Sophie Bensing

Haukeland University Hospital, Bergen, Hordaland, Norway

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Publications (22)81.76 Total impact

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    ABSTRACT: The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer-guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.
    Journal of immunology (Baltimore, Md. : 1950). 07/2014;
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    ABSTRACT: Context: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison's disease (AD). Objective: To compare the effects of continuous subcutaneous hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy. Design, patients and interventions: A prospective crossover randomized multicenter clinical trial comparing three months treatment with thrice daily (t.i.d.) OHC versus CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm. Main Outcome measures: Morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep and safety. Results: CSHI yielded normalization of morning ACTH and cortisol levels, and 24h salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI, but were clearly altered OHC. Several HRQoL indices in the vitality domain improved over time with CSHI. No benefit was found for either treatments for any subjective (PSQI questionnaire) or objective (actigraphy) sleep parameters. Conclusion: CSHI safely brought ACTH and cortisol towards normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy.
    The Journal of Clinical Endocrinology and Metabolism 02/2014; · 6.31 Impact Factor
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    ABSTRACT: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
    PLoS ONE 01/2014; 9(3):e88991. · 3.53 Impact Factor
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    ABSTRACT: Primary adrenal insufficiency (PAI), or Addison's 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 Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.
    Journal of Internal Medicine 11/2013; · 6.46 Impact Factor
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    ABSTRACT: Context:There are no published data on drug prescription in patients with Addison's disease (AD).Objective:Our objective was to describe the drug prescription patterns in Swedish AD patients before and after diagnosis compared with population controls.Design and Setting:We conducted a population-based cohort study in Sweden.Patients:Through the Swedish National Patient Register and the Swedish Prescribed Drug Register, we identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. Direct evidence of the AD diagnosis from patient charts was not available. We identified 11 996 matched controls by the Register of Population.Main Outcome Measure:We determined the ratio of observed to expected number of patients treated with prescribed drugs.Results:Overall, Swedish AD patients received more prescribed drugs than controls, and 59.3% of the AD patients had medications indicating concomitant autoimmune disease. Interestingly, both before and after the diagnosis of AD, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives, and drugs for obstructive airway disease (all P values < .05). Notably, an increased prescription of several antihypertensive drugs and high-ceiling diuretics was observed after the diagnosis of AD.Conclusion:Gastrointestinal symptoms and anemia, especially in conjunction with autoimmune disorders, should alert the physician about the possibility of AD. The higher use of drugs for cardiovascular disorders after diagnosis in patients with AD raises concerns about the replacement therapy.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; · 6.31 Impact Factor
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    ABSTRACT: Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, α-melanocyte stimulating hormone or β-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or γ-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing.
    Pituitary 01/2013; · 2.67 Impact Factor
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    ABSTRACT: Lymphocytic hypophysitis is an organ-specific autoimmune disease of the pituitary gland. A specific and sensitive serological test currently does not exist to aid in the diagnosis. To identify target autoantigens in lymphocytic hypophysitis and develop a diagnostic assay for these proteins. A pituitary cDNA expression library was immunoscreened using sera from four patients with lymphocytic hypophysitis. Relevant cDNA clones from screening, along with previously identified autoantigens pituitary gland-specific factor 1a and 2 (PGSF1a and PGSF2) and neuron-specific enolase (NSE) were tested in an in vitro transcription and translation immunoprecipitation assay. The corticotroph-specific transcription factor, TPIT, was investigated separately as a candidate autoantigen. Significantly positive autoantibody reactivity against TPIT was found in 9/86 hypophysitis patients vs 1/90 controls (P = 0.018). The reactivity against TPIT was not specific for lymphocytic hypophysitis with autoantibodies detectable in the sera from patients with other autoimmune endocrine diseases. Autoantibodies were also detected against chromodomain-helicase-DNA binding protein 8, presynaptic cytomatrix protein (piccolo), Ca(2+)-dependent secretion activator, PGSF2 and NSE in serum samples from patients with lymphocytic hypophysitis, but at a frequency that did not differ from healthy controls. Importantly, 8/86 patients with lymphocytic hypophysitis had autoantibodies against any two autoantigens in comparison with 0/90 controls (P = 0.0093). TPIT, a corticotroph-specific transcription factor, was identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. Further autoantigens related to vesicle processing were also identified as potential autoantigens with different immunoreactivity patterns in patients and controls.
