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E S Husebye

Publications and source records attributed to E S Husebye.

At least 19 recordsLinked to original sources
PubMed2006

Saliva cortisol measurement: simple and reliable assessment of the glucocorticoid replacement therapy in Addison's disease.

No ideal parameter is available for assessment of the glucocorticoid replacement therapy in Addison's disease. Serum cortisol day-curves can be used to monitor the therapy, but this technique is cumbersome and expensive. We evaluated the potential for saliva cortisol measurement in this setting. We found excellent correlation between serum and saliva cortisol after oral intake of cortisone acetate (no. 7) or iv administration of hydrocortisone (no. 4) (Pearson's R=0.83-0.98, p<0.002). A morning dose of 12.5 mg cortisone acetate yielded wide interindividual variations in cortisol levels in saliva. Saliva cortisol measurements were successfully adopted to evaluate and adjust doses in outpatients. We conclude that cortisol measurement in saliva is practical and reliable, and is preferable to serum cortisol measurement in the assessment of the glucocorticoid replacement therapy. Our results confirm that only a minority of patients require more than 12.5 mg of cortisone acetate (equivalent to 10 mg hydrocortisone) in the morning to have sufficient cortisol levels during the first part of the day.

Addison Disease↗
PubMed2005

Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of autoantibodies directed against an epitope of the glutamate/N-methyl-D-aspartic acid (NMDA) receptor subunit NR2A (which is highly expressed in human brain) in the sera of lupus patients, and to investigate the possible correlation of these antibodies with clinical and serological manifestations of systemic lupus erythematosus (SLE). METHODS: Sera were obtained from 109 consecutive SLE patients. Controls were 65 patients with myasthenia gravis, 19 with autoimmune polyendocrine syndrome type I (APS I), and 65 healthy donors. A 15 amino acid long peptide based on a sequence within the NR2A subunit of the NMDA/glutamate receptor was synthesised. Antibodies to this peptide were determined by enzyme linked immunosorbent assay. Antibodies against double stranded DNA (dsDNA) were measured by Chrithidia luciliae assay. Disease activity was determined using the SLE disease activity index (SLEDAI). RESULTS: Sera of 34/109 SLE patients (31%) reacted specifically with the NR2A peptide compared with only 4/65 myasthenia gravis patients (6.1%, p<0.001), 1/19 APS I patients (5.3%, p<0.02), and 3/65 healthy controls (4.6%, p<0.001). No correlation was found between the presence of NR2A and dsDNA or anti-cardiolipin specific autoantibodies. In addition, no significant correlation was observed between the presence of NR2A specific antibodies and the SLEDAI score or any lupus related clinical manifestations. CONCLUSIONS: A significant number of SLE patients (31%) have NR2A specific antibodies that do not correlate with anti-dsDNA antibodies. Additional studies of lupus patients with neurological disorders should elucidate the role of NR2A specific antibodies in lupus related CNS manifestations.

Adult↗
PubMed2004

Pyridoxal phosphatase is a novel cancer autoantigen in the central nervous system.

Autoantibodies against many proteins are common in sera from patients with various types of cancer. These antibodies are sometimes involved in the development of conditions associated with cancer, such as paraneoplastic neurologic disorders. We used a human brain cDNA expression library and serum from a paraneoplastic neurologic disorder patient to search for new autoantigens in the nervous system. Pyridoxal phosphatase was identified as a novel autoantigen. Expression studies showed that pyridoxal phosphatase was strongly expressed in various parts of the central nervous system. Sera contained antibodies against pyridoxal phosphatase in 22 of 243 (9.1%) patients with lung cancer and eight of 113 (7.1%) with other forms of cancer vs two of 88 (2.3%) healthy control subjects. In addition, 2-4% of patients with different autoimmune diseases had autoantibodies against pyridoxal phosphatase. None of the antipyridoxal phosphatase-positive patients were known to have a paraneoplastic neurologic disorder. Hence, autoantibodies against pyridoxal phosphatase correlate with cancer but not necessarily with the subset of patients with paraneoplastic neurological disorders although serum from such a patient was used to screen the cDNA library. This study showed that yet another enzyme involved in pyridoxal 5'-phosphate metabolism is an autoantigen. Thus, pyridoxal 5'-phosphate seems to be a common denominator for autoantigens involved in autoimmune diseases.

