Association Between Liver Fibrosis and Risk of Incident Stroke and Mortality: A Large Prospective Cohort Study

Abstract

Background: There is a well-established relationship between liver conditions and cardiovascular diseases. However, uncertainty persists regarding the contribution of liver fibrosis to major stroke types including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage at the population level.

Methods: In this large prospective cohort study, participants without previous stroke or coronary heart disease at baseline from the UK Biobank were included. We identified participants at high probability of advanced liver fibrosis using the Fibrosis-4 index >2.67 or aspartate aminotransferase to platelet ratio index ≥1.0. Multivariable Cox proportional hazard regression analyses were conducted to estimate hazard ratios (HRs) for liver fibrosis with the incidence of major stroke types, stroke-related death, and all-cause death.

Results: Among 379 953 participants (mean age, 56.2 [SD, 8.1] years; 44.6% men), 7396 (1.9%) had a Fibrosis-4 index >2.67 at baseline. During a median follow-up of 12.75 (interquartile range, 12.03-13.48) years, 7143 (1.9%) incident stroke cases were documented. Advanced liver fibrosis assessed by the Fibrosis-4 index was associated with an increased risk of ischemic stroke (HR, 1.94 [95% CI, 1.70-2.22]), intracerebral hemorrhage (HR, 2.14 [95% CI, 1.63-2.81]), subarachnoid hemorrhage (HR, 1.90 [95% CI, 1.27-2.84), stroke-related death (HR, 2.20 [95% CI, 1.73-2.80]), and all-cause death (HR, 2.59 [95% CI, 2.46-2.73]). Using the aspartate aminotransferase to platelet ratio index as an alternative score, liver fibrosis was correlated with magnified risk of intracerebral hemorrhage (HR, 3.76 [95% CI, 2.38-5.93]) and subarachnoid hemorrhage (HR, 3.05 [95% CI, 1.51-6.13]) compared with ischemic stroke (HR, 1.58 [95% CI, 1.17-2.14]). Restricted cubic spline analysis showed nonlinear associations of the Fibrosis-4 index and aspartate aminotransferase to platelet ratio index with stroke incidence and all-cause death.

Conclusions: Liver fibrosis is associated with increased risk of incident stroke and death among people without previous stroke or cardiovascular events, with particularly greater risk of intracerebral hemorrhage and subarachnoid hemorrhage. Noninvasive indices of liver fibrosis may serve as an easily accessible marker to detect individuals facing elevated risk of stroke and death in the primary prevention settings.

Keywords: death; liver fibrosis; population‐based study; stroke.

Figure 1. Study flowchart.

APRI indicates aspartate aminotransferase to platelet ratio index; and CHD, coronary heart disease.

Figure 2. Kaplan–Meier analysis to estimate cumulative hazard for stroke outcomes stratified by the Fibrosis‐4 index.

High risk of advanced liver fibrosis was defined as Fibrosis‐4 index >2.67.

Figure 3. Restricted cubic spline plots for the association between noninvasive fibrosis scores and risk of incident stroke and death.

Restricted cubic spline visualization of associations of Fibrosis‐4 index and APRI with all stroke, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, stroke‐related death, and all‐cause death. The Fibrosis‐4 index of 2.67 and the APRI of 1.0 were set as the threshold to determine high risk of advanced fibrosis. All models were adjusted for age at recruitment, sex, race, Townsend deprivation index, smoking status, alcohol intake frequency, physical activity, diet status, hypertension, diabetes, chronic kidney disease, antihypertensive and lipid‐lowering medication use, body mass index, waist–hip ratio, cholesterol, and C‐reactive protein. APRI indicates aspartate aminotransferase to platelet ratio index; and FIB‐4, Fibrosis‐4.