Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease
Open accessAbstract
BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.
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Initial 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 [135]
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Experimental — accuracy not yet measuredInitial data suggest that individuals with strong family history, early disease onset, or lack of accruing factors may benefit from a comprehensive genetic evaluation that may identify strong genetic determinants of SLD with potential implications for treatment and family counselling.
“Initial data suggest that individuals with a) strong family history, b) early disease onset, or c) lack of accruing factors may bene fi t from a comprehensive genetic evaluation ( e.g. whole-exome sequencing or targeted panel sequencing) that may identify strong genetic determinants of SLD with potential implications for treatment and family counselling. 135,208 -211”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [135]
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- Authors
- Tamaki, N., Ahlholm, N., Luukkonen, P. K., Porthan, K., Sharpton, S. R., Ajmera, V., Kono, Y., Dave, S., Ahmed, A., Sundaram, V., Wilkinson, M. J., Patton, H., Gupta, H., Cervantes, V., Hernandez, C., Lopez, S. J., Loomba, R., Baumgartner, A., Richards, L., Arkkila, P. E. T., Nemes, K., Isoniemi, H., Yki-Järvinen, H., & Loomba, R.
- Affiliations
- University of California San Diego (US)
- University of Helsinki (FI)
- Stanford Medicine (US)
- Cedars-Sinai Medical Center (US)
- VA San Diego Healthcare System (US)
- Corresponding author
- Loomba, Rohit
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2022-11-01
- Volume
- 132
- Issue
- 21
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC9621132
- OpenAlex
- W4307717780
- Cited by
- 69
- References
- 41
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 20 · 2023: 16
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Academy of Finland, Novo Nordisk, EVO and Sigrid Juselius Foundations (H.Y.-J.) and by the Innovative medicines Initiative 2 Joint Undertaking (309263,777377)
- NCATS, NIDDK, NHLBI, NIAAA (5UL1TR001442,U01DK061734,R01DK106419,R01DK121378,R01DK124318,P30DK120515,U01DK130190,P01HL147835,U01AA029019,K23DK119460)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- first-degree relatives, non-alcoholic fatty liver disease, advanced liver fibrosis, familial risk, magnetic resonance elastography, liver fibrosis screening, diabetes mellitus, age and sex predictors, noninvasive fibrosis assessment, fibrosis staging
- MeSH terms
- Fibrosis, Humans, Liver Cirrhosis, Male, Middle Aged, Prospective Studies, Elasticity Imaging Techniques, Non-alcoholic Fatty Liver Disease
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