Metabolic dysfunction-associated fatty liver disease and hepatocellular carcinoma: present and future

Metabolic dysfunction-associated fatty liver disease (MAFLD), previously termed non-alcoholic fatty liver disease, is one of the most common causes of chronic liver disease, affecting around 30% of the world’s adults (1). MAFLD encompasses a spectrum of liver conditions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) (2,3). HCC has become the third leading cause of cancer-related mortality worldwide (4). Most patients with HCC have a background of chronic liver disease due to hepatitis B and hepatitis C virus (HCV), alcohol abuse, or MAFLD. With the advent of highly effective pharmacotherapies for viral hepatitis and the increasing prevalence of obesity worldwide, MAFLD is becoming the fastest growing cause of cirrhosis and HCC. Recent data from the Italy (using the ITA.LI.CA database) showed that MAFLD was diagnosed in most patients with HCC (almost 70%), and it is predicted that MAFLD will explain nearly all the causes of HCC in Italy in the next decade (5). Studies from other countries have also shown a rapid increase in the percentage of patients with HCC attributed to MAFLD over the past two decades, and it is anticipated that MAFLD-related HCC will soon be the leading indication for liver transplantation (4,6).

The analysis from the ITA.LI.CA database suggested that around 90% of MAFLD-related HCC may develop in patients with advanced fibrosis or cirrhosis, thus highlighting the pathogenic role of liver fibrosis in cancer development (5). Previous studies have also observed that HCC incidence increased with fibrosis stage (4). Although liver biopsy represents the ‘gold standard’ method for staging liver fibrosis, it is an invasive diagnostic procedure with some associated acute risks. The use of non-invasive tests has been suggested for screening of liver fibrosis (7). In addition, a two-step approach using blood-based fibrosis tests [e.g., fibrosis index-4 (FIB-4)] followed by vibration-controlled transient elastography (VCTE) has been proposed to accurately identify advanced fibrosis in MAFLD patients. Studies have reported that increased non-invasive liver fibrosis scores, including FIB-4, were associated with a substantially increased risk of HCC (8).

Why is it that MAFLD/MASH is so important in the etiology and pathogenesis of HCC? Although HCC primarily arises in patients with advanced fibrosis and cirrhosis, there is evidence that MASH may increase the risk of HCC even in the absence of advanced fibrosis/cirrhosis (5). According to some studies, about 15–50% of HCC cases arise in MASH patients without cirrhosis (9). These patients do not have an indication for routine HCC surveillance based on the current guidelines (10). Therefore, early recognition of HCC in non-cirrhotic MASH patients is currently a major challenge. Risk factors for HCC include older age, obesity, type 2 diabetes, and genetic susceptibility [e.g., the patatin-like phospholipase domain-containing protein-3 (PNPLA3) and the transmembrane 6 superfamily member 2 protein (TM6SF2) genetic variants] (11). As such, these factors occurring independently of liver fibrosis, may be important in the pathogenesis of HCC (9). At present, the precise pathogenesis of HCC in MAFLD is not fully understood, but it seems phenotypically different from HCC occurring in people with HCV-related cirrhosis or other chronic liver diseases. Several factors have been proposed that might explain this discordance in MAFLD, including insulin resistance, the DNA damage response, increased oxidative stress, abnormal immune responses and changes in gut microbiota (11).

Compared to HCC occurring as a result of other etiologies, a lower proportion of patients with HCC are identified by surveillance strategies in MAFLD (5). This may be related to several reasons, one of which is the failure of liver ultrasound to detect small HCC in people with MAFLD because of the presence of increased subcutaneous fat and greater liver fat accumulation. Additionally, while there is general agreement about the application of surveillance programs in patients with MAFLD-related cirrhosis, there is currently no consensus regarding HCC surveillance in non-cirrhotic patients. Current guidelines recommend ultrasound surveillance every six months for patients with advanced fibrosis and cirrhosis (10). However, surveillance with ultrasound of a very large population with non-cirrhotic MAFLD is not feasible and would be hugely costly.

Future research is needed to develop a cost-effective test that can better stratify the risk of HCC in patients with non-cirrhotic MAFLD and identify subgroups of patients who may benefit from HCC surveillance. Recently, an international consortium has developed a new blood-based risk score (i.e., the LiverRisk score) using six simple laboratory variables (circulating levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl-transferase, glucose, total cholesterol, and platelet count) together with age and sex. This new blood-based risk score was validated against VCTE-assessed liver stiffness and was shown to efficiently predict HCC in the general population (12). However, an assessment of the cost-effectiveness of this score is needed.

