Iron and non-alcoholic fatty liver disease

Abstract

The mechanisms that promote liver injury in non-alcoholic fatty liver disease (NAFLD) are yet to be thoroughly elucidated. As such, effective treatment strategies are lacking and novel therapeutic targets are required. Iron has been widely implicated in the pathogenesis of NAFLD and represents a potential target for treatment. Relationships between serum ferritin concentration and NAFLD are noted in a majority of studies, although serum ferritin is an imprecise measure of iron loading. Numerous mechanisms for a pathogenic role of hepatic iron in NAFLD have been demonstrated in animal and cell culture models. However, the human data linking hepatic iron to liver injury in NAFLD is less clear, with seemingly conflicting evidence, supporting either an effect of iron in hepatocytes or within reticulo-endothelial cells. Adipose tissue has emerged as a key site at which iron may have a pathogenic role in NAFLD. Evidence for this comes indirectly from studies that have evaluated the role of adipose tissue iron with respect to insulin resistance. Adding further complexity, multiple strands of evidence support an effect of NAFLD itself on iron metabolism. In this review, we summarise the human and basic science data that has evaluated the role of iron in NAFLD pathogenesis.

Non-invasive Assessment of Liver Disease in Rats Using Multiparametric Magnetic Resonance Imaging: A Feasibility Study

“…Hepatic iron may have a pathogenic role in NAFLD and, intriguingly, NAFLD itself may affect iron metabolism (19). From a technical standpoint, both hepatic steatosis and fibrosis can have confounding effects on T2* relaxation times.…”

“…Unfortunately, there was only a minimal effect of a short treatment course of cilostazol in the MCD diet model and even histological endpoints were not significantly altered within this abbreviated timeframe. Although a number of MRI techniques have been evaluated individually in animal models to assess hepatic fibrosis (19), iron content (20) or fat (21), multiparametric MRI captures all of these parameters in a single contrast-free scan protocol. In a previous study in mice with fatty liver, non-invasive MR assessments (1H-MRS, PDFF and modified Dixon) had a higher correlation with liver triglyceride content than digital image analysis of Oil Red O stained liver sections (21).…”

Mouse models of hereditary hemochromatosis do not develop early liver fibrosis in response to a high fat diet

“…In approximately 30% of patients, NAFLD progresses from simple steatosis to non-alcoholic steatohepatitis (NASH), a chronic inflammatory condition that may further lead to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD patients often exhibit perturbed iron metabolism and accumulate liver iron deposits, which increases the risk for liver fibrosis [3,4].…”

The Rise in the Prevalence of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

“…There is a reported 52% heritability rate of NAFLD, but evidence pertaining to specific genetic mutations is scant according to multivariable models used after adjusting for sex, age, and ethnicity [13]. Although the mechanism is not well understood, genetic mutations in hemochromatosis (HFE) gene, which is responsible for iron uptake and transferrin plasma concentration, may also be associated with NAFLD development [105,106]. Several other factors have been indicated in the development and outcomes of NAFLD including epigenetic alterations [107,108], maternal perinatal nutrition [109][110][111], and gut microbiota [107,[112][113][114].…”