Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in mice by hypothyroidism.

AIMS/BACKGROUND: Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis. METHODS: Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A). RESULTS: Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/-18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6: 12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively). CONCLUSIONS: Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.     

Altered thyroid status modulates portal pressure in normal rats

Abstract: Background & Aims: Disturbances in thyroid function in humans and experimental animal models have been associated with alterations in liver function and portal circulation. We have previously shown that hypothyroidism can significantly reduce portal pressure in portal vein ligated rats as well as inhibit the development of cirrhosis and fulminant hepatic failure following toxic liver injury. The aim of this study was to determine the effects of increased and decreased thyroid function on portal pressure in rats with normal liver histology and portal circulation. Methods: Three groups of 12 Wistar rats each were studied over a 30 day period: euthyroid (Group 1), hyperthyroid (Group 2) and hypothyroid (Group 3). Hyperthyroidism was induced by subcutaneous injection of triiodothyronine (400 μg/100g body weight) every ten days during the study period. Hypothyroidism was induced by methimazole (0.04% in drinking water) from 2 weeks prior to and throughout the 30 day study. Serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were determined to confirm the induction of hyper- and hypothyroidism. Portal pressure was assessed by direct catheterization of the portal vein prior to sacrifice. Indirect confirmation of changes in portal circulation was obtained by determining splenic weight at the time of sacrificing the animals. Animals were sacrificed at 10 day intervals throughout the 30 day study. Results: Triiodothyronine treated rats were hyperthyroid compared to controls, with an elevation in serum T3 levels (3.8±0.9 mmol/L vs 1.3±0.4 mmol/L, p < 0.05). In rats treated with methimazole, hypothyroidism was confirmed by a 7-fold increase in serum TSH compared to controls (1.8 ± 0.4 vs 0.24 ± 0.04 mmol/L, p < 0.01). Portal pressure was significantly higher in the triiodothyronine treated rats compared to controls (12.8 ± 1.7 and 9.6 ± 0.75 cm H₂O, p < 0.001). Splenic weights in hyperthyroid rats were significantly higher than in controls (579 ± 44 vs 478 ± 46 mg, p < 0.01). Portal pressure was significantly lower in the methimazole treated group compared to the control group (8.13 ± 0.68 vs 9.6 ± 0.75 cm H₂O, p < 0.01) as were splenic weights (400 ± 33 vs 478 ± 46 mg, p < 0.01). Conclusion: These studies demonstrate that disturbed thyroid function exerts significant hemodynamic effects on the portal circulation in normal rats and complements results from previous similar studies in cirrhotic animals.     

Folic acid attenuated learning and memory impairment via inhibition of oxidative damage and acetylcholinesterase activity in hypothyroid rats

Hypothyroidism has been reported to be associated with cognitive decline. Considering the role of folic acid (FA) in cognitive performance, the present study was designed to investigate the effects of FA on hypothyroidism-induced cognitive impairment, oxidative damage, and alterations in acetylcholinesterase (AChE) activity in rat model of propylthiouracil (PTU)-induced hypothyroidism. In this study, PTU (0.05% in drinking water) and FA (5, 10, and 15 mg/kg, oral gavage) were administered for the rats during 7 weeks. Then, behavioral performance was tested using Morris water maze (MWM) and passive avoidance (PA) tasks. Finally, oxidative stress indicators and AChE activity were assayed in the brain tissues. The impairing effect of hypothyroidism on cognitive performance was markedly alleviated by FA especially at higher doses. In the MWM test, FA reduced escape latency and travelled distance, compared to the non-treated hypothyroid group. In the PA test, latency to enter dark chamber was significantly enhanced by FA compared to the non-treated hypothyroid group (p?<?0.05–p?<?0.001). Besides, FA attenuated AChE activity and malondialdehyde level but it increased activity of superoxide dismutase enzyme and total thiol content (p?<?0.05–p?<?0.001). In conclusion, our findings revealed that FA could improve learning and memory ability in hypothyroid rats. The observed protective effects may have been mediated through regulation of oxidative stress and AChE activity.

