Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression - PubMed (original) (raw)

doi: 10.1016/j.metabol.2020.154457. Epub 2020 Dec 1.

Ibrahim Choucair 2, Zeneng Wang 2, Ina Nemet 2, Lin Li 2, Janet Gukasyan 3, Taylor L Weeks 2, Naim Alkhouri 4, Nizar Zein 5, W H Wilson Tang 6, Michael A Fischbach 7, J Mark Brown 2, Hooman Allayee 3, Srinivasan Dasarathy 8, Valentin Gogonea 9, Stanley L Hazen 10

Affiliations

Bile acids profile, histopathological indices and genetic variants for non-alcoholic fatty liver disease progression

Nisreen Nimer et al. Metabolism. 2021 Mar.

Abstract

Objective: Metabolomic studies suggest plasma levels of bile acids (BAs) are elevated amongst subjects with non-alcoholic fatty liver disease (NAFLD) compared to healthy controls. However, it remains unclear whether or not specific BAs are associated with the clinically relevant transition from nonalcoholic fatty liver (i.e. simple steatosis) to non-alcoholic steatohepatitis (NASH), or enhanced progression of hepatic fibrosis, or genetic determinants of NAFLD/NASH.

Methods: Among sequential subjects (n=102) undergoing diagnostic liver biopsy, we examined the associations of a broad panel of BAs with distinct histopathological features of NAFLD, the presence of NASH, and their associations with genetic variants linked to NAFLD and NASH.

Results: Plasma BA alterations were observed through the entire spectrum of NAFLD, with several glycine conjugated forms of the BAs demonstrating significant associations with higher grades of inflammation and fibrosis. Plasma 7-Keto-DCA levels showed the strongest associations with advanced stages of hepatic fibrosis [odds ratio(95% confidence interval)], 4.2(1.2-16.4), NASH 24.5(4.1-473), and ballooning 18.7(4.8-91.9). Plasma 7-Keto-LCA levels were associated with NASH 9.4(1.5-185) and ballooning 5.9(1.4-28.8). Genetic variants at several NAFLD/NASH loci were nominally associated with increased levels of 7-Keto- and glycine-conjugated forms of BAs, and the NAFLD risk allele at the TRIB1 locus showed strong tendency toward increased plasma levels of GCA (p=0.02) and GUDCA (p=0.009).

Conclusions: Circulating bile acid levels are associated with histopathological and genetic determinants of the transition from simple hepatic steatosis into NASH. Further studies exploring the potential involvement of bile acid metabolism in the development and/or progression of distinct histopathological features of NASH are warranted.

Keywords: Bile acids; Fibrosis; Metabolomics; NAFLD; NASH.

Copyright © 2020 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of competing interest Drs. Wang and Hazen report being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr. Hazen also reports being a paid consultant for Procter & Gamble, having received research funds from Procter & Gamble, and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab and Procter & Gamble. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Fig. 1.

Fig. 1.. Glycine conjugated primary BAs are predominantly associated with the progress of hepatic fibrosis.

(A) Changes in total plasma BAs, primary (1°), secondary (2°) and glycine conjugated BAs through the progression of fibrosis. Pie chart plot representing the proportion of each bile acid in the plasma BA pool (expressed as a percentage of the total plasma BA pool) through the progression of fibrosis. Colors reflect the BAs patterns and pie sizes reflect changes in the sum of plasma BAs pool. Percentage values are for the most abundant or significant BAs in the circulating pool. (B) GCDCA, GCA, 7-Keto-DCA and GUDCA plasma levels increased significantly along with the increase in fibrosis severity. Box-whisker plots for individual plasma BAs showing significant differences between no fibrosis and fibrosis subjects, lower and upper lines of the box indicate the 25th and 75th percentiles, line in the middle indicates the median, upper and lower whiskers indicate 5th and 95th percentiles. P-values were calculated by the Kruskal-Wallis test (K.W.) with post hoc analysis using Dunn’s test and by test for trend for increasing BAs within each group.

Fig. 2.

