Metabolic phenotyping of patients with advanced chronic liver disease for better characterization of cirrhosis regression

Abstract

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 of 81 patients with cACLD, 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 treatment 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 (odds ratio [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 patients with ACLD genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated with 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 the identification of 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 biomarkers for detecting regression of fibrosis in cACLD.

Impact and implications: Regression of cirrhosis/advanced chronic liver disease (ACLD) after removal of the underlying cause of liver injury has been observed in human cirrhosis. However, detailed characterization of ACLD regression remains an unmet need. In this study, we provide a comprehensive phenotyping of individuals likely to experience ACLD regression. While obesity, carriage of GCKR variant rs1260326 and high liver stiffness were associated with lower likelihood of regression of ACLD, a signature of circulating lipid metabolites enabled differentiation of regressors from non-regressors after effective etiologic therapy. The lipid signature we discovered and externally validated could be used as non-invasive biomarker to detect regression of fibrosis in patients with compensated ACLD.

Keywords: biomarkers; fibrosis regression; lipid signature; obesity.