BILE ACIDS AND EXTRACELLULAR VESICLE CARGO AS BIOMARKERS ACROSS THE SPECTRUM OF ALCOHOL-ASSOCIATED LIVER DISEASE
DDW ePoster Library. Parraga X. 05/02/26; 4196054; Mo2021
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Abstract
Discussion Forum (0)
Background: Alcohol-associated liver disease (ALD) encompasses a wide clinical spectrum, yet the biological mechanisms driving progression, particularly in alcohol-associated hepatitis (AH), remain poorly defined. AH is characterized by cholestasis, but current diagnostic criteria rely almost entirely on clinical criteria, offering limited insight into metabolic disturbances that distinguish AH from other ALD phenotypes. Because bile acids (BAs), their synthesis intermediate C4, FGF19 signaling, and extracellular vesicles (EVs) reflect key processes in cholestasis and hepatocellular stress, we quantified circulating BAs, C4, and EV-associated BA cargo to characterize patterns across the ALD spectrum and define the metabolic signature of AH.
Methods:
Prospective cohort analysis of patients with ALD enrolled in a tertiary center in Chile between 2020-2024. It included ALD patients, defined as Alcohol Use Disorder (AUD), Alcohol-associated Cirrhosis (CR), and AH, and healthy controls. BAs were measured in serum with tandem mass spectrometry, as well as cargo of EVs isolated from plasma. FGF19 ELISA was performed. Analyte concentrations were log2-transformed and analyzed using left-censored Tobit regression models to account for values below the limit of quantification. Group differences were assessed using Tukey-adjusted pairwise contrasts, from which estimates and Z-values were obtained.
Results:
Among 148 patients, those across the ALD spectrum (AH=50, CR=34, AUD=31) showed substantially higher concentrations of total and conjugated BAs compared with controls (C=33). Notably, AH patients had significantly greater total BA levels than controls (log2FC=2.77, p=1.27e-02). In contrast, levels of total unconjugated BAs were similar across groups. The largest increases were observed for TCDCA and TCA in the AH subgroup when compared with controls (log2FC=5.41, p=2.49e-13 and log2FC=5.29, p<1.36e-13), and for TLCA in the CR subgroup when compared with controls (log2FC=2.33, p=3.69e-04). In AUD, LCA represented the most elevated BA relative to controls (log2FC=2.55, p=7.75e-03). Conversely, DCA showed the most pronounced reduction in the AH subgroup (log2FC=-3.67, p=1.26e-07). Levels of C4 were significantly decreased across all ALD subgroups, with the greatest decline in AH (log2FC=-3.76, p=9.06e-14). These reductions were inversely associated with increased FGF19 concentrations in ALD compared with controls, especially in AH (log2FC=1.14, p=2.82e-03). Finally, EV concentrations were highest in AH and AUD compared with controls and CR (log2FC=1.29, p=2.03e-08 and log2FC=1.08, p=1.05e-05).
Conclusion:
Patients with ALD display distinct BA profiles in serum and EV cargo, with AH showing the most pronounced alterations, supporting this approach as a robust framework for characterizing disease-specific patterns.
Methods:
Prospective cohort analysis of patients with ALD enrolled in a tertiary center in Chile between 2020-2024. It included ALD patients, defined as Alcohol Use Disorder (AUD), Alcohol-associated Cirrhosis (CR), and AH, and healthy controls. BAs were measured in serum with tandem mass spectrometry, as well as cargo of EVs isolated from plasma. FGF19 ELISA was performed. Analyte concentrations were log2-transformed and analyzed using left-censored Tobit regression models to account for values below the limit of quantification. Group differences were assessed using Tukey-adjusted pairwise contrasts, from which estimates and Z-values were obtained.
Results:
Among 148 patients, those across the ALD spectrum (AH=50, CR=34, AUD=31) showed substantially higher concentrations of total and conjugated BAs compared with controls (C=33). Notably, AH patients had significantly greater total BA levels than controls (log2FC=2.77, p=1.27e-02). In contrast, levels of total unconjugated BAs were similar across groups. The largest increases were observed for TCDCA and TCA in the AH subgroup when compared with controls (log2FC=5.41, p=2.49e-13 and log2FC=5.29, p<1.36e-13), and for TLCA in the CR subgroup when compared with controls (log2FC=2.33, p=3.69e-04). In AUD, LCA represented the most elevated BA relative to controls (log2FC=2.55, p=7.75e-03). Conversely, DCA showed the most pronounced reduction in the AH subgroup (log2FC=-3.67, p=1.26e-07). Levels of C4 were significantly decreased across all ALD subgroups, with the greatest decline in AH (log2FC=-3.76, p=9.06e-14). These reductions were inversely associated with increased FGF19 concentrations in ALD compared with controls, especially in AH (log2FC=1.14, p=2.82e-03). Finally, EV concentrations were highest in AH and AUD compared with controls and CR (log2FC=1.29, p=2.03e-08 and log2FC=1.08, p=1.05e-05).
