High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry.

OBJECTIVE: To study the presence and levels of GAD65 antibodies (GADA), IA-2 antibodies (IA-2-A), and islet cell antibodies (ICA) during the first years after clinical onset of type 1 diabetes in relation to age at diagnosis. RESEARCH DESIGN AND METHODS: Type 1 diabetic patients (n = 194) <40 years of age were consecutively recruited at the time of diagnosis by the Belgian Diabetes Registry and followed during the first 4 years of insulin treatment. ICA were determined by indirect immunofluorescence assay and IA-2-A, GADA, and insulin autoantibodies by a radioligand assay. RESULTS: Overall, 94% of initially antibody-positive patients (n = 180) remained positive for at least 1 antibody type 4 years after diagnosis. In the case of diagnosis after 7 years of age, GADA, IA-2-A, and ICA persisted in 91, 88, and 71%, respectively, of the initially antibody-positive patients. Antibody persistence was lower in those diagnosed at <7 years of age, amounting to 60% for GADA, 71% for IA-2-A, and 39% for ICA. In 57% of the initially antibody-positive patients, at least 1 type of autoantibody reached peak values after diagnosis. This occurred more frequently for clinical onset after 7 years of age and more often for GADA (49%) than for IA-2-A (29%) or ICA (19%). Of the patients, 24% that were negative for GADA at onset became GADA-positive during the following 4 years. Among the 7% initially antibody-negative patients, 2 of 14 subjects developed antibodies after clinical onset. CONCLUSIONS: In particular, for diagnosis after 7 years of age, islet cell-specific autoantibodies generally persist for many years after diagnosis. There is also a high frequency of increasing antibody levels and of conversion to antibody positivity in the first 4 years after diagnosis and start of insulin treatment. Thus, determination of antibodies at diagnosis can underestimate the number of cases with autoimmune type 1 diabetes, in particular with assays of lower sensitivity. The divergent temporal patterns of ICA, GADA, and IA-2-A suggest that the ICA test recognizes other antibody specificities besides GADA and IA-2-A and reflects other autoimmune processes; it also indicates that GADA assays have a higher diagnostic sensitivity in the period after clinical onset.

Cabergoline in the treatment of acromegaly: a study in 64 patients.

Cabergoline is a new, long acting, dopamine agonist that is more effective and better tolerated than bromocriptine in patients with hyperprolactinemia. Because dopamine agonists still have a place in the medical management of acromegaly, cabergoline might be a useful treatment. We, therefore, evaluated the effect of long term administration of cabergoline in a large group of unselected acromegalic patients. Sixty-four patients were included in a multicenter, prospective, open labeled study. A subgroup of 16 patients had GH-/PRL-cosecreting pituitary adenomas. Cabergoline was started at a dose of 1.0 mg/week and was gradually increased until normalization of plasma insulin-like growth factor I (IGF-I) levels, occurrence of unacceptable side-effects, or a maximal weekly dose of 3.5 mg (7.0 mg in 1 case) was reached. Treatment with cabergoline suppressed plasma IGF-I below 300 micrograms/L in 39% of cases and between 300-450 micrograms/L in another 28%. With pretreatment plasma IGF-I concentrations less than 750 micrograms/L, a suppression of IGF-I below 300 micrograms/L was obtained in 53% of cases, and a suppression between 300-450 micrograms/L was obtained in another 32%. By contrast, with pretreatment plasma IGF-I concentrations above 750 micrograms/L, only 17% of cases showed a suppression of IGF-I below 300 micrograms/L, and there was IGF-I suppression between 300-450 micrograms/L in another 21%. In GH-/PRL-cosecreting adenomas, 50% of cases suppressed plasma IGF-I levels below 300 micrograms/L, and another 31% did so between 300-450 micrograms/L, in contrast to only 35% and 27%, respectively in GH-secreting adenomas. Similar results were obtained concerning the secretion of GH. Tumor shrinkage was demonstrated in 13 of 21 patients, with a mass reduction by more than half in 5 GH-/PRL-cosecreting adenomas. Except for slight gastrointestinal discomfort and orthostatic hypotension in a few patients at the beginning of therapy, cabergoline treatment was well tolerated. Only 2 patients stopped medication because of nausea. The weekly dose of cabergoline ranged between 1.0-1.75 mg. A further increase in the dose was only effective in 1 GH-/PRL-cosecreting adenoma. The results of this study suggest that cabergoline is an effective, well tolerated therapy that should be considered in the management of acromegaly, especially if the pituitary adenoma cosecretes GH and PRL or if pretreatment plasma IGF-I levels are below 750 micrograms/L.

Marked elevation and cyclic variation of corticosteroid-binding globulin: an inherited abnormality?

