The Changing Clinical Spectrum of Adrenal Insufficiency

The clinical spectrum of primary adrenal insufficiency has changed substantially over the past decade as a result of the emergence of new disease patterns, improved understanding of clinical presentations, and the impact of molecular genetics. I comment here on five clinical entities that have emerged as new diagnostic or therapeutic challenges in the 1990s.

Adrenal insufficiency is increasingly recognized in patients with AIDS [1-3], and it correlates with stage of progression of HIV infection. More than 50% of patients with AIDS have pathologic evidence of necrotizing adrenalitis, but the degree of adrenal destruction is usually less than 50%. Clinical adrenal insufficiency occurs in less than 5% of patients with AIDS because its production requires that more than 90% of the adrenal cortex be destroyed. In adrenal insufficiency due to AIDS, a shift from mineralocorticoid and androgen production to glucocorticoid production occurs, possibly as a response to the stress of severe illness. However, hyponatremia in patients with AIDS is usually related to the syndrome of inappropriate vasopressin secretion and not to adrenal insufficiency [4].

The pathogenesis of adrenal insufficiency in AIDS can be related to three independent factors [1, 2]. First, cytomegalovirus infection accounts for more than 50% of cases of adrenal insufficiency in AIDS. Other pathogens that can cause this condition include Mycobacterium avium-intracellulare, M. tuberculosis, fungi, Toxoplasma species, and Pneumocystis species. Second, medications can alter steroid secretion or cause changes that mimic adrenal insufficiency. For example, the antifungal agent ketoconazole decreases adrenal steroidogenesis; rifampin, phenytoin, and opiates increase steroid catabolism; and trimethoprim decreases renal tubular potassium excretion and increases serum potassium concentrations. Third, cytokines (including interleukin-1, tumor necrosis factor, and interferon) released by macrophages in patients with AIDS may contribute by inhibiting the hypothalamic-pituitary-adrenal axis.

Universal screening for adrenal insufficiency in patients with AIDS is not recommended because of relatively low yield, but clinicians should bring a high index of suspicion to patients with AIDS who have typical electrolyte abnormalities or unexplained hypotension.

Adrenal hemorrhage or infarction is increasingly identified as a cause of adrenal insufficiency [5-8]. Typically, the patient is already gravely ill from an underlying condition. Severe stress is usually present in the form of thromboembolic disease, coagulopathy, traumatic shock, severe burn, or sepsis or as a result of recent surgery. Adrenal insufficiency presents in a vague, indolent manner with abdominal, flank, or back pain; decreased hematocrit; or electrolyte abnormalities confused by fluid management.

The pathophysiology of adrenal insufficiency is thought to be related to a stress-induced increase in adrenocorticotropic hormone (ACTH) levels, which increases adrenal blood flow to a degree that exceeds the capacity for venous drainage. Thrombosis may initiate hemorrhage. In the antiphospholipid antibody syndrome, a lupus anticoagulant is responsible for thrombosis and thrombocytopenia or hemorrhage.

Severely ill patients who have sudden unexplained deterioration should be screened for adrenal insufficiency.

Autoimmune polyendocrine syndrome type I (APS-1) is a rare, autosomal recessive, non-HLA-associated disorder that develops in childhood. Diagnosis requires the presence of two of the following: adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis. Associated disorders include gonadal insufficiency, type 1 diabetes mellitus, chronic active hepatitis, alopecia, vitiligo, malabsorption syndromes, and juvenile-onset pernicious anemia. The pathophysiology of this condition was recently discovered: Cytochrome P450 cholesterolside chain cleavage enzyme (P450-SSC), which converts cholesterol to pregnenolone, serves as a major autoantigen [9-12]. It is expressed in both the adrenal glands and gonads but not in other tissues involved in APS-I [11]. Because the serum of patients with APS-I does not react to other steroidogenic enzymes, including 21-hydroxylase, P-450-SSC is probably the antigen of a specific primary immune process.

Autoimmune polyendocrine syndrome type II (APS-II) consists of autoimmune adrenal insufficiency, thyroiditis, and type 1 diabetes mellitus with onset in adulthood. It is associated with HLA-B8 (DW3) and HLA-DR3. The major antigen recognized by autoantibodies is 21-hydroxylase (P450c21) [13], which is expressed only in the adrenal cortex, and data to date do not explain autoantibodies to other endocrine tissues. Of note, patients with APS-II have no blockade of steroidogenesis at P450c21.

