Thyroid function at the third trimester of pregnancy in a Northern French population.

OBJECTIVES: During pregnancy, the production rate of thyroid hormone increases when iodine intake is sufficient. However, the appropriateness of the free thyroxin (FT4) immunoassay is questionable. We have therefore evaluated prospectively the thyroid function in pregnancy and the relevance of the FT4 immunoassay. PATIENTS AND METHODS: The thyroid function of 114 pregnant, healthy Parisian women with mild iodine deficiency was studied at the third trimester of pregnancy, 55 of whom served as their own control three months after delivery, and the results were compared to North American reference values. RESULTS: All French pregnant women showed an increase in thyroxin binding globulin (TBG) serum levels. FT4 levels decreased by about 30% at the third trimester of pregnancy, as compared to 10-15% in the American population. Moreover, the increase in total thyroxin (TT4) secretion represented only 27%, as compared to 50% in the American population. Linear regression model analysis showed a positive correlation between levels of TT4 and TBG, TT4 and FT4, as well as FT4 and free thyroxin index (FTI). CONCLUSION: The hypothyroxinemia at the third trimester of pregnancy was more prominent in the Parisian population and insufficient iodine intake could be responsible for the deficient increase in TT4. It is therefore concluded that the inability of the thyroid to establish the required equilibrium could be corrected by systematic iodine supplementation before pregnancy. Finally, the strong correlation between FT4 and FTI suggests that the quality of FT4 test immunoassay is appropriate for estimating FT4 serum levels during pregnancy.

Polyspecificity of antimicrosomal thyroid antibodies in hepatitis C virus-related infection.

OBJECTIVES: The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-alpha therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-alpha therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-alpha therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis. METHODS: Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-alpha treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96). RESULTS: In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-alpha therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls. CONCLUSIONS: The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-alpha therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.

Use of the ligand immunofunctional assay for human insulin-like growth factor ((IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and igf-i bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics.

