Original Article
Pancreas, Biliary Tract, and Liver
A High Serum Level of Taurocholic Acid Is Correlated With the Severity and Resolution of Drug-induced Liver Injury

https://doi.org/10.1016/j.cgh.2020.06.067Get rights and content

Background & Aims

Alterations in the serum levels of bile acids are associated with drug-induced liver injury (DILI). We investigated the association between serum levels of bile acids and the severity and outcome of DILI, along with the potential role of variants in the ATP binding cassette subfamily B member 11 (ABCB11) gene and expression of its product, ABCB11 (also called BSEP).

Methods

We performed this prospective study of 95 patients (median age, 53 years; 73.7% female) with DILI from August 2018 through August 2019. Patients were matched for age, gender, and body mass index with healthy individuals (n = 100; healthy controls) and patients with chronic hepatitis B (n = 105; CHB controls). We collected demographic and biochemical data at baseline and 1 week, 1 month, 3 months, and 6 months after DILI onset and at the time of biochemical recovery, liver failure or liver transplantation. Serum levels of bile acids were measured using high-performance liquid-chromatography tandem mass-spectrometry. All 27 exons of ABCB11 were sequenced and expression of BSEP was analyzed by immunohistochemistry in liver biopsy specimens.

Results

Levels of 30 of the 37 bile acids analyzed differed significantly between patients with DILI and healthy controls. Changes in levels of taurocholic acid (TCA), glycocholic acid, taurochenodeoxycholate, and glycochenodeoxycholate associated with the increased levels of bilirubin and greater severity of DILI, and were also associated with CHB. Cox regression analysis showed that only change in the levels of TCA independently associated with biochemical resolution of DILI. Combination of TCA level (≥ 1955.41 nmol/L), patient age, and DILI severity was associated with abnormal blood biochemistry at 6 months after DILI onset (area under the curve, 0.81; 95% confidence interval, 0.71–0.88; sensitivity, 0.69; specificity, 0.81). ABCB11 missense variants were not associated with differences in the serum bile acid profiles, DILI severity, or clinical resolution. However, lower levels of BSEP in bile canaliculi in liver biopsies were associated with altered serum levels of bile acids.

Conclusions

In this prospective study performed in Chinese patients, we found that the serum levels of TCA were associated with the severity and clinical resolution of DILI. Reduced protein expression of BSEP in liver tissue, rather than variants of the ABCB11 gene were associated with altered serum levels of bile acids.

Section snippets

Study Population

In this single-center cohort study, we prospectively recruited patients with a clinical diagnosis of DILI at Beijing Friendship Hospital, Capital Medical University, from August 2018 to August 2019.

The inclusion criteria were as follows: (1) Chinese Han nationality aged 18 to 78 years, (2) outpatients or inpatients with a diagnosis of DILI, and (3) available blood samples from the acute phase (within 10 days of obtaining the peak value of transaminase or bilirubin).

The exclusion criteria were

Clinical Characteristics of Drug-Induced Liver Injury Patients, Healthy Controls, and Chronic Hepatitis B Patients

This study included 95 DILI patients, 100 healthy controls (Figure 1), and 105 non-cirrhotic CHB patients. Age, gender, and BMI were comparable among 3 groups. The demographic, biochemical, and clinical characteristics are summarized in Table 1, Supplementary Tables 2 and 3.

The median age of DILI patients was 53 years, and the majority (73.7%) were female. On the basis of the R value, 63, 17, and 15 cases were defined as having a hepatocellular, cholestatic, and mixed phenotype, respectively.

Discussion

In this study we found that the levels of certain conjugated BAs increased in a stepwise manner along with DILI severity. Furthermore, the level of serum TCA was independently associated with the clinical resolution of DILI. The alteration of serum BAs was associated with reduced liver expression of BSEP but not with genetic variants of ABCB11, encoding BSEP. Taken together, these results suggest that a high serum TCA level is positively associated with disease severity and can potentially

Acknowledgments

The authors thank Wei Chen, Donghu Zhou, and Siyu Jia from Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China, for their help in the experiments and interpretation of the results, and Dr Ipsita Panda from India for her generous help in critical revision and language polishing.

CRediT Authorship Contributions

Qiuju Tian (Data curation: Lead; Formal analysis: Lead; Writing – original draft: Lead)

Ruiyuan Yang (Data curation: Lead; Formal analysis: Lead),

Yan Wang

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    Conflicts of interest The authors disclose no conflicts.

    Funding Suppported by grants from the National Natural Science Foundation of China (No. 81670545), the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (No. XXZ0301), the National Science and Technology Major Special Project for New Drug Development (No. 2018ZX09201016), and the Key Technical and Executive Measures to Improve Early Phase Clinical Trials on Innovative Drugs for Liver Diseases (No. Z191100007619037).

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