OBJECTIVE

The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients.

METHODS

Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism.

RESULTS

Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism.

CONCLUSIONS

These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.

The cellular events mediating the rapid, thyroid hormone-dependent modulation of membrane-bound, type II iodothyronine 5'-deiodinase were studied in dibutyryl cyclic AMP(bt2cAMP)-treated brain astrocytes. Unstimulated cells had undetectable type II 5'-deiodinating activity. Treating the cells with bt2cAMP and hydrocortisone induced enzyme expression by increasing transcription of the enzyme or an essential enzyme related protein(s), with steady-state levels of type II 5'-deiodinase attained after 8 h of bt2cAMP treatment. Glial cells grown in the absence of thyroid hormone had 10-15-fold higher levels of 5'-deiodinating activity than cells grown in the presence of serum. The increased type II 5'-deiodinating activity observed in serum-free cultures was due to a prolonged enzyme half-life with no change in the rate of enzyme synthesis. Addition of thyroxine or 3,3',5'-triiodothyronine to the serum-free culture medium resulted in a concentration-dependent fall in steady-state enzyme levels, with EC50 values of approximately 0.4 nM. 3,5,3'-Triiodothyronine was at least 100-fold less effective. Chloroquine, NH4Cl, tunicamycin, colchicine, and monodansylcadavarine had no effect on the t1/2 of the enzyme, while both carbonyl cynanide m-chlorophenylhydrazone and cytochalasins completely blocked the inactivation of the type II 5'-deiodinase. These data indicate that in glial cells, an intact actin-cytoskeleton is required for thyroid hormone to modulate the energy-dependent regulation of the half-life of the short-lived, membrane-bound enzyme, type II 5'-deiodinase.

To determine the relative contributions of glucose, insulin, dexamethasone, and triiodothyronine to the induction of hepatic glucose-6-phosphate dehydrogenase, hepatocytes isolated from normal or adrenalectomized rats, either fasted or fed, were examined in culture. Addition of insulin (42 milliunits/ml, 0.9 microM) and dexamethasone (1 microM) to hepatocytes obtained from 3-day-fasted rats and cultured for 48 h in serum-free Dulbecco's medium resulted in a 7- to 11-fold increase in Glc-6-P dehydrogenase specific activity compared with a 2- to 3-fold increase in activity in control cultures incubated without added hormones. The effects of insulin and dexamethasone were independent of DNA synthesis, dose-dependent, and additive; each contributing about one-half of the total response. Medium glucose was neither sufficient nor necessary for the insulin- or dexamethasone-stimulated increase in Glc-6-P dehydrogenase specific activity. Addition of triiodothyronine (10 microM) preferentially blocked the dexamethasone-stimulated increase in Glc-6-P dehydrogenase specific activity. Insulin failed to stimulate the induction of Glc-6-P dehydrogenase in hepatocytes obtained from normal fed rats or from fasted and fed adrenalectomized rats. However, insulin caused a significant increase in the Glc-6-P dehydrogenase specific activity of these cells when dexamethasone was concurrently added to the culture medium.

A 51-year-old woman who had been treated with levothyroxine sodium because of hypothyroidism after total thyroidectomy for thyroidal cancer was admitted to our hospital for persistent hypothyroidism despite large dose administration of levothyroxine (600 microg/day). The patient complained of severe general fatigue and body weight gain. Free thyroxine, free triiodothyronine and thyrotropin levels were 0.97 ng/dl, 1.55 pg/ml and 24.51 microU/ml, respectively, under oral administration of levothyroxine. Levothyroxine loading test performed by liquid form, pulverized tablets via nasogastric tube and intravenous administration revealed no evidence of malabsorption or metabolic disorder of levothyroxine, although oral intake of tablets was ineffective due to her factitiousness. We report here a possible case of "pseudomalabsorption of levothyroxine" to emphasize the clinical recognition of this disorder in patients with resistant hypothyroidism.

Thyroxine (T4), free T4 (fT4), triiodothyronine (T3), free T3 (fT3), reverse T3 (rT3), thyrotropin (TSH), thyroxine binding globulin (TBG), and T3 uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT4 and fT3 concentrations were subnormal, whereas the respective protein-bound fractions were normal. T4, T3, and TBG increased during the abstinence period, T3 and TBG being significantly higher than in normals at the second measuring time. T3 uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT3 levels remained significantly lower than in healthy subjects. rT3 concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothalamic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT3 and fT4 levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T4--and partly those in T3--during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT3 concentrations may reach the level of statistical significance. These falls in rT3 concentrations may reflect an increase in rT3 metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT3 bioavailability. 4. Factors such as liver disease, protein caloric malnutrition, and "psychological stress" do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.