    European Journal of Endocrinology 12/2011; 166(3):391-8. · 3.14 Impact Factor
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    ABSTRACT: Patients with Addison's disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients. We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire. After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbach's coefficient-α and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients. Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant χ(2) probability. Crohnbach's α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and in women compared with men but no difference between patients with isolated AD and those with concomitant diseases. The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability.
    The Journal of Clinical Endocrinology and Metabolism 11/2011; 97(2):568-76. · 6.31 Impact Factor
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    ABSTRACT: The results of studies of bone mineral density in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study, we compare hip fracture risk in adults with and without AD. A population-based cohort study. Through the Swedish National Patient Register and the Total Population Register, we identified 3219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006 and 31 557 age- and sex-matched controls. Time to hip fracture was measured. We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture [hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; P < 0.001]. This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95 % CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD [odds ratio (OR) = 2.4; 95 % CI, 2.1-3.0] with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95 % CI, 1.8-4.2). Both clinically undiagnosed and diagnosed AD was associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.
    Journal of Internal Medicine 05/2011; 270(2):187-95. · 6.46 Impact Factor
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    ABSTRACT: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.
    Scandinavian Journal of Immunology 02/2011; 73(2):147-53. · 2.20 Impact Factor
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    ABSTRACT: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.
    European Journal of Immunology 01/2011; 41(1):235-45. · 4.97 Impact Factor
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    ABSTRACT: Autoimmune Addison's disease (AAD) tends to affect young and middle-aged women. It is not known whether the existence of undiagnosed or diagnosed AAD influences the outcome of pregnancy. The aim of the study was to compare the number of children and pregnancy outcomes in individuals with AAD and controls. We conducted a population-based historical cohort study in Sweden. Through the Swedish National Patient Register and the Total Population Register, we identified 1,188 women with AAD and 11,879 age-matched controls who delivered infants between 1973 and 2006. We measured parity and pregnancy outcome. Adjusted odds ratios (ORs) for infants born to mothers with deliveries 3 yr or less before the diagnosis of AAD were 2.40 [95% confidence interval (CI), 1.27-4.53] for preterm birth (≤37 wk), 3.50 (95% CI, 1.83-6.67) for low birth weight (<2500 g), and 1.74 (95% CI, 1.02-2.96) for cesarean section. Compared to controls, women who gave birth after their AAD diagnosis were at increased risk of both cesarean delivery (adjusted OR, 2.35; 95% CI, 1.68-3.27) and preterm delivery (adjusted OR, 2.61; 95% CI, 1.69-4.05). Stratifying by isolated AAD and concomitant type 1 diabetes and/or autoimmune thyroid disease in the mother did not essentially influence these risks. There were no differences in risks of congenital malformations or infant death. Women with AAD had a reduced overall parity compared to controls (P<0.001). Clinically undiagnosed and diagnosed AAD both entail increased risks of unfavorable pregnancy outcomes. AAD also influences the number of childbirths.
