Circulating MicroRNAs as Novel Biomarkers of Drug-Induced Liver Injury in Humans

Krauskopf, Julian; Kleinjans, Jos; Kok, Theo M. de

doi:10.1007/978-1-4939-7677-5_28

Cited by 4 publications

(6 citation statements)

References 53 publications

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“…Biomarkers of idiosyncratic DILI differ in their intentional use and may now best be classified as diagnostic or prognostic biomarkers [14,24]. Both biomarker types have been discussed in a variety of contexts [11][12][13][14][24][25][26][27][28][29][30][31][32][33], whereas the current analysis focuses on only diagnostic biomarkers. These must be used prior to prognostic biomarkers for DILI case evaluation since a prognosis depends on a correct diagnosis.…”

Section: Diagnostic Biomarkersmentioning

confidence: 99%

“…Scientific, regulatory, and consortia publications have focused on idiosyncratic or intrinsic DILI and diagnostic biomarkers that include microRNA-122 (microarray RNA-122), microRNA-192, CK-18 (Cytokeratin-18 full length), ccCK-18 (caspase-cleaved CytoKeratin-18), Cytokeratin-18 (fragments), GLDH (Glutamate dehydrogenase), total HMGB-1 (High Mobility Group Box), hyperacetylated HMGB-1, and ITGB3 (Integrin beta 3). Some of these are listed in Table 1 and have been discussed in the scientific literature [14,17,[24][25][26][27]33]. However, on 15 April 2019, confusion emerged due to the EMA issuing a retraction note regarding various potential biomarkers listed above due to external data manipulation [17].…”

Section: Potential Idiosyncratic Dili Biomarkersmentioning

confidence: 99%

“…Krauskopf [27] Preliminary data for idiosyncratic DILI, also low case number. Liu [13] MicroRNA-192 Liver specific release from damaged hepatocytes; validation reported as ongoing.…”

Section: Comments Reference (First Author)mentioning

confidence: 99%

“…Most reports described the mechanistic background responsible for cellular or subcellular origin of the parameter under consideration and reported on conflicting data open for further discussions. Little support existed for the provided parameters listed in other publications [26][27][28][29][30][31][32][33][34]. This included a recent commentary carefully discussing biomarker options without considering new regulatory aspects of EMA (European Medicines Agency) [34], as previously discussed [17].…”

Section: Current Challengesmentioning

confidence: 99%

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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

Teschke

Eickhoff

Brown

et al. 2019

IJMS

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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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Section: Diagnostic Biomarkersmentioning

confidence: 99%

Section: Potential Idiosyncratic Dili Biomarkersmentioning

confidence: 99%

“…Krauskopf [27] Preliminary data for idiosyncratic DILI, also low case number. Liu [13] MicroRNA-192 Liver specific release from damaged hepatocytes; validation reported as ongoing.…”

Section: Comments Reference (First Author)mentioning

confidence: 99%

Section: Current Challengesmentioning

confidence: 99%

See 2 more Smart Citations

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

Teschke

Eickhoff

Brown

et al. 2019

IJMS

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“…MicroRNAs originating mainly from the liver are found in the blood of patients with liver diseases, either included in exosomes or freely floating (41,52). They were promoted not only as diagnostic biomarkers (27,(52)(53)(54)(55)(56)(57)(58)(59)(60), but also as mechanistic biomarkers providing insights into to pathogenetic steps in liver injury (61,62). However, the enthusiasm for their use as diagnostic biomarkers was not shared by others because they lack superiority over existing parameters (63).…”

Section: Blood Micrornamentioning

confidence: 99%

Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues

Teschke¹,

Uetrecht²

2021

Ann Transl Med

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Clinical features of idiosyncratic drug induced liver injury (DILI) are well described in cases that have been assessed for causality using the Roussel Uclaf Causality Assessment Method (RUCAM), but our understanding of the mechanistic steps leading to injury is fragmentary. The difficulties describing mechanistic events can be traced back to the lack of an animal model of experimental idiosyncratic DILI that can mimic the genetic requirements of human idiosyncratic DILI. However, immune tolerance plays a dominant role in the immune response of the liver, and impairment of immune tolerance with immune checkpoint inhibitors increases DILI in both humans and animals. This may provide one method to study the individual steps involved. In general. the human DILI liver is a secret keeper providing little insight into what occurs in the diseased organ. Sufficient evidence exists that most idiosyncratic cases are mediated by the adaptive immune system, which depends on stimulation of the innate immune system, but the triggering factors are unknown. It is attractive to hypothesize that the gut microbiome plays a role; however, it is very difficult to study. Similarly, exosomes are likely to play an important role in communication between hepatic cells and the immune system, but there is a lack of data on blood exosomes in affected patients. Reactive metabolites are likely to play an important role. This is supported by the current analysis, which revealed an association between metabolism by cytochrome P450 and drugs most commonly involved in causing idiosyncratic DILI with causality verified by RUCAM. Circumstantial evidence suggests that reactive oxygen species (ROS) generated by cytochrome P450 could be responsible for the initial steps of injury, but details are unknown. In conclusion, most of the mechanistic steps leading to idiosyncratic DILI remain unclear.

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Holothuria leucospilota polysaccharides alleviate liver injury via AMPK and NF-κB signaling pathways in type 2 diabetic rats

Zhao

Zhu

Zhao

et al. 2021

Journal of Functional Foods

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Circulating MicroRNAs as Novel Biomarkers of Drug-Induced Liver Injury in Humans

Cited by 4 publications

References 53 publications

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

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

Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues

Holothuria leucospilota polysaccharides alleviate liver injury via AMPK and NF-κB signaling pathways in type 2 diabetic rats

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