Hepatocellular carcinoma in non-alcoholic fatty liver disease—a review of an emerging challenge facing clinicians

Daniel Geh, Derek M. Manas, Helen L. Reeves


Hepatocellular carcinoma (HCC) is the most common primary liver cancer and usually occurs in the context of chronic liver disease. Due to its increasing incidence and high mortality, HCC is a major public health concern. The improved prevention and treatment of chronic hepatitis infection, combined with the recent epidemic of the metabolic syndrome, has led to non-alcoholic fatty liver disease (NAFLD) becoming a rapidly growing cause of HCC. NAFLD is now the leading of cause of HCC in many developed countries and is predicted to become much more common worldwide. The rise of NAFLD presents major challenges for the screening, diagnosis and treatment of HCC. Current HCC screening programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently, NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies, including type 2 diabetes mellitus (T2DM), obesity, cardiovascular disease and cerebrovascular disease. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and transarterial chemoembolization (TACE) may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Further studies are needed to evaluate the effectiveness of current treatment strategies in NAFLD-HCC. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.