Improving NASH with a little help from thyromimetics

Traditionally, non-alcoholic steatohepatitis (NASH) has been associated with insulin resistance-related clinical conditions, such as overweight and type 2 diabetes. However, a quantitative association between subclinical low thyroid function and hepatic steatosis has been shown in a population-based study 1 Ludwig U Holzner D Denzer C et al. Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years. BMC Endocr Disord. 2015; 15: 41 Crossref PubMed Scopus (40) Google Scholar and in a study of people with type 2 diabetes, 2 Bril F Kadiyala S Portillo Sanchez P et al. Plasma thyroid hormone concentration is associated with hepatic triglyceride content in patients with type 2 diabetes. J Investig Med. 2016; 64: 63-68 Crossref PubMed Scopus (16) Google Scholar which is independent of metabolic comorbidities. 3 Chung GE Kim D Kim W et al. Non-alcoholic fatty liver disease across the spectrum of hypothyroidism. Journal of Hepatology. 2012; 57: 150-156 Summary Full Text Full Text PDF PubMed Scopus (152) Google Scholar Incident steatosis occurs more often with higher baseline thyrotropin concentrations. 4 Bano A Chaker L Plompen EP et al. Thyroid function and the risk of nonalcoholic fatty liver disease: the Rotterdam study. J Clin Endocrinol Metab. 2016; 101: 3204-3211 Crossref PubMed Scopus (76) Google Scholar , 5 Xu L Ma H Miao M Li Y Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: a prospective case-control study. J Hepatol. 2012; 57: 1153-1154 Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar In rodents, mild hypothyroidism increases adipose tissue lipolysis, with subsequent hepatic fat accumulation. These changes lead to hepatic insulin resistance and increased glucose production, which exacerbates liver fat through hepatic lipogenesis. 6 Ferrandino G Kaspari RR Spadaro O et al. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proc Natl Acad Sci USA. 2017; 114: e9172-e9180 Crossref PubMed Scopus (26) Google Scholar The histological severity of both steatohepatitis and fibrosis increases with increasing concentrations of thyrotropin, even in the sublinical or high normal range. 7 Kim D Kim W Joo SK Bae JM Kim JH Ahmed A Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin Gastroenterol Hepatol. 2018; 16: 123-131 Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar The findings that, in proportion to the severity of liver damage, the hepatic activity of a thyroid hormone activating deiodinase is reduced and that of a deiodinase that degrades thyroid hormone is increased further suggest that damaged hepatic tissue is in a state of deficiency in active thyroid hormones. 8 Bohinc BN Michelotti G Xie G et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocrinology. 2014; 155: 4591-4601 Crossref PubMed Scopus (26) Google Scholar These findings are problematic, because thyroid hormones can reduce liver steatosis mainly through the induction of lipophagy and restoration of a healthy mitochondrial capacity. 9 Sinha RA You S-H Zhou J et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Investig. 2012; 122: 2428-2438 Crossref PubMed Scopus (154) Google Scholar They might also interfere with fibrogenic pathways by inhibiting transforming growth factor β signalling, 10 Alonso-Merino E Martín Orozco R Ruíz-Llorente L et al. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. Proc Natl Acad Sci USA. 2016; 113: e3451-e3460 Crossref PubMed Scopus (48) Google Scholar thereby preventing fibrosis progression. Additionally, they carry distinct lipid-lowering actions over a broad range of atherogenic lipoproteins, such as LDL cholesterol, large VLDL, apolipoprotein B, and lipoprotein(a). Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trialResmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. Full-Text PDF