Unexplained high serum corticosteroid-binding globulin (CBG) concentrations [mean values, 78.8 and 55.7 mg/L; normal women, 38.8 +/- 3.8 (+/- SD) mg/L] were found repeatedly in two apparently healthy sisters who were not pregnant or taking exogenous estrogens. One had substantial variations in serum CBG and sex hormone-binding globulin concentrations during the menstrual cycle, which paralleled the normal cyclic changes in serum estradiol. The other woman was postmenopausal and had a high serum CBG concentration despite of low serum estradiol levels. We conclude those women have an inherited abnormality in CBG production.

Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin.

A method to calculate unbound cortisol from total cortisol (measured by competitive protein binding) and CBG (measured by radial immunodiffusion) based on the binding equilibrium has been evaluated. The calculated results (y) correlate well with those (x) obtained by centrifugal ultrafiltration at 37 degrees C (y = 1.04 x - 2.11 ng/ml; r = 0.975; n = 150). The concentration of CBG is similar in normal men (37.7 +/- 3.5 (SD) micrograms/ml; n = 12) and women (39.5 +/- 3.7 (SD) micrograms/ml; n = 7) and shows no diurnal variation, but marked diurnal variation is observed for total cortisol (193.7 +/- 35.0 (SD) ng/ml at 08.00 h vs 43.2 +/- 23.3 (SD) ng/ml at 22.00 h; n = 19) and particularly for unbound cortisol (16.5 +/- 5.6 (SD) ng/ml at 08.00 h vs 2.3 +/- 1.8 (SD) ng/ml at 22.00 h; n = 19). The concentration of CBG (89.1 +/- 11.2 (SD) micrograms/ml) and of total cortisol (395.6 +/- 103.3 (SD) ng/ml at 08.00 h; 110.3 +/- 16.6 (SD) ng/ml at 22.00 h) are clearly elevated in estrogen treated women (n = 11) but unbound cortisol levels (17.2 +/- 7.7 (SD) ng/ml at 08.00 h; 2.5 +/- 0.5 (SD) ng/ml at 22.00 h) are similar to the control group. The concentration of CBG is significantly decreased in patients with Cushing's syndrome (33.2 +/- 5.6 micrograms/ml; n = 17) and unbound cortisol is relatively more elevated than total cortisol in these patients. In adrenal insufficiently CBG is normal, but total and unbound cortisol are markedly decreased. There is a significant decrease of CBG in hyperthyroidism (35.7 +/- 5.5 micrograms/ml; n = 22), in cirrhosis (32.0 +/- 8.0 micrograms/ml; n = 14) and in renal disease and a significant increase in patients treated with antiepileptic drugs (47.5 +/- 6.3 micrograms/ml; n = 14), but total and unbound cortisol are normal in all these conditions. We conclude that unbound cortisol can be calculated in a simple and reliable way from total cortisol and CBG and permits a better evaluation of adrenal function, particularly in patients with altered CBG concentrations.

Mediastinal parathyroid localization: possible pitfall in technetium-thallium subtraction scintigraphy.

Two cases of mediastinal localization of parathyroid adenoma are presented, in which technetium-thallium subtraction scintigraphy yielded a positive result. Both patients had already undergone a negative surgical neck exploration. We suggest that, in case of negative subtraction scintigraphy and negative surgical exploration in proven primary hyperparathyroidism, subtraction scintigraphy should be repeated with emphasis on the superior mediastinum, and in all cases, the use of a non-zoom, large field of few procedure is recommended for technetium-thallium subtraction scintigraphy.

The use of 131I-meta-iodobenzylguanidine in clinical diagnosis and staging of neuroectodermal tumors. Two case reports.

131I-Meta-iodobenzylguanidine has proved to be useful for the diagnosis of different kinds of neoplasms of neuroectodermal origin. The value of this scintigraphic method as a complementary technic to conventional diagnostic tests for staging in a child with neuroblastoma is described. In another child an ontogenetically related tumor, a mediastinal ganglioneuroma, was also visualized.

Diffuse pulmonary uptake of 99mTc bone-imaging agents: case report and survey.

Over the past 5 years, we have encountered 6 cases of diffuse pulmonary uptake of 99m-Tc bone-scanning agents (incidence, 0.04%). To assess the significance of this phenomenon, we reviewed all of the cases reported since 1974 (Including our series, a total of 32 cases). Three groups can be discerned, the first consisting of 24 patients without radiological calcifications in the lungs and with hypercalcemia of different origins (mostly hyperparathyroidism). Of the eight autopsies performed in this group, seven revealed extensive calcifications in alveolar walls and lung vessels; the other autopsy showed no calcification at all and only bronchopneumonic lesions. The second group consists of 6 patients in chronic dialysis. The last group consists of 2 patients having diffuse pulmonary alveolar microlithiasis with extensive radiologic calcifications. The mechanism of lung uptake of 99m-Tc bone-imaging agents is probably the same as that of bone uptake (chemisorption on hydroxyapatite crystals), although other uptake mechanisms have also been discussed. Bone scintigraphy can be useful in the detection of early pulmonary calcifications, which have been associated with impaired pulmonary function and, due to their size, are generally not detected by X-ray.