Islet autoimmunity before and after pancreas transplantation in patients with Type I diabetes mellitus.
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Autoantigens↗
Biomedical subjects
F A Karlsson
Publications and source records attributed to F A Karlsson.
Iodine status, thyroid function and pregnancy: study of Swedish and Sudanese women.
OBJECTIVE: To examine and compare the effects of pregnancy on the thyroid hormone homeostasis in two different populations with variable iodine supply. DESIGN: A longitudinal prospective cohort study throughout pregnancy involving Swedish and Sudanese pregnant women. SETTING: The subjects were enrolled consecutively during their antenatal follow-up at health centres at Nyby in Uppsala, Sweden and Omdurman in Sudan. SUBJECTS: Fifty-one apparently healthy women from Uppsala, Sweden and twenty-eight pregnant women from Omdurman, Sudan were recruited during pregnancy. The mean age and weight of the Swedish women at the beginning of pregnancy were 29.9+/-5.4 y and 66.3+/-12.9 kg respectively. The corresponding figures for the Sudanese women were 28.0+/-4.9 y and 64.8+/-9.4 kg respectively. METHODS: Blood samples were drawn on four occasions from the Swedish group at 11-13, 24, 32, and 38 weeks of pregnancy, and on three occasions from the Sudanese group at 10-12, 20-24, and 36-39 weeks. Twenty-four hour urine samples were collected from the same subjects and on the same occasions as blood sampling. The urine samples were kept in a refrigerator until the volumes were measured, after which 20 mL aliquots were taken and kept frozen until analysed. MAIN OUTCOME MEASURES: Twenty-four hour urinary iodine output, TSH, FT4 and T3. RESULTS: The 24 h urinary iodine output at the different times during gestation were higher among the Swedish women, with mean values (95% confidence interval) of 1.40 (1.19-1.61), 1.33 (1.14-1.51), 1.45 (1.06-1.84) and 1.14 (0.88-1.39) micromol/d, than among the Sudanese cohort, with corresponding values of 0.49 (0.27-0.72), 0.29 (0.19-0.39), 0.56 (0.25-0.88) micromol/d. No significant changes in daily urinary iodine loss were observed in the two groups with progression of pregnancy. However, in the Swedish women the mean free T4 concentration fell from 11.81 pmol/l at the beginning of pregnancy to 8.82 pmol/l and the mean TSH rose from 1.11-1.95 mU/I between the beginning and end of pregnancy. Such changes were not detected among the Sudanese women, who had significantly lower mean TSH values than the Swedish women in weeks 36-39 of pregnancy (P < 0.02), and significantly higher FT4 values than the Swedish women both in weeks 20-24 and in weeks 36-39 (P < 0.005 and P < 0.001) respectively. CONCLUSIONS: The study suggests that determination of urinary iodine alone gives inadequate information about the capacity of an individual to utilize an available iodine supply and it also shows the existence of different patterns of thyroid response during pregnancy. The history of iodine availability prior to and during pregnancy seems to be an important determinant of the mechanism of thyroid gland response to ensure the extra iodine needed by the growing fetus.
Adult↗
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↗
Childhood Graves' disease--remission rate and risk factors.
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Child↗
Induction of beta-cell rest in type 1 diabetes. Studies on the effects of octreotide and diazoxide.
OBJECTIVE: To evaluate the inhibitory effects of octreotide and diazoxide on insulin secretion in patients with type 1 diabetes and measurable levels of circulating C-peptide. RESEARCH DESIGN AND METHODS: Diazoxide was given to six patients during a 7-day period (100 mg three times daily), followed by a 3-week washout. Subsequently, octreotide (50 micrograms, three times daily) was administered subcutaneously for 7 days. Pre- and post- prandial blood glucose and serum C-peptide concentrations were measured before medication (control) and on day 7 of each medication period. Glucagon-stimulated C-peptide was determined in the morning before medication and on the day after each treatment period. RESULTS: Diazoxide inhibited glucagon-stimulated C-peptide secretion (mean increment 0.08 nmol/l vs. 0.18 nmol/l, P < 0.05), whereas octreotide had no such effect. Both reduced the pre- and postprandial serum C-peptide concentrations (P < 0.05), octreotide being the more potent in this respect. A reduction in basal and meal-related blood glucose was observed during octreotide treatment, whereas the glucose concentrations tended to be higher during treatment with diazoxide than during the 24-h control period. CONCLUSIONS: The study indicates that the two drugs reduce insulin output by different mechanisms. Diazoxide inhibits hormonal release directly on the beta-cells, whereas octreotide exerts its effect indirectly, presumably by multiple actions on insulin sensitivity and insulin-releasing hormones. The results suggest that each drug is capable of inducing beta-cell rest in type 1 diabetes.