Animals↗
PubMed2004

Paraneoplastic antibodies against HuD detected by a sensitive radiobinding assay.

Patients with paraneoplastic encephalomyelitis(subacute sensory neuronopathy) (PEM/SSN), most commonly associated with small-cell lung cancer (SCLC), frequently harbor Hu antibodies, which are usually detected by indirect immunohistochemistry or immunoblot. We developed a new radioimmunobinding assay to detect Hu antibodies based on in vitro transcribed and translated (ITT) HuD. High levels of Hu antibodies were detected in all seven PEM/SSN patients tested, but not in any of 15 patients with other paraneoplastic syndromes, 20 patients with Sjögren's syndrome, 20 patients with miscellaneous tumors and 99 of 100 blood donors. One of the blood donors had low levels of Hu antibodies. The radiobinding assay detected Hu antibodies in 45 of 191 (24%) patients with SCLC, in comparison with immunofluorescence and immuno dot blot, where only 34 of 191 (18%) were detected. All patients with Hu antibodies detected by immunofluorescence and immuno dot-blot were also positive by the radioimmunobinding assay. The results demonstrate that this assay is very specific and sensitive for the detection of Hu antibodies.

Antibodies↗
PubMed2003

High frequency of coeliac disease among patients with autoimmune adrenocortical failure.

BACKGROUND: Coeliac disease (CD) is an autoimmune disease of the small intestine caused by gluten ingestion in genetically predisposed subjects. It can occur isolated or in combination with other autoimmune diseases. Autoimmune Addison's disease is frequently associated with other organ-specific autoimmune diseases. We have investigated the prevalence of CD among a large cohort of patients with autoimmune Addison's disease. METHODS: Seventy-six patients (44 women) with Addison's disease, 52% of whom had polyendocrine failure, were recruited from a registry of organ-specific autoimmune diseases in Norway. All sera were analysed for antibodies against gliadin (AGA), endomysium (EMA) and tissue transglutaminase (tTG). Patients with positive EMA and/or anti-tTG were offered endoscopy. The human leucocyte antigen (HLA) class II genotypes were determined. RESULTS: Five patients had antibodies against both endomysium and tissue transglutaminase. In these five patients, CD was verified by biopsy. One patient had known CD prior to the study. All six patients with CD carried the CD-associated HLA haplotype DR3-DQ2. The total prevalence of CD was 7.9%. CONCLUSION: CD is frequently associated with Addison's disease. The risk of developing CD seems to be higher than can be explained by the common DR3-DQ2 association alone. It is often asymptomatic or associated with unspecific symptoms. Addison patients should be screened for the presence of CD on a regular basis.

Addison Disease↗
PubMed2002

Endoscopic ultrasonography for preoperative diagnosis and localization of insulinomas.

BACKGROUND: Endoscopic ultrasonography (EUS) is generally accepted as a sensitive method for the detection of small pancreatic tumors. We report our experience with EUS for preoperative imaging of insulinomas. METHODS: Nine patients with clinical and biochemical signs of insulinoma were examined by EUS using a 7.5/12 MHz radial-scanning ultrasound endoscope prior to surgery. EUS outcome was evaluated on the basis of surgery (open or laparoscopic) and examination of the resected specimens. RESULTS: Two EUS-negative patients appeared, by reassessment of clinical and biochemical data, not to have an insulinoma and were not operated on. EUS correctly imaged and localized five of seven insulinomas that were surgically removed. One isoechoic tumor in the pancreatic head and one pedunculated tumor connected to the caudal side of the pancreatic body were missed by EUS. EUS could demonstrate the size and shape of the imaged tumors, as well as their relationship to adjacent structures, such as the pancreatic duct, bile duct, and large vessels. CONCLUSIONS: Our experience with seven insulinomas accords with previous reports claiming EUS to be the method of choice for preoperative imaging and localization of pancreatic islet cell tumors.