OBJECTIVE

To study glucose and bone metabolism in hyperthyroidism, assess their changes after treatment, and investigate their interrelationships.

METHODS

Thirty patients with hyperthyroidism matched with 32 normal control subjects were studied. After a 10- to 12-hour overnight fast, blood samples were collected for measurement of glucose, insulin, C-peptide, and intact proinsulin levels as well as for measurement of bone markers: serum alkaline phosphatase (ALP), osteocalcin, and procollagen type I C-terminal peptide (PICP) as markers of bone formation and serum C-terminal cross-linked telopeptide of type I collagen (ICTP) as a marker of bone resorption. A 3-hour 75-g oral glucose tolerance test was then performed, with measurement of glucose, insulin, and C-peptide levels every 30 minutes. Patients were studied at baseline and after treatment with an antithyroid drug (carbimazole) for 1 month and 6 months.

RESULTS

Pretreatment fasting glucose, insulin, C-peptide, and intact proinsulin levels were significantly higher in patients with hyperthyroidism than in control subjects. During the 3-hour oral glucose tolerance test, the area under the curve of glucose was significantly elevated in the patients, whereas the 3-hour areas under the curve of insulin and C-peptide were not significantly different between patients and control subjects. Fasting glucose, insulin, C-peptide, and intact proinsulin levels decreased significantly to levels similar to those of the control subjects after 1 month of antithyroid therapy and remained so at 6 months. Pretreatment ALP, osteocalcin, PICP, and ICTP were significantly higher in the patients than in the control subjects. After treatment, all markers of bone turnover decreased significantly to levels similar to those of the control subjects at 1 month (except ALP) and 6 months. Within the study group of patients, baseline PICP, osteocalcin, and ICTP demonstrated positive correlation trends with free triiodothyronine and free thyroxine.

CONCLUSIONS

Abnormal glucose metabolism and increased bone turnover are hallmarks of untreated hyperthyroidism. These factors normalize as early as 4 weeks after initiation of antithyroid therapy. Changes in bone markers, particularly those of resorption, are related to the degree of thyroid hyperactivity.

BACKGROUND

Previous studies on relatively small populations of patients with primary Sjögren's syndrome (pSS) suggested an association between pSS and Hashimoto's thyroiditis (HT). As some findings in the literature regarding the relationship between pSS and thyroid disease are contradictory, and there is little information on the sequence of pSS and HT, we conducted a study with a population of patients with pSS that was about three times larger than previously studied populations. Our objective was to determine the prevalence of HT and Graves' disease (GD) in patients with pSS and to assess the sequence of pSS and autoimmune thyroid diseases.

METHODS

A total of 479 patients with pSS were retrospectively studied. Thyroid ultrasound and scintigraphy were performed, and serum thyrotropin, free triiodothyronine, free thyroxine, antithyroid peroxidase antibody (TPOAb), and anti-thyroglobulin autoantibody (TgAb) measurements were carried out. Solitary thyroid nodules were investigated by fine-needle aspiration biopsy.

RESULTS

Thyroid dysfunction was found in 95 patients (21.25%). Thirty of these patients had HT and 18 had GD. HT predated pSS in eight patients, developed at approximately the same time in seven patients, and followed pSS in 15 patients. Almost all (90%) patients with HT had persistently elevated serum TgAb or TPOAb titers.

CONCLUSIONS

An association between HT and pSS was found based on the fact that the frequency of HT was greater among pSS patients (6.26%) than in the general population (1-2%). In contrast, no association between GD and pSS was found. We noted that both HT and GD can appear either before or after the onset of pSS. Since most cases of pSS predate the appearance of autoimmune thyroid diseases it is important to determine if pSS is a predisposing factor for the development of autoimmune thyroiditis.

OBJECTIVE

The aim of this prospective study is to evaluate the possible association between Ménière's disease (MD) and autoantibodies.

METHODS

Fifty-five patients with definite MD (51 unilateral and 4 bilateral) were matched with 55 patients with unilateral vestibular paresis without cochlear involvement and 55 healthy subjects. Blood samples were collected from all study subjects for the determination of serum TSH, free triiodothyronine, free thyroxine, anti-TSH receptor antibody, antithyroperoxidase antibody, antithyroglobulin antibody and of antibodies to non-organ-specific antigens, namely antinuclear antibodies, antibodies to extractable nuclear antigens and antineutrophilic cytoplasmic antibodies.

