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.     

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.     

Addisonian crisis precipitated by thyroxine therapy: a complication of type 2 autoimmune polyglandular syndrome

Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.     

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.     

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.     

Autoimmune polyglandular syndrome]

Among many etiologies for hypoparathyroidism, one of the inheritable forms of hypoparathyroidism, called as autoimmune polyglandular syndrome (APS), appears as a complex of hypofunction of several endocrine glands, candidiasis, pernicious anemia and vitiligo. Idiopathic hypoparathyroidism in APS typically presents by 20 years of age. Among the three most components of APS I, candidiasis is usually the first manifestation. Hypoparathyroidism almost invariably precedes the onset of Addison's disease. One should remember that Addison's disease can mask the presence of hypoparathyroidism and that glucocorticoid replacement therapy alone can cause hypocalcemic crisis.     

Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II

In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4(+) CD25(+) regulatory T cells (T(regs)) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. T(regs) from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II T(regs) were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.     

Polyglandular type I autoimmune syndrome]

Two HLA-identical sisters have developed the full picture of type I polyglandular autoimmune syndrome over a period of 12 years. Both girls have hypoparathyroidism and Addison's disease. One of them additionally developed diabetes mellitus, hypergonadotropic hypogonadism and hypothyroidism. Autoantibodies to the adrenal, parathyroid and thyroid glands are present in both patients, as well as antinuclear antibodies. HLA associations have been described recently for the type I polyglandular autoimmune syndrome, but this could not be confirmed in the present two cases. Although we assume that the same genetic defect is present in both girls, additional factors to the genetic disposition are important for the clinical expression of the disease. The linkage of the disease-causing gene with the HLA region is not very close.     

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.     

HYPERTHYROIDISM ASSOCIATED WITH HYPEREMESIS GRAVIDARUM

SUMMARY Hyperemesis gravidarum is an uncommon presentation of hyperthyroidism in pregnancy which is usually attributable to autoimmune (Graves') disease. While this condition necessitates treatment with antithyroid drugs, a syndrome of transient hyperthyroidism associated with hyperemesis gravidarum that resolves spontaneously is also recognised. Differentiation between these two conditions may prove problematic in practice. We report two cases of hyperthyroidism associated with severe hyperemesis gravidarum. Intractable hyperemesis continued in one patient despite normalisation of circulating free thyroid hormone concentrations with carbimazole. Neither patient exhibited clinical or immunological features of autoimmune thyroid disease, suggesting in retrospect that they had the syndrome of transient hyperthyroxinaemia associated with hyperemesis gravidarum rather than Graves' disease. The role of antithyroid drugs in the treatment of self-limiting transient hyperthyroidism associated with hyperemesis gravidarum requires clarification.     

Association of HELLP syndrome with autoimmune antibodies and glucose intolerance

OBJECTIVE: HELLP syndrome is a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP), whose pathogenesis is unclear. Autoimmunity is thought to play an important role. After the observation of development of type 1 diabetes in a patient with HELLP syndrome, we assumed a possible disease association based on autoimmune reactions. RESEARCH DESIGN AND METHODS: We examined 70 women with HELLP syndrome for the presence of autoimmune markers and glucose intolerance. Free thyroxine, triiodothyronine, thyroid-stimulating hormone, anti-thyroglobulin antibodies, thyroperoxidase antibodies, thyrotropin receptor antibodies, antinuclear antibodies (ANAs) and anti-DNA, islet cell antibodies, GADA, an oral glucose tolerance test, and HbA1c were determined postpartum. Patients with positive autoimmune markers or glucose intolerance were prospectively followed and repeated testing was performed. There were 60 women with a normal course of pregnancy matched for age, BMI, and number of pregnancies, which served as a control group. RESULTS: From the HELLP patients, 22 (31%) compared with only 6 (10%) control subjects had autoimmune antibodies (P < 0.01). There were 16 HELLP patients (23%) who exhibited only 1 kind of autoantibody (5 ANA, 9 thyroid antibodies, and 2 GADA), whereas in 6 HELLP patients (8.5%) 2 different antibodies were found. In all but 4 patients of the study group, these antibodies disappeared during 3 +/- 1.5 years of follow-up. Glucose intolerance was detected in 22 (31%) of the HELLP patients, 17 of them had impaired glucose tolerance (IGT), and 5 had diabetes, whereas only 4 subjects (6.5%) with IGT at postpartum were found in the control group (P < 0.01). During the follow-up, 2 HELLP patients were still diabetic and another 2 HELLP patients (1 GADA positive) had IGT versus 1 control subject. CONCLUSIONS: Our data give evidence that HELLP syndrome is associated with various autoimmune antibodies and glucose intolerance. Because glucose intolerance and/or autoimmune markers persisted during long-term follow-up in 6 patients with HELLP syndrome versus 1 in the control group, it may become advisable to reexamine patients with HELLP syndrome for detection of diabetes and autoimmune disorders.     