The prognosis of MAFLD-related HCC is controversial. The analysis from the ITA.LI.CA database reported that the median overall survival was significantly lower in patients with non-MAFLD HCC than in those with MAFLD-related HCC, and the protective effect of MAFLD on the liver-related survival was independent of the HCC stage and treatment type (5). However, other studies reported that after adjusting for possible confounding factors (including the tumor stage), no significant difference in survival was detected between patients with MAFLD-related HCC and those with non-MAFLD HCC (13).

At present, there are no approved drugs for MAFLD/MASH. However, some treatments, such as liraglutide, semaglutide and pioglitazone that have proved effective in NASH, are licensed for treating type 2 diabetes that may be present as a feature of MAFLD. Preventative interventions should focus on risk mitigation through managing obesity, type 2 diabetes, and dyslipidemia and early detection in patients at high risk for HCC, such as those with advanced fibrosis/cirrhosis. Patients with early HCC are more likely to be eligible for curative treatments such as ablation, surgical resection, or liver transplantation. However, patients with MAFLD-related HCC are more likely to be diagnosed at later stages, with larger tumors, and have more frequent extrahepatic metastases (11). These characteristics will limit treatment strategies, influencing the prognosis. Moreover, in combination with advanced age and comorbidities associated with MASH, such as type 2 diabetes, cardiovascular disease and chronic kidney disease, curative procedures need careful consideration (11,14,15).

In conclusion, future studies are needed in non-cirrhotic MAFLD to recognize patients at high risk of HCC and to better understand the pathogenesis of HCC in this patient group. A better understanding of the pathogenesis in patients with non-cirrhotic MAFLD at high HCC risk and earlier detection of HCC will likely lead to more effective treatment approaches and better clinical outcomes.

Acknowledgments

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 82070588, No. 82370577). G.T. is supported in part by grants from the School of Medicine, University of Verona, Verona, Italy. C.D.B. is supported in part by the Southampton NIHR Biomedical Research Centre, UK (NIHR203319).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Hepatobiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-539/coif). M.H.Z. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. G.T. is supported in part by grants from the School of Medicine, University of Verona, Verona, Italy. C.D.B. is supported in part by the Southampton NIHR Biomedical Research Centre (NIHR203319), UK. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73:202-9. [Crossref] [PubMed]
2. Rios RS, Zheng KI, Zheng MH. Non-alcoholic steatohepatitis and risk of hepatocellular carcinoma. Chin Med J (Engl) 2021;134:2911-21. [Crossref] [PubMed]
3. Feng G, Valenti L, Wong VW, et al. Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2023; Epub ahead of print. [Crossref]
4. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021;18:223-38. [Crossref] [PubMed]
5. Vitale A, Svegliati-Baroni G, Ortolani A, et al. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database. Gut 2023;72:141-52. [Crossref] [PubMed]
6. Lonardo A, Mantovani A, Petta S, et al. Metabolic mechanisms for and treatment of NAFLD or NASH occurring after liver transplantation. Nat Rev Endocrinol 2022;18:638-50. [Crossref] [PubMed]
7. Zhou YJ, Wong VW, Zheng MH. Consensus scoring systems for nonalcoholic fatty liver disease: an unmet clinical need. Hepatobiliary Surg Nutr 2021;10:388-90. [Crossref] [PubMed]
8. Loosen SH, Kostev K, Keitel V, et al. An elevated FIB-4 score predicts liver cancer development: A longitudinal analysis from 29,999 patients with NAFLD. J Hepatol 2022;76:247-8. [Crossref] [PubMed]
9. Anstee QM, Reeves HL, Kotsiliti E, et al. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019;16:411-28. [Crossref] [PubMed]
10. Loomba R, Lim JK, Patton H, et al. AGA Clinical Practice Update on Screening and Surveillance for Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology 2020;158:1822-30. [Crossref] [PubMed]
11. Llovet JM, Willoughby CE, Singal AG, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol 2023;20:487-503. [Crossref] [PubMed]
12. Serra-Burriel M, Juanola A, Serra-Burriel F, et al. Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study. Lancet 2023;402:988-96. [Crossref] [PubMed]
13. Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology 2016;63:827-38. [Crossref] [PubMed]
14. Zhou XD, Targher G, Byrne CD, et al. An international multidisciplinary consensus statement on MAFLD and the risk of CVD. Hepatol Int 2023;17:773-91. [Crossref] [PubMed]
15. Sun DQ, Targher G, Byrne CD, et al. An international Delphi consensus statement on metabolic dysfunction-associated fatty liver disease and risk of chronic kidney disease. Hepatobiliary Surg Nutr 2023;12:386-403. [Crossref] [PubMed]