RESULTS

Thirty-three subjects (60%) of the MD group had 1 or more elevated serum autoantibody levels, both organ and non-organ specific; 16 patients (29.1%) with unilateral vestibular paresis had 1 or more elevated serum autoantibody levels, while 13 healthy subjects (23.6%) had 1 or more elevated serum autoantibody levels.

CONCLUSIONS

Based on our data we speculate that there is a more than a chance association between MD and 'autoimmunity', thus suggesting a hypothetical role of the immune system in MD pathogenesis. In other words, a pathogenetic role of an 'immune dysregulation' in MD patients can be hypothesized.

Cardiovascular outcomes in mild thyroid dysfunction (treatment controversial) and moderate or severe dysfunction (treatment standard) remain uncertain.

To examine cross-sectional and prospective associations of thyroid function with cardiovascular risk factors and events.

In the Atherosclerosis Risk in Communities Study, we measured concentrations of thyrotropin, free thyroxine, and total triiodothyronine (T3) in stored serum samples originally collected in 1990-1992. We used multivariable linear regression to assess cross-sectional associations of thyroid function with cardiovascular risk factors and Cox regression to assess prospective associations with cardiovascular events. Follow-up occurred through 31 December 2014.

General community.

Black and white men and women from the United States, without prior myocardial infarction (MI), stroke, or heart failure.

Cross-sectional outcomes were blood pressure, glycemic markers, and blood lipids. Prospective outcomes were adjudicated fatal and nonfatal MI and stroke.

Among 11,359 participants (57 ± 6 years, 58% women), thyroid function was more strongly associated with blood lipids than blood pressure or glycemic measures. Mean adjusted differences in low-density lipoprotein cholesterol were +15.1 (95% confidence interval: 10.5 to 19.7) and +3.2 (0.0 to 6.4) mg/dL in those with moderate/severe and mild chemical hypothyroidism, relative to euthyroidism; an opposite pattern was seen in hyperthyroidism. Similar differences were seen in triglycerides and non-high-density lipoprotein cholesterol. With a 22.5-year median follow-up, 1102 MIs and 838 strokes occurred, with similar outcomes among baseline thyroid function groups and by T3 concentrations.

Hypothyroidism is associated with hyperlipidemia, but the magnitude is small in mild chemical hypothyroidism, and cardiovascular outcomes are similar between thyroid function groups.

Total thyroxine (TT4) and triiodothyronine (TT3) were found to be low in healthy elderly subjects with a preferential decrease of triiodothyronine. In order to determine the importance of these findings 22 healthy elderly subjects were examined. Free triiodothyronine (FT3), thyroid binding globulin (TBG) concentration and basal thyroid stimulating hormone (TSH) were measured by radioimmunoassay. Liver enzymes, cholesterol and total protein concentration were also assayed. TBG was significantly increased compared to a middle-aged group and did not correlate with TT4, TT3 and TSH. Basal TSH values were in the normal range and could be detected in all the elderly subjects in contrast to undetectable values in 40% of the younger subjects. FT3 determined directly did not correlate with the values calculated according to the law of mass action. According to the FT3 values the elderly subjects could be subdivided into three groups independent of their TT4, TT3, TBG and TSH values. FT3 was undetectable in one group, in the low normal to normal range in another and elevated in the third group. Our results suggest that 1) there is no correlation between TT4, TT3, elevated TBG and FT3 determined directly or by calculation, 2) basal TSH values seem to indicate possible hypothyroidism in elderly persons which is correlated with elevated cholesterol levels and 3) FT3 measured directly subdivides this metabolic state into three groups possibly depending on the intracellular concentration of T4.

BACKGROUND

Thyroid hemiagenesis is a rare congenital anomaly in which one lobe of thyroid gland fails to develop. Because variations of the prevalence of this anomaly have been reported, the aim of this study was to evaluate the prevalence rate of thyroid hemiagenesis in an apparently normal population from Northern Poland.

METHODS

Ultrasound examination of the thyroid gland was performed in 4004 unselected 7-15-year-old school-children from the seaside zone of Northern Poland.

RESULTS

Two cases of thyroid hemiagenesis were found, both being absence of the left lobe in two girls. Thyroid volumes, adjusted to body surface area, were within normal range; serum thyrotropin, free thyroxine, and free triiodothyronine were within normal limits. Physical examination, abdominal ultrasound, and echocardiography did not show extrathyroidal malformations. Thyroid ultrasound was normal in the girls, parents, and siblings.

