Table 1.

Major studies that evaluated the relationship between NAFLD and cerebrovascular disease

Study name (Year)	Study design	Population (N)	NAFLD definition	Main outcome definition	Key findings
Clinical Cerebrovascular Disease
Hu et al. (2018)	Meta-analysis (2 case-control, 7 cohort studies)	6,183	NR	CVA (including ischemic stroke and cerebral hemorrhage); NR	NAFLD was associated with increased risk of CVA (2.32, 95% CI 1.84–2.93, P < 0.001), including both hemorrhagic stroke (OR = 1.85, 95% CI 1.05–3.27, P = 0.034) and ischemic stroke (OR = 2.51, 95% CI 1.92–3.28, P < 0.001). Results confirmed when analysis also stratified by ethnicity, study design, and CVA classification.
Haddad et al. (2017)	Meta-analysis (6 prospective studies)	25,837	Ultrasound Excluded: excessive alcohol consumption, viral hepatitis, and chronic hepatotoxic drug use	Cardiovascular events, including subgroup analysis of ischemic stroke and TIA (cerebral hemorrhage was excluded); NR	NAFLD was associated with higher risk of ischemic stroke (RR: 2.09; 95% CI 1.46–2.98, P < 0.001).
Moshayedi et al. (2014)	Cross-sectional	110	Ultrasound Excluded: excessive alcohol consumption and viral hepatitis	Ischemic stroke by CT and verified by MRI to exclude tumor, hemorrhage, or previous ischemic stroke	NAFLD was associated with increased risk of ischemic stroke (OR 2.15 95% CI 1.25–3.71, P = 0.006) compared to sex and age-matched controls. Multivariate analysis that adjusted for metabolic risk factors revealed no association between NAFLD and ischemic stroke.
Parikh et al. (2019)	Cross-sectional	27,040	NFS > 0.676 and FIB-4 score > 3.25 Excluded: pregnant participants, viral hepatitis, possible acute liver injury, excessive alcohol consumption, use of medications associated with steatosis	Stroke (ischemic and hemorrhagic stroke unable to be differentiated) by self-reported survey	NAFLD was associated with increased risk of stroke in unadjusted models when using NFS and FIB-4 composite score (OR 5.75, 95% CI 4.66–7.09), FIB-4 (OR 6.54, 95% 3.81–11.22) score and NFS (OR 5.79, 95% 4.79–7.01). Multivariate analysis that adjusted for metabolic factors revealed an association between NAFLD and stroke only when NAFLD was defined by FIB-4 score (OR 1.87, 95% CI 1.00–3.50).
Xu et al. (2021)	Prospective cohort	79,905	Ultrasound Excluded: excessive alcohol consumption and other liver diseases	Ischemic stroke, defined based on signs, symptoms, and brain CT or MRI findings	NAFLD was associated with increased risk of stroke (HR 1.16, 95% CI 1.07–1.26) after adjusting for metabolic risk factors. Higher severity of NAFLD was associated with increasing risk of stroke (mild: HR 1.15, 95% CI 1.05–1.25; moderate: 1.19, 95% CI 1.06–1.34; severe: 1.21; 95% 1.08–1.50).
Abdeldyem et al. (2017)	Prospective cohort	242	Ultrasound Excluded: chronic viral hepatitis, drug toxicity, and excessive alcohol consumption	Severity of acute ischemic stroke by NIHSS score at admission and functional outcome by mRS score at discharge	At admission, the severity of stroke at admission was higher in participants with NAFLD (NIHSS 8.7±7.4) than those without NAFLD (NIHSS 5.5±6.5; P = 0.013). The functional outcome after stroke was worse in participants with NAFLD (mRS 3.6±2.3) than those without NAFLD (mRS 1.8±2.4). Multivariate analysis adjusting for potential confounders was not performed.
Li et al. (2018)	Retrospective	306	Ultrasound Excluded: chronic viral hepatitis, drug toxicity, excessive alcohol consumption, cholestatic diseases, and rhabdomyolysis	Severity of acute ischemic stroke by NIHSS score at admission, progression of stroke by increase in NIHSS score, and functional outcome by mRS score at discharge	NAFLD was associated with severity independent of metabolic risk factors (HR 2.327, 95% CI 1.252–4.324). The risk of progression of stroke was higher in those with NAFLD than those without, after adjustment for potential confounders (HR 2.378, 95% CI 1.260–4.486). Multivariate analysis revealed no association between NAFLD and functional outcome after stroke at discharge.