The ligand immunofunctional assay for plasma insulin-like growth factor (IGF) binding protein (IGFBP)-3 developed in our laboratory provides for specific measurement of intact, as opposed to proteolyzed, IGFBP-3. IGFBP-bound IGFs are dissociated and separated by acid pH ultrafiltration; thereafter, intact and proteolyzed IGFBP-3 are captured by a monoclonal antibody in a solid-phase assay and incubated with (125)I-IGF-I, which detects the intact protein but not its proteolytic fragments. This assay was combined with assays for IGF-I (RIA of the ultrafiltrate) and total IGFBP-3 (immunoradiometric assay) to quantify the percentage of proteolyzed IGFBP-3 (percent proteolyzed IGFBP-3) and to calculate the IGF-I/intact IGFBP-3 ratio as an index of the fraction of exchangeable IGF-I bound to IGFBP-3. This fraction represents most of the IGF-I that is bioavailable. Because GH and insulin control the hepatic production and plasma concentrations of IGF-I and IGFBP-3, we set out to determine whether variations in the secretion of the two hormones are involved in the regulation of IGFBP-3 proteolysis. The study included adult populations of 36 healthy subjects, 23 hypopituitary patients untreated with GH, 43 acromegalics (13 untreated), 42 insulin-treated type 1 diabetics [insulin-dependent diabetes mellitus (IDDM)] patients, and 50 type 2 diabetics [non-IDDM (NIDDM)] patients, 22 of whom were insulin-treated and the remaining 28 treated with sulfonylurea and/or metformin). Unlike IGF-I and (to a lesser extent) total IGFBP-3 levels, which decline with age, percent proteolyzed IGFBP-3 seemed relatively stable. In healthy adults, the mean +/- SEM was 29.4 +/- 1.9 for subjects less than 45 yr old and was slightly (but not significantly) lower, 25.7 +/- 3, for those of more than 45 yr. There was no difference between male and female subjects. In GH-deficient patients, despite severely depressed IGF-I levels, percent proteolyzed IGFBP-3 and IGF-I/intact IGFBP-3 ratios were within the normal range. Among acromegalics, percent proteolyzed IGFBP-3 was elevated: 36.6 +/- 3.3 for patients of less than 45 yr, 33.3 +/- 3.2 for patients of more than 45 yr (P = 0.02 vs. healthy subjects). Consequently, the effects of excessive IGF-I synthesis are exacerbated by the enlarged exchangeable fraction of IGFBP-3-bound IGF-I. There was no significant difference in percent proteolyzed IGFBP-3 between GH-deficient patients before and after GH treatment or between treated and untreated acromegalics. In IDDM patients, the means for percent proteolyzed IGFBP-3 were higher than those in healthy adults: 36.7 +/- 3.7 (P = 0.03) and 31.3 +/- 3.3 for subjects of less than 45 and more than 45 yr, respectively. In NIDDM patients, all of whom were more than 45 yr old, the means were 35.2 +/- 2.5 (P = 0.02) for insulin-treated patients and 33 +/- 2.5 for the group treated orally. Among the diabetics, increased IGFBP-3 proteolysis resulted in an IGF-I/intact IGFBP-3 ratio that was normal for IDDM patients of less than 45 yr and above normal (P = 0.01) for the others. Percentage proteolyzed IGFBP-3 and the IGF-I/intact IGFBP-3 ratio were inversely related to body mass index in IDDM patients (r = -0.42, P = 0.008; and r = -0.31, P = 0.05, respectively) and to percentage glycosylated hemoglobin in all insulin-treated diabetics (r = -0.25, P = 0.05; and r = -0.33, P = 0.008, respectively). There was also an inverse relationship between IGF-I/intact IGFBP-3 ratios and IGFBP-1 levels in healthy adults (r = -0.39, P = 0.03) and orally treated NIDDM patients (r = -0.37, P = 0.05). Percentage proteolyzed IGFBP-3 was positively correlated to total IGFBP-3 in healthy adults (r = 0.65, P = 0.0001) and in all the groups of patients. It was negatively correlated to IGF-I/total IGFBP-3 in healthy subjects (r = -0.40, P = 0.02) and diabetics (r = -0.30, P = 0.005). This suggests an autoregulatory mechanism controlling the bioavailability of IGFBP-3-bound IGF-I in the 140-kDa complexes. In the pathological conditions studied here, regulation of IGF-I bioavailability by limited proteolysis of IGFBP-3 contributes toward an appropriate adaptation to insulin deficiency and/or resistance but not to disturbances of GH secretion.

[Simultaneous onset of rheumatoid polyarthritis and type 1 diabetes]. / Installation simultanée d'une polyarthrite rhumatoïde et d'un diabète de type 1.

BACKGROUND: Rheumatoid arthritis and insulin-dependent diabetes mellitus are both autoimmune disorders of unknown etiology. We report the case of a patient who developed the two diseases simultaneously. CASE REPORT: A 64-year-old man with no remarkable medical history developed insulin-dependent diabetes disclosed by ketoacidosis that occurred 3 weeks after onset of a bilateral symmetrical polyarthritic syndrome characteristic of rheumatoid arthritis. DISCUSSION: These two disorders share common susceptibility of subjects with MHC class II molecules HLA DRB1*04. Immunological studies have also shown a common Th1 type cytokine-secretion pattern in both diseases. Epidemiological studies have not however clearly demonstrated a link between them.

Comparison of a new method for the direct and simultaneous assessment of LDL- and HDL-cholesterol with ultracentrifugation and established methods.

BACKGROUND: Automated electrophoresis combined with enzymatic cholesterol staining might improve routine assessment of LDL- and HDL-cholesterol (LDLC and HDLC), as an alternative to the Friedewald equation and precipitation. A new method (Hydrasys; SEBIA) that adapts the cholesterol esterase/cholesterol oxidase reaction within urea-free gels was evaluated. METHODS: Fresh sera from 725 subjects (512 dyslipidemics) were analyzed by electrophoresis, in parallel with sequential ultracentrifugation, beta-quantification, calculation, and precipitation. RESULTS: Electrophoresis was linear up to 4 g/L cholesterol, with a detection limit of 0.042 g/L cholesterol/band. Within-run, between-run, between-batch, and between-operator imprecision (CVs) were 1.6%, 2.0%, 1.5%, and 2.7% for LDLC, and 3.9%, 4.3%, 5.5%, and 4.9% for HDLC, and remained unchanged up to 6.3 g/L plasma triglycerides (TGs). Precision decreased with very low HDLC (<0.25 g/L). Serum storage for 3-7 days at +4 or -80 degrees C did not interfere significantly with the assay. Agreement with beta-quantification was stable for LDLC up to 5.07 g/L (r = 0.94), even at TG concentrations >4 g/L (r = 0.91). Bias (2.88% +/- 12%) and total error (7.84%) were unchanged at TG concentrations up to 18.5 g/L. Electrophoresis predicted National Cholesterol Education Program cut-points with <0.04 g/L error, exactly and appropriately classified 79% and 96% of the subjects, and divided by 2.4 (all subjects) and 5.8 (TGs >1.5 g/L) the percentage of subjects underestimated by calculation. One-half of the patients with TGs >4 g/L had LDLC >1.30 g/L. For HDLC, correlation was better with precipitation (r = 0.87) than ultracentrifugation (r = 0.76). Error (-0.10% +/- 26%) increased when HDLC decreased (<0.35 g/L). Direct assessment of the LDLC/HDLC ratio detected 45% more high-risk subjects than the calculation/precipitation combination. CONCLUSIONS: Electrophoresis provides reliable quantification of LDLC, improving precision, accuracy, and concordance over calculation, particularly with increasing plasma TGs. Implementation of methods to detect low cholesterol concentrations could extend the applications for HDLC assessment.

[Pancreatectomy and diabetes]. / Pancréatectomie et diabète.

Post total pancreatectomy diabetes is a clearly defined form of unstable diabetes, requiring low doses of insulin, with frequent and severe hypoglycemic events. This is due to both deficiency of pancreatic glucagon, hormone of primary importance for hepatic gluconeogenesis and glycogenolysis, and exocrine failure. The management of this form of diabetes is difficult, involving exact correction of malabsorption and low doses of insulin. Whenever possible, partial pancreatectomy should therefore to be preferred. After partial pancreatectomy, the likelihood of diabetes depends on the volume of the remaining pancreas, the type of resection and above all the preexisting pancreatic status. Prevention of postoperative hyperglycemia could minimize the risk of long-term diabetes. Pancreatic cancer is a particular case: the onset of diabetes could be a manifestation of occult pancreatic cancer and glucose metabolism may improve after tumour excision with preservation of some pancreatic tissue.

Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

Intensive insulin therapy in insulin-dependent diabetes mellitus, the results of the diabetes control and complications trial.

Long term complications are the first causes of mortality and morbidity in diabetic patients. In Europe, many diabetologists speculated for a long time that a tight blood glucose control was the best way to avoid these complications, but without any complete evidence. In 1993, the results of the Diabetes Control and Complications Trial (DCCT), the first controlled, randomized, long term trial designed to study the link between metabolic control and complications in a large cohort of patients, has confirmed this hypothesis: in insulin-dependent diabetes mellitus, intensive insulin-therapy, as compared with conventional therapy, significantly reduces the risk of developing microvascular and neuropathic complications. Nevertheless, in some patients, the risk of hypoglycemia may outweight the benefit of intensive insulin therapy, and the results of the DCCT raises some questions about indications, the risk/benefit ratio and the cost/benefit ratio of intensive treatment.

[Bartter syndrome]. / Le syndrome de Bartter.

