Surveillance for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease: Universal or Selective?

Abstract

Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the sixth most common cancer, the fourth leading cause of cancer-related deaths worldwide, and accounts globally for about 800,000 deaths/year. Early detection of HCC is of pivotal importance as it is associated with improved survival and the ability to apply curative treatments. Chronic liver diseases, and in particular cirrhosis, are the main risk factors for HCC, but the etiology of liver disease is rapidly changing due to improvements in the prevention and treatment of HBV (Hepatitis B virus) and HCV (Hepatitis C virus) infections and to the rising incidence of the metabolic syndrome, of which non-alcoholic fatty liver (NAFLD) is a manifestation. NAFLD is now a recognized and rapidly increasing cause of cirrhosis and HCC. Indeed, the most recent guidelines for NAFLD management recommend screening for HCC in patients with established cirrhosis. Screening in NAFLD patients without cirrhosis is not recommended; however, the prevalence of HCC in this group of NAFLD patients has been reported to be as high as 38%, a proportion significantly higher than the one observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Unfortunately, solid data regarding the risk stratification of patients with non-cirrhotic NAFLD who might best benefit from HCC surveillance are scarce, and specific recommendations in this field are urgently needed due to the increasing NAFLD epidemic, at least in Western countries. To further complicate matters, liver ultrasonography, which represents the current standard for HCC surveillance, has a decreased diagnostic accuracy in patients with NAFLD, and therefore disease-specific surveillance tools will be required for the early identification of HCC in this population. In this review, we summarize the most recent evidence on the epidemiology and risk factors for HCC in patients with NAFLD, with and without cirrhosis, and the evidence supporting surveillance for early HCC detection in these patients, reviewing the potential limitations of currently recommended surveillance strategies, and assessing data on the accuracy of potential new screening tools. At this stage it is difficult to propose general recommendations, and best clinical judgement should be exercised, based on the profile of risk factors specific to each patient.

Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

“…Advanced fibrosis (F3/4), old age, male gender, low platelets (less than 150,000/μL), high AST, diabetes, and the patatin-like phospholipase domain-containing protein 3 (PNPLA3) single nucleotide polymorphism (SNP) GG homozygote have been established as carcinogenic risk factors in Japan [ 9 , 19 , 21 ]. These results are consistent with the data from other Asian and western countries [ 15 , 16 , 24 , 25 , 26 ]. We should also clarify the risk factors for HCC incidence in NASH-cirrhosis patients.…”

“…Type IV collagen 7S was previously measured by the radioimmunoassay (RIA) method, but since August 2020, it has become possible to measure this marker via the high-sensitivity ELISA method. Future discussions should determine which parameter is best to use, but it is necessary to discuss not only diagnostic accuracy but also the cost-benefit balance, including medical economic efficiency [26,31].…”

Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment

“…For patients with cirrhosis, or with hepatitis B infection without cirrhosis, ultrasonography combined with serum alpha-fetoprotein levels is the currently recommended approach for widespread screening, although computed tomography (CT) and magnetic resonance imaging (MRI) may offer higher sensitivity for small lesions [ 3 , 4 ]. For patients with NAFLD, ultrasonography has decreased diagnostic accuracy, and in these cases, testing for the presence of genetic variants (e.g., I148M of PNPLA3 ) may inform on HCC risk [ 7 ]. The performance of histological biomarkers in combination with clinical data has shown promise for surveillance and early diagnosis [ 4 ].…”

Exploration and Verification of a Six-RNA Binding Proteins-based Prognosis Evaluating Model for Hepatocellular Carcinoma

“…Nowadays, hepatocellular carcinoma still threatens millions of people's life every year as the sixth prevalent malignant disease [16]. The current therapy on HCC mainly consists of surgery, ablation, interventional therapy and systematic treatment [17].…”