Drug-Induced Liver Injury: Highlights of the Recent Literature

Real, Mark; Barnhill, Michele; Higley, Cory; Rosenberg, Jessica J.; Lewis, James H.

doi:10.1007/s40264-018-0743-2

Cited by 96 publications

(82 citation statements)

References 166 publications

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“…This problem still haunts the LiverTox database because many assumed DILI cases, which had not been submitted to established causality assessments, are included and presented as DILI reference cases [2][3][4]. Therefore, other approaches, such as diagnostic algorithms and biomarkers, merit further attention [5][6][7].…”

Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

“…Intrinsic DILI is caused by drug overdose, with paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP, Tylenol ® ) as the most common drug responsible [5][6][7][36][37][38][39][40][41][42][43]. Occasionally, other drugs like amiodarone, anabolic steroids, cyclosporine, valproic acid, heparins, nicotinic acid, methotrexate, and tacrine have also been assumed to cause intrinsic DILI, with rare acute intoxications.…”

Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

“…Chances to uncover diagnostic biomarkers are better if high amounts of a drug cause intrinsic DILI as compared with idiosyncratic DILI, for which a drug is prescribed in normal dosages [14]. Numerous mechanistic pathways have been explored to determine potential diagnostic biomarkers [5][6][7]28,[46][47][48][49][50]. However, questions have been raised as to whether specific diagnostic biomarkers in patients with suspected DILI by paracetamol are really needed clinically if the case evaluation included the common medical practice of using RUCAM [40].…”

Section: Diagnostic Biomarkersmentioning

confidence: 99%

“…Paracetamol protein adducts in the serum and urinary biomarkers have also been considered of some clinical value in suspected DILI cases possibly initiated by paracetamol overdose [5][6][7][52][53][54][55][56][57]. It seems, however, that urinary mercapturic or GSH-NAPQI (N-acetyl-p-benzoquinonimine) adducts are the preferred biomarkers as they appear before serum protein adducts are detected.…”

Section: Diagnostic Biomarkersmentioning

confidence: 99%

“…Shortcomings of correct diagnoses are published for Internal Medicine and viewed as a crucial major problem [1] and are also relevant specifically for Hepatology [2,3] regarding drug induced liver injury (DILI) and herb induced liver injury (HILI) [4]. These challenges require efforts to close gaps between expectations and true medical care quality as suggested by experts in the field [5][6][7][8]. Expectations in clinical medicine are high, asking for excellent diagnoses as the basis for appropriate therapies.…”

Section: Introductionmentioning

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: Critical Issues In Clinical Settingsmentioning

confidence: 99%

Section: Critical Issues In Clinical Settingsmentioning

confidence: 99%

Section: Diagnostic Biomarkersmentioning

confidence: 99%

Section: Diagnostic Biomarkersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 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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Clinical Interpretation of Analytical Results

2020

Fundamentals of Analytical Toxicology

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Hepatoprotective effects of Juglans regia on carbon tetrachloride‐induced hepatotoxicity: In silico/in vivo approach

Pandey,

Thapa,

Kaundinnyayana

et al. 2024

Food Science & Nutrition

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Juglans regia L. is a well‐known therapeutic plant in Nepal, employed in traditional medicine for treating liver ailments. This study aimed to evaluate the in vivo and in silico liver‐protective effects of J. regia extract using a carbon tetrachloride (CCl4)‐induced hepatic damage rat model. Healthy male rats were randomly divided into six groups: normal control (distilled water 10 mL/kg), toxic control (distilled water 10 mL/kg), standard test (silymarin 100 mg/kg), and three groups receiving oral J. regia extracts (125, 250, and 500 mg/kg/day) for seven days. On the eighth day, carbon tetrachloride (CCl4) was administered intraperitoneally (i.p.) (1.5 mL/kg in 1:1 olive oil ratio for all groups, except the normal control). Rats were sacrificed on the ninth day, and blood was collected retro‐orbitally for liver blood injury tests and histopathological studies. Molecular docking was performed against cytochrome P450 2E1 (CYP450 2E1) enzyme for 16 selected phytoconstituents. J. regia, at doses of 125, 250, and 500 mg/kg, significantly reduced liver enzyme levels (alanine aminotransferase, alkaline phosphatase, direct bilirubin, and total bilirubin), while increasing serum albumin. Histological analysis revealed mitigation of carbon tetrachloride (CCl4)‐induced liver injury, reducing fatty degeneration and necrosis. Molecular docking supported the findings, with Beta‐sitosterol and Betulinic acid exhibiting the best binding affinity of −9.2 and −9.1 kcal/mol, respectively. In conclusion, result suggests that J. regia showed dose‐dependent hepatoprotective activity in CCl4‐induced hepatotoxicity and it could be utilized as a promising hepatoprotective agent. This study suggests the hepatoprotective potential of J. regia bark extracts, emphasizing the need for further clinical validation.

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Drug-Induced Liver Injury: Highlights of the Recent Literature

Cited by 96 publications

References 166 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

Clinical Interpretation of Analytical Results

Hepatoprotective effects of Juglans regia on carbon tetrachloride‐induced hepatotoxicity: In silico/in vivo approach

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