Infectious causes of adrenal insufficiency

More than 150 years ago, Thomas Addison first described the clinical features and pathogenesis of adrenal insufficiency. At that time, tuberculosis was the most common cause of this disease. The pathway to diagnosis and treatment of Addison's disease has been well described. However, determining the cause of the disorder remains a challenge. It is important to consider recently described infectious agents in the pathogenesis of Addison's disease. Mycobacterial, bacterial, viral, and fungal infections may lead to the development of adrenal insufficiency. Skin, pulmonary, and imaging findings can aid the clinician in making a prompt diagnosis of specific infections, which is crucial because early identification of infectious causes of Addison's disease may enable recovery of adrenal function. This review describes the clinical presentations of the multiple infectious causes of adrenal insufficiency.     

Rare occurrence of Addison's disease and diabetes mellitus in children.

We report on two children with both Addison's disease and diabetes mellitus, a rare occurrence in children. One of the children first developed Addison's disease and later developed diabetes mellitus, while the other had the onset of diabetes mellitus first and later Addison's disease. In the latter patient a direct relationship was shown between the insulin dose and adrenal cortical hormone. Organ-specific antibody studies are reported and the diagnosis and management of these combined endocrinopathies are discussed.     

Addison's disease

Addison's disease is an uncommon endocrine condition manifested by a variety of nonspecific symptoms, such as malaise, anorexia and nausea. Symptoms usually do not occur until most of the adrenal gland has been destroyed. Autoimmune disease has surpassed tuberculosis as the primary cause of Addison's disease. Nevertheless, tuberculosis still accounts for a significant proportion of cases. The rapid adrenocorticotropic hormone (ACTH) stimulation test is useful for identifying adrenal insufficiency. Maintenance therapy consists of hydrocortisone and fludrocortisone.     

Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.

Autoimmune polyendocrine syndrome type I (APS I) and idiopathic Addison's disease are both disorders with adrenal insufficiency but with differences in genetic background, clinical presentation, and extent of extraadrenal manifestations. In this study the major adrenal autoantigen identified with sera from patients with APS I was characterized by analyses using indirect immunofluorescence, Western blots of adrenal subcellular fractions and of recombinant proteins, immunoprecipitations of [35S]methionine-labeled lysates of a human steroid-producing cell line, and studies of enzymatic activity. Sera from patients with APS I, identifying cells in adrenal glands and testes involved in steroid synthesis, reacted in Western blots with a 53-kD antigen, which comigrated with the cytochrome P450 cholesterol side chain cleavage enzyme (SCC). The sera also immunoprecipitated this protein from lysates of radiolabeled adrenal cells. The enzymatic activity of SCC was inhibited by the APS I sera but not by control sera. Sera from patients with idiopathic Addison's disease did not react with the SCC. The results show that the autoimmune responses towards adrenal tissue in patients suffering from APS I and Addison's disease are remarkably selective and suggest that a determination of the antigen involved in a patient with autoimmune adrenal insufficiency will have diagnostic as well as prognostic implications.     

Endocrine disorders: causes of hyponatremia not to neglect

Hyponatremia is a common electrolyte abnormality with the potential for significant morbidity and mortality. Endocrine disorders, including adrenal deficiency and hypothyroidism, are uncommon causes of hyponatremia. Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. Addison's disease is an important diagnosis not to be missed since the consequences can be grave. On the other hand, hypothyroidism and secondary adrenocortical insufficiency originating from diseases of the hypothalamus and/or pituitary (hypopituitarism) require a high index of suspicion, because the clinical signs can be quite subtle. This review focuses on clinical and pathophysiological aspects of hyponatremia due to endocrine disorders.     

Addison's disease with enlarged adrenal glands in sonography and computer tomography. Differential diagnostic considerations based on 2 cases of tuberculous adrenalitis

One of the major causes of chronic adrenal insufficiency (Addison's disease) is tuberculous adrenalopathy. Since sonography and computed tomography have become generally available in recent years and are of potential help in the diagnosis of this disease the merits of these methods are discussed in the light of 2 cases of adrenal tuberculosis, followed by a review of the literature. Adrenal calcification is the most significant, although not specific sign of adrenal insufficiency due to tuberculosis. Computed tomography has proven to be the method of choice in the non-invasive diagnosis of tuberculous adrenalopathy and in the monitoring of tuberculostatic treatment in this disease. Sonography is helpful as a preliminary investigation.     

Epiglottic tuberculosis in a patient treated with steroids for Addison's disease

Isolated epiglottic tuberculosis (TBC) is uncommon and has rarely been described. We report the case of a 40-year-old man with tuberculous involvement of the epiglottis and primary adrenal insufficiency. Endoscopic examination showed a severely swollen epiglottis with granulomatous and partially necrotic mucosa. The patient has been treated with glucocorticoids for four years due to primary adrenocortical insufficiency. We therefore assume that tuferculous involvement of epiglottis is due to the reactivation of pulmonary TBC. We also discuss differential diagnosis and management of epiglottic TBC and Addison's disease.     

Reversible cardiomyopathy in a child with Addison's disease

An 11-year-old boy in acute adrenal crisis was subsequently diagnosed with Addison's disease and presumably had an unrecognized preceding chronic adrenal insufficiency. His adrenal insufficiency and hypovolemic shock were promptly diagnosed and treated in the emergency room. However, 24 h later, signs of congestive heart failure developed and an echocardiogram revealed cardiomyopathy. He responded to i.v. dopamine and his cardiomyopathy resolved over some days. Acute adrenal insufficiency and actual ventricular dysfunction had not been described in humans until last year; this is the second reported case of cardiomyopathy in a patient with acute adrenal insufficiency.     

Addisonian crisis due to adrenal gland metastasis in Hodgkin's disease

Adrenal insufficiency or Addison's disease is a rare illness associated with multiple pathology. We describe the case of a 61-year-old male with Hodgkin's disease and metastases in both adrenal glands who was diagnosed with adrenal insufficiency as a result of an acute addisonian crisis.     

Technical notes and clinical use of radioimmunologic determination of plasma ACTH]

Particular aspects of plasma ACTH radioimmunoassay are examinated. The results obtained with this method in adrenocortical diseases (Addison's disease, Cushing's syndrome, congenital adrenal hyperplasia) are reported and clinical value in etiological diagnosis of Cushing's syndrome is outlined. Moreover the results obtained in other syndromes of endocrinologic interest (massive obesity, Turner's and Klinefelter's syndromes, Laurence-Moon-Biedl syndrome, true precocious puberty, primary hypothyroidism, hypopituitary dwarphism) are reported and discussed.     

Bilateral adrenal hemorrhage after anticoagulation prophylaxis for bilateral knee arthroplasty

After joint arthroplasty, the risk of deep vein thrombosis and pulmonary embolism increases exponentially. Inadequate anticoagulation prophylaxis may not sufficiently reduce the risk of thrombosis, whereas excessive anticoagulation therapy may predispose the patient to a bleed. Bilateral adrenal hemorrhage is a relatively rare but potentially catastrophic life-threatening event. An 82-yr-old woman is described who was rehospitalized from a subacute rehabilitation facility complaining of epigastric pain radiating into her flank. Eight days previously, she had undergone an uncomplicated bilateral total knee arthroplasty and was subsequently administered subcutaneous heparin and warfarin. An abdominal computed tomographic scan subsequently demonstrated bilateral small adrenal hemorrhages. Acute adrenal insufficiency (Addison's disease) caused by hemorrhage within the adrenal cortices, although still uncommon, can be expected to increase as anticoagulation prophylaxis after joint arthroplasty becomes routine.     

TNF mediates a murine model of Addison's crisis

Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.     

Epigastric pain as presentation of an addisonian crisis in a patient with Schmidt syndrome

A 39-year-old woman presented with a 10-day history of epigastric pain accompanied by persistent fatigue and loss of appetite for 3 months. She had presented several weeks earlier with adhesive capsulitis, treated by local infiltration of corticosteroids. She was not taking any other medications. Results of heart, lung, and abdominal examinations were unremarkable, except for mild epigastric tenderness. Purple stretch marks were observed on examination of the skin. The only blood chemistry abnormalities were hyponatremia (125 mEq/L) and hyperkalemia (6.8 mEq/L). Based on the clinical and biologic picture, adrenal insufficiency was suspected. The patient was transferred to the intensive care unit and received hydrocortisone intravenously for 3 days. She was then given oral hydrocortisone and fludrocortisone. Biologic abnormalities reversed entirely; the final diagnosis was primary autoimmune adrenal insufficiency (Addison's disease) associated with autoimmune hypothyroidism (Schmidt syndrome). Adrenal insufficiency should be considered in patients with abdominal pain, especially when associated with electrolyte abnormalities.     

