Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.

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Investigating the Mechanism of Trimethoprim-Induced Skin Rash and Liver Injury

Toxicological Sciences ◽

10.1093/toxsci/kfaa182 ◽

2021 ◽

Author(s):

Yanshan Cao ◽

Ahsan Bairam ◽

Alison Jee ◽

Ming Liu ◽

Jack Uetrecht

Keyword(s):

Liver Injury ◽

Skin Rash ◽

Covalent Binding ◽

Reactive Metabolites ◽

Important Data ◽

Drug Induced ◽

Interindividual Differences ◽

Immune Mediated ◽

Sulfate Conjugate

Abstract Trimethoprim (TMP)-induced skin rash and liver injury are likely to involve the formation of reactive metabolites. Analogous to nevirapine-induced skin rash, one possible reactive metabolite is the sulfate conjugate of α-hydroxyTMP, a metabolite of TMP. We synthesized this sulfate and found that it reacts with proteins in vitro. We produced a TMP-antiserum and found covalent binding of TMP in the liver of TMP-treated rats. However, we found that α-hydroxyTMP is not a substrate for human sulfotransferases, and we did not detect covalent binding in the skin of TMP-treated rats. Although less reactive than the sulfate, α-hydroxyTMP was found to covalently bind to liver and skin proteins in vitro. Even though there was covalent binding to liver proteins, TMP did not cause liver injury in rats or in our impaired immune tolerance mouse model that has been able to unmask the ability of other drugs to cause immune-mediated liver injury. This is likely because there was much less covalent binding of TMP in the livers of TMP-treated mice than TMP-treated rats. It is possible that some patients have a sulfotransferase that can produce the reactive benzylic sulfate; however, α-hydroxyTMP, itself, has sufficient reactivity to covalently bind to proteins in the skin and may be responsible for TMP-induced skin rash. Interspecies and interindividual differences in TMP metabolism may be one factor that determines the risk of TMP-induced skin rash. This study provides important data required to understand the mechanism of TMP-induced skin rash and drug-induced skin rash in general.

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Circulatory Inflammatory Mediators in the Prediction of Anti-Tuberculous Drug-Induced Liver Injury Using RUCAM for Causality Assessment

Biomedicines ◽

10.3390/biomedicines9080891 ◽

2021 ◽

Vol 9 (8) ◽

pp. 891

Author(s):

Cheng-Maw Ho ◽

Chi-Ling Chen ◽

Chia-Hao Chang ◽

Meng-Rui Lee ◽

Jann-Yuan Wang ◽

...

Keyword(s):

Liver Injury ◽

Inflammatory Mediators ◽

Cox Regression ◽

Causality Assessment ◽

Area Under The Curve ◽

Assessment Method ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Tb Treatment ◽

Pre Treatment

Background: Anti-tuberculous (TB) medications are common causes of drug-induced liver injury (DILI). Limited data are available on systemic inflammatory mediators as biomarkers for predicting DILI before treatment. We aimed to select predictive markers among potential candidates and to formulate a predictive model of DILI for TB patients. Methods: Adult active TB patients from a prospective cohort were enrolled, and all participants received standard anti-tuberculous treatment. Development of DILI, defined as ≥5× ULN for alanine transaminase or ≥2.6× ULN of total bilirubin with causality assessment (RUCAM, Roussel Uclaf causality assessment method), was regularly monitored. Pre-treatment plasma was assayed for 15 candidates, and a set of risk prediction scores was established using Cox regression and receiver-operating characteristic analyses. Results: A total of 19 (7.9%) in 240 patients developed DILI (including six carriers of hepatitis B virus) following anti-TB treatment. Interleukin (IL)-22 binding protein (BP), interferon gamma-induced protein 1 (IP-10), soluble CD163 (sCD163), IL-6, and CD206 were significant univariable factors associated with DILI development, and the former three were backward selected as multivariable factors, with adjusted hazards of 0.20 (0.07–0.58), 3.71 (1.35–10.21), and 3.28 (1.07–10.06), respectively. A score set composed of IL-22BP, IP-10, and sCD163 had an improved area under the curve of 0.744 (p < 0.001). Conclusions: Pre-treatment IL-22BP was a protective biomarker against DILI development under anti-TB treatment, and a score set by additional risk factors of IP-10 and sCD163 employed an adequate DILI prediction.