Adult↗
PubMed2001

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma.

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.

Amino Acid Sequence↗
PubMed2001

Autoimmune polyendocrine syndrome type 1 (APS I) in Norway.

OBJECTIVE: The aim of the present study was to investigate Norwegian patients with autoimmune polyendocrine syndrome type I (APS I), with respect to occurrence and clinical presentation, reactivity towards different autoantigenes and mutations in the autoimmune regulator (AIRE) gene. PATIENTS: Twenty Norwegian patients from 15 families with APS I (11 males, nine females; mean age 26 years, range 4--54) were included by contacting all major hospitals in Norway. METHODS: Clinical data was collected from both patients and their physicians by the use of questionnaires and patient records. Autoantibodies were analysed using radioimmunoassays based on antigen synthesized by in vitro transcription and translation. AIRE mutations were determined by DNA sequence analysis. RESULTS: The prevalence of APS I in Norway was estimated to be about 1 : 80,000 individuals. We found about the same distribution of disease characteristics as has been reported in Finnish patients. The diagnosis was delayed in many individuals. In two thirds of the cases, the patients were admitted in Hospital with acute adrenal insufficiency or hypocalcaemic crisis. Forty percent of these patients already had one of the main disease manifestations. Four different mutations in the AIRE gene were found in the Norwegian cohort. A 13-bp deletion in exon 8 (1085--1097(del)) was the most frequent mutation, present in 22/40 (55%) of the alleles. Eighty-five percent of the patients had either autoantibodies against 21 hydroxylase or aromatic L-amino acid decarboxylase. Five of eight women (age > 13 years) had ovarian failure, and all of these had antibodies against side-chain cleavage enzyme (P = 0.0002). CONCLUSION: Norwegian patients with APS I clinically resemble patients from Finland and other European countries. The diagnosis APS I must be considered in children and adolescents with chronic mucocutaneous candidiasis, autoimmune adrenocortical failure or hypoparathyroidism in order to avoid fatal complications. Analysis of autoantibodies and mutational analysis of the AIRE gene are valuable diagnostic tools, especially in the early stages of the disease.

Adolescent↗
PubMed2000

Inhibition of aromatic L-amino acid decarboxylase activity by human autoantibodies.

A full-length rat cDNA clone encoding aromatic L-amino acid decarboxylase (AADC) (E.C. 4.1.1.28) was used for in vitro transcription and translation. The enzyme had catalytic activity (0. 2 pmol serotonin/microl lysate per min), and was stimulated 2.5-fold by the addition of excess pyridoxal phosphate. On size exclusion chromatography, AADC eluted as a single activity peak with an apparent mol. wt of 93 kD. This activity peak was immunoprecipitated by sera from patients with autoimmune polyendocrine syndrome type I (APS I) containing autoantibodies against AADC. Serum and purified IgG from these patients inhibited the enzyme activity (non-competitively) by 10-80%, while sera from APS I patients without autoantibodies and controls did not. This finding confirms and extends previous observations that APS I patients have inhibitory antibodies against key enzymes involved in neurotransmitter biosynthesis.

Adolescent↗
PubMed2000

Oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease.

OBJECTIVE: Patients with primary adrenocortical failure (Addison's disease) have abnormally low levels of DHEA and androgens relative to age. To define a suitable dose, the effect of oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease (n = 9) was evaluated. DESIGN AND MEASUREMENTS: DHEA was administered as a daily oral dose of either 50 mg (n = 5) or 200 mg (n = 4). Blood sampling and measurements of insulin sensitivity (as measured with euglycemic insulin clamp technique) and body composition (as measured by dual energy X-ray absorptiometry) were performed before and during DHEA treatment and at a 3-month follow up. RESULTS: DHEA and DHEA(S) levels were restored to normal in those patients receiving 50 mg whereas DHEA(S) level was slightly above the normal reference value in those receiving 200 mg. Circulating levels of androgens (androstenedione, testosterone and testosterone/SHBG ratio) were normalized in all patients. A slight rise in IGF-1 levels was seen in both groups as was a decrease in the levels of low and high density lipoproteins. No effect on blood glucose levels or insulin sensitivity was seen and no change of body composition was observed. No serious side-effects were seen, but some of the patients experienced increased apocrine sweat secretion (n = 7), itchy scalp (n = 2) and acne (n = 7), all of which were reversed when DHEA was discontinued. CONCLUSION: A daily replacement dose of 50 mg of DHEA results in near physiological levels of DHEA, DHEA(S) androstenedione and testosterone in women with Addison's disease, without severe side-effects.

