Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that hyperthyroidism is detrimental for liver fibrosis and in this study we have investigated the mechanisms regulating triiodothyronine (T3) and L-thyroxine (T4) activation of hepatic stellate cells (HSC). Expression of alpha-smooth muscle actin (alphaSMA) and p75 neurotrophin receptor (p75NTR) was determined by western blot analyses and transient transfection of the promoters. Rho activation was assayed using a pull-down assay and by ELISA. Expression of thyroid hormone receptor alpha1 decreases, whereas T4 receptor integrin alphaVbeta3 increases, with transdifferentiation of HSC to myofibroblasts. T3 and T4 enhance HSC activation, without affecting proliferation or phosphorylation of mitogen-activated protein kinase, signal transducer and activator of transcription 3 or Akt. Addition of 10(-7) M T3 or T4 to thyroid hormone-depleted serum induces a twofold increase in activation marker alphaSMA, as well as upregulation of p75NTR protein levels. Both hormones enhance transcription of alphaSMA and p75NTR. We report a novel signaling pathway for thyroid hormones, activation of Rho. T4 induces activation of Rho acting through alphavbeta3 integrin, and the activation is abolished by the T4 antagonist, tetraiodothyroacetic acid, by peptide RGD and by a function-blocking antibody to integrin beta3. T3 and T4 increase phosphorylation of non-muscle myosin light chain II, a downstream signal to Rho/Rho-kinase activation. T3 also induces expression of tumor necrosis factor-alpha. In vivo, administration of T3 or T4 together with thioacetamide (TAA) enhances fibrosis after 3 weeks, compared with the TAA-treated group, accompanied by increased alphaSMA in T3- and T4-treated groups, and of p75NTR in T4-treated rats. Thyroid hormones enhance activation of HSC through increased p75NTR and alphaSMA expression and activation of Rho, therefore accelerating development of liver fibrosis.
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PMID:Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho. 2023 20

Congenital hypothyroidism is the most common hereditary endocrine disorder. In a small number of cases, mutations have been identified that are associated with maldevelopment and maldescent of the thyroid. Some of these mutations present as syndromes with a multisystem phenotype such as NKX2-1, PAX8, and FOXE. The association of permanent neonatal diabetes and congenital hypothyroidism was first reported in 2003 and subsequently led to the identification GLIS3 as the mutation responsible for this presentation. GLIS3 is a member of the GLI-similar zinc finger protein family encoding for a nuclear protein with five zinc finger domains and maps to chromosome 9p24. Given the role of GLIS3 in transcriptional activation and repression during embryogenesis, in humans, GLIS3 mutations present with multisystem involvement that also includes renal cystic dysplasia, progressive liver fibrosis and osteopenia. Thyroid findings in GLIS3 patients include thyroid aplasia, diminished colloid with interstitial fibrosis at post-mortem, and apparently normal gross thyroid anatomy on ultrasonography but with temporary TSH resistance on treatment. To date no biological mechanism has explained this variable presentation.
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PMID:The role of GLIS3 in thyroid disease as part of a multisystem disorder. 2864 6

Background: Fibrotic diseases have an unclear etiology and poor prognosis. Fluctuations in thyroid function may play a role in the development of fibrosis, but evidence is fragmented and inconclusive. This systematic review and meta-analysis aimed to investigate the association of thyroid function with fibrotic diseases of the liver, heart, and lung in humans. Methods: We searched PubMed, Medline Ovid, Embase Ovid, and Web-of-Science for studies published from inception to 14 June 2019, to identify observational studies that investigated the association of thyroid function with fibrosis of the liver, heart, and lung in humans. Study quality was evaluated by the Newcastle-Ottawa Scale. The Mantel-Haenszel method was used to pool the odds ratios (ORs) of studies investigating the association of hypothyroidism with liver fibrosis. Results: Of the 2196 identified articles, 18 studies were included in the systematic review, of which 11 studies reported on liver fibrosis, 4 on myocardial fibrosis, and 3 on pulmonary fibrosis. The population sample size ranged from 36 to 7259 subjects, with median mean age 51 years (range, 36-69) and median percentage of women 53 (range, 17-100). The risk of bias of studies was low to moderate to high. Higher serum thyrotropin and lower thyroid hormone levels were generally associated with higher likelihood of fibrosis. Compared with euthyroidism, overt and subclinical hypothyroidism was associated with a higher likelihood of fibrosis in the liver (six of seven studies), heart (three of three studies), and lung (three of three studies). Based on the results of the seven studies included in the meta-analysis, overt and subclinical hypothyroidism was associated with an increased risk of liver fibrosis (pooled OR, 2.81; 95% confidence interval [CI], 1.74-4.53; heterogeneity, I2 31.4%; pooled OR, 2.12; CI, 1.45-3.12; heterogeneity, I2 0%; respectively), without evidence of publication bias. Conclusions: This study suggests that low thyroid function is associated with increased likelihood of chronic fibrotic diseases of the liver, heart, and lung. However, the evidence is mainly based on cross-sectional data. Prospective studies and randomized clinical trials are needed to investigate the potential efficacy of thyroid hormone and its analogs on the occurrence and progression of fibrosis.
Thyroid 2020 06
PMID:Thyroid Function and the Risk of Fibrosis of the Liver, Heart, and Lung in Humans: A Systematic Review and Meta-Analysis. 3191 97