Synthetic mineralocorticoid

Fludrocortisone acetate (Florinef) is a synthetic steroid with a potent mineralocorticoid action, and used for treatment of Addison's disease and salt losing form of congenital adrenal hyperplasia. It is also used for severe hypotension to restore adequate plasma volume. Caution is necessary for possible side effects of hypernatremia, hypokalemia, hyperglycemia and congestive heart failure when used chronically. A synthetic steroid which selectively binds and activates renal MR-LBD but not GR, or non-epithelial MR, although not found at present, may be a promising mineralocorticoids to be used in the above disorders.     

Diseases of the adrenal cortex

The adrenal cortex is functionally a three-dimensional gland that secretes glucocorticoids, mineralocorticoids, and sex steroids. Of these three classes of steroids only the gluco- and mineralocorticoid hormones are necessary to sustain life. The availability of sensitive and specific radioimmunoassays has permitted accurate measurement of practically every steroid hormone secreted by the adrenal cortex. As in other endocrinopathies, suppression studies are employed when hyperfunction is suspected, while provocative tests are used to detect hypofunction. These dynamic studies enable the clinician to evaluate the functional status of the adrenal cortex. The anatomic configuration of the adrenal cortices is delineated by high-resolution computed tomography (and magnetic resonance imaging), obviating the need for invasive procedures such as venography or arteriography. The disorders of the adrenal cortex can be viewed from the dual perspectives of hyperfunction and hypofunction. Clinical expressions of hyperfunctional adrenocortical syndromes include Cushing's syndrome, primary hyperaldosteronism, and the adrenogenital syndrome. The expressions of hypofunctional syndromes include Addison's disease and selective hypoaldosteronism. The diagnosis and treatment of these disorders are outlined in this issue.     

RENIN, ANGIOTENSIN, CORTICOSTEROIDS, AND ELECTROLYTE BALANCE IN ADDISON'S DISEASE

Two patients with previously untreated Addison's disease werestudied. Both showed defective adrenal responsiveness to infusionsof corticotrophin and angiotensin, and both had abnormally lowplasma sodium and high plasma renin concentrations. Plasma potassiumwas elevated in one and normal in the other. Steroid replacement therapy was accompanied by an increase inNa_E, correction of plasma electrolyte concentrations, and areduction of plasma renin concentration to normal. K_E was virtuallyunchanged in the first weeks of treatment in either patient. In Case 1 treatment caused a movement of water and sodium fromICF to ECF, and probably of potassium from ECF to ICF. ECF volumeincreased more than TBW. Angiotensin infusion caused abdominal pain in this man, suggestingthat the elevated plasma renin may contribute to the characteristicabdominal pain of Addison's disease. In Case 2 treatment restored the normal nyothemeral rhythm ofurine flow, and caused a slight initial loss of TBW and weight.     

Studies on Auditory Thresholds in Normal Man and in Patients with Adrenal Cortical Insufficiency: The Role of Adrenal Cortical Steroids

Auditory thresholds for sinusoidal tones were determined in eight patients with adrenal cortical insufficiency (four with Addison's disease and four with panhypopituitarism) and compared to those in normal volunteers. In adrenal cortical insufficiency (ACI) the auditory detection sensitivity is significantly more acute than that of normal subjects over most of the frequency range, but especially in the region of greatest hearing sensitivity of normal subjects, 1,000 to 2,000 cycles per second (cps).     

Thyrotoxicosis in a patient with Addison's disease

We report the case of a patient who suffered recurrent episodes of hypoadrenal crisis, despite conventional replacement therapy for Addison's disease. She was found to have hyperthyroidism and after this was treated, she had no further relapse. Thyrotoxicosis should be considered when patients taking replacement therapy for Addison's disease present in hypoadrenal crisis.     

Unilateral adrenal hemorrhage: an unusual presentation

An asymptomatic adrenal mass was discovered in an elderly patient during evaluation of an abnormal urinary sediment. Exploratory laparotomy revealed an adrenal hematoma as the cause of the mass. No clear cause of the adrenal hemorrhage was identified, and postoperatively there was no evidence of adrenal insufficiency. Though rare, signs of adrenal hemorrhage may include an asymptomatic adrenal mass, and should be considered in the differential diagnosis of this problem.     

Coeliac disease and autoimmune Addison's disease: a clinical pitfall

BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association. DESIGN: Prospective screening of patients with confirmed Addison's disease. METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening. RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption. DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.