A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.

CONTEXT: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. OBJECTIVE: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). PATIENTS: All known Norwegian patients with APS1. RESULTS: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. CONCLUSIONS: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

Epidemiology and Health-Related Quality of Life in Hypoparathyroidism in Norway.

OBJECTIVE: The epidemiology of hypoparathyroidism (HP) is largely unknown. We aimed to determine prevalence, etiologies, health related quality of life (HRQOL) and treatment pattern of HP. METHODS: Patients with HP and 22q11 deletion syndrome (DiGeorge syndrome) were identified in electronic hospital registries. All identified patients were invited to participate in a survey. Among patients who responded, HRQOL was determined by Short Form 36 and Hospital Anxiety and Depression scale. Autoantibodies were measured and candidate genes (CaSR, AIRE, GATA3, and 22q11-deletion) were sequenced for classification of etiology. RESULTS: We identified 522 patients (511 alive) and estimated overall prevalence at 102 per million divided among postsurgical HP (64 per million), nonsurgical HP (30 per million), and pseudo-HP (8 per million). Nonsurgical HP comprised autosomal dominant hypocalcemia (21%), autoimmune polyendocrine syndrome type 1 (17%), DiGeorge/22q11 deletion syndrome (15%), idiopathic HP (44%), and others (4%). Among the 283 respondents (median age, 53 years [range, 9-89], 75% females), seven formerly classified as idiopathic were reclassified after genetic and immunological analyses, whereas 26 (37% of nonsurgical HP) remained idiopathic. Most were treated with vitamin D (94%) and calcium (70%), and 10 received PTH. HP patients scored significantly worse than the normative population on Short Form 36 and Hospital Anxiety and Depression scale; patients with postsurgical scored worse than those with nonsurgical HP and pseudo-HP, especially on physical health. CONCLUSIONS: We found higher prevalence of nonsurgical HP in Norway than reported elsewhere. Genetic testing and autoimmunity screening of idiopathic HP identified a specific cause in 21%. Further research is necessary to unravel the causes of idiopathic HP and to improve the reduced HRQOL reported by HP patients.

Genetic, anthropometric and metabolic features of adult Norwegian patients with 21-hydroxylase deficiency.

OBJECTIVE: The aim of this study was to determine the genetic, anthropometric and metabolic features in an unselected population of adult Norwegian patients with 21-hydroxylase deficiency (21OHD). PATIENTS, METHODS AND DESIGN: Sixty-four 21OHD patients participated (23 men and 41 women; median age 38.5 years; range 19-72 years) in a cross-sectional study including DNA sequencing of CYP21A2, anthropometric measurements including dual X-ray absorptiometry scanning and biochemical analyses. The results were compared with reference cohorts from the general population. RESULTS: We identified four novel and plausibly disease-causing CYP21A2 mutations. Gene deletions/conversions (42.1% of alleles), the splice mutation I2 splice (23.0%) and point mutation I172 N (22.2%) were common. The genotype corresponded to clinical phenotype in 92% of the patients. The prevalence of osteopenia was 48% in males and 34% in females. Both men and women had normal BMI but markedly increased fat mass compared with the normal population. Diastolic blood pressure was higher than normal. Thirty-nine per cent of the women had testosterone levels above the normal range; 13% of the men had testosterone levels below normal. Reduced final height was more pronounced in men (median -11.2 cm, -1.77 SDS) than in women (-6.3 cm, -1.07 SDS). CONCLUSIONS: In this population-based survey of 21OHD, we identified four novel mutations and high concordance between genotype and phenotype. The patients had increased fat mass, increased diastolic blood pressure, reduced final height and high frequency of osteopenia among males. These results show unfavourable metabolic features in 21OHD patients indicating a need for improvement of treatment and follow-up.

Increased serum and bone matrix levels of transforming growth factor {beta}1 in patients with GH deficiency in response to GH treatment.

