Association Between Steatohepatitis Biomarkers and Hepatocellular Carcinoma After Hepatitis C Elimination

Eiichi Ogawa; Koji Takayama; Satoshi Hiramine; Takeo Hayashi; Kazuhiro Toyoda


Aliment Pharmacol Ther. 2020;52(5):866-876. 

In This Article

Abstract and Introduction


Background: A strong association between chronic hepatitis C (CHC) and hepatic steatosis has been reported. However, the influence of steatohepatitis on hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) elimination remains unclear.

Aim: To evaluate the development of HCC after HCV cure using a new steatohepatitis-related biomarker.

Methods: This cohort study analysed the prospective database of 290 CHC patients without a history of HCC who achieved HCV elimination by direct-acting antivirals. We calculated the FibroScan-aspartate aminotransferase (FAST) score 12 weeks after the end of treatment (pw12). The risk of HCC was analysed using the multivariable Cox proportional hazard model.

Results: HCV genotype (GT)1 was most prevalent at 72.4%, followed by GT2 (26.6%). Median follow-up period was 4.2 years (IQR 3.1–4.5). The cumulative HCC incidence for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35 (log-rank test: P < 0.001). The annual HCC incidence rate for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35, in patients with liver stiffness measurement (LSM) ≥10 kPa (adjusted hazard ratio [HR] 4.41, 95% confidence interval [CI] 1.30–15.0, P = 0.018). After adjusting for variables, including age, albumin, alpha-fetoprotein, the patatin-like phospholipase domain-containing the 3 (PNPLA3) rs738409 genotype, and pw12 fibrosis markers with FIB-4, non-alcoholic fatty liver disease fibrosis score, and LSM, FAST score ≥ 0.35 was associated with the development of HCC (adjusted HR 4.42, 95% CI 1.02–19.9, P = 0.043).

Conclusions: Steatohepatitis-related biomarkers with the FAST score are helpful for predicting the development of HCC after HCV elimination.


Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma (HCC), even since the introduction of all-oral direct-acting antivirals (DAAs) in 2013.[1] Real-world HCV cure rates now range from 85% to almost 100%, irrespective of the DAA regimen, fibrosis status, or the presence of active HCC.[2,3] As a result, achieving sustained viral response (SVR) significantly decreases the risk for HCC, and the number of patients requiring a liver transplant has fallen sharply.[4–7]

Cirrhosis, FIB-4 index ≥ 3.25 and elevated serum alpha-fetoprotein (AFP) level have recently been reported to be associated with a higher risk of developing liver-related complications.[8–10] This indicates that fibrosis status is useful for predicting the development of HCC. On the other hand, approximately 10%-30% of the patients who achieve HCV elimination through DAA therapy have a persistently elevated alanine aminotransferase (ALT) level, mainly due to fatty liver associated with metabolic syndrome.[11,12] However, little data on the relevance of the relation of concurrent liver steatosis and the development of HCC by patients treated with DAAs have been published to date because of the lack of a confirmed steatohepatitis assessment strategy.

In general, a single nucleoside polymorphism located in the patatin-like phospholipase domain-containing the 3 (PNPLA3) gene (rs738409 C > G, encoding for p.I148M) is one of the most crucial host genetic factors with an impact on advanced steatohepatitis.[13,14] The rs738409 G allele has been related to poorer prognosis even in other liver diseases such as chronic hepatitis C (CHC) and autoimmune hepatitis.[15–17] The link between this mutation and HCC development after HCV cure, however, remains to be established. In addition, a new non-invasive steatohepatitis biomarker based on data on liver stiffness measurement (LSM) and the controlled attenuation parameter (CAP) by transient elastography (FibroScan) has been proposed.[18] This FibroScan-aspartate aminotransferase (FAST) score provides efficient identification of high-risk patients with progressive non-alcoholic steatohepatitis (NASH), elevated non-alcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 4) and advanced fibrosis (stage 2 or higher). In this study, we used the steatohepatitis-related markers to evaluate the development of HCC by patients with CHC who achieved SVR by DAA treatment.