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World J Gastroenterol. Jul 21, 2022; 28(27): 3410-3421
Published online Jul 21, 2022. doi: 10.3748/wjg.v28.i27.3410
Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives
Masayuki Ueno, Haruhiko Takeda, Atsushi Takai, Hiroshi Seno
Masayuki Ueno, Haruhiko Takeda, Atsushi Takai, Hiroshi Seno, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 6068507, Japan
Author contributions: Ueno M drafted the manuscript and prepared the tables; Takeda H and Takai A designed the outline and coordinated the writing of the manuscript; Seno H supervised data interpretation and revised the manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Atsushi Takai, MD, PhD, Assistant Professor, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 6068507, Japan.
Received: February 2, 2022
Peer-review started: February 2, 2022
First decision: April 10, 2022
Revised: April 24, 2022
Accepted: June 15, 2022
Article in press: June 15, 2022
Published online: July 21, 2022

High rates of excessive calorie intake diets and sedentary lifestyles have led to a global increase in nonalcoholic fatty liver disease (NAFLD). As a result, this condition has recently become one of the leading causes of hepatocellular carcinoma (HCC). Furthermore, the incidence of NAFLD-associated HCC (NAFLD-HCC) is expected to increase in the near future. Advanced liver fibrosis is the most common risk factor for NAFLD-HCC. However, up to 50% of NAFLD-HCC cases develop without underlying liver cirrhosis. Epidemiological studies have revealed many other risk factors for this condition; including diabetes, other metabolic traits, obesity, old age, male sex, Hispanic ethnicity, mild alcohol intake, and elevated liver enzymes. Specific gene variants, such as single-nucleotide polymorphisms of patatin-like phospholipase domain 3, transmembrane 6 superfamily member 2, and membrane-bound O-acyl-transferase domain-containing 7, are also associated with an increased risk of HCC in patients with NAFLD. This clinical and genetic information should be interpreted together for accurate risk prediction. Alpha-fetoprotein (AFP) is the only biomarker currently recommended for HCC screening. However, it is not sufficiently sensitive in addressing this diagnostic challenge. The GALAD score can be calculated based on sex, age, lectin-bound AFP, AFP, and des-carboxyprothrombin and is reported to show better diagnostic performance for HCC. In addition, emerging studies on genetic and epigenetic biomarkers have also yielded promising diagnostic potential. However, further research is needed to establish an effective surveillance program for the early diagnosis of NAFLD-HCC.

Keywords: Nonalcoholic fatty liver disease, Hepatocellular carcinoma, Risk factors, Biomarkers, Tumor markers, Genetics

Core Tip: This review summarizes the risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC). The highlighted risk factors include liver fibrosis, diabetes, age, sex, race, alcohol intake, elevated liver enzymes, and specific genetic variants. Currently available diagnostic biomarkers include alpha-fetoprotein (AFP), des-carboxyprothrombin, and the AFP isoform L3. The combined use of these biomarkers may increase the diagnostic sensitivity of NAFLD-HCC detection. However, more discussion will be necessary on the cost-effectiveness of these approaches. This review also summarizes emerging means of discovering novel biomarkers using omics techniques. A better understanding of these risk factors and diagnostic biomarkers will facilitate the effective surveillance of NAFLD-HCC.