Subclinical liver traits are associated with structural and hemodynamic brain imaging markers

Abstract Background & Aims Impaired liver function affects brain health and therefore understanding potential mechanisms for subclinical liver disease is essential. We assessed the liver–brain associations using liver measures with brain imaging markers, and cognitive measures in the general population. Methods Within the population‐based Rotterdam Study, liver serum and imaging measures (ultrasound and transient elastography), metabolic dysfunction‐associated fatty liver disease (MAFLD), non‐alcoholic fatty liver disease (NAFLD) and fibrosis phenotypes, and brain structure were determined in 3493 non‐demented and stroke‐free participants in 2009–2014. This resulted in subgroups of n = 3493 for MAFLD (mean age 69 ± 9 years, 56% ♀), n = 2938 for NAFLD (mean age 70 ± 9 years, 56% ♀) and n = 2252 for fibrosis (mean age 65 ± 7 years, 54% ♀). Imaging markers of small vessel disease and neurodegeneration, cerebral blood flow (CBF) and brain perfusion (BP) were acquired from brain MRI (1.5‐tesla). General cognitive function was assessed by Mini‐Mental State Examination and the g‐factor. Multiple linear and logistic regression models were used for liver‐brain associations and adjusted for age, sex, intracranial volume, cardiovascular risk factors and alcohol use. Results Higher gamma‐glutamyltransferase (GGT) levels were significantly associated with smaller total brain volume (TBV, standardized mean difference (SMD), −0.02, 95% confidence interval (CI) (−0.03 to −0.01); p = 8.4·10 −4 ), grey matter volumes, and lower CBF and BP. Liver serum measures were not related to small vessel disease markers, nor to white matter microstructural integrity or general cognition. Participants with ultrasound‐based liver steatosis had a higher fractional anisotropy (FA, SMD 0.11, 95% CI (0.04 to 0.17), p = 1.5·10 −3 ) and lower CBF and BP. MAFLD and NAFLD phenotypes were associated with alterations in white matter microstructural integrity (NAFLD ~ FA, SMD 0.14, 95% CI (0.07 to 0.22), p = 1.6·10 −4 ; NAFLD ~ mean diffusivity, SMD −0.12, 95% CI (−0.18 to −0.05), p = 4.7·10 −4 ) and also with lower CBF and BP (MAFLD ~ CBF, SMD −0.13, 95% CI (−0.20 to −0.06), p = 3.1·10 −4 ; MAFLD ~ BP, SMD −0.12, 95% CI (−0.20 to −0.05), p = 1.6·10 −3 ). Furthermore, fibrosis phenotypes were related to TBV, grey and white matter volumes. Conclusions Presence of liver steatosis, fibrosis and elevated serum GGT are associated with structural and hemodynamic brain markers in a population‐based cross‐sectional setting. Understanding the hepatic role in brain changes can target modifiable factors and prevent brain dysfunction.