Seo et al. (2016)	Cross-sectional	4,472	Ultrasound Excluded: excessive alcohol consumption and viral hepatitis	Cognitive learning, memory, attention, and concentration (SDLT), psychomotor speed (SRTT), visuospatial function (SDST)	NAFLD was associated with reduced cognitive learning, poor memory, attention, and concentration independent of metabolic risk factors (β = 0.726, 95% CI 0.105–1.347). There was no association between NAFLD and psychomotor speed or visuospatial function after adjustments for metabolic covariates.
Gerber et al. (2021)	Cross-sectional	2,809	CT using LA ≤ 51 Excluded: pregnant participants, viral hepatitis, cirrhosis, excessive alcohol consumption, use of medications associated with steatosis	Processing speed (DSST), verbal memory (RAVLT), executive function (Stroop Test)	After adjustments for metabolic covariates, there was no association between NAFLD and performance on cognitive tests.
Subclinical Cerebrovascular Disease
Airaghi et al. (2018)	Case-control	34	Liver biopsy	Cerebral perfusion by MRI spectroscopy	NAFLD was associated with reduced cerebral perfusion confined to limited brain areas, such as left semioval center and posterior cingulate cortex (beta coefficient -5.7, 95% CI -11, -0.08).
Sinn et al. (2016)	Retrospective cohort	8,020	Ultrasound Excluded: excessive alcohol consumption, viral hepatitis, history of cirrhosis	Carotid plaque defined as CIMT ≥0.5mm by carotid artery ultrasound	NAFLD was associated with the presence of subclinical carotid atherosclerosis compared to age-adjusted controls (HR 1.23, 95% CI 1.13–1.35, P < 0.001). Multivariate analysis adjusted for metabolic variables, such as diabetes, hypertension, and dyslipidemia revealed no association.
Zhang et al. (2020)	Cross-sectional	12,990	Ultrasound Excluded: excessive alcohol consumption, viral/autoimmune/drug-induced hepatitis	Carotid plaque defined as CIMT ≥1.5mm by carotid artery ultrasound	NAFLD was associated with the presence of subclinical carotid atherosclerosis independent of metabolic risk factors, such as glucose levels, lipid profiles, and BMI (OR 1.89, 95% CI 1.59–2.24).
Weinstein et al. (2018)	Cross-sectional	766	CT using liver to phantom ratio ≤0.33 Excluded: excessive alcohol consumption	Cerebral brain volume, hippocampal and white matter hyperintensity volumes, covert brain infarcts by brain MRI	NAFLD was associated with smaller total cerebral brain volume after adjustment for vascular risk factors, including hypertension, dyslipidemia, diabetes, and cardiovascular disease (beta coefficient -0.26 (0.11), P =0.02). There was no relationship between NAFLD and hippocampal or white matter hyperintensity volumes or covert brain infarcts.
Jang et al. (2019)	Cross-sectional	1,260	Ultrasound FIB-4 ≥1.45: high-intermediate probability of advanced fibrosis FIB-4 < 1.45: low probability of advanced fibrosis Excluded: excessive alcohol consumption, viral hepatitis, history of cirrhosis	WMH, lacunes, and microbleeds by brain MRI	NAFLD was associated with moderate to severe WMH independent of other cardiometabolic risk factors (OR 1.64, 95% CI 1.10–2.42). Participants with high-intermediate probability of advanced fibrosis had odds of WMH (OR 1.77, 95% CI 1.13–2.78) than those with low probability of advanced fibrosis (OR 1.14, 95% 0.72–1.82). There was no relationship between NAFLD and the presence of lacunes or microbleeds.

Abbreviations: NR: not reported; CVA: cerebrovascular accident; NAFLD: non-alcoholic fatty liver disease; TIA: transient ischemic attack; CT: computed tomography; MRI: magnetic resonance imaging; NFS: nonalcoholic fatty liver disease fibrosis score; FIB-4: fibrosis-4 score, NIHSS: NIH stroke scale; mRS: modified Rankin score; SDLT: serial digit learning test; SRTT: simple reaction time; SDST: symbol digit substitution test; LA: liver attenuation; HU: Hounsfield Units; DSST: digit symbol substitution test; RAVLT: Rey Auditory Verbal Learning Test; CIMT: carotid intima-media thickness; BMI: body mass index; WMH: white matter hyperintensities