NAFLD-Associated HCC: Progress and Opportunities

Abstract

Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.

Lack of response to immunotherapy in non-alcoholic steatohepatitis related hepatocellular carcinoma

“…Based on these, the decline in immune response or surveillance function reported in the present study is likely an important factor in NAFLD carcinogenesis. This is in addition to the various factors currently considered to be carcinogenic mechanisms of NASH-HCC, including genetic and epigenetic mechanisms, microbiomes, metabolic pathways, molecular signaling pathways, endocrine pathways, and immunological pathways (6)(7)(8). Moreover, NAFLD is known to exhibit not only carcinogenesis from liver cirrhosis (9) but also carcinogenesis at a mild stage of fibrosis in approximately 25-50% of cases (10)(11)(12).…”

Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

“…Thus, the greatest HCC prevalence is in the Asian regions and sub-Saharan Africa due to the endemic HBV infection. In contrast, HCV infection and nonalcoholic fatty liver disease (NAFLD) are major risk factors associated with HCC in western countries [1,16]. Another infectious factor considered to augment the risk of developing HCC is represented by the Hepatitis D-delta virus (HDV), a hybrid virus that acts as a satellite of HBV by incorporating the HBV surface antigen (HBsAg) and infecting only the persons that present an infection with HBV [17].…”

Novel Antidiabetic Strategies and Diabetologists' Views in Nonalcoholic Steatohepatitis

“…39 Biannual US-based surveillance proved beneficial in NAFLD patients with advanced fibrosis and cirrhosis, but bears several limitations, e.g., questionable cost-effectiveness as well as mode of identification of patients at risk considering the large size of the population to be examined and the variable time course of NAFLD progression. 38…”