     

Effects of thyroid status and thyrostatic drugs on hepatic glucuronidation of lodothyronines and other substrates in rats : Induction of phenol UDP-glucuronyltransferase by methimazole

Glucuronidation of iodothyronines in rat liver is catalyzed by at least three UDP-glucuronyltransferases (UGTs): bilirubin UGT, phenol UGT, and androsterone UGT. Bilirubin and phenol UGT activities are regulated by thyroid hormone, but the effect of thyroid status on hepatic glucuronidation of iodothyronines is unknown. We examined the effects of hypothyroidism induced by treatment of rats with propylthiouracil (PTU) or methimazole (MMI) or by thyroidectomy as well as the effects of T4-induced hyperthyroidism on the hepatic UGT activities for T4, T3, bilirubin,p-nitrophenol (PNP), and androsterone. Bilirubin UGT activity was increased in MMI- or PTU-induced hypothyroid and thyroidectomized rats, and decreased in hyperthyroid animals. T4 and, to a lesser extent, T3 UGT activities were increased in MMI- or PTU-induced hypothyroid rats, and T4 but not T3 glucuronidation also showed a significant increase in thyroidectomized rats. T4 but not T3 UGT activity was slightly decreased in hyperthyroid rats. While PNP UGT activity was decreased in thyroidectomized rats and increased in hyperthyroid animals, it was also markedly increased by MMI and slightly increased by PTU-induced hypothyroidism. In T4-substituted rats, MMI did not affect T4, T3, bilirubin and androsterone UGT activities but again strongly induced PNP UGT activity, indicating that this represented a direct induction of PNP UGT by the drug independent of its thyrostatic action. Androsterone UGT activity was hardly affected by thyroid status. Our results suggest a modest, negative control of the hepatic glucuronidation of thyroid hormone by thyroid status, which may be mediated by changes in bilirubin UGT activity. To our knowledge, this is the first report of the marked induction of a hepatic enzyme by MMI, which is not mediated by its thyroid hormone-lowering effect.     

Effect of hypothyroidism on the solid form of Ehrlich tumor in intact or castrated adult female mice

The effect of hypothyroidism on the solid form of the Ehrlich tumor in intact or castrated adult female mice was studied. Hypothyroidism was induced by treatment with propylthiouracil (PTU). Forty mice were divided into four groups: castrated hypothyroid, intact hypothyroid, castrated euthyroid, and intact euthyroid. The mice were inoculated with suspension cells into the left footpad. The tumor growth curve was determined by measuring the inoculated footpad during 12 days. At the end of the experimental period the mice were sacrificed. Hypothyroidism was associated with a reduction in size of the tumor only in the castrated animals. Although the neoplastic growth was lower, mean nuclear diameter, number of nucleolar organizer regions (NORs), and area of mitosis were higher. In conclusion, hypothyroidism resulted in a delayed growth of the tumor, but it did not affect the malignant features of the neoplastic cells. In addition, the isolated effect of castration caused only mild alterations, whereas hypothyroidism associated with castration resulted in a more prominent delay in the growth rate of the Ehrlich tumor.     

Follow up of patients with postpartum thyroiditis: a population-based study

In this survey we studied the prevalence of permanent hypothyroidism and prognostic factors for its occurrence 3–5 yr after postpartum thyroiditis (PPT); 54 of 120 women with PPT and 50 of 920 healthy women from among 1040 women followed 4–5 yr earlier for PPT were recalled. Demographic information, signs, and symptoms of thyroid disorders and results of physical exams were documented. Serum T₃, T₄, RT₃U, TSH, and antithyroperoxidase (antiTPO ab) and antithyrogluboline (antiTg ab) antibodies were measured. Twenty-two percent of the cases and four percent of the control group had permanent hypothyroidism, p<0.01. Based on the TSH level we divided the case group into two subgroups: PPT-Hypothyroidism (PPT-Hypo) and PPT-Eutyhroidism (PPT-EU); PPT-Hypo had greater titer of antiTPO ab than PPT-Eu (437±283 vs 126±221 IU/mL, p<0.001). Comparison of mean peak serum TSH level and antiTPO ab during the postpartum thyroiditis phase between PPT-Hypo and PPT-Eu in the case group was significant (56±24 vs 23±28 mU/L, p<0.001, and 1960±1270 vs 640±959 IU/L, p<0.001, respectively). Results of this survery show a high prevalence of permanent hypothyroidism following PPT in Tehran. High titers of antiTPOAb and TSH levels at postpartum period are prognostic factors for occurrence of permanent hypothyroidism.     