Adult↗
Marked gender differences in ambulatory morning growth hormone values in young adults.
The influence of gender on serum concentrations of growth hormone (GH) and 12 other endocrine analytes was investigated in sera drawn from 291 healthy medical students in the ambulatory state in the morning, after fasting overnight. GH was measured with a sensitive noncompetitive fluoroimmunoassay. The median GH value was 80-fold higher in women 21-26 years old than in age-matched men (14.4 vs 0.18 mIU/L), compared with a female/male ratio of 2.2 for 17beta-estradiol and a male/female ratio of 14 for testosterone. Furthermore, the values for sex hormone-binding globulin, follicle-stimulating hormone, luteinizing hormone, prolactin, and insulin-like growth factor 1 (IGF-1) were higher, whereas the values for free thyroxine, triiodothyronine, thyroid-stimulating hormone, and parathyroid hormone were lower in the women. The median GH value was 68-fold higher in women 27-43 years old than in age-matched men (10.9 vs 0.16 mIU/L). Women taking contraceptives with ethinyl estradiol and desogestrel or levonorgestrel had higher GH values, and the desogestrel group had lower IGF-1 values than women not taking contraceptives. The median GH values in these groups were 125- and 117-fold higher, respectively, than in men 21-26 years old. The results suggest that routine morning activity produces a marked GH response in >90% of young women but in very few age-matched men. The effect on GH was even more pronounced in women taking oral contraceptives, suggesting that the intake of ethinyl estradiol contributes to higher GH concentrations in these women.
Adult↗
[Treatment of Graves disease. An endocrinologic-surgical perspective].
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Antithyroid Agents↗
Iodine nutrition in Sudan: determination of thyroid-stimulating hormone in filter paper blood samples.
In this study we examined the technique of measuring thyroid-stimulating hormone (TSH) on filter paper blood samples for use in evaluating the iodine nutrition status of newborns and adults living in iodine-deficient areas. Filter paper blood samples were obtained between the 5th and 7th day after birth from 103, 43 and 103 term newborns living in Khartoum (mild iodine deficiency), Kosti (moderate iodine deficiency) and Darfur (severe iodine deficiency), respectively. TSH was measured with a commercial assay and the levels were compared with those obtained with the same method in 1147 samples from term Swedish newborns, obtained on the 3rd to the 5th day of life. The mean (95% confidence interval) TSH levels of the three Sudanese groups and the Swedish group were 7.1 (4.8-9.4), 8.3 (6.6-10.1), 11.9 (0.9-22.9) and 4.51 (3.8-5.3) mU l-1, respectively. The mean TSH for all three Sudanese groups was higher than the Swedish mean (p < 0.001). TSH levels determined in filter paper blood samples from adults living in an iodine-deficient area showed a correlation (p < 0.001; r = 0.55) to levels in corresponding serum samples (range 0.52-14.1 mU l-1, median 3.4 mU l-1). No significant correlation was found, however, between blood spot levels and serum levels within the reference range (< 5 mU l-1). A modification of the commercial procedure consisting in using three instead of two monoclonal antibodies did not sufficiently improve the assay for measurements of TSH within the reference range. Thus, there is a need to develop the filter paper technique further to make it a useful test for monitoring iodine deficiency in populations expected to have TSH levels close to the reference range. In the examination of neonates, however, with their birth-induced surge of TSH, the current assay promises to be a convenient tool for discovering iodine deficiency within a community.
Filtration↗
Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women.
