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

Abstract

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.

Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research

“…Alcoholic-induced organ damage, as well as the MEOS, are subjects of continuous research and review of research [146,147]. It is mandatory that clinical, basic, and translational scientists collaborate on a common agenda for the future.…”

“…Interactions between alcohol and prescription drugs are common, particularly the additive effects with benzodiazepines and also with some of the antihistamine drugs; other interactions may occur with tricyclic antidepressants [137]. An important additional element of the hepatotoxic threat of alcohol is its enhancement of the hepatotoxic effects of other hepatotoxins (e.g., CCl 4 ) and even some drugs (e.g., acetaminophen) [138][139][140][141][142][143][144][145][146][147][148].…”

Herb-induced Liver Injury in Asia and Current Role of RUCAM for Causality Assessment in 11,160 Published Cases

“…This certainly applies for evaluations and descriptions of any new diagnostic biomarker, as well. 65 Some diagnostic biomarkers are well established for HILI and DILI, but others came under scientific fire due to recent actions of the European Medicines Agency (known as the EMA) through the correct and official retraction of its earlier Letter of Support to promote biomarker research and use. 65 The retraction by EMA was the consequence of faulty results based on studies misconducted by not-further identified liver injury experts.…”

“…65 Some diagnostic biomarkers are well established for HILI and DILI, but others came under scientific fire due to recent actions of the European Medicines Agency (known as the EMA) through the correct and official retraction of its earlier Letter of Support to promote biomarker research and use. 65 The retraction by EMA was the consequence of faulty results based on studies misconducted by not-further identified liver injury experts. 11,65 This official retraction represents currently, and in near future, a tricky dilemma for the scientific liver injury community.…”

“…65 The retraction by EMA was the consequence of faulty results based on studies misconducted by not-further identified liver injury experts. 11,65 This official retraction represents currently, and in near future, a tricky dilemma for the scientific liver injury community.…”