Hemodynamic effects of hypothyroidism induced by methimazole in normal and portal hypertensive rats

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1±0.2 vs 4.8±0.3 ml/min/100 g body wt (P<0.01) and 13.4±0.9 vs 10.9±0.8 mm Hg; (P<0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.     

Assessment of Left Ventricular Systolic Asynchrony in Patients with Clinical Hypothyroidism

Background: Hypothyroidism has a large number of adverse effects on the cardiovascular system such as impaired cardiac contractility. Left ventricular (LV) asynchrony is defined as loss of the simultaneous peak contraction of corresponding cardiac segments. Objective: To assess systolic asynchrony in patients with overt hypothyroidism. Methods: Asynchrony was evaluated in 31 patients with overt hypothyroidism and 26 controls. Clinical hypothyroidism was defined as serum thyroid‐stimulating hormone (TSH) more than 4.2 μIU/mL with reduced free T4 less than 1.10 ng/dL. All the patients and controls were subjected to an echocardiographic study including tissue synchronization imaging (TSI). The time to regional peak systolic velocity (Ts) in LV via the six‐basal‐six‐mid‐segmental model was measured on ejection phase TSI images, and four TSI parameters of systolic asynchrony were computed. LV asynchrony was described by these four TSI parameters. Results: The demographic characteristics and conventional echocardiographic parameters of both groups were similar (except total and LDL cholesterol, TSH, free T3, and free T4). All TSI parameters of LV asynchrony were prolonged in hypothyroid patients compared to controls. The standard deviation (SD) of the 12 LV segments Ts was (53.5 ± 14.1 vs. 29.3 ± 15.5, P < 0.0001); the maximal difference in Ts between any 2 of the 12 LV segments was (154.5 ± 37.3 vs. 91.9 ± 45.2, P < 0.0001); the SD of Ts of the 6 basal LV segments was (47.9 ± 15.9 vs. 27.1 ± 16.4, P < 0.0001); and the maximal difference in Ts between any 2 of the 6 basal LV segments was (118.4 ± 37.9 vs. 69.3 ± 39.0, P < 0.0001). The prevalence of LV asynchrony was significantly higher in patients with hypothyroidism compared with controls (83.9% vs. 26.9%, P < 0.0001). Conclusion: Patients with overt hypothyroidism show evidence of LV asynchrony by TSI. (ECHOCARDIOGRAPHY 2010;27:117‐122)     

Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism

OBJECTIVE: Previous studies of the treatment of hyperthyroidism with a single daily dose of antithyroid drugs have demonstrated a favourable result with methimazole (MMI). However, the efficacy of a single daily dose of propylthiouracil (PTU) was inconsistent. The present prospective randomized study was conducted to compare the efficacy of a single daily dose of MMI and PTU in the induction of euthyroidism in patients with Graves' disease. SUBJECTS: Seventy-one patients with newly diagnosed Graves' disease were studied. METHODS AND MEASUREMENTS: Patients were randomized to two groups to receive once daily dose of either 15 mg MMI or 150 mg PTU for 12 weeks. The therapeutic efficacy was determined biochemically by serum total T3, total T4 and TSH levels at baseline and at 4, 8 and 12 weeks during the study period. RESULTS: There was no significant difference in baseline characteristics. Serum total T3 levels of the MMI group were significantly lower than those of the PTU group after four weeks of the treatment (3.54 +/- 0.72 vs. 5.49 +/- 2.74 nmol/l, P < 0.05) through the end of the study (2.22 +/- 1.42 vs. 4.30 +/- 1.78 nmol/l, P < 0.05). The changes in serum total T4 levels occurred in the same direction as serum total T3 levels but a significant difference was observed only after eight weeks of the treatment (MMI vs. PTU; 101.67 +/- 54.05 vs. 176.32 +/- 66.92 nmol/l, P < 0.05). At the end of the study, more patients in the MMI group had both serum total T3 and T4 levels less than the upper limit of the normal range compared to the PTU group (77.1% vs. 19.4%). Hypothyroidism was observed in 31.4% of the patients in the MMI group but not in the PTU group. CONCLUSIONS: During 12-weeks' treatment of Graves' hyperthyroidism, a single daily dose of 15 mg of MMI was much more effective in the induction of euthyroidism than a single daily dose of 150 mg of PTU. Once daily regimen of MMI not only decreased serum T3 and T4 levels more rapidly but also induced euthyroidism four times more effectively than did the once daily regimen of PTU. In the doses used in this study, MMI is preferable to PTU when a once-daily regimen of antithyroid drug is considered for the treatment of hyperthyroidism.     

Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism

Using a modification of the fluorometric method of Anton and Sayre,⁴ we have measured the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction. There was no significant difference in plasma E in hyperthyroid or hypothyroid subjects, the values being similar to those observed in normal subjects. There was a striking relationship between age and plasma NE in the euthyroid individuals (r = 0.685, p < 0.001, n = 41). Observed plasma NE concentrations were similar in control subjects (21.05 ± 1.6 ng/100 ml; mean ± SEM) and hyperthyroid patients (22.33 ± 2.0 ng/100 ml). However, plasma NE was significantly increased in hypothyroidism (35.46 ± 3.9 ng/100 ml; p < 0.01) and remained statistically different when the age factor was excluded (31.31 ± 2.67 ng/100 ml; p < 0.025). There was no correlation between plasma NE and serum thyroxine (T₄), free thyroxine (FT₄), or triiodothyronine (T₃), in any of the three groups studied. These data indicate that hyperthyrodism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possibly in an attempt to compensate for the lack of thyroid hormones.     

Effects of hypothyroidism on somatotrophs and lactotrophs of rat pituitary

Hypothyroidism was induced in male Wistar rats with propylthiouracil (PTU) in the diet and the adenohypophyses were inimunostained for growth hormone and prolactin. In addition, autoradiography with [³H]thymidine demonstrated cells undergoing DNA synthesis. Feeding of PTU for 18 days reduced the immunostainable somatotrophs from 50% to virtually zero, whereas there was no change in the number of lactotrophs. In hypothyroidism, somatotrophs did not disappear from the gland but due to an almost complete degranulation, they were not recognizable by the immunoperoxidase technique. After withdrawal of PTU, these cells regranulated and became identifiable again as somatotrophs by immunostaining. In the hypothyroid pituitary labeled after 18 days of PTU, the labeling index was markedly decreased, compared to the normal gland and to the hypothyroid gland labeled before PTU was started. Thus it appears that hypothyroidism reduces but does not completely abolish DNA synthesis in somatotrophs, and has no effect on the replication of lactotrophs.     

Congenital von Willebrand's disease and clinical hypothyroidism

Data from case reports and systematic reviews suggest an association of Hypothyroidism and Acquired von Willebrand's syndrome. It is not known if congenital von Willebrand's disease is associated with hypothyroidism in a similar way. The aim of this study was to identify the association of congenital von Willebrand's disease (VWD) with clinical hypothyroidism. A total of 350 cases of congenital VWD were initially screened from our institution database from 1985 to 2010. A careful review of patient records was carried out to see if patients truly had congenital VWD and coexisting clinical hypothyroidism. Patients with uncertain diagnoses or other bleeding disorders were excluded, leading to 197 patients remaining in the final sample. A random age‐ and sex‐matched parallel control group was also obtained from the hospital database. Of 197 patients (mean age 43.8 ± 17.5 years, women 72%) of congenital VWD, 32/197 (16%) were diagnosed with clinical hypothyroidism, while only 11/197 (5.6%) of the matched controls were clinically hypothyroid. Univariate and multivariate analysis demonstrated that VWD was an independent predictor of developing clinical hypothyroidism (OR 3.45; 95% CI 1.65–7.22, P = 0.001). The proportion of patients diagnosed with clinical hypothyroidism was more in the VWD group (P < 0.0001). Our analysis shows a strong association of clinical hypothyroidism in patients with congenital VWD, but future studies will be required to delineate a pathological mechanism. In our opinion, clinicians should consider checking thyroid function in the newly diagnosed and established cases of congenital VWD.     