Fig. 2.. Significant changes in plasma BA profile are associated with the severity of fibrosis in NAFLD.

(A) Distinct changes in total plasma BAs through the progression from steatosis to NASH. Pie charts representing the proportion of each BA in the plasma BA pool (expressed as a percentage of the total plasma BA pool). The pie size is the measure of plasma BAs pool concentration. Percentage values are for the most abundant or significant BAs in the circulating pool. (B) Plasma levels of 7-Keto-DCA and 7-Keto-LCA are significantly increased in NASH compared to steatosis and both are both associated with increasing NAS. P values are calculated by the Kruskal-Wallis test (K.W.) with post hoc analysis using Dunn’s test and by test for trend for increasing BAs within each group.

Fig. 3.

Fig. 3.. Significant changes in plasma total BA profile with the severity of inflammation in NAFLD.

(A) Significantly increased plasma total BA, total primary BAs, glycine conjugated primary BAs (GCA+GCDCA) and taurine primary BAs (TCA+TCDCA) with higher grades of hepatic inflammation. (B) Significant increase in individual BAs (GCA, TCA, GCDCA and TCDCA) with severity of inflammation. Data presented as box-whiskers plots with the median. P values are calculated by the Kruskal-Wallis test (K.W.) with post hoc analysis using Dunn’s test.

Fig. 4.

Fig. 4.. Plasma BA association with hepatic ballooning and steatosis in NAFLD.

(A) Plasma levels of 7-Ketodeoxycholic acid (7-Keto-DCA), 7-Ketolithocholic acid (7-Keto-LCA), iso-deoxycholic acid (Iso-DCA) and isolithocholic acid (Iso-LCA) are significantly increased in ballooning. (B) Plasma 7-Keto-DCA, and 7-LCA are significantly associated with advanced ballooning grades. (C) Significantly increased plasma 7-Keto-LCA with advanced steatosis (G2,3) compared to simple steatosis (G1) in NAFLD and (D) its concentration was significantly associated with advanced grades. Data presented as box-whiskers plots with the median. P values are calculated by the Mann-Whitney test (M.W.) for two group comparions and Kruskal-Wallis test (K.W.) with post hoc analysis using Dunn’s test for muti group comparisons.

Fig. 5.

Fig. 5.. Relationship between individual plasma BAs levels and fibrosis risk.

Heat map showing Spearman correlation between plasma levels of individual BAs and age, body mass index (BMI), alanine aminotransferase (ALT), aspartate transaminase (AST), fasting glucose, insulin, hemoglobin A1c (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), cholesterol (Chol), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). The correlation strength is shown by the color bar, with blue/red representing positive/negative association, respectively, and white no association. *P<0.05, **P<0.01. Rho values of Spearman’s rank correlation coefficient.

Fig. 6.

Fig. 6.. Association of structurally defined plasma BAs histopathology components of NAFLD.

Forest plots of odds ratios (OR) of 4th quartile (Q4) versus 1st quartile (Q1) for fibrosis, NASH, inflammation, ballooning and steatosis phenotypes. Bars represent 95% confidence interval (CI). Black lines with closed/open circle represent unadjusted/adjusted OR, respectively. Adjustments are done by multivariable logistic regression model (adjusted for age, gender, body mass index (BMI), homeostatic model assessment for insulin resistance (HOMA-IR) and alanine aminotransferase (ALT).

Fig. 7.

Fig. 7.. The relationships between metabolic pathways of specific BAs and NAFLD histology phenotypes.

Upward arrows show significant changes in the progression of NAFLD phenotypes. (A) BAs originating from cholic acid (CA). (B) BAs originating from chenodeoxycholic acid (CDCA). Dashed arrows represent gut microbiota pathways involved in the synthesis of secondary BAs, and the solid arrows represent pathways in the host (liver). Gut microbiota enzymes: 7-α-HSDH, 7α-hydroxysteroid dehydrogenase; 3-α-HSDH, 3-α-hydroxysteroid dehydrogenase; liver enzyme BAAT, bile acid-CoA: amino acid _N_-acyltransferase.

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