Thirty-six patients with adult-onset GH deficiency (GHD) were examined before and after 9 months of treatment with recombinant GH. The study was conducted as a double blind, placebo-controlled, 21-month trial with a cross-over design, with each treatment period lasting for 9 months. The same dose, adjusted for body surface area, was given to men (n = 21) and women (n = 15), and the effects on body composition and biochemical parameters were evaluated with respect to gender. The extent of GHD, assessed before therapy from basal GH secretion and GH release in response to provocative tests, did not differ between the two groups. The men, however, had higher serum insulin-like growth factor I concentrations than the women (mean +/- SD, 126 +/- 71 vs. 61 +/- 32 micrograms/L; P = 0.0003), less body fat, and greater lean body mass. Upon treatment, insulin-like growth factor I concentrations increased more in men than in women (by 305 +/- 136 and 198 +/- 96 micrograms/L, respectively; P = 0.02). The men lost more body fat than the women (7.4 +/- 4.1% vs. 3.3 +/- 3.8%; P = 0.002), whereas the difference in gain in lean body mass failed to reach statistical significance. Serum levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and plasminogen activator inhibitor-1 decreased in the male group (P = 0.003, P = 0.03, P = 0.0009, and P = 0.01, respectively), but not in the females. Serum markers of bone formation, namely osteocalcin, procollagen type I, bone-specific alkaline phosphatase, and a marker of bone resorption, telopeptide of collagen type I, increased more markedly in men than in women. Lipoprotein(a) increased to a similar extent in the male and female groups. The data demonstrate that men and women with GHD display marked differences in their responsiveness to GH replacement therapy. These differences should be taken into consideration when optimizing the treatment of GHD patients.
Adult↗
Beta-cell rest: a strategy for the prevention of autoimmune diabetes.
An autoantigen being recognized by specific receptors is the key reaction of an autoimmune disease. Whereas much efforts have been made to develop immunosuppressive regimens which reduce the amount of effector cells, and/or inhibit receptor activation, surprisingly little attention has been paid to reduce the ligand-receptor interaction by interfering with the amount of antigen being presented from the target cells. In this review, we discuss clinical observations in autoimmune endocrine disease which illustrate that target cell alterations can modify the disease activity and comment on recent clinical trials which indicate that beta-cell rest may be beneficial to the course of human autoimmune diabetes mellitus.
Autoantibodies↗
Control of iodine deficiency using iodination of water in a goitre endemic area.
Salt iodination is the method of choice for prevention of iodine deficiency in most parts of the world. However, establishment of such a program frequently involves considerable changes in the marketing and distribution patterns and requires years to achieve. This study was conducted to evaluate the efficiency of using well-defined water sources containing iodine-saturated silicon matrices for providing adequate iodine supply to an iodine deficient population in Kordofan State, Western Sudan. A system of water iodination using silicon matrices containing 30% sodium iodide placed in polyethylene baskets was used in four villages using either traditional wells or hand pumps. Before and every 6 months after iodination of water, urine and blood samples were obtained for determination of iodine and thyroid-related hormones, respectively. Goitre assessment on the village populations were performed at the start and 2 years later. Improvements in iodine status were recorded in all the study villages. The water iodine concentrations increased and a higher iodine content was observed in the hand pumps compared to the traditional wells. The median urinary iodine concentrations increased significantly, from 0.19, 0.20, 0.19, 0.11 to 1.20, 1.10, 0.37, 0.30 mumol/l in the four villages, respectively. The percentages of subjects with serum TSH above 4 mU/l were decreased from more than 30% before iodination to less than 15% at 2 years after iodine supply and the mean serum thyroxine hormone values rose. The rates of goitre decreased from 69% to less than 25%. The study shows that this system is effective, cheap, safe and practically applicable under conditions prevailing in rural areas in developing countries with iodine deficiency.
Female↗
Long-term octreotide therapy in growth hormone-secreting pituitary adenomas: evaluation with serial MR.
PURPOSE: To compare the changes in tumor volume with length of octreotide treatment in patients with acromegaly, to analyze signal alterations of the pituitary mass during treatment, and to determine an optimal MR imaging protocol. METHODS: Eighteen patients with growth hormone (GH)-secreting pituitary adenomas were studied with MR imaging before and during octreotide treatment. The length of follow-up was 9 to 70 months. Tumor volume, extension, and signal characteristics were evaluated. RESULTS: The total pituitary volume decreased in 16 patients by a mean of 37%. In 11 patients the tumor could be demarcated from the normal gland, and mean tumor reduction was 51%. Most of the tumor reduction took place within the first year, but an additional effect was noted in four patients during the following 3 years. Tumor reexpansion, hemorrhage, or necrosis did not occur. Serum GH levels were effectively lowered within the first year, with slight additional reductions thereafter. CONCLUSION: In long-term octreotide treatment of GH-secreting pituitary adenomas, tumor shrinkage occurs primarily during the first year, but effects are noted up to 4 years. The treatment may be considered an alternative to surgery in the select group of patients in whom the peripheral effects of chronic GH elevation, as determined by serum insulinlike growth factor I (IGF-I), are controlled. We suggest MR imaging with T1-weighted coronal and sagittal images at baseline and after 3 and 12 months, with additional MR imaging if GH or IGF-I levels rise during treatment. At baseline, both noncontrast and contrast-enhanced images should be obtained. Unenhanced images may be sufficient during follow-up unless tumor reexpansion occurs or surgery is anticipated.