Evidence for Impaired Pancreatic Beta Cell Function in South African Indians with Impaired Glucose Tolerance

In a prospective study of South African Indians with impaired glucose tolerance (IGT), the serum insulin response during a 75 g oral glucose tolerance test (OGTT) was examined in 128 subjects who were classified as IGT 1 year previously (year 0) and in 60 matched control subjects. Based on the results at year 1, study subjects were divided into three groups, using World Health Organization criteria for glucose tolerance: IGT (n = 47), diabetes (n = 41), and transient IGT (normal glucose tolerance) (n = 40). When compared with the control group, despite higher plasma glucose concentrations, the IGT group showed similar fasting insulin, but lower 30-min insulin response (57.4 ± 1.9 mUI^?1 vs 86.5 ± 1.8, p<0.001) and lower 30-min insulin/glucose ratio (7.4 ± 5.2 vs 13.3 ± 8.7, p < 0.001). The insulinogenic index was lower in the IGT group than in the control group at 30, 60, 90, and 120 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively). The 2-h insulin response was higher in the IGT group (106.7 ± 1.9 mUI^?1 vs 59.2 ± 1.9, p < 0.01). The IGT group displayed a delayed pattern of insulin response with maximum levels only at 2-h. Insulin area was similar in the two groups. In the transient IGT group, despite similar plasma glucose levels, the insulin responses at 0, 15, 30, and 60 min (p < 0.01, p < 0.001, p < 0.001, p < 0.001, respectively) were lower than in the control group; the 30-min insulin/glucose ratio (7.1 ± 5.1 vs 13.3 ± 8.7, p < 0.001) and 60-min insulinogenic index (46.9 ± 86.3 vs 123.4 ± 206.3, p < 0.001) were also lower in the transient IGT group. This study has shown that IGT in South African Indians is characterized by a diminished early phase insulin response and delayed (2-h) hyperinsulinaemia during OGTT. Such findings would suggest that in this population group impaired early beta cell function is an important pathophysiological abnormality underlying IGT.     

Growth Hormone Levels in Patients with Type 1 Diabetes are Age Related

Possible effects of age on the growth hormone (GH) levels in Type 1 diabetes were examined. The study was performed in 71 patients with Type 1 diabetes (40 C-peptide negative (CpN), without residual beta cell activity; 31 C-peptide positive (CpP), with preserved beta cell activity) and 11 healthy subjects. The patients and controls were divided into three age groups (A = 21–30; B = 31–40; C = 41–50 years). Blood glucose and growth hormone (GH) were measured at hourly intervals during 24 h in all subjects in hospital conditions. GH levels decreased significantly with age in patients with Type 1 diabetes (mean 24-h GH group A: 7.3 ± 1.0, group B:5.3 ± 0.6, group C:3.7 ± 0.4 mU 1^?1; A vs C: p = 0.0007; B vs C: p = 0.03). In all age groups GH levels were significantly higher in CpN than either in CpP diabetic patients or controls (group A CpN: 8.3 ± 1.2, CpP: 4.7 ± 1.0, controls: 2.2 ± 0.3 mU 1^?1; p < 0.001; group B CpN: 7.3 ± 0.8, CpP: 3.2 ± 0.5, controls: 1.6 ± 1.0 mU 1^?1; p < 0.0002; group C CpN: 5.2 ± 0.5, CpP: 2.5 ± 0.4, controls: 1.4 ± 0.4 mU 1^?1; p < 0.001). Mean GH levels were significantly higher in C-peptide positive patients than in controls in all age groups (p < 0.001). GH levels decreased with age in patients with diabetes and controls, but the decrease was significant only in patients with diabetes (A vs C CpN: p = 0.018, CpP: p = 0.026). We conclude that age is a factor in addition to residual beta cell activity, which influences the magnitude of GH hypersecretion in Type 1 diabetes.     

Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C

Aims/hypothesis Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome. Methods Plasma levels of adiponectin, leptin, resistin, IL-1β, IL-6 and TNF-α in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome. Results Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7±1.0 in FDLP cases vs 7.1±0.72 μg/ml in controls, p=0.02), leptin (1.23±0.4 vs 9.0±1.3 ng/ml, p=0.002) and IL-6 (0.59±0.12 vs 1.04±0.17 pg/ml, p=0.047) and elevated TNF-α (34.8±8.1 vs 13.7±2.7 pg/ml, p=0.028), whereas IL-1β and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=−0.44, p=0.036; FDLP, r=−0.67, p=0.025), insulin resistance (controls, r=−0.62, p=0.003; FDLP, r=−0.70, p=0.025) and other features of the metabolic syndrome. TNF-α concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1β and resistin did not demonstrate any correlations with the metabolic syndrome in either group. Conclusions/interpretation Low adiponectin and leptin and high TNF-α were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-α production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.     

Impact of neonatal onset hypothyroidism on Sertoli cell number, plasma and testicular interstitial fluid androgen binding protein concentration

The impact of neonatal onset hypothyroidism from day 1 postpartum through different postnatal developmental events on rat testis was studied in vivo. Hypothyroidism was induced in neonates by feeding the lactating mother or directly with 0.05% methimazole (MMI) through drinking water from the day of birth and were killed at day 10, 15, 30, 40 and 60 postpartum. Hypothyroidism was confirmed by radioimmunoassay of thyroid hormones and TSH. Sertoli cell number, plasma and testicular interstitial fluid (TIF) androgen binding protein (ABP) concentration was quantified. Sertoli cell number was consistently decreased in all hypothyroid rats. Plasma ABP was also decreased irrespective of the duration of hypothyroidism. Unlike plasma ABP, TIF ABP concentration in hypothyroid rats increased at day 10, and 15 postpartum and decreased in other age groups. Plasma FSH level was increased significantly in all hypothyroid groups. The present investigation points out that suppression of T3 during the critical period of Sertoli cell proliferation affects their number and functional activity.     

Experimental evidence of obstructive sleep apnea syndrome as a second hit accomplice in nonalcoholic steatohepatitis pathogenesis

Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 ± 58 U/l vs. 103 ± 16 U/l in the control group; p < 0.01) and AST (637 ± 37 U/l vs. 175 ± 13 U/l in the control group; p < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1P, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-α; and an increase in α1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.Abstract published under the permission of the editor of Am J Physiol Gastrointest Liver Physiol     

Outcome of radioiodine-131 therapy in hyperfunctioning thyroid nodules: a 20 years' retrospective study

OBJECTIVE: To investigate the risk of hypothyroidism after radioiodine (131I) treatment for hyperfunctioning thyroid nodules. DESIGN: Retrospective analysis of patients treated with 131I for hyperfunctioning thyroid nodules and followed up for a maximum of 20 years. PATIENTS: A total of 346 patients treated with 131I in the years 1975-95, for a single hyperfunctioning nodule. MEASUREMENTS: Hypothyroidism was defined as TSH levels > 3.7 mU/l. Kaplan-Meier survival analysis was used to analyse permanence of euthyroidism after 131I. A stepwise Cox proportional hazard model was used to identify factors influencing the progression to hypothyroidism. RESULTS: The cumulative incidence of hypothyroidism was 7.6% at 1 year, 28% at 5 years, 46% at 10 years and 60% at 20 years. Age (P < 0.01), 24-th 131I uptake (P < 0.05) and previous treatment with methimazole (MMI, P < 0.1) were associated with a faster progression towards hypothyroidism, while thyroid and nodule size, thyroid status at diagnosis and degree of extranodular thyroid parenchymal suppression had no influence. In hyperthyroid patients with partial parenchymal suppression, however, previous MMI treatment was the most important prognostic factor (P < 0.01). CONCLUSIONS: After 20 years of follow-up, 60% of patients treated with 131I for a single hyperfunctioning nodule are hypothyroid. Factors increasing the risk of hypothyroidism are age, 131I uptake and MMI pretreatment. The prognostic value of this last factor, however, depends on the degree of suppression of the extranodular thyroid parenchyma at the scan.     

