Familial coaggregation of MASLD with hepatocellular carcinoma and adverse liver outcomes: nationwide multigenerational cohort study
Open accessAbstract
BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) is the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. However, whether family members of individuals with MASLD also share an increased risk of developing HCC is unknown. METHODS: This nationwide multigenerational cohort study involved family members of all Swedish adults diagnosed with biopsy-proven MASLD (1969-2017), and matched general population comparators. Using the Swedish Multi-generation Register, we identified 38,018 first-degree relatives (FDRs: parents, siblings, offspring) and 9,381 spouses of patients with MASLD, as well as 197,303 comparator FDRs and 47,572 comparator spouses. We used Cox proportional hazards models to calculate adjusted hazard ratios (aHRs) for HCC, major adverse liver outcomes (cirrhosis, decompensated liver disease or liver transplantation), liver-related mortality, extrahepatic cancer, and non-liver-related mortality. RESULTS: = 0.03). MASLD FDRs also had higher rates of major adverse liver outcomes (73 vs. 51/100,000 PY; aHR 1.52, 95% CI 1.36-1.69) and liver-related mortality (20 vs. 11/100,000 PY; aHR 2.14, 95% CI 1.67-2.74). MASLD FDRs with any concomitant chronic liver condition experienced accelerated progression of liver disease (aHR 1.47, 95% CI 1.29-1.67). MASLD spouses were at higher risks of major adverse liver outcomes (86 vs. 74/100,000 PY; aHR 1.23, 95% CI 1.01-1.51) and liver-related mortality (25 vs. 19/100,000 PY; aHR 1.93, 95% CI 1.15-3.23), but not of HCC (aHR 1.43, 95% CI 0.87-2.35). CONCLUSIONS: There is distinct familial clustering of adverse liver-related outcomes in families of individuals with biopsy-proven MASLD, with higher relative risks of HCC, progressive liver disease, and liver-related mortality, but absolute risks are low. IMPACT AND IMPLICATIONS: Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly termed NAFLD) clusters in families with high genetic susceptibility and shared environmental risk factors, but the risks of developing hepatocellular carcinoma and other major liver-related outcomes in family members of individuals with MASLD are largely unknown. This large nationwide multigenerational cohort study involving family members (first-degree relatives and spouses) of individuals with biopsy-proven MASLD and of matched general population comparators found slightly increased risks of hepatocellular carcinoma in first-degree relatives, and of developing cirrhosis and liver-related mortality in all family members of individuals with biopsy-proven MASLD. The findings of this study provide large-scale evidence to inform clinical practice guidelines for recommendations on the early identification of individuals at higher risk of liver-related morbidity and mortality.
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Familial aggregation of SLD supports a genetic disease, particularly for early-onset SLD.
“Familial aggregation of SLD supports a genetic disease, particularly for early-onset SLD. 9”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [9]
The Introduction describes familial clustering and heritability of MASLD, while the Discussion says genetic susceptibility may contribute to disease progression alongside environmental factors and comorbidities (page unavailable in our copy). Neither passage establishes SLD as a genetic disease, and the paper does not support the claim that this is particularly true for early-onset SLD. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInitial evidence indicates that first-degree relatives of individuals with advanced liver fibrosis due to MASLD are at increased risk of both MASLD (2- to 3-fold higher) and advanced liver fibrosis (12-fold higher), independently of metabolic risk factors.
“Finally, there is initial evidence that fi rst-degree relatives of individuals with advanced liver fi brosis due to MASLD are at increased risk of both MASLD (2to 3-fold higher) and advanced liver fi brosis ( 12-fold higher), independently of metabolic risk factors.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [9]
The Discussion reports a prior study finding a 12-fold higher risk of advanced fibrosis in first-degree relatives of people with MASLD-associated cirrhosis. It describes familial clustering of MASLD but does not give the claimed 2- to 3-fold MASLD risk or establish that the fibrosis association is independent of metabolic risk factors. Its discussion of independence from comorbid diabetes concerns HCC, not advanced fibrosis; no page number is available in our copy. (LLM, conf=0.86)
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Reply to: “Familial clustering of MASLD: Rethinking strategies for population screening”
Ebrahimi, F., & Ludvigsson, J. F. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.02.027
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Associations of lipoprotein subclasses with risk of cardiovascular disease in individuals with MASLD
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Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis
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Ebrahimi, F., Eichhorn, C., Sun, J., Bergman, D., Marxer, C. A., Hagström, H., Carrero, J. J., & Ludvigsson, J. F. (2026) · JHEP Reports · doi:10.1016/j.jhepr.2026.102070
- Authors
- Ebrahimi, F., Hagström, H., Sun, J., Bergman, D., Shang, Y., Yang, W., Roelstraete, B., & Ludvigsson, J. F.
- Affiliations
- Karolinska Institutet (SE)
- Karolinska University Hospital (SE)
- Corresponding author
- Ebrahimi, Fahim
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-12
- Volume
- 79
- Issue
- 6
- Pages
- 1374-1384
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W4386226882
- Cited by
- 65
- References
- 53
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 27 · 2023: 5 · 2018: 1
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P500PM_210866)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- non-alcoholic fatty liver disease, hepatocellular carcinoma, familial aggregation, first-degree relatives, spouses, major adverse liver outcomes, liver cirrhosis, decompensated liver disease, liver transplantation, liver-related mortality, extrahepatic cancer, chronic liver disease progression, genetic susceptibility, family risk factors
- MeSH terms
- Adult, Carcinoma, Hepatocellular, Humans, Liver Cirrhosis, Liver Neoplasms, Cohort Studies, Non-alcoholic Fatty Liver Disease
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