CONCLUSIONS

The study showed a 0.05% prevalence of thyroid hemiagenesis in asymptomatic schoolchildren population from iodine-sufficient area of Northern Poland.

In order to assess the value of thyroid function testing during amiodarone therapy, we reviewed all available tests in 128 patients treated with this drug. Nine patients (7.0%) developed biochemical hyperthyroidism with elevation of both free thyroxine index (FT4I) and free triiodothyronine index (FT3I) and marked suppression of serum thyroid stimulating hormone (TSH) after 1-46 months of therapy; six of these nine patients had clear clinical evidence of thyroid overactivity. Where serial tests were available before development of hyperthyroidism, this complication developed suddenly, despite previously stable normal indices of thyroid function, and could not be predicted by currently-available biochemical tests such as T4, T3, sensitive TSH, thyroglobulin or sex hormone binding globulin (SHBG) assays. Clinical features such as unexplained weight loss, proximal myopathy, exacerbation of arrhythmia, or heat intolerance appear to be the key to prompt diagnosis of this complication. Hyperthyroxinemia without T3 excess was found in 32.8% of patients without progression to true hyperthyroidism. Serum TSH remained detectable by sensitive assay in 17 out of 18 patients with amiodarone-induced euthyroid hyperthyroxinemia and was significantly higher than in patients with equivalent hyperthyroxinemia due to thyroxine therapy. Serial levels of SHBG were higher in patients with true hyperthyroidism than in those with euthyroid hyperthyroxinemia. The effect of combined treatment with propylthiouracil (800 mg/day) and potassium perchlorate (800 mg/day) was evaluated in five of the six clinically hyperthyroid patients. Biochemical euthyroidism was achieved after 7-19 weeks, a response slower than previously reported, indicating that this drug combination does not result uniformly in prompt resolution of amiodarone-induced hyperthyroidism.

Epithelial cells isolated from fragments of hamster pancreas interlobular ducts were freed of fibroblast contamination by plating them on air-dried collagen, maintaining them in serum-free Dulbecco's modified Eagle's (DME):F12 medium supplemented with growth factors, and selecting fibroblast-free aggregates of duct cells with cloning cylinders. Duct epithelial cells plated on rat type I collagen gel and maintained in DME:F12 supplemented with Nu Serum IV, bovine pituitary extract, epidermal growth factor, 3,3',5-triiodothyronine, dexamethasone, and insulin, transferrin, selenium, and linoleic acid conjugated to bovine serum albumin (ITS+), showed optimal growth as monolayers with a doubling time of about 20 h and were propagated for as long as 26 wk. Early passage cells consisted of cuboidal cells with microvilli on their apical surface, complex basolateral membranes, numerous elongated mitochondria, and both free and membrane-bound ribosomes. Cells grown as monolayers for 3 mo. were more flattened and contained fewer apical microvilli, mitochondria, and profiles of rough surfaced endoplasmic reticulum; in addition, there were numerous autophagic vacuoles. Functional characteristics of differentiated pancreatic duct cells which were maintained during extended monolayer culture included intracellular levels of carbonic anhydrase and their capacity to generate cyclic AMP (cAMP) after stimulation by 1 X 10(-6) M secretin. From 5 to 7 wk in culture, levels of carbonic anhydrase remained stable but after 25 to 26 wk decreased by 1.9-fold. At 5 to 7 wk of culture, cyclic AMP increased 8.7-fold over basal levels after secretin stimulation. Although pancreatic duct cells cultured for 25 to 26 wk showed lower basal levels of cAMP, they were still capable of generating significant levels of cAMP after exposure to secretin with a 7.0-fold increase, indicating that secretin receptors and the adenyl cyclase system were both present and functional. These experiments document that pancreatic duct monolayer cultures can be maintained in a differentiated state for up to 6 mo. and suggest that this culture system may be useful for in vitro physiologic and pathologic studies.

The T-Screen represents an in vitro bioassay based on thyroid hormone dependent cell proliferation of a rat pituitary tumour cell line (GH3) in serum-free medium. It can be used to study interference of compounds with thyroid hormone at the cellular level, thus bridging the gap between limitations of assays using either isolated molecules (enzymes, transport proteins) or complex in vivo experiments with all the complex feedback mechanisms present. Compounds are tested both in the absence and presence of thyroid hormone (EC(50) concentration of T(3)) to test for both agonistic and antagonistic potency. Thyroid hormones (3,3'-5-triiodothyronine: T(3) and 3,3',5,5'-tetraiodothyroxine: T(4)) and compounds resembling the structure of thyroid hormones (3,3'-5-triiodothyroacetic acid: Triac; 3,3',5,5'-tetraiodothyroacetic acid: Tetrac) induced cell growth, with the rank order Triac>> T(3)>> Tetrac>> T(4) (relative potency = 1.35>> 1>> 0.29>> 0.07), which is identical to published affinities of these compounds for nuclear thyroid hormone receptors. Exposure to 5,5'-diphenylhydantoin (DPH) in the presence of 0.25nM T(3) resulted in up to 60% decreased cell growth at 200μM DPH. No effect of DPH on basal metabolic activity of GH3 cells was observed at this concentration. Fentinchloride (IC(50) = 21nM) decreased cell growth induced by 0.25nM T(3), whereas parallel exposure to these concentrations in the absence of T(3) did not alter basal metabolic activities of GH3 cells. Apolar sediment extracts from the Dommel (34%) and Terneuzen (14%) decreased cell growth in the presence of 0.25nM T(3), whereas the extract from Hoogeveen increased cell growth (26%) and the extract from North Sea Channel had no effect. The T-Screen proved to be a fast and functional assay for assessing thyroid hormone receptor active potencies of pure chemicals or environmental mixtures.

Sensitivity of cardiac muscle to digitalis glycosides depends on the thyroid state. The mechanism of this interaction was investigated at the cellular level using spontaneously beating monolayers of cultured chick embryo ventricular cells. Cells were grown for 48 h in serum-free medium containing concentrations of triiodothyronine (T3) from zero to 10(-7) M, and the total number of sodium pump sites, sodium content, and contractile amplitude in the presence and absence of various concentrations of ouabain were determined. T3 caused a concentration-dependent increase in the number of specific ouabain binding sites; the maximal increase to 160% of control was observed in response to 10(-8) M T3. T3 lowered steady-state cellular sodium content in a concentration-dependent manner, also. Ouabain (1 microM) exposure elevated cellular sodium content in all cells, but the increase was greatest in cells grown in T3-free medium and least in cells grown in 10(-8) M T3. The positive inotropic and toxic effects of ouabain in cells grown in 10(-8) M T3 were diminished at any given ouabain concentration, and thus, the dose-response curve was shifted to the right. These results indicate that T3 causes induction of additional sodium pump sites that are functional. The increased tolerance of hyperthyroid cells and reduced tolerance of hypothyroid cells to cardiac glycosides can be explained by these changes in the number of sodium pump sites and cellular sodium content, and consequently, calcium influx via sodium-calcium exchange.

Abnormalities of thyroid hormone levels have been reported in the acquired immunodeficiency syndrome (AIDS), but there has been debate as to whether they are appropriate for the clinical status of the patients. Inappropriate maintenance of circulating 3,3',5-triiodothyronine (T3) levels could contribute to weight loss. Although many patients with AIDS have a history of wasting, recent data indicate that prolonged periods of stable weight occur in AIDS and that short-term weight loss is present in a subset of patients with anorexia, many of whom have active secondary infection (AIDS-SI). Therefore we analyzed thyroid hormone levels in a cohort of subjects that have been characterized in terms of recent weight loss and caloric intake. Asymptomatic patients with human immunodeficiency virus infection (HIV+) had short-term stable weights, normal caloric intake, and normal serum T3 levels. In AIDS, average short-term weight was stable, caloric intake was normal, and T3 levels were decreased by 19%. In AIDS-SI, both short-term weight loss and anorexia were significant, and this group showed a 45% decrease in T3 levels. The free T3 (FT3) index was decreased by 30% in AIDS and by 50% in AIDS-SI. Free thyroxine (FT4) levels were decreased while thyroxine-binding globulin (TBG) capacity was increased in HIV+ and AIDS; TBG sialylation was unchanged. Thyrotropin (TSH) levels were slightly increased in AIDS, although levels remained within the normal range. 3,3',5'-triiodothyronine (rT3) levels were decreased in HIV+, AIDS, and AIDS-SI. Thus asymptomatic patients with HIV infection whose weight is stable maintain normal T3 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated how a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects thyroid hormone regulation, especially in relation to the localization of thyroid stimulating hormone (TSH) in the pituitary and that of thyroxin (T4) of the thyroid in the rat. Female Sprague-Dawley rats were given a single oral administration of TCDD ranging from 1.0 to 4.0 microg/kg body weight (bw), and then tissue specimens were removed on day 7 post-administration. Thyroid hormone concentrations were measured in serum, and the expression of the TCDD-responsive genes, UDP-glucuronosyltransferase-1 (UGT1) and cytochrome P4501A1 (CYP1A1) were examined in the liver. TCDD administration resulted in an increase in both immunostaining intensity and the number of TSH-positive cells in the anterior pituitary. T4 was found to localize only in the follicular lumen of the thyroid in vehicle-treated control rats, while TCDD administration caused a foamy change in the colloid of some follicles, an indication of accelerating the biosynthesis of T4 in the thyroid. By morphometrical analysis, the ratio of parenchymal/lumenal area of the thyroid was found to increase in response to TCDD. TCDD treatment as low as 2.0 microg TCDD/kg bw induced a significant decrease in both serum total T4 (TT4) and free T4 (FT4) concentrations in the rats, with a significant increase in serum TSH levels in the 4.0 microg TCDD/kg bw rats. Serum total triiodothyronine (TT3) level was unchanged in all groups. The UGT1 gene was significantly induced at a TCDD dose as low as 1.0 microg/kg bw in a dose-dependent manner. TCDD concentrations in the serum, liver and adipose tissues were detected in a dose-related fashion. The present immunohistochemical results clearly support the earlier biochemical findings on the perturbation of the thyroid-pituitary axis by TCDD and suggest that UGT1 is an immediate target of a low TCDD exposure that triggers the perturbation.

