Effect of Hypertension on Long-Term Adverse Clinical Outcomes and Liver Fibrosis Progression in Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Background: Hypertension is common in metabolic dysfunction-associated steatotic liver disease (MASLD), but its specific effects on long-term clinical outcomes and disease progression remain unclear.AimThis study examined the association of hypertension with the risk of adverse clinical outcomes and liver stiffness/fibrosis progression in subjects with MASLD.

Methods: Three multicenter prospective cohorts were analyzed: the UKB cohort to assess the risk of adverse clinical outcomes, the Serial VCTE cohort to assess liver stiffness progression, and the Paired Liver Biopsy cohort to assess histologic liver fibrosis progression. Adverse clinical outcomes were defined as all-cause mortality, cardiovascular events, and/or liver-related events. Liver stiffness progression was defined as an increase in liver stiffness measurement (LSM) from <10 kPa to ≥10 kPa or an increase of ≥20% for baseline LSM ≥10 kPa. Liver fibrosis progression was defined as a 1-stage fibrosis stage increase. Cox regression and Kaplan-Meier analyses were used to assess the impact of baseline hypertension on the outcomes.

Results: 117,405 participants followed for 14.8 years were included in the final analysis. In the UKB cohort (n=107,566), hypertension was associated with long-term adverse clinical outcomes (aHR=1.28, P<0.001). In the Serial VCTE cohort (n=8,169), hypertension was associated with a higher risk of liver stiffness progression (aHR=1.23, P<0.001), while in the Paired Liver Biopsy cohort (n=1,670), hypertension was associated with a greater risk of histologic liver fibrosis progression (aHR=1.42, P=0.003). Subgroup and sensitivity analyses supported these findings.

Conclusions: Hypertension significantly increases the risk of adverse clinical outcomes and liver stiffness/fibrosis progression in subjects with MASLD.

Funding: This paper was funded by grants from the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801). CDB is supported in part by the Southampton National Institute for Health and Care Research (NIHR) Biomedical Research Centre (NIHR203319). Shenghong Ju is supported in part by grants from the National Natural Science Foundation of China (92359304, 823B2040).

