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

Pinar Yilmaz*, Louise J.M. Alferink, Lotte G.M. Cremers, Sarwa D. Murad, Wiro J. Niessen, M. Arfan Ikram, Meike W. Vernooij

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)


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.

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.

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.

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.

Original languageEnglish
Pages (from-to)1256-1268
Number of pages13
JournalLiver International
Issue number6
Publication statusPublished - Jun 2023

Bibliographical note

Funding Information:
The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. The funding sources had no involvement in the collection, analysis, writing, interpretation, or the decision to submit the paper for publication.

Publisher Copyright:
© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.


Dive into the research topics of 'Subclinical liver traits are associated with structural and hemodynamic brain imaging markers'. Together they form a unique fingerprint.

Cite this