Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The ‘two-hit’ hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The “multiple hit” hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is defined as the accumulation of fat in the liver in patients who do not consume excessive alcohol
While patients with simple fatty liver have similar life expectancy to the general population, those with non-alcoholic steatohepatitis (NASH) have an impaired survival, due primarily to cardiovascular and liver-related causes. This concept was recently challenged by two studies with longitudinal follow-up, which showed that advanced fibrosis, but not the presence of NASH predicted overall mortality in patients with NAFLD [5, 6]
We explore the potential mechanisms that are implicated in the pathogenesis and progression of NAFLD and that delineate the multiple-hit hypothesis
Summary
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is defined as the accumulation of fat in the liver in patients who do not consume excessive alcohol. While patients with simple fatty liver have similar life expectancy to the general population, those with NASH have an impaired survival, due primarily to cardiovascular and liver-related causes This concept was recently challenged by two studies with longitudinal follow-up, which showed that advanced fibrosis, but not the presence of NASH (as diagnosed by the NAS score) predicted overall mortality in patients with NAFLD [5, 6]. The ‘second hit’ activates inflammatory cascades and fibrogenesis [8] This has been supported by animal models of obesity, such as the leptin deficient ob/ob mice, characterized by increased hepatic lipid accumulation, where a second insult is necessary to initiate inflammation and fibrosis [9]. We explore the potential mechanisms that are implicated in the pathogenesis and progression of NAFLD and that delineate the multiple-hit hypothesis
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