Declaration of Interest: Dr Yip reported serving as an advisory committee member and a speaker for Gilead Sciences outside the submitted work. Dr Tsochatzis reported receiving personal fees as an advisory board member for Boehringer, Novo Nordisk, Pfizer, and Siemens; receiving speaker fees from Echosens, Novo Nordisk, and AbbVie outside the submitted work. Dr YY received personal consultancy fees from Novo Nordisk and Zydus; Dr Hagström reported personal fees from AstraZeneca, personal fees from Bristol Myers-Squibb, personal fees from MSD, personal fees from Novo Nordisk, personal fees from Boehringer Ingelheim, personal fees from KOWA, and personal fees from GW Phara outside the submitted work, and grants from AstraZeneca, grants from Echosens, grants from Gilead Sciences, grants from Intercept, grants from MSD, grants from Novo Nordisk, and grants from Pfizer outside the submitted work. Dr Boursier reported receiving grants and personal fees from Echosens outside the submitted work. Dr Calleja reported receiving other from Echosens Clinical Trials during the conduct of the study; grants from Roche Pharma and other from Gilead Advisory Board outside the submitted work. Dr WK. Chan reported serving as consultant or advisory board member for Zuellig Pharma, Abbott, Roche, AbbVie, Boehringer Ingelheim, and Novo Nordisk; and a speaker for Novo Nordisk, Abbott, Echosens, Viatris, and Hisky Medical. Dr Sanyal reported receiving grants from Intercept, personal consulting fees from Gilead, grants from Merck, personal consulting fees from Pfizer, grants and personal consulting fees from Eli Lilly, grants and personal consulting fees from Novo Nordisk, Boehringer Ingelheim, Novartis, Histoindex, and stock options from Genfit, Tiziana, Durect, Inversago, and personal consulting fees from Genentech, ALnylam, Regeneron, Zydus, LG chem, Hanmi, Madrigal, Path AI, 89 Bio, and stock options from Galmed outside the submitted work. Dr De Lédinghen reported receiving nonfinancial support from Echosens during the conduct of the study. Dr Newsome reported receiving grants from Novo Nordisk, advisory board and personal consulting fees, honoraria for lectures and travel expenses from Novo Nordisk, personal consulting and advisory board fees from Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol-Myers Squibb, Pfizer, MSD, Sun Pharma, Eli Lilly, Madrigal, GSK, and nonfinancial support for educational events from AiCME outside the submitted work. Dr Castéra reported receiving personal fees for consulting and speakers bureau from Echosens during the conduct of the study; personal consultancy fees from Boston pharmaceutical and Gilead, speaker bureau and consultancy personal fees from GSK, personal speaker bureau fees from Inventiva, personal consultancy fees from Madrigal, personal Consultancy fees from MSD and Novo Nordisk, personal consultancy fees from Pfizer, Sagimet, and Siemens Healthineers outside the submitted work. Dr Fournier reported being in the full- time employment of Echosens during the conduct of the study. Dr G. Wong reported receiving personal fees from Echosens during the conduct of the study; and grants from Gilead Sciences Research outside the submitted work. Dr M. Chan reported being employed in the full-time by employment of Echosens during the conduct of the study. Dr Romero-Gomez reported receiving personal fees from Echosens outside the submitted work. Dr Kim reported personal fees from Gilead Sciences, personal fees from GSK, personal fees from Bayer, personal fees from Eisai, personal fees from AbbVie, personal fees from Echosens, personal fees from MSD, personal fees from Bristol-Myers Squibb, and personal fees from AstraZeneca outside the submitted work, and grants from AbbVie, grants from Bristol-Myers Squibb, and grants from Gilead Sciences outside the submitted work. Dr. Tacke’s lab has received research funding (to the institution) from AstraZeneca, MSD, Gilead and Agomab. Dr. Tacke has received honoraria for consulting or lectures from AstraZeneca, Abbvie, Alnylam, Boehringer, Falk, MSD, GSK, Pfizer, Novo Nordisk and Sanofi. Dr V. Wong reported receiving personal speaker fees from Abbott, consultant and speaker fees from AbbVie, personal consultant fees from Boehringer Ingelheim, Echosens, Gilead Sciences, grants from Gilead Sciences, personal consultant fees from Intercept, Inventiva, Novo Nordisk, personal consultant fees from Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, personal speaker fees from Unilab, personal consultant fees from Visirna, and being a cofounder of Illuminatio outside the submitted work. CDB has received grant support from Echosens. Dr L Adams has received personal speaker fees from Novo Nordisk, CSL Behring and has been on Advisory boards for Novo Nordisk. YY received personal consultancy fees from Novo Nordisk and Zydus. No other disclosures were reported. Masato Yoneda reported receiving honoraria for Kowa, and grants from Gilead Sciences. Atsushi Nakajima reported receiving honoraria for Mochida Pharmaceutical, Kowa, Biofermin, MSD, Behringer Ingelheim, Novo Nordisk, GSK, EA pharma, Taiho, and Tsumura, grants for Gilead Sciences, Mochida Pharmaceuticals, Kowa, Astellas Pharma, ASKA pharmaceutical, Biofermin, and EA pharma. Goh GB served as a consultant or advisory board member for Boehringer Ingelheim, Novo Nordisk, MSD and Roche Diagnostics; and a speaker for Abbott, Novo Nordisk and Echosens.

Ethical Approval: All UKB participants provided written informed consent, and the study was conducted under the ethical oversight of the UKB, with ethical approval granted on February 28, 2024 (Ref 151193).

Keywords: hypertension, metabolic dysfunction-associated steatotic liver disease, prognosis, vibration-controlled transient elastography, liver biopsy, liver fibrosis