Acromegaly↗
[Future diabetes therapy--a personal viewpoint].
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Autoimmunity↗
Growth hormone treatment affects brain neurotransmitters and thyroxine [see comment].
OBJECTIVE: Binding sites specific for growth hormone have been identified in the brain, but the action of GH on the central nervous system is still poorly understood. DESIGN: In a double-blind, placebo-controlled 21-month trial with a cross-over design, with each treatment period lasting for 9 months, we investigated the long-term effect of GH on the cerebrospinal fluid (CSF) concentrations of some brain neurotransmitters and thyroid hormones of importance for mood and cognition. PATIENTS: Twenty-four patients with documented GH deficiency acquired in adult life took part. RESULTS: Analysis of CSF collected at the end of the two treatment periods showed that the GH concentration was related to the administered dose of rhGH (r = 0.56, P = 0.0044). After rhGH treatment the concentration of the dopamine metabolite homovanillic acid (HVA) had decreased from 218 +/- 80 to 193 +/- 82 nmol/l (P = 0.002) and that of the excitatory acid aspartate had increased from 233 +/- 81 to 313 +/- 116 nmol/l (P = 0.032). No effects were observed on the concentrations of 5-hydroxyindoleacetic acid (the serotonin metabolite) and of 3-methoxy-4-hydroxyphenyl glycol (the noradrenaline metabolite), or on those of glutamate, glycine and beta-endorphin. However, both CSF and serum levels of free T4 decreased, from 19.8 +/- 6.1 to 16.6 +/- 5.7 nmol/l (P = 0.0002) and 17.0 +/- 5.0 to 13.7 +/- 4.3 nmol/l (P = 0.0001), respectively. The concentration of total T3 was not measurable in CSF but increased in serum from 1.41 to 1.53 nmol/l (P = 0.01). CONCLUSION: The study demonstrates a passage of GH from the circulation into the CSF. The observed changes in homovanillic acid and free T4 are similar to those reported after successful treatment of depressive disorders with antidepressant drugs, and may reflect a beneficial effect of GH on mood and behaviour.
Adult↗
Adrenal autoantibodies and organ-specific autoimmunity in patients with Addison's disease.
OBJECTIVE: Autoimmune destruction of the adrenal gland is the major cause of Idiopathic Addison's disease, but the significance of 21-hydroxylase autoantibodies and their correlation with the presence of other autoantibodies have not so far been investigated in a larger population of patients with Addison's disease. We have now characterized a cohort of patients with idiopathic Addison's disease (n = 97) regarding the specificity of autoantibodies against the adrenal cortex and, as Addison's disease can be either an isolated condition or part of a polyendocrine disorder, we investigated the presence of organ-specific polyendocrine autoimmunity in this patient population. DESIGN: Cross-sectional study. MEASUREMENTS: Autoantibodies were analysed with indirect immunofluorescence (IF) on tissue preparations, ELISA and in Western blots using bacterially expressed proteins. RESULTS: Eighty-four per cent (81/97) of the patient sera recognized the steroid-producing cells of the adrenal cortex in indirect IF. The antigen was identified as 21-hydroxylase by 72% (70/97) of the patient sera in Western blots. Seven sera that were negative on adrenocortical IF identified 21-hydroxylase on Western blot, while eight IF-positive sera were 21-hydroxylase-negative. Five sera weakly recognized 17 alpha-hydroxylase in Western blots, but all of these were also positive for 21-hydroxylase. In 13 cases (12 women), the sera also reacted with testicular Leydig cells, and nine of these identified the side-chain cleavage (SCC) enzyme. Other clinically evident organ-specific autoimmune disorders were present in 40% of the 97 patients and abnormal titres of organ-specific antibodies were found in 60% of the patients. CONCLUSIONS: In idiopathic Addison's disease, auto-antibodies against 21-hydroxylase are found in a majority of cases and this represents an important diagnostic tool. The enzyme 17 alpha-hydroxylase does not seem to constitute a major autoantigen in Addison's disease. In a subgroup of patients with autoantibodies to gonads, antibodies to SCC are produced, often in parallel with antibodies to 21-hydroxylase. In yet another subgroup the specificity of autoantibodies giving positive immunofluorescence is still unknown. Three patients revealed a polyendocrine syndrome which clinically resembles autoimmune polyendocrine syndrome (APS) type I, but serologically corresponds to APS type II. Polyendocrine disorders are often associated with Addison's disease, and screening, including quantification of autoantibodies, may help to identify those at risk of developing associated autoimmune disorders.