OBJECTIVE: Patients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor ß1 (TGFß1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1 in vivo and in vitro. DESIGN AND METHODS: The effects of GH substitution (9-12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFß1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFß1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigated in vitro. RESULTS: In vivo GH substitution increased TGFß1 protein levels in cortical bone and serum. In vitro, GH/IGF1 stimulation induced a significant increase in TGFß1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFß1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFß1 was observed in the presence of IGF1. CONCLUSION: GH substitution increases TGFß1 in vivo and in vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells.

High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency.

BACKGROUND: Increased frequencies of adrenal tumours and testicular adrenal rest tumours (TART) have been reported in patients with 21-hydroxylase deficiency (21OHD). OBJECTIVE: Patients, methods and design From a cross-sectional population-based study of 101 adult Norwegian patients with 21OHD, sixty-two participated in this study (23 men, 39 women; age range 18-75); thirty-two were salt wasting (SW) and 30 simple virilizing (SV); they were assessed with adrenal computed tomography (CT), testicular ultrasound and hormone measurement in the morning after overnight medication fast. RESULTS: Nine adrenal tumours were detected in seven (11%) patients (bilateral in 2); four were myelolipomas and one a phaeochromocytoma. Seventeen (27%) had normal adrenal size, whereas 36 (58%) had persisting hyperplasia, and seven (11%) adrenal hypoplasia. Abnormal adrenals were more common in SW than in SV. TART occurred exclusively in SW and was present in seven (57%) of these men. Testicular volumes were small compared with normative data. Morning ACTH and 17-hydroxyprogesterone levels correlated positively with adrenal dimensions and frequency of TART. CONCLUSION: In this unselected population of patients with classical 21OHD, we found high frequencies of adrenal tumours, particularly myelolipomas, and of hyperplasia and hypoplasia, and TART in SW. It is important that physicians are aware that benign adrenal and testicular tumours occur frequently in 21OHD. Furthermore, these findings may reflect inappropriate glucocorticoid therapy, making a case for the advancement of novel physiological treatment modalities.

Interleukin 1 receptor antagonist is associated with changes in body composition during physiological GH substitution in patients with adult-onset growth hormone deficiency.

OBJECTIVE: We examined the effect of GH substitution on adipose tissue-derived hormones and cytokines and sought to identify predictors for changes in body composition during therapy. Long-standing adult-onset GH deficiency (AO-GHD) is associated with increased body fat mass (FM) which, through production of hormones and inflammatory cytokines from adipose tissue, may contribute to different manifestations of the metabolic syndrome. DESIGN, PATIENTS AND MEASUREMENTS: Fifty-five patients with AO-GHD (24 women, 31 men, mean age 49 years) were enrolled in a placebo-controlled, double-blind crossover study. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4-month washout period. Adipose tissue-derived cytokines were measured by enzyme immunoassay. RESULTS: GH treatment was associated with a significant decrease in IL-1 receptor antagonist (IL-1Ra) compared to placebo, which correlated with declining body FM (truncal and total) after GH substitution. The change in IL-1Ra was the strongest predictor of the variation in BFM in regression models. No changes were observed for leptin, adiponectin, soluble TNF receptor 1 or interleukin (IL)-8. CONCLUSION: The data indicate a possible unrecognized association between IL-1Ra and changes in body composition during GH substitution and suggest further research on the interaction between the GH-IGF axis and the IL-1 system.

Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry.

