Abstract
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and fibrosis. “Obese/Metabolic NAFLD” is closely associated with obesity and insulin resistance and therefore predisposes to type 2 diabetes and cardiovascular disease. NAFLD can also be caused by common genetic variants, the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2). Since NAFL, irrespective of its cause, can progress to NASH and liver fibrosis, its definition is of interest. We reviewed the literature to identify data on definition of normal liver fat using liver histology and different imaging tools, and analyzed whether NAFLD caused by the gene variants is associated with insulin resistance. Histologically, normal liver fat content in liver biopsies is most commonly defined as macroscopic steatosis in less than 5% of hepatocytes. In the population-based Dallas Heart Study, the upper 95th percentile of liver fat measured by proton magnetic spectroscopy (1H-MRS) in healthy subjects was 5.6%, which corresponds to approximately 15% histological liver fat. When measured by magnetic resonance imaging (MRI)-based techniques such as the proton density fat fraction (PDFF), 5% macroscopic steatosis corresponds to a PDFF of 6% to 6.4%. In contrast to “Obese/metabolic NAFLD”, NAFLD caused by genetic variants is not associated with insulin resistance. This implies that NAFLD is heterogeneous and that “Obese/Metabolic NAFLD” but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as steatosis not caused by excess alcohol intake (>30 g/day in men and >20 g/day in women), hepatitis B or C, autoimmune hepatitis, iron overload, drugs or toxins [1]
The ensuing review will focus on defining normal liver fat content and discussing how liver fat content is related to insulin sensitivity in “Obese/Metabolic NAFLD” and the common genetic forms of NAFLD
Normal liver fat content based on liver histology can be defined as macroscopic steatosis in less than 5% of hepatocytes
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as steatosis not caused by excess alcohol intake (>30 g/day in men and >20 g/day in women), hepatitis B or C, autoimmune hepatitis, iron overload, drugs or toxins [1]. Fibrosis stage is considered to be the most important histological feature predicting advanced liver disease [5,6] It has been recently shown, that NAFL defined as macroscopic steatosis in more than 5% of hepatocytes progresses to NASH and fibrosis [7,8,9], as hypothesized by earlier indirect evidence [10]. Genetic variation in transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926 [T], encoding E167K) is increases liver fat and the risk of NASH (“TM6SF2 NAFLD”) [13]. These two conditions do not appear to be characterized by insulin resistance, both genetic and metabolic causes of NAFLD may exist in the same person [14]. The ensuing review will focus on defining normal liver fat content and discussing how liver fat content is related to insulin sensitivity in “Obese/Metabolic NAFLD” and the common genetic forms of NAFLD
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