Extrahepatic disease clusters and mortality in people with steatotic liver diseases: a prospective analysis of 64,749 females and 113,587 males in the UK Biobank
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Published version
Author(s)
Type
Journal Article
Abstract
Background
Steatotic liver disease (SLD) is the most prevalent chronic liver disease worldwide and linked to various liver and extrahepatic diseases. However, the clustering of extrahepatic conditions and their impact on mortality in individuals with SLD remain poorly understood.
Methods
We used UK Biobank data to identify sex-specific disease clusters among individuals with SLD and multimorbidity (having ≥ 2 extrahepatic diseases) using latent class analysis. Multivariable Cox models were used to assess associations between multimorbidity, disease clusters and all-cause mortality and mortality from cardiovascular diseases (CVD), extrahepatic cancers, liver-related diseases and hepatocellular carcinoma.
Results
Among 178,336 (36.3% female) individuals with SLD, during a median follow-up of 13.8 years, multimorbidity increased mortality by 100% (hazard ratio (95% confidence interval): 2.00 (1.93, 2.08)) and 80% (1.80 (1.71, 1.90)) in males and females, respectively, and increased the risk of death from CVD, extrahepatic cancers and liver-related diseases. Among 36,002 (43.9% female) of the 178,336 with multimorbidity, we identified five disease clusters in both sexes: related to respiratory, mental health, cancer/osteoarthritis and cardiovascular diseases. Males had separate heart and stroke clusters, whereas females had a combined heart/stroke cluster and a unique thyroid cluster. CVD was the leading cause of death in cardiovascular clusters, whereas extrahepatic cancers were the most common cause of death in other clusters. Among all disease clusters, cardiovascular clusters exhibited the highest all-cause mortality risk: 2.90 (2.64, 3.20) for the heart/stroke cluster in females and 2.63 (2.48, 2.78) for the heart cluster and 2.36 (2.16, 2.58) for the stroke cluster in males. All clusters exhibited increased mortality of CVD and extrahepatic cancers.
Conclusions
Multimorbidity doubled the death rate in people with SLD. Common multimorbidity clusters of mental health, respiratory, cancer and cardiovascular diseases were found and were associated with varying mortality, with cardiovascular-related clusters showing the highest risk. Females exhibited a unique thyroid disease cluster. These findings highlight the need for tailored prevention and management strategies in SLD populations.
Steatotic liver disease (SLD) is the most prevalent chronic liver disease worldwide and linked to various liver and extrahepatic diseases. However, the clustering of extrahepatic conditions and their impact on mortality in individuals with SLD remain poorly understood.
Methods
We used UK Biobank data to identify sex-specific disease clusters among individuals with SLD and multimorbidity (having ≥ 2 extrahepatic diseases) using latent class analysis. Multivariable Cox models were used to assess associations between multimorbidity, disease clusters and all-cause mortality and mortality from cardiovascular diseases (CVD), extrahepatic cancers, liver-related diseases and hepatocellular carcinoma.
Results
Among 178,336 (36.3% female) individuals with SLD, during a median follow-up of 13.8 years, multimorbidity increased mortality by 100% (hazard ratio (95% confidence interval): 2.00 (1.93, 2.08)) and 80% (1.80 (1.71, 1.90)) in males and females, respectively, and increased the risk of death from CVD, extrahepatic cancers and liver-related diseases. Among 36,002 (43.9% female) of the 178,336 with multimorbidity, we identified five disease clusters in both sexes: related to respiratory, mental health, cancer/osteoarthritis and cardiovascular diseases. Males had separate heart and stroke clusters, whereas females had a combined heart/stroke cluster and a unique thyroid cluster. CVD was the leading cause of death in cardiovascular clusters, whereas extrahepatic cancers were the most common cause of death in other clusters. Among all disease clusters, cardiovascular clusters exhibited the highest all-cause mortality risk: 2.90 (2.64, 3.20) for the heart/stroke cluster in females and 2.63 (2.48, 2.78) for the heart cluster and 2.36 (2.16, 2.58) for the stroke cluster in males. All clusters exhibited increased mortality of CVD and extrahepatic cancers.
Conclusions
Multimorbidity doubled the death rate in people with SLD. Common multimorbidity clusters of mental health, respiratory, cancer and cardiovascular diseases were found and were associated with varying mortality, with cardiovascular-related clusters showing the highest risk. Females exhibited a unique thyroid disease cluster. These findings highlight the need for tailored prevention and management strategies in SLD populations.
Date Issued
2025-07-31
Date Acceptance
2025-07-21
Citation
BMC Medicine, 2025, 23
ISSN
1741-7015
Publisher
BMC
Journal / Book Title
BMC Medicine
Volume
23
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Publication Status
Published
Article Number
450
Date Publish Online
2025-07-31