Abstract
Background: Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis. However, its underlying development mechanism is poorly understood.Aims: To find serum metabolite signatures of chronic DILI with or without cirrhosis, and to elucidate the underlying mechanism.Methods: Untargeted metabolomics coupled with pattern recognition approaches were used to profile and extract metabolite signatures from 83 chronic DILI patients, including 58 non-cirrhosis (NC) cases, 14 compensated cirrhosis (CC) cases, and 11 decompensated cirrhosis (DC) cases.Results: Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis (including 30 metabolites) and decompensation (including 25 metabolites), were identified. There was a significantly positive correlation between cirrhosis-associated fingerprint (eigenmetabolite) and the aspartate aminotransferase-to-platelet ratio index (APRI) (r = 0.315, P = 0.003). The efficacy of cirrhosis-associated eigenmetabolite coupled with APRI to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]. The decompensation-associated fingerprint (eigenmetabolite) can effectively identify the compensation and decompensation periods (AUC value 0.954). The results of the metabolic fingerprint pathway analysis suggest that the blocked tricarboxylic acid cycle (TCA cycle) and intermediary metabolism, excessive accumulation of bile acids, and perturbed amino acid metabolism are potential mechanisms in the occurrence and development of chronic DILI-associated cirrhosis.Conclusions: The metabolomic fingerprints characterize different stages of chronic DILI progression and deepen the understanding of the metabolic reprogramming mechanism of chronic DILI progression to cirrhosis.
Highlights
drug-induced liver injury (DILI) is one of the most common and serious adverse reactions to drugs [1,2,3,4,5], and an important cause of clinically acute liver injury and failure [2, 6, 7]
Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis and decompensation, were identified
The efficacy of cirrhosis-associated eigenmetabolite coupled with aminotransferase-to-platelet ratio index (APRI) to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]
Summary
DILI is one of the most common and serious adverse reactions to drugs [1,2,3,4,5], and an important cause of clinically acute liver injury and failure [2, 6, 7]. Most patients with DILI recover after drug withdrawal. Around 8 ∼ 20% of patients progress to chronicity [2, 8,9,10]. 44% (7/16) of these chronic DILI patients who underwent liver biopsies had cirrhosis and 6% (1/16) manifested fibrosis. A high proportion of patients with chronic DILI may progress into cirrhosis. The mechanism of chronic DILI progression is still unclear. Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis.
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