Addison Disease↗
PubMed2000

Autoantibodies against aromatic L-amino acid decarboxylase identifies a subgroup of patients with Addison's disease.

Autoantibodies against aromatic L-amino acid decarboxylase (AADC) are present in about 50 percent of sera from patients with autoimmune polyendocrine syndrome type I (APS I) but absent in sera from patients with different organ-specific autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, and Graves' disease. AADC is expressed in the pancreatic beta-cells, the liver, and the nervous system; and the presence of AADC antibodies has been shown to correlate to hepatitis and vitiligo in APS I patients. Among 101 investigated patients with autoimmune Addison's disease, 15 had high titers of AADC antibodies. According to the clinical characteristics of these patients, only 3 had APS I. The remaining 12 had either isolated Addison's disease or associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and 17alpha-hydroxylase were present in 3 of 12. Two patients had only autoantibodies against AADC. DNA was available from 3 of these 12 patients. One of the patients, a woman with Addison's disease, autoimmune thyroiditis, and premature menopause was heterozygous for a point mutation (G1021A, Val301Met) in the first plant homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene. The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients who may have a milder atypical form of APS I or represent a distinct entity. Measurement of autoantibodies against AADC should be included in the evaluation of Addison's disease.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

[Primary adrenal cortex insufficiency--a diagnostic challenge].

Primary adrenocortical insufficiency (Addison's disease) is characterised by weakness, tiredness, fatigue, weight loss, hypotension, hyperpigmentation and a craving for salt. Without treatment lethality is 100%; correctly treated, life expectancy is normal. Addison's disease may appear isolated or as part of a polyendocrine syndrome. Because several of the symptoms are unspecific and develop over the course of several years, many patients are not diagnosed before a life-threatening adrenal crisis develops. Autoimmune destruction of the adrenal cortex is the main cause of adrenocortical failure in the industrialised world. This condition is characterised by circulating autoantibodies against the steroidogenic enzyme 21-hydroxylase. These autoantibodies can now easily be quantified. More unusual causes of adrenocortical failure are tuberculosis, bleeding, metastasis and adrenoleukodystrophy. Using three cases we highlight the clinical, diagnostic and therapeutic aspects of adrenocortical failure.

Addison Disease↗
PubMed1998

A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.

OBJECTIVES: To characterize a family with hereditary paraganglioma, and to search for germline mutations in the von Hippel-Lindau disease (VHL) tumour suppressor gene and the ret proto-oncogene. DESIGN: Patient records and histopathological reports were reviewed. Available tumour samples were reinvestigated using immunohistochemical techniques. The VHL gene was investigated by single strand conformational polymorphism analysis of PCR products amplified from exons 1, 2 and 3 and the 3' untranslated region. The ret gene was analysed by amplifying and sequencing exons 10, 11 and 16. PATIENTS: A family with paragangliomas in three consecutive generations was investigated. RESULTS: The affected individuals were found to have multiple extra-adrenal paragangliomas. All three affected individuals had retroperitoneal tumours, and two also had paraganglioma in the neck. No mutations of the VHL or ret genes were detected. CONCLUSIONS: The described family may represent a novel dominantly inherited neuroendocrine tumour syndrome.

Adolescent↗
PubMed1998

A cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism is associated with autoimmune Addison's disease in English patients.

