A genetic hypothesis for burnt‐out steatohepatitis

Abstract

A genetic hypothesis for burnt-out steatohepatitisEnvironmental stressors such as obesity and insulin resistance, exposure to hepatotoxins, and hepatitis C virus infection increase hepatocyte lipid content, with a significant change in triglyceride, cholesterol as well as other lipid species. Resultant fatty liver disease (FLD) variably progresses to steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). 1 Evidence for shared determinants of FLD and end-stage liver complications first arose from human genetics, 2 that the main risk variants for FLD had a proportional impact on fibrosis and HCC, and fibrosis/HCC development was very closely linked to the impact on the lipid content of hepatocytes. 3,4 However, this theory is challenged by the observation that hepatic fat accumulation and biochemical markers of liver damage and inflammation tend to decrease with the progression of liver fibrosis. [5][6][7] Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS (LV). The European Union, programme 'Photonics' under grant agreement '101016726' (LV). Gilead_IN-IT-989-5790 (LV).

Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct‐acting antivirals

“…This observation suggests that the prevalence of MAFLD, which in patients with cirrhosis does not require the demonstration of increased hepatic fat accumulation (e.g., US) when a positive history is reported, may be higher than previously expected. This hypothesis is consistent with evidence that the ability to accumulate lipids within intracellular lipid droplets resulting in hepatic fat accumulation decreases progressively with the progression of liver fibrosis in individuals with FLD, while lipotoxicity leading to the clinical complications of liver disease does not 17 . Indeed, hepatic fat content progressively returns into the normal range in those with most advanced liver disease 26 .…”

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non‐alcoholic steatohepatitis mouse model

“…Several explanations have been proposed for “burnt‐out NASH” and the development of portal hypertension, including alterations in hepatic vasculature and mitochondrial metabolism, reduced exposure to insulin and stimulation of catabolic pathways, and increased levels of adiponectin, the insulin‐sensitizing adipokine that is cleared by the liver. It has recently been discovered that the decrease in hepatic fat with fatty liver disease progression may, at least, be partially mediated by genetic mechanisms, that is, somatic mutagenesis 27 . We suspected that HMGB1 prevented NASH progression by reducing inflammation, hepatocyte damage, and fibrosis; thus, steatosis persisted in the treated liver.…”

“…In addition, long-term administration of this with fatty liver disease progression may, at least, be partially mediated by genetic mechanisms, that is, somatic mutagenesis. 27 We suspected that HMGB1 prevented NASH progression by reducing inflammation, hepatocyte damage, and fibrosis; thus, steatosis persisted in the treated liver.…”

Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs

“…However, advanced liver fibrosis in NASH is often accompanied by a reduction in hepatic fat to the point of complete fat loss (burnt-out NASH). This paradox can be partially explained by the identification of somatic mutations in genes involved in the regulation of lipid metabolism (forkhead transcription factor O1, FOXO1; cell-death-inducing DFFA-like effector b, CIDEB; and glycerol-3-phosphate acyltransferase, GPAM) in patients with advanced NAFLD [ 35 ].…”