    The Journal of Clinical Endocrinology and Metabolism 12/2010; 95(12):5249-57. · 6.31 Impact Factor
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    ABSTRACT: Patients with autoimmune polyglandular syndrome type I (APS1) often display high titers of autoantibodies (autoAbs) directed against aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and glutamic acid decarboxylase (GAD). Neurological symptoms, including stiff-man syndrome and cerebellar ataxia, can occur in subjects with high levels of GAD autoAbs, particularly when patient sera can immunohistochemically stain gamma-aminobutyric acid (GABA) neurons. However, it was not known if APS1 sera can also stain major monoamine systems in the brain. Therefore, in this work we applied sera from 17 APS1 patients known to contain autoAbs against AADC, TH, TPH, and/or GAD to rat brain sections and processed the sections according to the sensitive immunohistochemical tyramide signal amplification method. We found that autoAbs in sera from 11 patients were able to stain AADC-containing dopaminergic, serotonergic, and noradrenergic as well as AADC only (D-group) neurons and fibers in the rat brain, in several cases with a remarkably high quality and sensitivity (dilution up to 1:1,000,000); and, since they are human antibodies, they offer a good opportunity for performing multiple-labeling experiments using antibodies from other species. Six APS1 sera also stained GABAergic neuronal circuitries. Similar results were obtained in the mouse and primate brain. Our data demonstrate that many APS1 sera can immunostain the major monoamine and GABA systems in the brain. Only in a few cases, however, there was evidence that these autoAbs can be associated with neurological manifestations in APS1 patients, as, e.g., shown in stiff-man syndrome. J. Comp. Neurol. 513:1-20, 2009. (c) 2009 Wiley-Liss, Inc.
    The Journal of Comparative Neurology 02/2009; 513(2):spc1. · 3.66 Impact Factor
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    ABSTRACT: Patients with autoimmune polyglandular syndrome type I (APS1) often display high titers of autoantibodies (autoAbs) directed against aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and glutamic acid decarboxylase (GAD). Neurological symptoms, including stiff-man syndrome and cerebellar ataxia, can occur in subjects with high levels of GAD autoAbs, particularly when patient sera can immunohistochemically stain gamma-aminobutyric acid (GABA) neurons. However, it was not known if APS1 sera can also stain major monoamine systems in the brain. Therefore, in this work we applied sera from 17 APS1 patients known to contain autoAbs against AADC, TH, TPH, and/or GAD to rat brain sections and processed the sections according to the sensitive immunohistochemical tyramide signal amplification method. We found that autoAbs in sera from 11 patients were able to stain AADC-containing dopaminergic, serotonergic, and noradrenergic as well as AADC only (D-group) neurons and fibers in the rat brain, in several cases with a remarkably high quality and sensitivity (dilution up to 1:1,000,000); and, since they are human antibodies, they offer a good opportunity for performing multiple-labeling experiments using antibodies from other species. Six APS1 sera also stained GABAergic neuronal circuitries. Similar results were obtained in the mouse and primate brain. Our data demonstrate that many APS1 sera can immunostain the major monoamine and GABA systems in the brain. Only in a few cases, however, there was evidence that these autoAbs can be associated with neurological manifestations in APS1 patients, as, e.g., shown in previous studies in stiff-man syndrome.
    The Journal of Comparative Neurology 12/2008; 513(1):1-20. · 3.66 Impact Factor
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    ABSTRACT: Primary adrenocortical insufficiency is mostly caused by an autoimmune destruction of the adrenal cortex. The disease may appear isolated or as a part of an autoimmune polyendocrine syndrome (APS). APS1 is a rare hereditary disorder with a broad spectrum of clinical manifestations. In APS2, primary adrenocortical insufficiency is often combined with autoimmune thyroid disease and/or type 1 diabetes. We analysed mortality and cancer incidence in primary adrenocortical insufficiency patients during 40 years. Data were compared with the general Swedish population. A population based cohort study including all patients with autoimmune primary adrenocortical insufficiency (3299) admitted to Swedish hospitals 1964-2004. Mortality risk was calculated as the standardized mortality ratio (SMR) and cancer incidence as the standardized incidence ratio (SIR). A more than 2-fold increased mortality risk was observed in both women (SMR 2.9, 95% CI 2.7-3.0) and men (SMR 2.5, 95% CI 2.3-2.7). Highest risks were observed in patients diagnosed in childhood. SMR was higher in APS1 patients (SMR 4.6, 95% CI 3.5-6.0) compared with patients with APS2 (SMR 2.1, 95% CI 1.9-2.4). Cancer incidence was increased (SIR 1.3, 95% CI 1.2-1.5). When tumours observed during the first year of follow-up were excluded, only the cancer risk among APS1 patients remained increased. Cause-specific cancer incidence analysis revealed significantly higher incidences of oral cancer, nonmelanoma skin cancer, and male genital system cancer among patients. Breast cancer incidence was lower than in the general population. Our study shows a reduced life expectancy and altered cancer incidence pattern in patients with autoimmune primary adrenocortical insufficiency.
