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

1
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-63450 Hanau, Germany
2
Department of Complementary and Integrative Medicine, University of Hawai’i at Manoa, Honolulu, HI 96813, USA
3
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M2 R1 W6, Canada
4
Institute of Occupational, Social and Environmental Medicine, Goethe-University Frankfurt/Main, D-60590 Frankfurt/Main, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(1), 212; https://doi.org/10.3390/ijms21010212
Received: 2 December 2019 / Revised: 21 December 2019 / Accepted: 23 December 2019 / Published: 27 December 2019
(This article belongs to the Special Issue Molecular Mechanisms and Biomarkers in Drug-Induced Organ Injury)
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. View Full-Text
Keywords: biomarkers; liver injury; drug induced liver injury; herb induced liver injury; alcoholic liver injury; alcoholic liver disease biomarkers; liver injury; drug induced liver injury; herb induced liver injury; alcoholic liver injury; alcoholic liver disease
MDPI and ACS Style

Teschke, R.; Eickhoff, A.; Brown, A.C.; Neuman, M.G.; Schulze, J. Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support. Int. J. Mol. Sci. 2020, 21, 212. https://doi.org/10.3390/ijms21010212

AMA Style

Teschke R, Eickhoff A, Brown AC, Neuman MG, Schulze J. Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support. International Journal of Molecular Sciences. 2020; 21(1):212. https://doi.org/10.3390/ijms21010212

Chicago/Turabian Style

Teschke, Rolf, Axel Eickhoff, Amy C. Brown, Manuela G. Neuman, and Johannes Schulze. 2020. "Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support" International Journal of Molecular Sciences 21, no. 1: 212. https://doi.org/10.3390/ijms21010212

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