Elsevier

Metabolism

Volume 65, Issue 8, August 2016, Pages 1151-1160
Metabolism

Nonalcoholic Fatty Liver Disease: From Pathogenesis to Emerging Treatment
Nonalcoholic fatty liver disease and hepatocellular carcinoma

https://doi.org/10.1016/j.metabol.2016.01.010Get rights and content

Abstract

The fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC), which is at least partly attributable to the rising prevalence of non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to malignant transformation into hepatocellular cancer. The estimated annual HCC incidence in the progressive form of NAFLD – non-alcoholic steatohepatitis (NASH) – is about 0.3%. The risk of HCC development is higher in men and increases with age, more advanced fibrosis, progressive obesity, insulin resistance and diabetes mellitus. Studies on the molecular mechanism of HCC development in NAFLD have shown that hepatocarcinogenesis is associated with complex changes at the immunometabolic interface. In line with these clinical risk factors, administration of a choline-deficient high-fat diet to mice over a prolonged period results in spontaneous HCC development in a high percentage of animals. The role of altered insulin signaling in tumorigenesis is further supported by the observation that components of the insulin-signaling cascade are frequently mutated in hepatocellular cancer cells. These changes further enhance insulin-mediated growth and cell division of hepatocytes. Furthermore, studies investigating nuclear factor kappa B (NF-κB) signaling and HCC development allowed dissection of the complex links between inflammation and carcinogenesis. To conclude, NAFLD reflects an important risk factor for HCC, develops also in non-cirrhotic livers and is a prototypic cancer involving inflammatory and metabolic pathways.

Strengths/weaknesses and summary of the translational potential of the messages in the paper

The systematic review summarizes findings from unbiased clinical and translational studies on hepatocellular cancer in non-alcoholic fatty liver disease. This provides a concise overview on the epidemiology, risk factors and molecular pathogenesis of the NAFL-NASH-HCC sequence. One limitation in the field is that few HCC studies stratify patients by underlying etiology, although the etiology of the underlying liver disease is an important co-determinant of clinical disease course and molecular pathogenesis. Molecular profiling of NAFL and associated HCC holds great translational potential for individualized surveillance, prevention and therapy.

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.

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