    Clinical Endocrinology 09/2008; 69(5):697-704. · 3.40 Impact Factor
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    ABSTRACT: Lymphocytic hypophysitis (LyH) is a rare inflammatory disease, considered to be autoimmune. LyH has mainly been reported in females and in relation to pregnancy or the post-partum period. We describe a 73-yr-old woman and a 63-yr-old male who were evaluated at our clinic because of pituitary hormone deficits. Both patients had pituitary masses suggestive of a pituitary adenoma on magnetic resonance imaging (MRI). Transsphenoidal pituitary surgery was performed and histopathological examinations revealed LyH in both cases. Clinical, laboratory, radiological and the histopathological findings in these two patients are discussed in detail. In addition, we report on a 79-yr-old man with partial hypopituitarism and empty sella. Screening of a human pituitary cDNA library with his serum revealed autoantibodies against secretogranin II. This is a protein commonly present in human gonadotrophs, thyreotrophs and corticotrophs. Since the patient selectively showed the corresponding pituitary insufficiencies, we speculate on an autoimmune background. Further studies may ascertain the importance of secretogranin II autoantibodies as markers for LyH.
    Journal of endocrinological investigation 03/2007; 30(2):153-62. · 1.65 Impact Factor
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    ABSTRACT: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies (Aabs) toward intracellular enzymes are a hallmark for APS1 and serve as diagnostic markers and predictors for disease manifestations. In this study, we aimed to identify pituitary autoantigens in patients with APS1. A pituitary cDNA expression library was screened with APS1 sera and a tudor domain containing protein 6 (TDRD6) cDNA clone was isolated. Positive immunoreactivity against in vitro translated TDRD6 fragments was shown in 42/86 (49%) APS1 patients but not in patients with other autoimmune diseases or in healthy controls. By using immunohistochemistry, sera from 3/6 APS1 patients with growth hormone (GH) deficiency showed immunostaining of a small number of guinea pig anterior pituitary cells, and 40-50% of these cells were GH-positive. No such immunostaining was seen with sera from healthy controls. The APS1 Aab-positive, GH-negative cells may represent a novel subpopulation of anterior pituitary cells. In addition, 4/6 patient sera showed staining of a fiber-plexus in the pituitary intermediate lobe recognizing enzymes of monoamine and GABA synthesis. Thus, we have identified TDRD6 as a major autoantigen in APS1 patients and shown that several sera from GH-deficient patients stain specific cell populations and nerves in the pituitary gland.
    Proceedings of the National Academy of Sciences 02/2007; 104(3):949-54. · 9.81 Impact Factor
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    ABSTRACT: The aim of this article is to review recent advancements in pituitary autoantibody assays. Recent findings The newest assay is based on the in-vitro transcription and translation of pituitary specific proteins followed by immunoprecipitation with patient sera. The two proteins, PGSF1a and PGSF2, were identified as pituitary specific from a human pituitary gland cDNA library. Autoantibodies were found in one patient with biopsy proven lymphocytic hypophysitis and seven with suspected hypophysitis, including idiopathic hypopituitarism. Patients with rheumatoid arthritis, especially if rheumatoid factor negative, also had autoantibodies to PGSF1a. An immunoblotting method identified the autoantigen enolase (both a and neuron-specific), as a marker of neuroendocrine autoimmunity but an in-vitro transcription and translation assay has shown that enolase autoantibodies are nonspecific. Enolase autoantibodies have also been found in Sheehan's syndrome. Immunoblotting identified a novel 36 kDa pituitary cytosolic autoantigen in adrenocorticotropin (ACTH) deficiency and pituitary membrane proteins of 68, 49 and 43 kDa in patients with lymphocytic hypophysitis. Indirect immunofluorescence using baboon pituitary has been revisited and somatotroph autoantibodies found in patients with idiopathic growth hormone (GH) deficiency. High titre antibodies were thought to be clinically significant. Enyme-linked immunosorbent assays using human pituitary adenoma cells or rat tissue have identified antibodies in patients with type 1 diabetes, Hashimoto's thyroiditis and various pituitary disorders but not hypophysitis. Summary The search for reliable and specific pituitary autoantibody markers continues.