The simultaneous occurrence of multiple adenomas in the pituitary gland is a rare event. We report the coexistence of three non functioning pituitary microadenomas in a 37-year-old woman, referred to us for oligomenorrhea and headache. Biochemical evaluation revealed prolactin (131 U/liters), follicle-stimulating hormone (4.1 U/liters), luteinizing hormone (3.9 U/liters), 17beta-estradiol (74 pg/mL), free (2.0 pg/mL) and total testosterone (0.5 ng/mL), dehydroepiandrosterone-sulfate (3.5 microg/mL), 17OH-progesterone (0.8 ng/mL), cortisol (13.1 microg/dL), free triiodothyronine (4.8 pmol/L), free thyroxine (18.5 pmol/liters), thyrotropin (1.6 mU/L), and growth hormone (0.2 ng/mL) levels in the normal range, as for as the response to dynamic endocrine tests. MRI showed an enlarged sella turcica, occupied by three distinct hypointense areas that measured less than 5 mm in diameter in the left, medium and right side of the pituitary, respectively. This finding was confirmed 6 months later by a second MRI that revealed also a light increase in microadenomas dimensions. The patient, therefore, underwent neurosurgery by transfenoidal approach. Histologic examination showed no morphologic differences between the specimens obtained from the different microadenomas. Immunohistochemistry evaluation revealed a positive staining for the common alpha-subunit of glycoproteic hormones and negative for the other pituitary hormones tested, while electron microscopy showed cells with a poor secretory apparatus and a variable grade of cell differentiation. In conclusion, we report the fifth case described with multiple pituitary adenomas diagnosed in vivo and the first with three coexisting tumors revealed by MRI before neurosurgery. The occurrence of multiple pituitary tumors emphasizes the role of pituitary and extrahypophiseal factors in the clonal expansion of genetically altered cells.

Hypercholesterolaemia is a common finding in patients with anorexia nervosa (AN). To investigate the type, frequency and pathophysiological mechanisms of changes in lipoprotein metabolism in AN we performed a cross-sectional study in fifty-eight female patients (mean age 24.2 years, BMI 15.3 (sd 1.5) kg/m(2)) and fifty-eight healthy age-matched controls (CO; BMI 22.2 (sd 1.7) kg/m(2)). Total cholesterol and LDL-cholesterol were higher in AN (5.5 (sd 1.3) v. 5.0 (sd 0.8) mmol/l, P=0.023; 3.6 (sd 1.1) v. 3.2 (sd 0.7) mmol/l, P=0.025 respectively). LDL particles were significantly more enriched in cholesterol and triacylglycerol in AN. In multiple regression analysis with LDL-cholesterol as the dependent and BMI, total body fat ( %), lathosterol:cholesterol ratio (endogenous cholesterol synthesis), 7alpha-hydroxy-4-cholesten-3-one (bile acid synthesis), non-esterified glycerol, free triiodothyronine and free thyroxine as independent variables, BMI was the only significant predictor in CO (R(2) 0.36, overall P=0.001). In AN the variability of LDL-cholesterol was significantly predicted by total body fat, free thyroxine, BMI, free triiodothyronine and non-esterified glycerol (R(2) 0.55, overall P<0.001). Subgroup analysis between restricting (AN-R) and binge-eating-purging patients (AN-B) indicated that in AN-R changes in lipoproteins, BMI and total body fat were more pronounced. AN-R patients had lower bile acid synthesis than AN-B (P=0.02). We conclude that elevated cholesterol concentrations in AN are generally due to an increase in LDL-cholesterol, which is mostly determined by the severe loss of body fat and the resulting changes in thyroid hormones, increased lipolysis and decreased endogenous cholesterol synthesis with resulting decrease in LDL removal. The clinical subtype of AN plays a major role in the mechanisms leading to hypercholesterolaemia.

Probiotic bacteria and phytosterols are natural hypocholesterolemic agents with potential cardiovascular benefits. Accordingly, the present study was conducted to evaluate the effect of supplementation of probiotics and phytosterols alone or in combination on serum and hepatic lipid profiles and thyroid hormones of hypercholesterolemic rats. Mixed probiotics treatment consisted of 8 probiotic strains: 2 strains of each of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus gasseri, and Lactobacillus reuteri. The rats were fed for 8 wk with the given treatments in addition to a high-fat-high-cholesterol basal diet to induce hypercholesterolemia. Results showed that supplementation significantly reduced serum total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol, and triglycerides compared with the controls. The symbiotic treatment was more effective in lowering LDL-C, whereas mixed probiotics treatment more effectively lowered serum total cholesterol and LDL-C than the phytosterol-containing treatment. The phytosterol-containing treatments induced the increased activity of thyroid glands, as evident by elevated levels of serum total thyroxine, total triiodothyronine, and free triiodothyronine. In conclusion, the lipid profile can effectively be reduced to lower the incidence of cardiovascular disease using combinations of Lactobacillus-based probiotics and phytosterols in functional foods.

OBJECTIVE

To develop a strategy to identify cases of endogenous subclinical hyperthyroidism and free triiodothyronine (free T3) thyrotoxicosis in otherwise healthy ambulatory patients.

METHODS

In a retrospective study we reviewed the records of ambulatory patients who had thyroid stimulating hormone (TSH) levels determined between October 1, 1991 and August 31, 1992. Each patient also had a simultaneous free thyroxine (free T4) measurement. Patients were excluded from consideration if they had active, concurrent non-thyroidal illness, psychiatric disease, known hypothalamic/pituitary lesions, were under treatment for hyper- or hypothyroidism, were on drugs known to affect TSH levels, or were pregnant. Patients without exclusions were diagnosed with free T3 toxicosis if they had: (1) a markedly subnormal TSH level (less than or equal to 0.1 mU/L), (2) a normal free T4, (3) a normal total T3, (4) evidence of a primary thyroid abnormality (e.g., autonomous function on a thyroid scan), and (5) an elevated free T3 level by tracer equilibrium dialysis. Patients meeting conditions 1-4, but with normal free T3 levels, were considered to have subclinical hyperthyroidism.

RESULTS

One thousand twenty-five patients had TSH and simultaneous free T4 determinations, and 148 of these had markedly subnormal TSH but normal free T4 levels. Three patients met the criteria for free T3 toxicosis and three had subclinical hyperthyroidism. All six patients had either multinodular glands or a single nodule on thyroid exam. Four patients were treated with radioactive iodine or surgery, resulting in reversal of the TSH suppression in three cases.

CONCLUSIONS

Apparently healthy ambulatory patients with subnormal TSH levels should be worked up with measurements of free T4 and total T3. If these are normal, a T3 level (by tracer equilibrium dialysis) be obtained to distinguish subclinical hyperthyroidism from overt free T3 toxicosis. A thyroid scan and radioiodine uptake measurement can be obtained to substantiate the diagnosis. Some patients with these conditions will benefit from treatment.

OBJECTIVE

We compared the performance of tandem mass spectrometry versus immunoassay for measuring thyroid hormones in a diverse group of inpatients and outpatients.

METHODS

Thyroxine (T4), triiodothyronine (T3), free thyroxine (FT4), and free triiodothyronine (FT3) were measured by liquid chromatography tandem mass spectrometry and immunoassay in 100 patients and the two assays were compared.

RESULTS

T4 and T3 values measured by the two different assays correlated well with each other (r=0.91-0.95). However, the correlation was less good at the extremes (r=0.51-0.75). FT4 and FT3 concentrations measured by the two assays correlated less well with each other (r=0.75 and 0.50 respectively). The studied analytes had poor inverse correlation with the log-transformed TSH values (r=-0.22-0.51) in the population as a whole. The strongest correlations were seen in the groups of outpatients (r=-0.25-0.61). The weakest degree of correlation was noted in the inpatient group, with many correlations actually being positive.

