Nonalcoholic fatty liver disease: Evolving paradigms

Abstract

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.

Keywords: Biomarkers; Clinical correlates; Diagnosis; Epidemiology; Genetics; Liver histology; Management; Metabolic Syndrome; Nonalcoholic fatty liver disease; Pathogenesis; Screening; Type 2 diabetes.

Figure 1

Nonalcoholic fatty liver disease as a pathogenically and clinically heterogeneous condition. Schematic representation of the pathogenic and clinical heterogeneity of different NAFLD populations. Left: “Metabolic” NAFLD is associated with adipose tissue dysfunction and IR and may progress towards hepatic and extrahepatic complications. Right: “Genetic” NAFLD seems to be disconnected from adipose tissue dysfunction and IR, is associated with an increased risk of liver disease progression but is probably spared from extrahepatic complications. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; HCC: Hepatocellular carcinoma.

Figure 2

Nonalcoholic fatty liver disease pathogenesis: from two to multiple parallel hits. Schematic representation of the increasing grade of complexity gained in moving from earlier theories[27] to more updated pathogenic paradigms[28]. Top: Former “two hits” hypothesis: steatosis, the first ‘hit’, sensitizes the liver to the second “hits”: oxidative stress, endotoxin, ATP depletion and adduct formation[44]. Bottom: The "multiple hits" 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 IR, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors[28]. NAFLD: Nonalcoholic fatty liver disease; TLRs: Toll-like receptors.

Figure 3

The closed loop nonalcoholic fatty liver disease-metabolic syndrome circuit. Schematic representation illustrating the mutual cause-and-effect relationship of NAFLD with the Metabolic syndrome[4,31,146,147]. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis.