triiodothyronine--reverse and Liver-Neoplasms

In consumptive hypothyroidism associated with infantile hepatic hemangiomas (IHH), elevated reverse triiodothyronine (rT3) is known due to elevated D3. This report shows that rT3 is a new indicator of IHH progression and that three divided doses of LT3 per day were more effective than a single dose.. A 23 day-old boy was diagnosed with diffuse IHH and severe hypothyroidism with high rT3. Propranolol and LT4 were administered. Hemangiomas gradually diminished and rT3 decreased, but the thyroid-stimulating hormone remained elevated, and free triiodothyronine (fT3) did not normalize after 2 weeks of treatment. Liothyronine (LT3) was started as a single dose and then divided into three doses after 1 week, which stabilized thyroid function.. rT3 levels were less variable and decreased in conjunction with tumor shrinkage; thus, rT3 is an indicator of therapeutic outcomes for IHH. LT3 administered in divided doses aided in managing IHH-associated hypothyroidism.

Topics: Hemangioma; Humans; Hypothyroidism; Liver Neoplasms; Male; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-l-diiodothyronine (T(2)), as well as 3,3',5-L-triiodothyronine (T(3)), was able to both prevent and reverse hepatic steatosis in rats fed a high-fat diet, and this effect depends on a direct action of iodothyronines on the hepatocyte. However, the involvement of thyroid hormone receptors (TRs) in mediating the lipid-lowering effect of iodothyronines was not elucidated. In this study, we investigated the ability of T(2) and T(3) to reduce the lipid overloading using the rat hepatoma FaO cells defective for functional TRs. The absence of constitutive mRNA expression of both TRα1 and TRβ1 in FaO cells was verified by RT-qPCR. To mimic the fatty liver condition, FaO cells were treated with a fatty acid mixture and then exposed to pharmacological doses of T(2) or T(3) for 24 h. Lipid accumulation, mRNA expression of the peroxisome proliferator-activated receptors (PPAR-α, -γ, -δ) the acyl-CoA oxidase (AOX), and the stearoyl CoA desaturase (SCD1), as well as fuel-stimulated O(2) consumption in intact cells, were evaluated. Lipid accumulation was associated with an increase in triacylglycerol content, PPARγ mRNA expression, and a decrease in PPARδ and SCD1 mRNA expression. The addition of T(2) or T(3) to lipid-overloaded cells resulted in i) reduction in lipid content; ii) downregulation of PPARα, PPARγ, and AOX expression; iii) increase in PPARδ expression; and iv) stimulation of mitochondrial uncoupling. These data demonstrate, for the first time, that in the hepatocyte, the lipid-lowering actions of both T(2) and T(3) are not mediated by TRs.

Topics: Aldehyde Oxidase; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Diiodothyronines; Fatty Liver; Gene Expression Regulation; Hepatocytes; Hypolipidemic Agents; Liver Neoplasms; PPAR delta; PPAR gamma; Rats; Receptors, Thyroid Hormone; RNA, Messenger; Stearoyl-CoA Desaturase; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Triiodothyronine, Reverse; Uncoupling Agents

Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy.

Topics: Hemangioma; Humans; Hypothyroidism; Infant; Iodide Peroxidase; Liver Neoplasms; Male; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The aim of this study was to investigate changes in thyroid hormone metabolism in relation to the development of hepatocellular carcinoma (HCC) in patients with HCV-related liver cirrhosis.. The study group (Group A) comprised 31 patients (25 M, 6 F; median age 62.1 years, range 54.0-81.5 years) affected by HCV-related liver cirrhosis with superimposed HCC. Acute and chronic systemic disease, other than cirrhosis, inducing 'euthyroid sick syndrome' was excluded in all patients. Serum TSH, FT4, FT3, rT3, and thyroxine-binding globulin (TBG) levels were retrospectively evaluated in frozen aliquots drawn at the time of tumour diagnosis and every 6 months for 3-7 years before HCC diagnosis. The control group (Group B) comprised 29 patients affected by HCV-related liver cirrhosis without HCC, matched for sex, age and grade of liver dysfunction.. At the time of HCC diagnosis, all patients in Group A were euthyroid with serum TSH, FT4, FT3 and TBG values not significantly different from those of cirrhotic patients of Group B. However, at diagnosis Group A patients had serum rT3 values that were significantly higher than those in Group B (35.0 ng/dl, range 12.0-162.0 vs. 19.0 ng/dl, range 10.0-51.0; Group A vs. Group B; P < 0.001). Serum rT3 values above the normal range were found in 12 patients in Group A (38.7%) but in only one of the patients from Group B (3.4%) (chi2 10.2; P = 0.001). The serum rT3 levels were not significantly correlated to the Child grade of liver cirrhosis (rho 0.1; P = 0.5). The intrasubject analysis demonstrated that a significant increase in serum rT3 levels occurred at the time of HCC diagnosis but serum FT4, FT3 and TSH values did not change significantly. A receiver operating curve (ROC) demonstrated that a 6-monthly increase in serum rT3 levels of at least +22.5% identified patients with HCC with a diagnostic accuracy of 81.7%.. Our study has demonstrated that development of hepatocellular carcinoma is accompanied by a significant increase in serum rT3 levels in patients with low-grade HCV-related liver cirrhosis who had no other illness causing the 'euthyroid sick syndrome'.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Female; Hepacivirus; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; ROC Curve; Triiodothyronine, Reverse

Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.

