Mendoza, Yuly P; Tsouka, Sofia; Semmler, Georg; Seubnooch, Patcharamon; Freiburghaus, Katrin; Mandorfer, Mattias; Bosch, Jaime; Masoodi, Mojgan; Berzigotti, Annalisa (2024). Metabolic phenotyping of patients with Advanced Chronic Liver Disease for better characterization of Cirrhosis Regression. (In Press). Journal of hepatology Elsevier 10.1016/j.jhep.2024.06.028
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BACKGROUND & AIMS
Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD).
METHODS
In a case-control pilot study with 81 cACLD patients, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n=44) with those showing no improvement ("non-regressors"; n=37) after a minimum of 24 months of successful therapy of the cause of liver disease. Data were validated using an external validation cohort (n=30).
RESULTS
Regardless of the cause of cACLD, the presence of obesity (OR 0.267 95%CI:0.072-0.882; P=0.049), high liver stiffness (OR 0.960, 95%CI:0.925-0.995; P=0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95%CI:0.030-0.773; P=0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 ACLD patients genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated to lipid metabolism -especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to identifying 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers.
CONCLUSIONS
We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarker for detecting regression of fibrosis in cACLD.
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