Bartter's syndrome, sometimes a familial autosomal recessive condition, is characterized by hypokalaemia with normal kaliuresis, hyperreninaemia with secondary hyperaldosteronism, vascular resistance to angiotensin and overproduction of prostaglandins by the kidneys. This syndrome is rare but sometimes envisaged in patients with unexplained hypokalaemia, the main difficulty being to exclude intoxication with diuretics which is very similar in all respects. Its physiopathology is unknown, and the various hypotheses put forward since it was first described (vascular insensitiveness to angiotensin, defect of sodium or chloride reabsorption, excess of atrial natriuretic factor, general abnormality of membrane permeability) were unable to demonstrate their primary character, each disorder described seeming, subsequently, secondary to another. For this reason, treatment is difficult and disappointing, but although the hypokalaemia is sometimes worrying, Bartter's syndrome is usually a benign condition.

[Thyroid cancer revealed by a suppressive hot nodule]. / Cancer thyroïdien révélé par un nodule chaud extinctif.

We report the case of a 62-year old woman in euthyroidism who presented with a thyroid cancer located within a hot nodule. The nodule was partially extinctive, and the triiodothyronine test showed incomplete suppression. Fine needle cytology showed no malignant cells. Systematic lobectomy was performed, and the diagnosis of cancer was made at pathology. This rare situation does not mean that all non-toxic hot nodules must be removed, but if surgery is decided an extemporaneous histological examination is mandatory. Besides, such cases provide an additional argument in favour of surgery or treatment of toxic adenomas.

[Surgical imperatives in pancreatic transplantation in dogs]. / Impératifs chirurgicaux de la transplantation pancréatique chez le chien.

The authors report their experience of segmental pancreatic autotransplantation in dogs. The most reliable model seems to be: segmental heterotopic pancreas transplantation with bladder diversion of the exocrine secretion and spleno-splenic arterio-venous fistula allowing monitoring of the exocrine secretion and a reduction in the thrombosis rate.

Thyroglobulin, thyrotropin and thyrotropin binding inhibiting immunoglobulins assayed at the withdrawal of antithyroid drug therapy as predictors of relapse of Graves' disease within one year.

"Sensitive" thyrotropin (TSH), thyroglobulin (TG) and even thyrotropin binding inhibiting immunoglobulins (TBII) assays are now widely available. The objective of the present study was to determine the most accurate of these three parameters to predict the relapse of Graves' disease during the year following treatment discontinuation and to evaluate whether the assay of three markers is able to improve the prediction. TSH, TG and TBII were measured in the sera of 67 Graves' disease patients after at least 12 months of medical treatment. In 52 patients, TBII had also been determined before the beginning of the medical treatment. Under treatment, all the patients were clinically and biologically euthyroid, but in 9 goitrous patients it was impossible to lower the doses of carbimazole without an immediate relapse. The TSH levels of these 9 patients were still low in all cases but one; TG and TBII levels were abnormal in all. In the other 58 patients, the treatment was discontinued; 22 relapsed within one year, more frequently when a goiter was present. The most reliable parameter for the prediction of relapse was found to be TBII, as its specificity was high (94.5%), although its sensitivity was poor (45%); TG was more sensitive (64%) but far less specific (57%); TSH and "initial" TBII appeared to be of a little interest. When TBII was elevated prior to the withdrawal of treatment, the determination of TG was useful: abnormal values of both TBII and TG were always associated with a relapse. When TBII testing was negative, the relapse risk fell to 0.26, and to 0.08 when three criteria were matched: no goiter, negative TBII, normal TG.

Testosterone and its binding in hyperthyroid women before and under antithyroid drug therapy.

The serum concentrations of the different forms of circulating testosterone, total testosterone, free testosterone and non-sex-hormone binding globulin bound testosterone (albumin bound + free fractions) which is considered as the bioavailable hormone, were measured in 15 hyperthyroid women before and after anti-thyroid drug therapy and in 15 age-matched healthy women. Sex-hormone binding globulin and albumin were quantified. Total testosterone was significantly higher in hyperthyroid women before treatment, whereas free testosterone and non sex-hormone binding globulin bound testosterone were significantly decreased. After recovery, all the parameters returned to the normal range. In hyperthyroid patients, the variations in the different fractions of testosterone can be related to the rise of sex-hormone binding globulin. These variations could be explained by the displacement of the equilibrium defined by the binding equation.

