Abstract
Simple SummaryNonalcoholic fatty liver disease (NAFLD) is a disorder of excess lipid accumulation within the liver. Rates of NAFLD have rapidly increased with the sudden rise in obesity and metabolic syndrome. NAFLD may lead to liver inflammation, fibrosis, and dysfunction, and in select cases, the development of liver cancer in the form of hepatocellular carcinoma (HCC). NAFLD is established as a leading cause of liver cancer, and its contribution is expected to grow. Abnormal hepatic lipid metabolism has been repeatedly associated with the progression of NAFLD to primary liver cancer. The current treatment of NAFLD is focused primarily on reducing liver inflammation and fibrosis. Using therapies that additionally target metabolic or lipid signaling pathways that are responsible for tumor development may work to reduce the risk of liver cancer in these patients.Nonalcoholic fatty liver disease (NAFLD) is on the rise and becoming a major contributor to the development of hepatocellular carcinoma (HCC). Reasons for this include the rise in obesity and metabolic syndrome in contrast to the marked advances in prevention and treatment strategies of viral HCC. These shifts are expected to rapidly propel this trend even further in the coming decades, with NAFLD on course to become the leading etiology of end-stage liver disease and HCC. No Food and Drug Administration (FDA)-approved medications are currently available for the treatment of NAFLD, and advances are desperately needed. Numerous medications with varying mechanisms of action targeting liver steatosis and fibrosis are being investigated including peroxisome proliferator-activated receptor (PPAR) agonists and farnesoid X receptor (FXR) agonists. Additionally, drugs targeting components of metabolic syndrome, such as antihyperglycemics, have been found to affect NAFLD progression and are now being considered in the treatment of these patients. As NAFLD drug discovery continues, special attention should be given to their relationship to HCC. Several mechanisms in the pathogenesis of NAFLD have been implicated in hepatocarcinogenesis, and therapies aimed at NAFLD may additionally harbor independent antitumorigenic potential. This approach may provide novel prevention and treatment strategies.
Highlights
In the United States, primary liver cancer ranks fifth in cancer-related mortality [1], with hepatocellular carcinoma (HCC) comprising the majority of these tumors [2]
This stems from the notion that HCC develops more commonly in advanced liver disease, i.e., late-stage fibrosis or cirrhosis, and HCC screening is currently only recommended for Nonalcoholic fatty liver disease (NAFLD) patients with cirrhosis [7,70]
HCC was classically thought of as a disease initiated by viral hepatitis, effective antiviral therapies are available and NAFLD continues to gain ground as a leading cause of chronic liver disease and HCC
Summary
In the United States, primary liver cancer ranks fifth in cancer-related mortality [1], with hepatocellular carcinoma (HCC) comprising the majority of these tumors [2]. Nonalcoholic fatty liver disease (NAFLD) has recently emerged as a leading etiology [3], and some predict NAFLD will become the predominant cause of HCC in the decade This is in part due to advancement of vaccination programs and direct-acting antiviral therapies contributing to a decrease in chronic viral hepatitis cases, coupled with the continuing rise in obesity in developing nations [4,5]. The widespread prevalence of metabolic dysfunction and the limitations imposed by the current definition of NAFLD have led an international consensus panel to propose a revised classification named metabolic-associated fatty liver disease (MAFLD) [12] This revised classification advocates for diagnosis based primarily on the presence of metabolic dysfunction rather than the absence of secondary causes of liver disease, thereby making the diagnosis one of inclusion rather than exclusion. Cryptogenic cirrhosis is being recognized as a form of “burnt-out NASH”, which describes the loss of steatosis in NASH patients with advanced fibrosis, and may account for the historical underestimation of disease burden [4,14,19]
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