CONCLUSIONS

The worst between-assay correlation was demonstrated at low and high hormone concentrations, in the very concentration ranges where accurate assay performance is typically most clinically important. Based on the lesser susceptibility of mass spectrometry to interferences from conditions such as binding protein abnormalities, we speculate that mass spectrometry better reflects the clinical situation. In this mixed population of inpatients and outpatients, we also note failure of assays to conform to the anticipated inverse linear relationship between thyroid hormones and log-transformed TSH.

BACKGROUND

In Graves' thyrotoxicosis tachycardia, weight loss and mental symptoms are common. Recovery takes time and varies between patients. Treatment with methimazole reduces thyroid hormone levels. According to previous research, this reduction has been faster if selenium (Se) is added.

OBJECTIVE

The objective was to investigate whether supplementing the pharmacologic treatment with Se could change the immune mechanisms, hormone levels and/or depression and anxiety.

METHODS

We prospectively investigated 38 patients with initially untreated thyrotoxicosis by measuring the thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroid receptor antibodies and thyroid peroxidase auto-antibodies before medication and at 6, 18 and 36 weeks after commencing treatment with methimazole and levo-thyroxine, with a randomized blinded oral administration of 200 µg Se/day or placebo. The selenoprotein P concentration was determined in plasma at inclusion and after 36 weeks. The patients were also assessed with questionnaires about depression, anxiety and self-rated symptoms before medication was started and after 36 weeks.

RESULTS

FT4 decreased more in the Se group at 18 weeks (14 vs. 17 pmol/l compared to the placebo group, p = 0.01) and also at 36 weeks (15 vs. 18 pmol/l, p = 0.01). The TSH increased more in the Se group at 18 weeks (0.05 vs. 0.02 mIU/l, p = 0.04). The depression and anxiety scores were similar in both groups. In the Se group, the depression rates correlated negatively with FT3 and positively with TSH. This was not seen in the placebo group.

CONCLUSIONS

Se supplementation can enhance biochemical restoration of hyperthyroidism, but whether this could shorten clinical symptoms of thyrotoxicosis and reduce mental symptoms must be investigated further.

BACKGROUND

A high incidence of thyroid autoantibodies and/or disorders was observed in subjects with hepatitis C virus-related chronic hepatitis during interferon-alpha therapy.

OBJECTIVE

To evaluate whether thyroid autoimmunity and dysfunction, induced by interferon-alpha therapy, could be viewed as predictors for treatment response and as valid prognostic markers of liver disease progression.

METHODS

A total of 136 subjects (96 males/40 females; median age 48 years; range 23-64) affected by biopsy-proven chronic hepatitis C (33.1% with compensated liver cirrhosis).

METHODS

All subjects were treated with interferon-alpha therapy at 6 MU 3 times weekly for 12 months and then followed up for an average period of 60 months (range 12-108). Routine laboratory tests, virological assessment, liver ultrasound, thyroid function tests (serum free-triiodothyronine, free-thyroxine, serum thyrotropin), and autoimmunity were performed for all subjects.

RESULTS

Percentage of thyroid autoimmunity and thyroid dysfunction in long-term responders was not significantly different compared to that in non-responders (47.0% and 11.8% vs 35.3% and 5.9%, respectively; non significant). The multivariate model demonstrated that the absence of cirrhosis was the only factor significantly related to successful response to therapy (odds ratio: 14.9; 95% confidence interval: 1.9-115.0 for chronic hepatitis C vs presence of cirrhosis). Moreover, the occurrence of thyroid autoimmunity during interferon therapy was similar both in patients with or without worsening of liver disease (33.3% and 39.8%, respectively; p = not significant). No subject with on-going liver disease developed thyroid dysfunction during treatment, as opposed to the 10/118 (8.4%) with a better course of liver disease; however, this difference was not statistically significant. The multivariate model showed that age was the only covariate significantly associated with unfavourable outcome of liver disease (odds ratio: 18.6; 95% confidence interval: 2.3-151.9, for those over 48 years vs younger patients).

CONCLUSIONS

There is no evidence that the immune mechanism involved in the pathogenesis of thyroid autoimmune phenomena is the same as that regulating the therapeutic clearance of HCV or modulating the unfavourable course of HCV-related chronic hepatitis. However, our study confirmed that liver disease seems to progress more slowly in younger subjects.