OBJECTIVE: Primary adrenal insufficiency [Addison's disease (AD)] is rare, and systematic studies are few, mostly conducted on small patient samples. We aimed to determine the clinical, immunological, and genetic features of a national registry-based cohort. DESIGN: Patients with AD identified through a nationwide search of diagnosis registries were invited to participate in a survey of clinical features, health-related quality of life (HRQoL), autoantibody assays, and human leukocyte antigen (HLA) class II typing. RESULTS: Of 664 registered patients, 64% participated in the study. The prevalence of autoimmune or idiopathic AD in Norway was 144 per million, and the incidence was 0.44 per 100,000 per year (1993-2007). Familial disease was reported by 10% and autoimmune comorbidity by 66%. Thyroid disease was most common (47%), followed by type 1 diabetes (12%), vitiligo (11%), vitamin B12 deficiency (10%), and premature ovarian insufficiency (6.6% of women). The mean daily treatment for AD was 40.5 mg cortisone acetate and 0.1 mg fludrocortisone. The mean Short Form 36 vitality scores were significantly diminished from the norm (51 vs. 60), especially among those with diabetes. Concomitant thyroid autoimmunity did not lower scores. Anti-21-hydroxylase antibodies were found in 86%. Particularly strong susceptibility for AD was found for the DR3-DQ2/ DRB1*0404-DQ8 genotype (odds ratio, 32; P = 4 x 10(-17)), which predicted early onset. CONCLUSIONS: AD is almost exclusively autoimmune, with high autoimmune comorbidity. Both anti-21-hydroxylase antibodies and HLA class II can be clinically relevant predictors of AD. HRQoL is reduced, especially among diabetes patients, whereas thyroid disease did not have an impact on HRQoL. Treatment modalities that improve HRQoL are needed.

Glucocorticoid replacement therapy and pharmacogenetics in Addison's disease: effects on bone.

UNLABELLED: Context Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone. OBJECTIVE: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105). MAIN OUTCOME MEASURES: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity. RESULTS: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean -0.28 (95% confidence intervals (CI) -0.42, -0.16); UK and New Zealand: -0.21 (95% CI -0.36, -0.06)). Lumbar spine Z-scores were reduced (Norway: -0.17 (-0.36, +0.01); UK and New Zealand: -0.57 (-0.78, -0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine. CONCLUSIONS: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.

Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death.

CONTEXT: Primary adrenal insufficiency (Addison's disease) is a rare autoimmune disease. Until recently, life expectancy in Addison's disease patients was considered normal. OBJECTIVE: To determine the mortality rate in Addison's disease patients. DESIGN AND METHODS: i) Patients registered with Addison's disease in Norway during 1943-2005 were identified through search in hospital diagnosis registries. Scrutiny of the medical records provided diagnostic accuracy and age at diagnosis. ii) The patients who had died were identified from the National Directory of Residents. iii) Background mortality data were obtained from Statistics Norway, and standard mortality rate (SMR) calculated. iv) Death diagnoses were obtained from the Norwegian Death Cause Registry. RESULTS: Totally 811 patients with Addison's disease were identified, of whom 147 were deceased. Overall SMR was 1.15 (95% confidence intervals (CI) 0.96-1.35), similar in females (1.18 (0.92-1.44)) and males (1.10 (0.80-1.39)). Patients diagnosed before the age of 40 had significantly elevated SMR at 1.50 (95% CI 1.09-2.01), most pronounced in males (2.03 (1.19-2.86)). Acute adrenal failure was a major cause of death; infection and sudden death were more common than in the general population. The mean ages at death for females (75.7 years) and males (64.8 years) were 3.2 and 11.2 years less than the estimated life expectancy. CONCLUSION: Addison's disease is still a potentially lethal condition, with excess mortality in acute adrenal failure, infection, and sudden death in patients diagnosed at young age. Otherwise, the prognosis is excellent for patients with Addison's disease.

Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene.