Low thyrotropin (TSH) levels in goiter. Relationship with scintigraphic findings and other biological parameters.

Low TSH levels are frequently encountered in patients presenting with goiter. We assayed TSH in 599 goitrous patients who were referred to us for scintigraphy and ultrasonography. When TSH levels were low or when a hot nodule was discovered at scintigraphy, free T3, free T4 and sex hormone-binding globulin (SHBG) were also assayed. TSH levels were always low in overt hyperthyroidism with elevated free T3. TSH levels were also low in patients with normal free T3 and free T4 in circumstances leading to mild hyperthyroidism such as hot nodules that suppressed extranodular thyroid tissue uptake, toxic multinodular goiter, De Quervain thyroiditis and some patients on amiodarone treatment. Low TSH levels were also encountered in 29% of the clinically euthyroid patients presenting with a multinodular goiter with normal iodine uptake, no hot area and normal free T3 levels. In diffuse goiter, low TSH and normal free T3 levels were more frequently associated when iodine uptake was low, mainly due to subacute thyroiditis which can be clinically silent. Low TSH levels were rarely observed in patients with "simple" goiter or uninodular goiter without hot areas. SHBG, which was elevated in 94% of the Graves' disease patients tested, was normal in all but two patients with low TSH and normal free T3 levels. This assay appeared to be of little relevance in goiter. In addition to imaging techniques which are usually performed first, TSH should be systematically assayed in goiter, except in cases of solitary cold nodules. When low, the patient is at risk of developing overt hyperthyroidism. Conversely, when an isolated low TSH level is observed, scintigraphy should be performed.

Determination of testosterone in serum not bound by sex-hormone-binding globulin: diagnostic value in hirsute women.

We compared the diagnostic value of information given by total testosterone (I), free testosterone (II), the free androgen index (III), and testosterone not bound by sex-hormone-binding globulin (SHBG) (IV) as measured by a new differential ammonium sulfate precipitation technique, each step of which is conducted at 37 degrees C. SHBG and albuminemia were also measured. To examine the clinical value of IV, we analyzed single blood samples from 15 hirsute women and 15 age-matched healthy control volunteers. Values for I, II, III, and IV testosterone were all significantly higher in the hirsute group (P less than 0.01), whereas SHBG was decreased (P less than 0.01) and albumin concentrations were similar for the two groups. Overlap between values for normal and for hirsute women was 33.3% for I, 13.3% for II, and 0% for III and IV. The presented data suggest that IV measured by ammonium sulfate precipitation is the preferred discriminator for detecting hyperandrogenism, because this assay is technically simpler and less expensive than the II assay for routine investigation. It closely reflects the pool of bioavailable testosterone; thus, its main use might be as a screening test for androgen excess in women.

Clinical value of thyrotropin binding inhibiting immunoglobulins (TBII) assay in hyperthyroidism.

More than 500 sera were assayed for TBII under routine conditions using "Trak" assay in order to evaluate the sensitivity, specificity and prognostic interest of this determination in hyperthyroidism. The sensitivity for the diagnosis of Graves' disease was 83.5%, better in ophthalmopathic patients (93%) than in non ophthalmopathic patients (75%). The specificity was 99.4% with only one false positive in a hypothyroid patient. TBII level significantly decreases with carbimazole treatment except in patients who remain hyperthyroid. Determination of TBII before stopping carbimazole treatment or after surgery has a prognostic significance as a positive value indicates a relapse in almost all cases. Conversely, a fall of TBII to normal levels with treatment is insufficient to assess recovery. High levels are frequently observed after radioiodine therapy but do not indicate a poor prognosis.