OBJECTIVE: Recent studies have demonstrated an association between a microsatellite polymorphism of the CTLA-4 gene, specifically a 106 base pair allele, and both Graves' disease and autoimmune hypothyroidism. The aim of the present study was to determine whether the same polymorphism of the CTLA-4 gene was associated with autoimmune Addison's disease. DESIGN AND PATIENTS: We analysed a microsatellite polymorphism (variant lengths of a dinucleotide (AT)n repeat) within exon 3 of the CTLA-4 gene in the following groups: 21 English patients with non-associated Addison's disease, 18 with autoimmune polyglandular syndrome type 2 (APS2) and 173 healthy control subjects; 26 Norwegian patients with non-associated Addison's disease, 9 with autoimmune polyglandular syndrome type 1 (APS1), 17 with APS2 and 100 controls; 3 Finnish patients with non-associated Addison's disease, 5 with APS2 and 71 controls; 10 Estonian patients with non-associated Addison's disease, 2 with APS2 and 45 controls. MEASUREMENTS: The CTLA-4 microsatellite gene polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. RESULTS: The frequency of the 106 base pair allele was significantly increased in the groups of English patients with either non-associated Addison's disease or APS2 (P = 0.02 and 0.04, respectively), when compared to healthy controls with no clinical evidence or family history of either Addison's disease or any other autoimmune disorder. For Norwegian patients with either non-associated Addison's disease, APS1 or APS2, there was no association (P = 0.69, 0.62 and 0.97, respectively). This was also the case for Finnish patients with either non-associated Addison's disease or APS2 (P = 0.23 and 0.28, respectively) and for Estonian patients with either non-associated Addison's disease or APS2 (P = 0.34 and 0.29, respectively). CONCLUSIONS: These results indicate that differences exist in the frequency of the 106 base pair allele in different population groups and in only the English population was the 106 base pair allele associated with Addison's disease.

Abatacept↗
PubMed1997

Cytochrome P450IA2 and aromatic L-amino acid decarboxylase are hepatic autoantigens in autoimmune polyendocrine syndrome type I.

Autoimmune chronic active hepatitis (AI-CAH) is a feared component of autoimmune polyendocrine syndrome type I (APS I). In this study, immunoreactivity was assessed in sera from eight APS I patients, of whom three had AI-CAH, in an attempt to identify hepatic autoantigens. We performed indirect immunofluorescence staining of human and rat liver sections, Western blots on subcellular fractions of human and rat liver, immunoprecipitations of labelled aromatic L-amino acid decarboxylase (AADC) and cytochrome P450IA2 (CYP IA2) expressed by an in vitro transcription and translation system and studies of enzymatic activity. Autoantibodies against AADC were present in sera from all eight APS I patients, while immunoreactivity against CYP IA2 was only found in sera from the three APS I patients with AI-CAH. Enzymatic activity of CYP IA2 was inhibited by sera from APS I patients with AI-CAH but not by control sera. Our results show that CYP IA2 and AADC constitute hepatic autoantigens in patients with APS I and that immunoreactivity against CYP IA2 is associated with the presence of AI-CAH.

Animals↗
PubMed1997

Autoantibodies against aromatic L-amino acid decarboxylase in autoimmune polyendocrine syndrome type I.

Patients with autoimmune polyendocrine syndrome type I (APS I) have autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic beta-cells. The aim of the present study was to investigate the presence of anti-AADC antibodies in a large cohort of patients with APS I, and in patients with isolated insulin-dependent diabetes mellitus (IDDM). We found autoantibodies against AADC in 35 of 69 patients (51%) with APS I but in none of 138 patients with isolated IDDM or 91 healthy controls. Among the patients with APS I, anti-AADC antibodies were more often found in those with hepatitis (11/12, 92%), than in those without hepatitis (24/57, 42%) (P = 0.003). Similarly, of 15 patients with vitiligo, 12 (80%) had anti-AADC antibodies, compared with 23/54 (43%) without vitiligo (P = 0.021). Of the 9 APS I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Interestingly, AADC is present in relatively large amounts in the liver, where its function is unknown. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in APS I patients, whereas the role of AADC in the development of IDDM in these patients remains to be determined.

Adult↗