CONTEXT: The autoimmune polyendocrine syndrome type I (APS I) is a rare disease that previously was difficult to diagnose. Autoantibody screening as well as mutational analysis of the disease gene autoimmune regulator (AIRE) are important diagnostic tools for this life-threatening syndrome. OBJECTIVE: The objective of the study was to identify all patients with APS I in Norway and correlate their clinical features with their autoantibody profiles and mutations in the AIRE gene. PATIENTS: We identified 36 Norwegian patients from 24 families with APS I (20 males, 16 females) during a nationwide survey for patients with Addison's disease and polyendocrine syndromes, seven of them only after their death. RESEARCH DESIGN AND METHODS: Clinical data were collected from questionnaires and patient records. AIRE mutations were determined by DNA sequencing. Most autoantibodies were measured in RIAs against recombinant autoantigens, but anti-type I interferon (IFN) antibodies were titrated in ELISA or antiviral interferon neutralization assays. RESULTS: The prevalence of APS I in Norway was estimated to be about 1:90,000. Several patients exhibited a milder phenotype with few APS I disease components and onset only in late adolescent or adulthood. The others showed about the same distribution of disease components as reported in Finnish patients. Eleven different mutations were identified in the AIRE gene, six of these were novel, i.e. c.22C>T (p.Arg8Cys), c.290T>C (p.Leu97Pro), c.402delC (p.Ser135GlnfsX12), c.879 + 1G>A (p.IVS7 + 1G>A), c.1249dupC (p.Leu417ProfsX7), and c.1336T>G (p.Cys446Gly). The 13-bp deletion in exon 8 (c.967-979del13) was the most prevalent mutation, present in 23 of 48 (48%) of the alleles. The presence of neutralizing autoantibodies against IFN-omega was the most specific marker of APS I, being found in all but one Norwegian patient. Some other common APS I-associated autoantibodies appeared de novo during long-term follow-up of younger patients. CONCLUSIONS: Norwegian patients with APS I clinically resemble those from Finland and other European countries, but some have milder phenotypes. In total, six new mutations were identified in the Norwegian APS I patients. Anti-type I IFN autoantibodies are easily detectable; their APS I specificity and persistently high titers render them reliable markers of APS I, even in prodromal or atypical cases. Both the clinical features and the AIRE mutations are more diverse in the Norwegian population than previously thought.

Positive effects of a physiological dose of GH on markers of atherogenesis: a placebo-controlled study in patients with adult-onset GH deficiency.

OBJECTIVE: GH deficiency is associated with an increased cardiovascular mortality. Fifty-five patients with adult-onset GH deficiency (AO-GHD) (24 female, 31 male, mean age 49 years) were enrolled in a placebo-controlled double-blind crossover study to investigate the effects of GH therapy on a variety of cardiovascular risk factors representing different aspects of atherogenesis, including apolipo-proteins (Apo A-1, Apo B), markers of subclinical inflammation (high-sensitivity C-reactive protein (CRP) and interleukin-6) and markers of endothelial function (intercellular adhesion molecule-1, von Willebrand factor and sCD40L (a pro-atherogenic factor and marker for plaque destabilization)). METHODS: GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. GH and placebo were administered for 9 months each, separated by a 4 month washout period. RESULTS: The final mean dose of GH was 50% higher for women and IGF-I increased to the same level in both sexes. Compared with placebo, substitution with GH showed a significant effect on Apo B (mean change -0.15 (-0.22 to -0.08) mg/l) and CRP (-1.8 (-3.3 to -0.3) mg/l). The baseline level of and change in IGF-I during treatment with GH contributed significantly to the improvement in both markers. No effects were found on interleukin-6 or Apo A-1, or on markers of endothelial function. No gender differences were observed for any of the markers at baseline or following intervention. CONCLUSIONS: GH substitution to naïve patients with AO-GHD at a low, individually titrated dose aiming at normalizing IGF-I was followed by significant reductions in Apo B and CRP, indicating a positive effect of GH on cardiovascular risk.

[Polycystic ovarian syndrome and diabetes]. / Polycystisk ovariesyndrom og diabetes mellitus.