    Current Opinion in Endocrinology and Diabetes 01/2006; 13(4).
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    ABSTRACT: An autoimmune cause of adrenocorticotropin (ACTH)-deficiency is presented, as it is known to be a characteristic feature of lymphocytic hypophysitis, a disease of the pituitary gland considered to be autoimmune. The aim of this study was twofold: (1) to evaluate the occurrence of pituitary autoantibodies and (2) to correlate it to clinical and immunological features in a large group of patients with ACTH-deficiency of possible autoimmune aetiology. Sixty-five patients with ACTH-deficiency and 57 healthy subjects participated in the study. Pituitary autoantibodies were measured by an immunoblotting assay with human pituitary cytosol as antigen. Autoantibodies to a novel 36-kDa pituitary autoantigen were seen in sera from 18.5% (12/65) patients and only 3.5% (2/57) of control subjects (P = 0.0214). When taking only those subjects with strong immunoreactivity into account, the significance was lost; P = 0.3642. Immunoreactivity to a 49-kDa pituitary autoantigen was observed in 21.5% (14/65) of ACTH-deficient patients compared with 8.8% (5/57) of control subjects (P = 0.0910). This 49-kDa pituitary autoantigen has recently been identified as neurone-specific enolase and a candidate marker for neuroendocrine autoimmunity. Clinical parameters in patients with positive versus those with negative pituitary immunoreactivity did not differ. However, autoantibodies to thyroglobulin were positively correlated to immunoreactivity against the 36-kDa pituitary autoantigen (P = 0.014). Our findings of pituitary autoantibodies in patients' sera support the theory that an autoimmune destruction of corticotrophs may be the underlying cause of hormonal deficit in some patients with ACTH-deficiency.
    European Journal of Clinical Investigation 03/2005; 35(2):126-32. · 3.37 Impact Factor
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    ABSTRACT: The cause of empty sella syndrome (ESS) remains largely unknown. We measured eleven organ-specific autoantibodies in serum in order to evaluate possible autoimmune components in ESS. Thirty patients with ESS and 50 healthy blood donors participated in the study. Detection of pituitary autoantibodies was performed by immunoblotting with human pituitary cytosol as antigen. Thyroid peroxidase (TPO) and TSH receptor (TRAK) autoantibodies were analysed by radioimmunoassay. The remaining eight autoantibodies were detected by in vitro transcription and translation of the autoantigens and immunoprecipitation. The majority of the ESS patients (18/30) exhibited no immunoreactivity at all. None of the remaining 12 ESS patients reacted against more than one autoantigen. No immunoreactivity was found more frequently among ESS patients than healthy blood donors. Pituitary autoantibodies were not correlated to the ESS patients' pituitary function or sellar size, although the results indicated a tendency of increased autoimmunity in patients with hypopituitarism and normal sella size respectively. Detection of autoantibodies is a valuable tool in the diagnostic work-up of autoimmune diseases. By analysing a large number of organ-specific autoantibodies we found no evidence of ESS being associated with any specific autoimmune disease. The pathogenesis of ESS is believed to be heterogeneous and our findings suggest autoimmune components to be of minor importance. In some selective cases, ESS in combination with hypopituitarism may be the result of an autoimmune disease in the pituitary gland but this needs further investigation.
    Experimental and Clinical Endocrinology & Diabetes 06/2004; 112(5):231-5. · 1.56 Impact Factor

Publication Stats

187 Citations
81.76 Total Impact Points

Institutions

  • 2014
    • Haukeland University Hospital
      • Department of Medicine
      Bergen, Hordaland, Norway
  • 2013
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 2006–2013
    • Karolinska Institutet
      • Department of Molecular Medicine and Surgery
      Solna, Stockholm, Sweden
  • 2004–2008
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden