisis or impending crisis at the time of diagnosis. With gradual adrenocortical destruction, the initial phase is that of decreased adrenal reserve; that is, basal steroid secretion is normal, but secretion does not increase in response to stress. Thus, acute adrenal crisis can be precipitated by the stresses of surgery, trauma, or infection, which require increased corticosteroid secretion. With further loss of cortical tissue, even basal secretion of glucocorticoids becomes deficient, leading to the manifestations of chronic adrenocortical insufficiency. Mineralocorticoid deficiency may occur early or late in the course. Destruction of the adrenals by hemorrhage results in sudden loss of both glucocorticoid and mineralocorticoid secretion, accompanied by acute adrenal crisis.
With decreasing cortisol secretion, plasma levels of ACTH are increased because of decreased negative feedback inhibition of their secretion. In fact, an elevation of plasma ACTH may be the earliest and most sensitive indication of suboptimal adrenocortical reserve.
Cortisol deficiency causes weakness, fatigue, anorexia, nausea and vomiting, hypotension, hyponatremia, and hypoglycemia. Mineralocorticoid deficiency produces renal sodium wasting and potassium retention and can lead to severe dehydration, hypotension, hyponatremia, hyperkalemia, and acidosis.
Chronic primary adrenocortical insufficiency—The chief symptoms (Table 9–4) are hyperpigmentation, weakness and fatigue, weight loss, anorexia, and gastrointestinal disturbances.
Hyperpigmentation is the classic physical finding, and its presence in association with the above manifestations should suggest primary adrenocortical insufficiency. Generalized hyperpigmentation of the skin and mucous membranes is one of the earliest manifestations of Addison disease. It is increased in sun-exposed areas and accentuated over pressure areas such as the knuckles, toes, elbows, and knees. It is accompanied by increased numbers of black or dark-brown freckles. The classic hyperpigmentation of the buccal mucosa and gums is preceded by generalized hyperpigmentation of the skin; adrenal insufficiency should also be suspected when there is increased pigmentation of the palmar creases, nail beds, nipples, areolae, and perivaginal and perianal mucosa. Scars that have formed after the onset of ACTH excess become hyperpigmented, whereas older ones do not.
General weakness, fatigue and malaise, anorexia, and weight loss are invariable features of the disorder. Weight loss may reach 15 kg with progressive adrenal failure. Gastrointestinal disturbances, especially nausea and vomiting, occur in most patients; diarrhea is less frequent. An increase in gastrointestinal symptoms during an acute adrenal crisis may confuse the diagnosis by suggesting a primary intra-abdominal process.
Hypotension is present in about 90% of patients and is accompanied by orthostatic symptoms and occasionally syncope. In more severe chronic cases and in acute crises, recumbent hypotension or shock is almost invariably present. Vitiligo occurs in 4% to 17% of patients with autoimmune Addison disease but is rare in Addison disease due to other causes. Salt craving occurs in about 20% of patients.
Severe hypoglycemia may occur in children. This finding is unusual in adults but may be provoked by fasting, fever, infection, or nausea and vomiting, especially in acute adrenal crisis. Hypoglycemia occurs more commonly in secondary adrenal insufficiency.
Amenorrhea is common in Addison disease. It may be due to weight loss and chronic illness or to primary ovarian failure. Loss of axillary and pubic hair may occur in women as a result of decreased secretion of adrenal androgens.
Partial adrenal insufficiency may have subtle clinical manifestations. Adrenal insufficiency should be considered in the differential diagnosis of unexplained weight loss and in patients with hypotension and fever.
Acute adrenal crisis—Acute adrenal crisis represents a state of acute adrenocortical insufficiency and occurs in patients with Addison disease who are exposed to the stress of infection, trauma, surgery, or dehydration due to salt deprivation, vomiting, or diarrhea.
The symptoms are listed in Table 9–5. Anorexia and nausea and vomiting increase and worsen the volume depletion and dehydration. Hypovolemic shock frequently occurs, and adrenal insufficiency should be considered in any patient with unexplained vascular collapse. Abdominal pain may occur and mimic an acute abdominal emergency. Weakness, apathy, and confusion are common. Fever is also common and may be due to infection or to hypoadrenalism per se. Hyperpigmentation is present unless the onset of adrenal insufficiency is rapid and should suggest the diagnosis.
Additional findings that suggest the diagnosis are hyponatremia, hyperkalemia, lymphocytosis, eosinophilia, and hypoglycemia.
Shock and coma may rapidly lead to death in untreated patients (see Chapter 24).
Acute adrenal hemorrhage (Table 9–6)—Bilateral adrenal hemorrhage and acute adrenal destruction in an already compromised patient with major medical illness follow a progressively deteriorating course. The usual manifestations are abdominal, flank, or back pain and abdominal tenderness. Abdominal distention, rigidity, and rebound tenderness are less frequent. Hypotension, shock, fever, nausea and vomiting, confusion, and disorientation are common; tachycardia and cyanosis are less frequent.
With progression, severe hypotension, volume depletion, dehydration, hyperpyrexia, cyanosis, coma, and death ensue.
The diagnosis of acute adrenal hemorrhage should be considered in the deteriorating patient with unexplained abdominal or flank pain, vascular collapse, hyperpyrexia, or hypoglycemia, particularly in the setting of an underlying coagulopathy.
Table 9–4 Clinical Features of Primary Adrenocortical Insufficiency. ||Download (.pdf)
Table 9–4 Clinical Features of Primary Adrenocortical Insufficiency.
|Weakness, fatigue, anorexia, weight loss||100|
Table 9–5 Clinical Features of Acute Adrenal Crisis. ||Download (.pdf)
Table 9–5 Clinical Features of Acute Adrenal Crisis.
|Hypotension and shock|
|Dehydration, volume depletion|
|Nausea, vomiting, anorexia|
|Weakness, apathy, depressed mentation|
Table 9–6 Clinical Features of Adrenal Hemorrhage. ||Download (.pdf)
Table 9–6 Clinical Features of Adrenal Hemorrhage.
|Hypotension and shock||74|
|Nausea and vomiting||46|
|Cyanosis or lividity||28|
|Abdominal, flank, or back pain||77|
|Abdominal or flank tenderness||38|
Laboratory and Electrocardiographic Findings and Imaging Studies
Gradual adrenal destruction—Hyponatremia and hyperkalemia are classic manifestations of the glucocorticoid and mineralocorticoid deficiency of primary adrenal insufficiency and should suggest the diagnosis. Hematologic manifestations include normocytic, normochromic anemia, neutropenia, eosinophilia, and a relative lymphocytosis. Azotemia with increased concentrations of blood urea nitrogen and serum creatinine is due to volume depletion and dehydration. Mild acidosis is frequently present. Hypercalcemia of mild to moderate degree occurs in about 6% of patients.
Abdominal radiographs reveal adrenal calcification in half the patients with tuberculous Addison disease and in some patients with other invasive or hemorrhagic causes of adrenal insufficiency. CT is a more sensitive detector of adrenal calcification and adrenal enlargement. Bilateral adrenal enlargement in association with adrenal insufficiency may be seen with tuberculosis, fungal infections, cytomegalovirus, malignant and nonmalignant infiltrative diseases, and adrenal hemorrhage.
Electrocardiographic features are low voltage, a vertical QRS axis, and nonspecific ST-T wave abnormalities secondary to abnormal electrolytes.
Acute adrenal hemorrhage—Hyponatremia and hyperkalemia occur in only a small number of cases, but azotemia is a usual finding. Increased circulating eosinophils may suggest the diagnosis. The diagnosis is frequently established only when imaging studies reveal bilateral adrenal enlargement.