Screening for autoimmune adrenal insufficiency requires knowledge of the risk for adrenal failure in asymptomatic patients with adrenal autoantibodies [14]. The appearance of persistent high titers of adrenal autoantibodies (>1:16) signals high risk for adrenal failure (6% to 19% per year) and calls for functional monitoring. Adrenal autoantibodies may disappear, but the permanence of this change requires further study. Corticosteroid therapy has been associated with the disappearance of adrenal autoantibodies in a few patients, but no controlled studies have been done [15]. Subtle adrenal impairment may precede the onset of clinical manifestations, as evidenced by increased plasma ACTH levels or renin activity in the presence of normal baseline steroid levels.

Adrenoleukodystrophy is an X-linked peroxisomal disorder characterized by progressive demyelination of the central nervous system and adrenal insufficiency [16-20]. Different clinical phenotypes-cerebral adrenoleukodystrophy and adrenomyeloneuropathy-have been described within the same kindred.

Cerebral adrenoleukodystrophy is characterized by the onset of neurologic symptoms and adrenal insufficiency by age 5 to 12 years. Central demyelination results in seizures, cortical blindness, dementia, coma, and death, usually before puberty. In contrast, the clinical onset of adrenomyeloneuropathy occurs by age 15 to 30 years. Spinal cord and peripheral neuronal involvement in adrenomyeloneuropathy slowly progresses over 5 to 15 years. Patients with adrenomyeloneuropathy develop mixed motor and sensory peripheral neuropathy, bladder dysfunction, adrenal insufficiency, hypogonadism, and color blindness. Ultimately, one third of patients with adrenomyeloneuropathy develop central demyelination.

The basic defect in both types of adrenoleukodystrophy is a deficiency of very-long-chain fatty acid acyl CoA, a peroxisomal enzyme that catabolizes very-long-chain fatty acids to ketones. In the absence of this enzyme, very-long-chain fatty acids are not catabolized and accumulate in circulating cholesterol esters. The adrenal insufficiency of adrenoleukodystrophy develops gradually. Adrenal cell death may be related to the accumulation of very-long-chain fatty acids and esterified cholesterol. It may also be associated with the limitation of substrate availability because of slow hydrolysis of cholesterol esters or an increase in cell membrane microviscosity induced by very-long-chain fatty acids and leading to decreased steroid secretion.

Adrenoleukodystrophy is diagnosed by measuring increased circulating concentrations of very-long-chain fatty acids, especially hexacosanoic acid (C 26:0). Magnetic resonance imaging of the brain shows a typical pattern of demyelination. Because adrenal insufficiency may precede neurologic symptoms, adrenomyeloneuropathy should be considered in any young man who presents with adrenal insufficiency. Patients may have compensated adrenal hypofunction that is not identified by ACTH-stimulated cortisol levels but is detectable by increased plasma ACTH levels.

Adrenoleukodystrophy can be managed by restricting dietary intake of saturated fats. Monounsaturated fatty acid oils can also be helpful because they compete with fatty acid precursors in the microsomal elongation pathway and thus reduce the quantity of very-long-chain fatty acids that present to the peroxisome for catabolism. Glycerol trioleate and trierucate are effective. Family members at risk should receive genetic counseling.

Familial glucocorticoid deficiency is a rare autosomal recessive disorder of adrenal unresponsiveness to ACTH [21, 22]. Patients who have it present in early childhood with hyperpigmentation; hypoglycemia; failure to thrive; and frequent, severe infections. Associated findings include tall stature and advanced bone age. In some patients, resistance to ACTH seems to be related to a mutation in the ACTH receptor.

The spectrum of adrenal insufficiency continues to evolve. Physicians should be alert to changes in the clinical presentation of this condition and to situations in which diagnostic screening is warranted. As the power of our tools for investigating pathophysiology continues to increase, we can expect the spectrum to change further. Even in the small world of the adrenal, we indeed live in interesting times.

• Copyright ©2004 by the American College of Physicians