Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging TreatmentNonalcoholic fatty liver disease and hepatocellular carcinoma
Section snippets
Background and Introduction
Fatty liver is histologically characterized by increased hepatocellular storage of triglycerides, where – according to a recent consensus paper – the histo-pathological diagnosis “steatosis” is defined by the finding of lipid deposition in > 5% of hepatocytes whereas the involvement of more than 50% of hepatocytes is referred to as “fatty liver” [1]. Hepatic steatosis and fatty liver are typically associated with high alcohol intake, but can also occur in patients without significant alcohol
Prevalence and Incidence
The incidence and prevalence of HCC in NAFLD depend on the stage of underlying fatty liver disease, patient characteristics and comorbidities (Table 1 and Table 2). According to a recent meta-analysis in cohorts of patients with non-cirrhotic stages of NAFLD, the cumulative HCC mortality was 0%–3% for study periods up to 20 years. In cohorts with NASH cirrhosis the cumulative incidence ranges from 2.4% over 7 years to 12.8% over 3 years [10]. Hence, disease stage is the most important risk factor
Molecular Mechanism of NAFLD-Induced Hepatocarcinogenesis
Clinical, observational and epidemiological studies support a concept where multiple mechanisms drive tumorigenesis and HCC development in NAFLD. Among these, inflammation and endocrine alterations as well as abnormalities in carbohydrate, lipid, and iron metabolism will be reviewed here. Molecular studies in human HCC tissue and animal models of HCC associated with NAFLD show that carcinoma development is not only associated with significant changes in hepatocyte biology but also with profound
Gut Microbiota in NAFLD-Induced Hepatocarcinogenesis
Recent results from studies in animal models of hepatocellular cancer suggest a strong link between tumor progression and gut microbiota. Clinical studies validating findings from animal models in human hepatocellular carcinoma are emerging. In one study fecal microbial composition of 105 patients with early HCC and 45 with advanced HCC was compared with that of 131 healthy controls. In accordance with the results from animal studies, moderate dysbiosis was associated with more advanced HCC. In
Summary and Conclusions
HCC is an increasingly recognized complication of NAFLD, where clinical and histopathological studies have led to the identification of male sex, age, degree of inflammation, hepatic iron accumulation and fibrosis as risk factors. In addition, comorbidities that increase the risk of progression from NAFL to HCC include obesity, diabetes and insulin resistance. Insulin signaling is also at the heart of the molecular changes associated with hepatocarcinogenesis in NAFL. Qualitative genetic
Disclosures
The authors declare no conflict of interest in relation to this work.
References (89)
- et al.
The natural history of nonalcoholic fatty liver: a follow-up study
Hepatology
(1995) - et al.
The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology
Gastroenterology
(2012) - et al.
Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management
J Hepatol
(2015) - et al.
Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review
Clin Gastroenterol Hepatol
(2012) - et al.
Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis
Hepatology
(2002) - et al.
Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C
Hepatology
(2003) - et al.
Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis
J Hepatol
(2009) - et al.
Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma
Clin Gastroenterol Hepatol
(2011) - et al.
Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma
Gastroenterology
(2015) - et al.
Obesity-associated mechanisms of hepatocarcinogenesis
Metabolism
(2014)