Normal and abnormal regulation of β-MSH in man

The regulation of plasma beta-melanocyte-stimulating hormone (beta-MSH) in man has been studied utilizing a radioimmunoassay previously described (1). In normal subjects plasma beta-MSH values ranged from 20 to 110 pg/ml. Metyrapone increased and dexamethasone decreased plasma beta-MSH levels. Surgical stress stimulated beta-MSH secretion. Plasma beta-MSH levels were elevated in patients with untreated Addison's disease and untreated congenital adrenal hyperplasia, and these levels fell to normal during glucocorticoid therapy. In patients with Cushing's syndrome due to pituitary adrenocorticotropic hormone (ACTH) excess, plasma beta-MSH was slightly elevated before treatment. In those patients who developed pituitary tumors and hyperpigmentation after bilateral adrenalectomy, plasma beta-MSH was greatly elevated. In patients with Cushing's syndrome due to adrenal tumor, plasma beta-MSH was subnormal. In patients with the ectopic ACTH syndrome, the levels of plasma beta-MSH were high. Plasma beta-MSH had a diurnal variation in normal subjects, patients with Addison's disease, and patients with congenital adrenal hyperplasia; but the normal diurnal variation was lost in patients with Cushing's disease. In patients with high plasma beta-MSH, simultaneous determinations of plasma ACTH showed close correlation between the degree of elevation of ACTH and that of beta-MSH. In extracts of tumors from patients with the ectopic ACTH-MSH syndrome the quantities of the two hormones were roughly equivalent. In patients with hyperpigmentation due to a variety of disorders other than pituitary-adrenal abnormalities, plasma beta-MSH was normal. It is concluded that the secretion of beta-MSH is regulated by the same factors that regulate ACTH.     

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.     

Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome in a patient with paroxysmal nocturnal hemoglobinuria: a case report

Primary biliary cirrhosis (PBC)–autoimmune hepatitis (AIH) overlap syndrome is frequently associated with extrahepatic autoimmune disorders. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disease that is characterized by complement-mediated hemolysis due to erythrocyte membrane defects. However, autoimmune liver disease was not previously reported to be associated with PNH. A 37-year-old female patient was referred to our hospital with elevated liver enzymes and hematuria. On the basis of the symptoms and results of laboratory tests, radiographic studies, and pathologic results, she was diagnosed with PBC–AIH overlap syndrome and PNH. She was treated with a combination of ursodeoxycholic acid and prednisolone. The patient was symptom-free, with laboratory findings within near-normal range. The patient had recovered well at the 24-month follow-up evaluation. While we acknowledge that this was a single case, these findings expand our knowledge of immunological diseases that are associated with PNH and suggest an immune-mediated pathogenic pathway between PNH and PBC–AIH overlap syndrome. The combination of ursodeoxycholic acid and prednisolone can achieve therapeutic success. Routine follow-up of these patients is necessary to document disease progression.     

Endocrinopathy in POEMS syndrome: the Mayo Clinic experience

OBJECTIVE: To determine the prevalence and characteristics of endocrinopathies at diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. PATIENTS AND METHODS: From January 1, 1960, through June 30, 2006, we identified 170 patients with POEMS syndrome in the Mayo Clinic dysproteinemia database. We abstracted information about endocrine abnormalities from their medical records. RESULTS: Of the 170 patients with POEMS syndrome during the entire study period, the 64 patients seen after 2000 had more complete endocrine evaluations; of these 64 patients, 54 (84%) had a recognized endocrinopathy (38 men; median age, 50 years; interquartile range, 43-59 years). Hypogonadism was the most common endocrine abnormality; 26 (79%) of 33 men had subnormal total testosterone levels, and 10 men had gynecomastia. Among the 35 patients with measured prolactin levels, 7 men and 3 women had elevated levels. Hypothyroidism was noted in 17 men and 11 women. Abnormalities in glucose metabolism were present in 24 (48%) of 50 patients; 16 patients had impaired fasting glucose levels, and 8 were diagnosed as having diabetes. Adrenal insufficiency (defined by an abnormal response of cortisol to stimulation with standard high-dose [250 microg] synthetic adrenocorticotropic hormone) was noted in 6 of 9 patients tested. Fourteen (27%) of 51 patients tested had hypocalcemia. Twenty-nine (54%) of 54 patients had evidence of multiple endocrinopathies in the 4 major endocrine axes (gonadal, thyroid, glucose, and adrenal). CONCLUSION: The high prevalence of endocrinopathy in our study, to our knowledge the largest published series of POEMS cases, calls for a thorough endocrine investigation in patients presenting with this syndrome.     

Chronic fatigue syndrome: an endocrine disease off limits for endocrinologists?

Endocrinologists were not included in the multidisciplinary working groups that prepared two recent reports on chronic fatigue syndrome, despite its unequalled clinical overlap with Addison's disease, which is a classic endocrine disorder. The failure to include at least one endocrinologist in those panels may explain why in their extensive reports there is not a single word about the 42 clinical features that chronic fatigue syndrome shares with Addison's disease, including all the signs and symptoms listed in the case definition of this syndrome.     

Receptors, antibodies, and disease

Abnormal antibody production is now recognized as the basis of specific endocrine and neurological diseases and their complications. Among the autoimmune diseases, the best understood from a mechanistic point of view are myasthenia gravis, Graves' disease, several variants of insulin resistance, and a variant of bronchial asthma. In each of these human disorders, the clinical symptoms can be traced to the actions of antireceptor antibodies produced by a deranged immune system. The autoantibodies produced in these diseases are functionally heterogeneous. They may produce the clinical symptoms of hormone or neurotransmitter insufficiency either by blocking the binding of these agents to target cell surface receptors or by accelerating the internalization and degradation of these receptors. In other cases, the autoantibodies may produce the clinical signs of hormone excess by mimicking the actions of the hormone, in an uncontrollable fashion. In some cases, functionally different types of autoantibodies will appear in the same patient at different stages of the disease. For all of these autoantibodies, of whatever function, assays for their presence in serum are available, in forms suitable for clinical chemists, as well as for researchers; these will be described in this review. In addition to the known anti-receptor autoimmune diseases, there are a large number of other autoimmune diseases for which there is fragmentary evidence that their clinical symptoms have an anti-receptor autoantibody etiology. Several examples of this group will be discussed, and assays suitable for establishing the presence of anti-receptor antibodies in the sera of such patients will be provided. The disorders to be considered are: type I diabetes mellitus, chronic atrophic gastritis, autoimmune Addison's disease, autoimmune hypoparathyroidism, type II pseudohypoparathyroidism, resistant ovary syndrome, connective tissue diseases, and the HLA-B8/DR3 antigen haplotype as a potential marker for autoimmune diseases of the anti-receptor type.     

Tuberculous Addison's disease

Addison's disease is a possible diagnosis in any patient who presents with weakness, weight loss, hyperpigmentation, hyponatremia, and hypotension. Laboratory findings, including depressed levels of cortisol and aldosterone, help to confirm the diagnosis. Computed tomography may reveal adrenal calcification and abnormal-sized adrenal glands. In most cases, autoimmune destruction of the adrenal cortex is the cause of Addison's disease; however, as in the patient described here, tuberculosis is a possible cause.