Kristian Løvås

Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry

OBJECTIVE Primary adrenal insufficiency [Addisons 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.

Subjective health status in Norwegian patients with Addison’s disease*

objective  Many patients with Addison’s disease have complaints that might be related to the disease or to its treatment. However, only a few studies have addressed the subjective health status of patients with adrenocortical failure. The aim of the present study was to assess the subjective health status with special emphasis on fatigue among patients with Addison’s disease.

Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency

Primary adrenal insufficiency (PAI), or Addisons disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow‐up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21‐hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life‐threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow‐up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self‐adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addisons disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortiums investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow‐up.

High prevalence and increasing incidence of Addison's disease in western Norway

objective Estimates of the prevalence of Addisons disease in Caucasians have varied from 39 to 117 per million. We have carried out an epidemiological study to obtain a confident point prevalence estimate in the Norwegian population for the end of 1999, and to find out whether the incidence is changing.

Continuous subcutaneous hydrocortisone infusion in Addison’s disease

OBJECTIVE The conventional replacement therapy in Addisons disease (AD) does not restore the normal diurnal cortisol rhythm. We explored the feasibility and safety of continuous s.c. hydrocortisone infusion (CSHI) as a novel mode of glucocorticoid replacement therapy. DESIGN AND METHODS Seven patients with AD were treated with CSHI in an open-labelled clinical study for up to three months. Adequacy of glucocorticoid replacement was assessed by 24 h blood and saliva sampling in one patient and by salivary cortisol day curves in six outpatients. Subjective health status was monitored by the Short Form-36 questionnaire. RESULTS CSHI re-established the circadian variation and normal levels of cortisol in the patients, with minor day-to-day variation. Most of the patients could reduce their glucocorticoid dose considerably without adverse reactions. The treatment was well tolerated and positively evaluated by the patients. CONCLUSIONS CSHI is technically feasible and safe in patients with AD. A daily dose of approximately 10 mg/m(2) body surface area/day restores the circadian variation and normal levels of salivary cortisol in most patients, which is close to the estimated daily requirement. We hypothesise that selected patients will benefit from restoration of the circadian cortisol rhythm.

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

CONTEXT Primary adrenal insufficiency (Addisons disease) is a rare autoimmune disease. Until recently, life expectancy in Addisons disease patients was considered normal. OBJECTIVE To determine the mortality rate in Addisons disease patients. DESIGN AND METHODS i) Patients registered with Addisons 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 Addisons 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 Addisons 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 Addisons disease.

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

UNLABELLED Context Patients with primary adrenal insufficiency (Addisons 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 Addisons 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 Addisons 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.

Polymorphisms in CLEC16A and CIITA at 16p13 Are Associated with Primary Adrenal Insufficiency

CONTEXT/OBJECTIVES It is known that different autoimmune diseases often share the same susceptibility genes. In this study we aimed to investigate if loci found associated with common autoimmune diseases in recent genome-wide association studies also could be susceptibility loci for autoimmune Addisons disease (primary adrenal insufficiency). DESIGN/PATIENTS A total of 139 tagging single nucleotide polymorphisms (SNPs) in 11 candidate genes (IL2, IL21, IL2RA, CLEC2D, CD69, ERBB3, PTPN11, SH2B3, CLEC16A, CIITA, and PTPN2) were genotyped in a case/control study design consisting of Norwegian Addisons disease patients (n = 332) and Norwegian healthy control individuals (n = 1029). Five SNPs were subsequently selected for analysis in a United Kingdom sample set consisting of Addisons disease patients (n = 210) and controls (n = 191). RESULTS Polymorphisms in CLEC16A and CIITA remained significantly associated with Addisons disease in the Norwegian sample set at the 0.05 level, even after correction for multiple testing. CLEC16A and CIITA are both located at 16p13, but linkage disequilibrium patterns and logistical regression analyses suggest that SNPs in these two genes are independently associated with Addisons disease. We were not able to confirm these associations in the United Kingdom material, however, this may well be due to the limited sample size and lack of statistical power. CONCLUSION Two alleles at 16p13 are independently associated with the risk of Addisons disease in the Norwegian population, suggesting this chromosomal region to harbor common autoimmunity gene(s), CLEC16A and CIITA being possible independent candidates.

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.

Mutation screening of PTPN22 : association of the 1858T-allele with Addison's disease

The tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene was recently identified as an important genetic susceptibility factor in several autoimmune diseases. The increased risk has been broadly explained by the 1858T-allele (rs2476601). As two smaller studies on Addisons disease (AD) have shown diverging results, we aimed to elucidate the predisposing effect of the single-nucleotide polymorphism (SNP) 1858CT in a larger population of AD patients, especially focusing on the AD patients with known autoimmune etiology. We also screened for unknown rare or common variants in the PTPN22 gene that could predispose for AD. The case–control study of Norwegian AD patients (n=332) and controls (n=990) showed a significant association between autoimmune AD (n=302) and the PTPN22 1858T risk allele (P=0.016). The association of AD with 1858T was supported by a meta-analysis combining our genotype data with that of others published previously (P=0.003). The mutation screening of PTPN22 in AD patients (n=332) and controls (n=112) revealed eight missense variants, five of which have not been reported previously. In conclusion, the 1858T-allele is a PTPN22 genetic susceptibility factor for autoimmune AD. Other rare variants in PTPN22 do occur, and may also be involved in the pathogenesis.