Drug-induced liver injury: Summary of a single topic clinical research conference

Watkins, Paul B.; Seeff, Leonard B.

doi:10.1002/hep.21095

Cited by 259 publications

(202 citation statements)

References 104 publications

(116 reference statements)

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“…Other new technologies for predicting hepatotoxicity related to transcriptomics, proteomics and metabolomics may emerge [11,22].…”

Section: Cytochrome P450mentioning

confidence: 99%

“…In a few patients with DDS hepatotoxicity signs of hypersensitivity such as peripheral and hepatic eosinophilia and autoimmune parameters such as antinuclear antibodies, antimitochondrial antibodies, smooth muscle antibodies, anti-liver kidney microsome (LKM)-1 and anti-LKM-2 are present, but their use as surrogate markers has not yet been sufficiently validated [10,22].…”

Section: Immunological Featuresmentioning

confidence: 99%

“…These include misdiagnosis through inappropriate causality assessment by the practising and hospital physicians [2,48] and the regulatory agencies [6] with insufficient documented cases in databases [1,6], differences in causality assessment of identical cases between various national drug regulatory agencies [6], the installation of expert groups that may differ in their causality assessments [22,55], problems of interest between manufacturers and regulatory agencies [25], and insufficient causality assessment by case reports published in scientific journals [6,56]. The main test and post test as frameworks for causality assessment in DDS hepatotoxicity are therefore of benefit for patients, the health communities, manufacturers and drug regulatory agencies, recognizing early and minimizing consecutively the risks of hepatotoxicity and ALF by DDS.…”

Section: Prosmentioning

confidence: 99%

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Causality assessment in hepatotoxicity by drugs and dietary supplements

Teschke

Schwarzenboeck

Hennermann

2008

Brit J Clinical Pharma

147

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Structured causality assessment of hepatotoxicity by drugs and dietary supplements (DDS) is a major clinical challenge, since temporal associations as the sole criteria for a valid evaluation are not acceptable. Initially, a clear intuition for an ad hoc evaluation is necessary, but only provisional, and must be followed by a diagnostic algorithm using a pretest, main test and post test. The evaluation is based on a variety of items such as latency period, course of alanine aminotransferase and alkaline phosphatase after DDS discontinuation, risk factors, co-medication, previous information on hepatotoxicity of the DDS, response to rechallenge, and exclusion of other diseases. It is essential that practising and hospital physicians as well as other key health professionals, such as pharmacists, gather all information required for a sound causality assessment, obviating major discussions by expert panels, manufacturers and health agencies in face of scanty and fragmentary data. Because pharmacogenetic alterations may trigger metabolic hepatotoxicity by a few DDS, levels in plasma and urine should be measured and may be helpful for diagnosis. Concomitant genotyping of cytochrome P450 and other enzymes may also be useful in future to minimize the risk of unwanted side-effects, including toxic liver disease elicited by DDS. Hepatotoxicity is a rare, unpredictable and inherent risk associated with the use of various drugs and dietary supplements (DDS) at recommended doses [1][2][3][4][5][6][7][8][9], and several excellent reviews have covered the broad spectrum of DDS hepatotoxicity [10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Potentially hepatotoxic drugs include prescribed and over-the-counter medications, which are intensively studied before marketing both experimentally and in several thousands of healthy persons and patients regarding unwanted sideeffects, including hepatotoxicity [24,25]. Nevertheless, rare toxic liver injury cannot be excluded with certainty, as after marketing hepatotoxic reactions occur, for example, in 1:10 000 patients treated for specific diseases [11,18]. Moreover, there is little if any legal regulation of dietary supplements, which comprise a basket of herbs and teas as botanical supplements and weight loss supplements containing herbs and various substances [26][27][28][29][30][31][32]. In face of > 1100 potentially hepatotoxic drugs [17] and the emerging consumption of dietary supplements [13,26], DDS hepatotoxicity has a major impact not only on morbidity, including hospitalization, disability and liver transplantation, but also on mortality, liability and litigation.Early recognition and comprehensive documentation of DDS hepatotoxicity is mandatory at all stages of the disease, but current procedures for efficient, transparent and impartial causality assessment in suspected DDS hepatotoxicity are inadequate. At present, practising and hospital physicians, expert groups, manufacturers and healthcare agencies each use their own individual causality approach, open to dis...

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“…Other new technologies for predicting hepatotoxicity related to transcriptomics, proteomics and metabolomics may emerge [11,22].…”

Section: Cytochrome P450mentioning

confidence: 99%

Section: Immunological Featuresmentioning

confidence: 99%

Section: Prosmentioning

confidence: 99%

See 1 more Smart Citation

Causality assessment in hepatotoxicity by drugs and dietary supplements

Teschke

Schwarzenboeck

Hennermann

2008

Brit J Clinical Pharma

147

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“…These intracellular events explain the massive cell death and liver failure observed after paracetamol poisoning [17] . The recent observation that paracetamol toxicity is modulated by CAR gives rise to new concepts that are important for the general understanding of druginduced liver injury [78] . Accordingly, the presence of gene polymorphisms may explain inter-individual differences in susceptibility to paracetamol toxicity.…”

Section: Direct Toxicitymentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

125

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Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O 2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca 2+ -dependent ATPase, reduced capability to sequester Ca 2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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“…A majority of drugs are safe and do not cause significant liver injury ( 1,2 ) or may only produce asymptomatic elevation of liver tests. Occasionally, however, drugs produce clinically significant liver injury ( 3 ), resulting in either cessation of treatment regimen, morbidity, or mortality. Furthermore, liver injury secondary to drugs is an important cause of termination in clinical trials and a major cause of drug withdrawal after marketing ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality

Devarbhavi

Dierkhising

Kremers

et al. 2010

American Journal of Gastroenterology

209

190

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Although drug-induced liver injury (DILI) is rare, it may result in signifi cant morbidity or death. The causes and outcome vary according to regions, with acetaminophen and complementary medicines common in the West and the Far East, respectively. This study evaluates the causes, outcomes, predictors, and models for 90-day mortality from DILI from India. METHODS:Consecutive patients with DILI from 1997 to 2008 based on International Consensus Criteria from a medical college hospital setting were studied. RESULTS:Of the 313 patients, 58 % were males. Leading causes were a combination of four anti-tuberculous drugs (ATDs) (58 % ), anti-epileptics ( SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

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Drug-induced liver injury: Summary of a single topic clinical research conference

Cited by 259 publications

References 104 publications

Causality assessment in hepatotoxicity by drugs and dietary supplements

Causality assessment in hepatotoxicity by drugs and dietary supplements

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Single-Center Experience With Drug-Induced Liver Injury From India: Causes, Outcome, Prognosis, and Predictors of Mortality

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