Longitudinal changes in fatty liver index are associated with risk of hepatocellular carcinoma: A nationwide cohort study in Korea

Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver diseaseJournal of HepatologyVol. 78Issue 3PreviewCurrently, there is no consistent information on the course of fibrosis-4 (FIB-4) score changes in non-alcoholic fatty liver disease (NAFLD) or their association with subsequent risk of cirrhosis and/or hepatocellular carcinoma (HCC). Thus, we aimed to evaluate the association between longitudinal changes in FIB-4 and subsequent risk of HCC and a composite endpoint of cirrhosis and HCC in patients with NAFLD. Full-Text PDF Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder associated with significant morbidity and mortality, including hepatocellular carcinoma (HCC). Recently, Cholankeril et al.[1]Cholankeril G. Kramer J.R. Chu J. Yu X. Balakrishnan M. Li L. et al.Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease.J Hepatol. 2023; 78: 493-500Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar evaluated the association of changes in the fibrosis-4 (FIB-4) score with the subsequent risk of cirrhosis or HCC. In their extensive retrospective cohort study of patients with NAFLD, after a 3-year landmark period, longitudinal changes in FIB-4 levels were found to be strongly associated with progression to cirrhosis and HCC. They analyzed the HCC risk based on the degree of fibrosis progression in patients with NAFLD. We consequently developed a keen interest in exploring whether HCC occurrence is influenced by the development or regression of steatosis corresponding to the early stage of NAFLD. The Fatty Liver Index (FLI) is a numerical scoring system, composed of body mass index, waist circumference, triglyceride levels, and gamma-glutamyl transferase levels, that estimates the amount of fat present in the liver.[2]Bedogni G. Bellentani S. Miglioli L. Masutti F. Passalacqua M. Castiglione A. et al.The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population.BMC Gastroenterol. 2006; 6: 33Crossref PubMed Scopus (1671) Google Scholar The FLI has been adopted as a diagnostic tool to evaluate the probability of NAFLD in many studies.3Han E. Han K.D. Lee Y.H. Kim K.S. Hong S. Park J.H. et al.Fatty Liver & Diabetes Statistics in Korea: Nationwide Data 2009 to 2017.Diabetes Metab J. 2023; 47: 347-355Crossref PubMed Scopus (3) Google Scholar, 4Lee S.M. Cho G.J. Wi W.Y. Norwitz E.R. Koo B.K. Lee J. et al.Metabolic dysfunction-associated fatty liver disease as a risk factor for adverse outcomes in subsequent pregnancy: a nationwide cohort study.Hepatol Int. 2023; 17: 367-376Crossref PubMed Scopus (0) Google Scholar, 5Cho E.J. Jung G.C. Kwak M.S. Yang J.I. Yim J.Y. Yu S.J. et al.Fatty Liver Index for Predicting Nonalcoholic Fatty Liver Disease in an Asymptomatic Korean Population.Diagnostics (Basel). 2021; 11Google Scholar Herein, we evaluated the association between FLI changes and HCC occurrence using data from the Korean National Health Insurance Service database. We included adults aged 20 years and above who participated in two rounds of health screening: Period 1 (2011–2012) and Period 2 (2013–2014). Patients with chronic liver disease, including alcohol-related liver disease, viral hepatitis, and autoimmune hepatitis, were excluded from the study. HCC was defined using International Classification of Diseases, 10th revision, diagnostic codes C22, C220, C227, or C229, along with special reimbursement codes V193 or V194, signifying a cancer diagnosis monitored by the government. To investigate the impact of FLI changes on HCC, participants were divided into two cohorts based on their FLI levels during the first health screening, with FLI = 30 as cut-off.[5]Cho E.J. Jung G.C. Kwak M.S. Yang J.I. Yim J.Y. Yu S.J. et al.Fatty Liver Index for Predicting Nonalcoholic Fatty Liver Disease in an Asymptomatic Korean Population.Diagnostics (Basel). 2021; 11Google Scholar,[6]Wu J. Li H. Xu Z. Ran L. Kong L.Q. Population-specific cut-off points of fatty liver index for the diagnosis of hepatic steatosis.J Hepatol. 