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Causality assessment in drug-induced liver injury using a structured expert opinion process: Comparison to the Roussel-Uclaf causality assessment method

Hepatology ◽

10.1002/hep.23577 ◽

2010 ◽

Vol 51 (6) ◽

pp. 2117-2126 ◽

Cited By ~ 217

Author(s):

Don C. Rockey ◽

Leonard B. Seeff ◽

James Rochon ◽

James Freston ◽

Naga Chalasani ◽

...

Keyword(s):

Liver Injury ◽

Expert Opinion ◽

Causality Assessment ◽

Assessment Method ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Process Comparison

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A case report of a drug‐induced liver injury (DILI) caused by multiple antidepressants with causality established by the updated Roussel Uclaf causality assessment method (RUCAM) and in vitro testing

Clinical Case Reports ◽

10.1002/ccr3.3348 ◽

2020 ◽

Vol 8 (12) ◽

pp. 3105-3109

Author(s):

Miguel González‐Muñoz ◽

Jaime Monserrat Villatoro ◽

Eva Marín‐Serrano ◽

Stefan Stewart ◽

Belén Bardón Rivera ◽

...

Keyword(s):

Case Report ◽

Liver Injury ◽

Causality Assessment ◽

Assessment Method ◽

In Vitro Testing ◽

Drug Induced ◽

Drug Induced Liver Injury

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Roussel Uclaf Causality Assessment Method for Drug-Induced Liver Injury: Present and Future

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00853 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 15

Author(s):

Gaby Danan ◽

Rolf Teschke

Keyword(s):

Liver Injury ◽

Causality Assessment ◽

Assessment Method ◽

Drug Induced ◽

Drug Induced Liver Injury

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Genetic polymorphisms of UGT1A1 and susceptibility to anti-tuberculosis drug-induced liver: A RUCAM-based case–control study

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738418816288 ◽

2018 ◽

Vol 32 ◽

pp. 205873841881628 ◽

Cited By ~ 3

Author(s):

Bilin Tao ◽

Shixian Chen ◽

Guancheng Lin ◽

Miaomiao Yang ◽

Lihuan Lu ◽

...

Keyword(s):

Liver Injury ◽

Genetic Polymorphisms ◽

Case Control Study ◽

Causality Assessment ◽

Conditional Logistic Regression ◽

Assessment Method ◽

Case Control ◽

Bile Acid Metabolism ◽

Drug Induced ◽

Control Study

Uridine 5’-diphospho-glucuronosyl-transferase 1A1 (UGT1A1) plays an important role in the biliary excretion of bilirubin, suggesting genetic polymorphisms of UGT1A1 may have an impact on bile acid metabolism, which may be related to the development of anti-tuberculosis drug-induced liver injury (ATLI). This study explores the associations between genetic polymorphisms of UGT1A1 and ATLI in a Chinese anti-tuberculosis population. A 1:2 matched case–control study was conducted among 290 ATLI cases and 580 controls, of which causality assessment of ATLI cases was based on the updated Roussel Uclaf Causality Assessment Method (RUCAM). Conditional logistic regression was applied to calculate odds ratio (OR) and 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. The Bonferroni correction was used to adjust P values for multiple testing. Compared with those carrying rs6719561 TT genotype, patients with TC genotype had lower risk of ATLI (adjusted OR = 0.723, 95% CI: 0.531–0.985, P = 0.040). The haplotype TAG (rs3755319-rs2003569-rs4148323) could marginally significantly increase the risk of ATLI (adjusted OR = 5.071, 95% CI: 1.007–25.531, P = 0.049), while haplotype TC (rs4148329-rs6719561) could reduce the risk of ATLI (adjusted OR = 0.719, 95% CI: 0.527–0.982, P = 0.038). Patients with polymorphisms at rs4148328 or rs3755319 were at a reduced risk of moderate and severe liver injury under different genetic models. Based on this case–control study, genetic polymorphisms of UGT1A1 may be associated with susceptibility to ATLI in the Chinese anti-tuberculosis population.

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