BACKGROUND: Polycystic ovary syndrome is the most common endocrine condition in women of fertile age. The syndrome is associated with insulin resistance, hyperinsulinaemia and diabetes. This paper reviews the association between polycystic ovary syndrome and diabetes; implications for clinical practice are suggested. MATERIAL AND METHODS: The review is based on Medline searches, our own studies, and clinical experience. RESULTS: Polycystic ovary syndrome is present in one third of women with type 1 diabetes and in almost half of all women with type 2 diabetes. In women with polycystic ovary syndrome, the prevalence of type 2 diabetes is considerably increased and gestational diabetes may occur in as many as 40%. In women with previous gestational diabetes, the risk of type 2 diabetes as well as polycystic ovarian syndrome is increased. INTERPRETATION: Women with polycystic ovary syndrome are at increased risk of developing type 2 diabetes and gestational diabetes and should be followed up accordingly. Pregnant women with polycystic ovary syndrome should have an oral glucose tolerance test as soon as the pregnancy has been confirmed. The procedure should be repeated at gestational weeks 20 and 32. Treatment with metformin should be initiated in women with type 2 diabetes who want to conceive. For the same reason metformin may also be initiated in women with type 1 diabetes.

Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial.

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebo-controlled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95+/-33 vs 68+/-41 microg/l respectively; P < 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9+/-2.9 kg and lean body mass was increased by 1.8+/-2.8 kg (P = 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P = 0.01), relative to body weight by 9% (P = 0.004), and there was a trend toward increased endurance performance by 7% (P = 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

[Primary adrenal failure--causes, diagnostics and therapy]. / Primaer binyrebarksvikt - årsaker, diagnostikk og behandling.

BACKGROUND AND METHODS: An overview of primary adrenal failure with emphasis on replacement therapy is presented. The article is based on a review of recent literature and authors' personal experience. RESULTS AND CONCLUSIONS: Addison's disease is usually caused by an autoimmune destruction of the adrenal cortex. It is relatively rare (prevalence 14 per 100,000 inhabitants), but often considered as a differential diagnosis when evaluating fatigue, tiredness and loss of weight. Addison's disease is treated by repletion of glucocorticoids and mineralocorticoids. The recommended starting dose is 25 mg cortisone acetate per day divided into three (12.5 + 6.25 + 6.25 mg) or two doses (12,5 mg x 2). Mineralocorticoid replacement is given as fludrocortisone 0.05 - 0.2 mg in one dose per day. Treatment with 20 - 50 mg dehydroepiandrosterone has been studied in adrenal failure, but the evidence for positive effects is weak, and it can not be recommended as standard treatment in primary adrenal failure.

Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial.

The physiological role of dehydroepiandrosterone (DHEA) is not well understood, but studies suggest positive effects on subjective health and bone metabolism. We have conducted a clinical trial with DHEA replacement in adrenal failure with the primary aim of evaluating effects on subjective health status and sexuality. Thirty-nine women with adrenal failure were randomized to 9 months of treatment with 25 mg DHEA (n = 19) or placebo (n = 20). Treatment effects were assessed by validated questionnaires of subjective health and sexuality. DHEA replacement yielded a wide variation of effects on the subjective health scales, which were not different from the effects of placebo. Almost all patients receiving DHEA obtained normal androgen levels. Eighty-nine percent of the patients receiving DHEA experienced side-effects, in particular increased sweat odor and scalp itching. DHEA replacement did not significantly change the levels of blood lipids, IGF-I, and markers of bone metabolism. In conclusion, we do not find evidence of beneficial effects of DHEA on subjective health status and sexuality in adrenal failure. However, DHEA may be beneficial for subgroups of patients with adrenal failure, but these remain to be identified. Premenopausal androgen levels can be restored with 25 mg DHEA daily in most female patients, but side-effects are frequent.

Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features.

Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison's disease) in industrialized countries. We have investigated a large Norwegian cohort of patients with Addison's disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6-85 yr (mean 45 yr) with, either isolated Addison's disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03). Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2) and DRB1*04-DQA1*03-DQB1*0302 (DR4-DQ8) haplotypes were positively correlated to Addison's disease, whereas the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB1*04 subtype DRB1*0404 was increased among Addison patients relative to controls. We verify that autoimmunity is the main cause of Addison's disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison's disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).