Changes in endothelial function and its association with plasma osteoprotegerin in hypothyroidism with exercise-induced silent myocardial ischaemia

Objective Hypothyroidism is associated with an increased risk for cardiovascular disease. Exercise‐induced silent myocardial ischaemia (SI) is an early stage of coronary artery disease. Recently, many studies have shown that endothelial dysfunction is an early physiological event in atherosclerosis, and osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. The aim of this study was to investigate the alteration of endothelial function and its association with plasma OPG in hypothyroidism with SI. Methods Forty‐eight female postmenopausal hypothyroid patients with normal rest electrocardiography (ECG) were selected. Of these, 19 cases had SI. Twenty healthy females without SI were selected as controls. High‐resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperaemia and after sublingual glyceryltrinitrate (GTN). Plasma OPG concentration was measured in duplicate by a sandwich enzyme‐linked immunosorbent assay (ELISA). Results Flow‐mediated arterial dilation (FMD) in the total hypothyroid group, the hypothyroidism with SI group and the hypothyroidism without SI group was 3·51 ± 0·62%, 3·20 ± 0·54% and 3·72 ± 0·60%, respectively, significantly lower than that in the controls (5·08 ± 0·61%) (P < 0·01). Compared with the hypothyroidism without SI group, FMD in the hypothyroidism with SI group was significantly lower (P < 0·05). Plasma OPG levels in the total hypothyroid group, patients with SI and patients without SI were significantly higher than in the control group (P < 0·05). Compared with patients without SI, OPG levels were significantly higher in patients with SI (P < 0·05). On multiple regression analysis, low density lipoprotein cholesterol (LDL‐C), lipoprotein (a) [Lp(a)], C‐reactive protein (CRP), OPG, TSH, free T3 (FT3) and thyroid peroxidase antibody (TPO‐Ab) were found to be significant factors that were associated with FMD. Logistic analysis also showed that LDL‐C, TSH, OPG, CRP and FMD were independently and significantly associated with SI in hypothyroidism. Conclusion Impaired endothelial function and increased levels of OPG exist in hypothyroid patients, especially those with SI. These findings support the growing concept that endothelial dysfunction may be associated with vascular disease, and subsequently elevated plasma OPG may have a role in the development of vascular dysfunction in hypothyroid patients.     

Role of EpCAM+ CD133+ extracellular vesicles in steatosis to steatohepatitis transition in NAFLD

Background and Aims

Extracellular vesicles (EVs) have emerged as a potential source of circulating biomarkers in liver disease. We evaluated circulating AV+ EpCAM+ CD133+ EVs as a potential biomarker of the transition from simple steatosis to steatohepatitis.

Methods

EpCAM and CD133 liver proteins and EpCAM+ CD133+ EVs levels were analysed in 31 C57BL/6J mice fed with a chow or high fat, high cholesterol and carbohydrates diet (HFHCC) for 52 weeks. The hepatic origin of MVs was addressed using AlbCrexmT/mG mice fed a Western (WD) or Dual diet for 23 weeks. Besides, we assessed plasma MVs in 130 biopsy-proven NAFLD patients.

Results

Hepatic expression of EpCAM and CD133 and EpCAM+ CD133+ EVs increased during disease progression in HFHCC mice. GFP+ MVs were higher in AlbCrexmT/mG mice fed a WD (5.2% vs 12.1%) or a Dual diet (0.5% vs 7.3%). Most GFP+ MVs were also positive for EpCAM and CD133 (98.3% and 92.9% respectively), suggesting their hepatic origin. In 71 biopsy-proven NAFLD patients, EpCAM+ CD133+ EVs were significantly higher in those with steatohepatitis compare to those with simple steatosis (286.4 ± 61.9 vs 758.4 ± 82.3; p < 0.001). Patients with ballooning 367 ± 40.6 vs 532.0 ± 45.1; p = 0.01 and lobular inflammation (321.1 ± 74.1 vs 721.4 ± 80.1; p = 0.001), showed higher levels of these EVs. These findings were replicated in an independent cohort.

Conclusions

Circulating levels of EpCAM+ CD133+ MVs in clinical and experimental NAFLD were increased in the presence of steatohepatitis, showing high potential as a non-invasive biomarker for the evaluation and management of these patients.