Addison Disease↗
Autoantibodies against adrenal medulla in type 1 and type 2 diabetes mellitus: no evidence for an association with autonomic neuropathy.
OBJECTIVE: To examine the role of autoimmunity in the development of autonomic neuropathy in diabetes mellitus. DESIGN: Retrospective cross-sectional study. SETTING: The Department of Medicine, University Hospital, Uppsala, and the Department of Endocrinology, University of Lund, Malmö General Hospital, Malmö, Sweden. SUBJECTS AND MAIN OUTCOME MEASURES: We examined 135 patients with type 1 (n = 96) or type 2 (n = 39) diabetes mellitus. Tests for cardiovascular autonomic functions were performed, and patient sera were analysed for the presence of autoantibodies against the adrenal medulla by indirect immunofluorescence, Western blot and immunoprecipitation techniques. RESULTS: Sera from 13% (12/96) of the type 1 and 20% (8/39) of the type 2 patients showed a positive cytoplasmic immunofluorescence (IF) staining of the adrenal medullary cells, as did 20% (30/151) of sera from healthy controls. Fifty-eight and 64% of type 1 and type 2 patients, respectively, had cardiovascular autonomic neuropathy, but no correlation between autonomic neuropathy and positive IF against the adrenal medulla was observed, with the exception of significant drops in diastolic blood pressure 8 min after tilt (P < 0.005) in type 1 patients. The various IF-positive sera reacted with several different proteins when analysed with Western blot technique using a total homogenate of the bovine adrenal medulla. These did not correspond to any of the proteins involved in the synthesis or storage of catecholamines which were considered as putative autoantigens. CONCLUSION: The finding of similar frequencies of immunoglobulins binding to adrenal medulla in both type 1 and 2 diabetic patients as well as in normal controls, argues against a role of anti-adreno-medullary antibodies in the pathogenesis of autonomic diabetic neuropathy.
Adrenal Medulla↗
Autoimmune endocrine disease.
Endocrine cells may become targets for autoimmune processes resulting in cellular dysfunction and diseases which cause considerable morbidity. The thyroid follicular cells, the parietal cells of the gastric mucosa, the insulin-producing islet cells and the adrenal cortical cells are most often affected. This rank order may indicate a relationship between antigen mass and prevalence of disease in a given organ (15).
Autoantibodies↗
Graves' disease in children and adolescents. Late results of surgical treatment.
All children and adolescents with Graves' disease in the county of Uppsala (catchment area population 250,000) treated between 1970 and 1994 were evaluated in a retrospective study. The material comprised 31 patients with a mean age of 11 years (range 4-16), 29 (94%) of whom were girls, and four (13%) of the patients had Down's syndrome. Treatment was primarily conservative and surgery was considered if prolonged medical treatment failed. Lasting remission after antithyroid drug therapy (median 6.5 years; range 4.5-8 years) was noted in 6/31 patients (19%), three (10%) of whom subsequently developed hypothyroidism. Twenty-four of the remaining patients (77%) ultimately underwent subtotal (N = 20) or total thyroidectomy (N = 4) after experiencing one or more episodes of recurrent hyperthyroidism during medical treatment (median 6 years; range 0.5-11 years). After surgery one patient developed permanent hypocalcemia requiring low-dose vitamin D supplementation. During a postoperative follow-up period of 12.2 years ( median; range 1-17 years), there were two cases of recurrent thyrotoxicosis, 1 and 10 years after surgery. The results underline that gender and Down's syndrome are risk factors of juvenile Graves' disease and that the disorder often is difficult to control by long-term medical therapy. In such cases thyroid surgery offers a safe and prompt reversal of the thyrotoxicosis. A proportion of the patients may ultimately develop hypothyroidism, substantiating a need for long-term follow-up of persons afflicted with Graves' disease early in life.
Adolescent↗