Conclusion:
Patients with ALD display distinct BA profiles in serum and EV cargo, with AH showing the most pronounced alterations, supporting this approach as a robust framework for characterizing disease-specific patterns.
Background: Alcohol-associated liver disease (ALD) encompasses a wide clinical spectrum, yet the biological mechanisms driving progression, particularly in alcohol-associated hepatitis (AH), remain poorly defined. AH is characterized by cholestasis, but current diagnostic criteria rely almost entirely on clinical criteria, offering limited insight into metabolic disturbances that distinguish AH from other ALD phenotypes. Because bile acids (BAs), their synthesis intermediate C4, FGF19 signaling, and extracellular vesicles (EVs) reflect key processes in cholestasis and hepatocellular stress, we quantified circulating BAs, C4, and EV-associated BA cargo to characterize patterns across the ALD spectrum and define the metabolic signature of AH.
Methods:
Prospective cohort analysis of patients with ALD enrolled in a tertiary center in Chile between 2020-2024. It included ALD patients, defined as Alcohol Use Disorder (AUD), Alcohol-associated Cirrhosis (CR), and AH, and healthy controls. BAs were measured in serum with tandem mass spectrometry, as well as cargo of EVs isolated from plasma. FGF19 ELISA was performed. Analyte concentrations were log2-transformed and analyzed using left-censored Tobit regression models to account for values below the limit of quantification. Group differences were assessed using Tukey-adjusted pairwise contrasts, from which estimates and Z-values were obtained.
Results:
Among 148 patients, those across the ALD spectrum (AH=50, CR=34, AUD=31) showed substantially higher concentrations of total and conjugated BAs compared with controls (C=33). Notably, AH patients had significantly greater total BA levels than controls (log2FC=2.77, p=1.27e-02). In contrast, levels of total unconjugated BAs were similar across groups. The largest increases were observed for TCDCA and TCA in the AH subgroup when compared with controls (log2FC=5.41, p=2.49e-13 and log2FC=5.29, p<1.36e-13), and for TLCA in the CR subgroup when compared with controls (log2FC=2.33, p=3.69e-04). In AUD, LCA represented the most elevated BA relative to controls (log2FC=2.55, p=7.75e-03). Conversely, DCA showed the most pronounced reduction in the AH subgroup (log2FC=-3.67, p=1.26e-07). Levels of C4 were significantly decreased across all ALD subgroups, with the greatest decline in AH (log2FC=-3.76, p=9.06e-14). These reductions were inversely associated with increased FGF19 concentrations in ALD compared with controls, especially in AH (log2FC=1.14, p=2.82e-03). Finally, EV concentrations were highest in AH and AUD compared with controls and CR (log2FC=1.29, p=2.03e-08 and log2FC=1.08, p=1.05e-05).
Conclusion:
Patients with ALD display distinct BA profiles in serum and EV cargo, with AH showing the most pronounced alterations, supporting this approach as a robust framework for characterizing disease-specific patterns.
Methods:
Prospective cohort analysis of patients with ALD enrolled in a tertiary center in Chile between 2020-2024. It included ALD patients, defined as Alcohol Use Disorder (AUD), Alcohol-associated Cirrhosis (CR), and AH, and healthy controls. BAs were measured in serum with tandem mass spectrometry, as well as cargo of EVs isolated from plasma. FGF19 ELISA was performed. Analyte concentrations were log2-transformed and analyzed using left-censored Tobit regression models to account for values below the limit of quantification. Group differences were assessed using Tukey-adjusted pairwise contrasts, from which estimates and Z-values were obtained.
Results:
Among 148 patients, those across the ALD spectrum (AH=50, CR=34, AUD=31) showed substantially higher concentrations of total and conjugated BAs compared with controls (C=33). Notably, AH patients had significantly greater total BA levels than controls (log2FC=2.77, p=1.27e-02). In contrast, levels of total unconjugated BAs were similar across groups. The largest increases were observed for TCDCA and TCA in the AH subgroup when compared with controls (log2FC=5.41, p=2.49e-13 and log2FC=5.29, p<1.36e-13), and for TLCA in the CR subgroup when compared with controls (log2FC=2.33, p=3.69e-04). In AUD, LCA represented the most elevated BA relative to controls (log2FC=2.55, p=7.75e-03). Conversely, DCA showed the most pronounced reduction in the AH subgroup (log2FC=-3.67, p=1.26e-07). Levels of C4 were significantly decreased across all ALD subgroups, with the greatest decline in AH (log2FC=-3.76, p=9.06e-14). These reductions were inversely associated with increased FGF19 concentrations in ALD compared with controls, especially in AH (log2FC=1.14, p=2.82e-03). Finally, EV concentrations were highest in AH and AUD compared with controls and CR (log2FC=1.29, p=2.03e-08 and log2FC=1.08, p=1.05e-05).
Conclusion:
Patients with ALD display distinct BA profiles in serum and EV cargo, with AH showing the most pronounced alterations, supporting this approach as a robust framework for characterizing disease-specific patterns.
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