Topics: Animals; Carcinoma, Hepatocellular; Contrast Media; Hyperthyroidism; Iodide Peroxidase; Iopanoic Acid; Kidney; Liver; Liver Neoplasms; Male; Rats; Thyroid Gland; Triiodothyronine, Reverse; Tumor Cells, Cultured

Basal T4, T3, TSH, prolactin and growth hormone levels were determined in several groups: patients with postnecrotic cirrhosis with hepatocellular carcinoma (n = 14); patients with postnecrotic cirrhosis but without hepatocellular carcinoma (n = 26); cholangiolar carcinoma (n = 9); and normal controls age-matched to within 5 yr of the liver disease subjects studied. In addition, TRH stimulation (400 micrograms TRH) was performed; TSH, prolactin and growth hormone responses over a 180-min time interval were evaluated for each subject. The responses observed varied between liver disease groups. The presence or absence of hepatocellular carcinoma was found to determine, at least in part, the type of response observed. Similarly, the presence or absence of hepatic encephalopathy determined, and/or reflected, at least in part, the type of response observed. Finally, for purposes of continuity, basal and TRH-stimulated levels of TSH, prolactin, growth hormone, T4 and T3 are compared in 3 settings of cirrhosis: alcoholic, nonalcoholic postnecrotic cirrhosis, and postnecrotic cirrhosis with hepatocellular carcinoma.

Topics: Carcinoma, Hepatocellular; Growth Hormone; Hepatic Encephalopathy; Humans; Liver Diseases; Liver Neoplasms; Pituitary Hormones; Prolactin; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The metabolism of 3, 5-[3'-125I]triiodothyronin (T3) and 3-[3', 5'-125I]triiodothyronine (rT3) was studied in cultured monkey hepatocarcinoma cells (NCLP-6E), and the deiodinations of these iodothyronines were also investigated in cultured cell homogenates and in rat liver homogenates. The metabolites were analyzed by ion exchange column chromatography. For nonphenolic ring deiodination of 3, 5-[3'-125I]triiodothyronine, the order of the inhibitory effect of excess unlabeled iodothyronine or its analog was as follows: 3,3',5-triiodothyroinine greater than triiodothyroacetic acid greater than tetraiodothyroacetic acid greater than thyroxine. This order did not differ between in the intact cells (NCLP-6E) and their homogenates. The order of effectiveness of the excess unlabeled compounds on phenolic ring deiodination of 3-[3', 5'-125I]triiodothyronine in the intact cells was as follows: tetraiodothyroacetic acid greater than triiodothyroacetic acid, 3, 3', 5-triiodothyronine greater than thyroxine. This order was the same among monkey hepatocarcinoma cell homogenates, rat hepatoma cell homogenates and rat liver homogenates, and triiodothyroacetic acid was obviously more effective than 3, 3', 5-triiodothyronine. It was concluded that 3, 3', 5-triiodothyronine had the highest affinity for nonphenolic ring deiodinase among iodothyronines and their analogs used in the present study and that tetraiodothyroacetic acid and the highest affinity for phenolic ring deiodinase. It seems, therefore, that the metabolites derived from the thyroid hormones might contribute to deiodinations which involve activation and inactivation of the hormones.

Topics: Animals; Cell Line; Chromatography, Ion Exchange; Haplorhini; Iodide Peroxidase; Liver; Liver Neoplasms; Peroxidases; Rats; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Cultured monkey hepatocarcinoma cells were incubated with [3',5'-125I] diiodo-L--thyronine and with [3,5-125I] diiodo-L-thyronine. In both instances monodeiodination as well as sulfoconjugation took place. [3.-125I] iodothyronine and [3',5'-125I] diiodothyronine were identified as metabolites of [3'-5'-125I]-L-thyroxine in the cells, but neither [3-125I]-iodothyronine nor [3,5-125I] diiodothyronine was detected after incubation of the cells with ]3,5-125I]-L-thyroxine. No products of diphenyl ether splitting were observed in the medium after incubation of the cells with either [3,5-125I] diiodo-L-thyronine or [3,5-125I]-L-thyroxine.

Topics: Animals; Cell Line; Diiodothyronines; Haplorhini; Liver Neoplasms; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Chronic Disease; Hepatitis; Humans; Liver Cirrhosis; Liver Neoplasms; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse