Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, and is strongly associated with the metabolic syndrome. In the last decade, it has become apparent that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, and the majority of deaths in NAFLD patients are related to cardiovascular disease (CVD) and cancer. These findings have fuelled concerns that NAFLD may be a new, and added risk factor for extrahepatic diseases such as CVD, chronic kidney disease (CKD), colorectal cancer, endocrinopathies (including type 2 diabetes mellitus [T2DM] and thyroid dysfunction), and osteoporosis. In this review we critically appraise key studies on NAFLD-associated extrahepatic disease. There was marked heterogeneity between studies in study design (cross-sectional versus prospective; sample size; presence/absence of well-defined controls), population (ethnic diversity; community-based versus hospitalbased cohorts), and method of NAFLD diagnosis (liver enzymes versus imaging versus biopsy). Taking this into account, the cumulative evidence to date suggests that individuals with NAFLD (specifically, nonalcoholic steatohepatitis) harbor an increased and independent risk of developing CVD, T2DM, CKD, and colorectal neoplasms. We propose future studies are necessary to better understand these risks, and suggest an example of a screening strategy. (HEPATOLOGY 2014;59:1174-1197

Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis.

Non‐alcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries, and accumulating evidence suggests it as the hepatic manifestation of the metabolic syndrome (MS). Although the published prevalence of hepatocellular carcinoma (HCC) is low in NAFLD/NASH patients, most of these data have been derived from areas endemic for viral hepatitis. We recruited 162 adults with HCC between February 2007 and March 2008, investigated the underlying etiologies and determined the prevalence of the MS and related features within each group. Patients with NAFLD/NASH‐associated HCC exhibited a higher prevalence of metabolic features (Type 2 diabetes mellitus, hypertension, dyslipidemia, coronary artery disease) compared to non‐NAFLD/NASH‐HCC. Intriguingly, a significant number (41.7%; p < 0.005) of individuals with NAFLD/NASH‐HCC had no evidence of cirrhosis. Patients with alcohol‐induced liver disease also displayed many features (14/19, 73.7%) of the MS, although, in contrast to NAFLD/NASH‐HCC, alcohol‐associated HCC was highly associated with cirrhosis (95.0%; p = 0.064). NAFLD/NASH as the hepatic entity of the MS may itself pose a risk factor for HCC, even in the absence of cirrhosis. The MS may also promote development of HCC among those with alcoholic liver disease. Increased awareness of liver manifestations in the MS may instigate early interventions against developing HCC.