Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors
Open accessAbstract
Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
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Factors associated with a higher risk of HCC occurrence in MASLD include presence and duration of T2D, obesity or both, older age, concurrent alcohol intake and/or smoking, FIB-4 > 3.25, and LSM > 10 kPa and increasing change in LSM.
“Table 8. Factors associated with a higher risk of HCC occurrence in MASLD.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [532]
The Introduction and Table 2 (Genetics; page not available in our copy) identify older age, smoking, alcohol abuse, diabetes, and obesity as HCC risk factors; the HCC and Steatosis section also mentions a long history of diabetes in NAFLD-related advanced fibrosis or cirrhosis. The paper does not support the specific FIB-4 > 3.25 or LSM > 10 kPa thresholds, or increasing LSM as a risk factor. (LLM, conf=0.88)
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- Authors
- Dongiovanni, P.
- Affiliations
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Corresponding author
- Dongiovanni, Paola
- ORCID
- Dongiovanni, Paola
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2014
- Volume
- 20
- Issue
- 36
- Pages
- 12945
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC4177475
- OpenAlex
- W2018207417
- Cited by
- 145
- References
- 124
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 7 · 2022: 11 · 2021: 13 · 2020: 16 · 2019: 12 · 2018: 19 · 2017: 12 · 2016: 17 · 2015: 16
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novo Nordisk Fonden (NNF14OC0009321)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatocellular carcinoma, non-alcoholic fatty liver disease, insulin resistance, PNPLA3 I148M variant, telomerase reverse transcriptase, cellular senescence, gut microbiota, obesity, type 2 diabetes, iron overload, hepatocarcinogenesis, genetic susceptibility, environmental risk factors
- MeSH terms
- Animals, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Phenotype, Prognosis, Risk Factors, Disease Progression, Risk Assessment, Genetic Predisposition to Disease, Gene-Environment Interaction, Non-alcoholic Fatty Liver Disease
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