Association between Liver Fibrosis and Incident Dementia in the UK Biobank Study

Abstract

Background: There is growing recognition of the role of chronic liver disease in brain health, but the impact of liver fibrosis on dementia risk was unclear. We evaluated the association between liver fibrosis and incident dementia using data from a large prospective cohort study. Methods: We performed a retrospective cohort study using data from the UK Biobank study, which prospectively enrolled approximately 500,000 adults starting 2007 and continues to follow them. Liver fibrosis was defined using validated cutoffs of the Fibrosis-4 (FIB-4) liver fibrosis score. The primary outcome was incident dementia, ascertained using a validated approach based on participants' hospital record and mortality data. Secondary outcomes were Alzheimer's disease and vascular dementia. We excluded participants with prevalent dementia. We used Cox proportional hazards models to evaluate the association between liver fibrosis and incident dementia while adjusting for potential confounders. In additional models, the FIB-4 score was used as a continuous independent variable. Prespecified interaction analyses tested for effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status. Results: Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Standard liver chemistries were largely in the normal range. However, 2.17% (95% CI, 2.13-2.22%) had liver fibrosis based on their FIB-4 score. The rate of dementia per 1,000 person-years was 1.76 (95% CI, 1.50-2.07) in participants with liver fibrosis and 0.52 (95% CI, 0.50-0.54) in those without. After adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with an increased risk of dementia (HR, 1.52; 95% CI, 1.22-1.90). An independent association was also noted between FIB-4, treated as a continuous variable, and dementia (HR per unit, 1.29; 95% CI, 1.20-1.39). Effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status was not seen. Conclusion: Liver fibrosis in middle age was associated with an increased risk of incident dementia, independent of metabolic syndrome and shared risk factors. Liver fibrosis may be an underrecognized risk factor for dementia.

Dementia Frequently Coexists With Hepatic Encephalopathy but Not Other Cirrhosis Complications in US Veterans

“…This is likely given that the cohort is based in 2019, where direct-acting antiviral use is widely prevalent. Regarding NASH, the usual association with brain pathology is through cerebrovascular compromise, which was separately included and were significantly associated with dementia in the multivariable model (5,6). On the other hand, as expected, alcohol use disorder and alcohol-related cirrhosis were both associated with dementia likely due to the pervasive nature of the extent of alcohol's injury on the brain (24).…”

“…Cirrhosis is a major cause of morbidity, mortality, and financial burden in the Veterans Health Administration (1,2). This is further complicated by the increasing age and comorbid conditions of these patients (3,4) and may be a risk factor for incident cognitive dysfunction and dementia (5,6). Patients with cirrhosis often develop hepatic encephalopathy (HE), which imposes strain on both patients and caregivers with broad-ranging quality of life and prognostic implications (7).…”