2021; 75: 726-728Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar HCC was evaluated during the follow-up period. Of the total population of 814,129 individuals, 514,264 had a baseline FLI value < 30, whereas 299,865 had an FLI ≥ 30. At the 2-year follow-up, 11.9% experienced an increase and 17.9% exhibited a decrease in FLI. Over a follow-up period of up to 6 years after the 2-year landmark, 582 individuals with an initial FLI value < 30 and 959 with an FLI ≥ 30 developed HCC (Fig. 1A). Interestingly, the patients with decreased FLI had a lower HCC risk (aHR, 0.68; 95% confidence interval [CI], 0.57–0.82) than those with maintained FLI, which remained consistent in the sensitivity analysis using the 1:3 matched cohort (aHR, 0.70; 95%CI, 0.58–0.84) (Fig. 1B). On the other hand, the patients with an increased FLI exhibited a higher HCC risk (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.01–1.55) compared to those with consistently stable FLI values. Similarly, in a sensitivity analysis utilizing a 1:3 matched cohort (all standardized mean differences < 0.1), the exposed group demonstrated a higher HCC risk (aHR, 1.26; 95%CI, 1.01–1.58) than the matched control group (Fig. 1C). These results were consistent even when analyzed without excluding patients with chronic liver disease (Fig. S1 A, B, C). NAFLD has rapidly become the most prevalent liver condition worldwide, affecting approximately 38% of the global population. Recently, a new nomenclature, metabolic dysfunction-associated steatotic liver disease, was introduced to replace the term NAFLD and reduce stigma.[7]Rinella M.E. Lazarus J.V. Ratziu V. Francque S.M. Sanyal A.J. Kanwal F. et al.A multi-society Delphi consensus statement on new fatty liver disease nomenclature.J Hepatol. 2023; Google Scholar The number of patients with fatty liver disease is expected to increase in future. Although only a small proportion of patients with NAFLD develop cirrhosis or HCC, the overall number of at-risk individuals is increasing.[8]Wong V.W. Ekstedt M. Wong G.L. Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD.J Hepatol. 2023; 79: 842-852Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Previous studies have demonstrated that the HCC risk is higher in patients with NAFLD than in controls.[9]Kanwal F. Kramer J.R. Mapakshi S. Natarajan Y. Chayanupatkul M. Richardson P.A. et al.Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease.Gastroenterology. 2018; 155: 1828-1837.e1822Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Moreover, NAFLD-related HCC is often detected at advanced stages and can arise without liver cirrhosis, distinguishing it from other liver conditions.[10]Huang D.Q. El-Serag H.B. Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.Nat Rev Gastroenterol Hepatol. 2021; 18: 223-238Crossref PubMed Scopus (717) Google Scholar These findings highlight the potential of substantial health-related complications associated with NAFLD. In this study, we used the FLI as a surrogate marker of hepatic steatosis, which represents early-stage NAFLD, and investigated the HCC incidence according to the development or regression of steatosis over two different time intervals. We observed significant differences in HCC occurrence depending on short-term fluctuations in liver fat content. Remarkably, this risk modification was easily assessed using the simple FLI. Over a 2-year interval, a 25% increase in HCC risk was observed when fatty liver disease emerged, whereas a 32% reduction in HCC risk was noted when fatty liver disease improved. Thus, early and proactive interventions for fatty liver disease are crucial. Furthermore, in cases with persistent fatty liver, the results also emphasized the necessity of intensified intervention and HCC surveillance. In conclusion, changes in the FLI are closely associated with the risk of developing HCC and may be an important clinical indicator of the HCC risk in patients with NAFLD. Additionally, these findings highlight the need for early intervention to manage liver fat, which can help reduce the risk of HCC development. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education [grant numbers 2017R1D1A3B04028873 and 2022R1I1A1A01069493]. J.H.P. designed the study; M.G.K. collected and analyzed the data; C.H.L., M.G.K., and C.S. drafted the manuscript; J.H.P. and J.S.K. supervised the study. All authors reviewed and approved the final manuscript. The authors declare no competing interests. None aHR,adjusted hazard ratioCI,confidence intervalFIB-4,fibrosis-4FLI,Fatty Liver IndexHCC,hepatocellular carcinomaNAFLD,non-alcoholic fatty liver disease adjusted hazard ratio confidence interval fibrosis-4 Fatty Liver Index hepatocellular carcinoma non-alcoholic fatty liver disease The following is/are the supplementary data to this article: Download .docx (.16 MB) Help with docx files