Acetaminophen syn. Paracetamol: Acute Liver Injury and Acute on Chronic Liver Failure with Case Analysis and Causality Assessment Using RUCAM

Teschke, Rolf

doi:10.1007/978-3-030-50983-5_12

Cited by 4 publications

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“…Consequently, patients with idiosyncratic DILI used their drugs commonly for some days, weeks, or months, while in the context of an acute intoxication the drug intake is mostly limited to one or two days exceeding the daily allowance of daily dose but can also develop after high cumulative drug doses taken over a longer period [ 6 , 7 ]. To facilitate an overview of drugs most implicated in DILI with verified diagnosis as assessed for causality using RUCAM, a list of selected drugs is provided in alphabetical order ( Table 1 ) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], with additional details published earlier [ 53 , 54 ].…”

Section: Definitionsmentioning

confidence: 99%

“…Antimetabolites include azathioprine, 6-mercaptopurine, and methotrexate. Data were partially derived from published reports [ 53 , 54 ] that provided case and RUCAM details for each drug implicated in DILI [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Of note, some drugs like acetaminophen, amiodarone, anabolic steroids, atorvastatin and other statins, azathioprine/6-mercaptopurine, methotrexate, and valproic acid, which basically cause intrinsic DILI, may also trigger idiosyncratic DILI if used in recommended doses.…”

Section: Definitionsmentioning

confidence: 99%

“…The risk of drugs causing human idiosyncratic DILI has been shown in abundant cases published worldwide and assessed for causality using RUCAM [ 1 ], conditions confirmed for selected drugs as listed with consideration of some drugs implicated in intrinsic DILI that were not assessed by RUCAM ( Table 1 ) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Therefore, molecular toxicology in human idiosyncratic and intrinsic DILI caused by the use of drugs are best studied in RUCAM based DILI cases.…”

Section: Definitionsmentioning

confidence: 99%

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Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Teschke

2023

IJMS

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Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.

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Section: Definitionsmentioning

confidence: 99%

Section: Definitionsmentioning

confidence: 99%

Section: Definitionsmentioning

confidence: 99%

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Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Teschke

2023

IJMS

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“…Thus, the conclusion was reached that the validity of these results is compromised and should be interpreted cautiously. APAP poisoning may cause life-threatening intrinsic DILI including ALF [167][168][169][170] with ascertained diagnosis through causality assessment using RUCAM [171], and experimentally reproducible in animals showing prolonged alcohol consumption as a risk factor [172,173]. DILI by APAP is triggered by exhaustion of the hepatic content of glutathione, a powerful antioxidant commonly scavenging ROS and the reactive intermediate N-acetyl-p-benzo quinone imine (NAPQI) (Table 3), a toxic metabolite of APAP [103].…”

Section: Magnesium Isoglycyrrhizinatementioning

confidence: 99%

“…The lavage method is also the approach commonly applied in intoxicated patients who ingested aliphatic halogenated hydrocarbons like carbon tetrachloride [178,179]. Since APAP is metabolically activated by CYP 2E1, the proposal has been made to inhibit this CYP isoform by intravenous application of cimetidine as soon as the intoxication is verified by actual exploration [171]. Whether charcoal depuration through application of carbo medicinalis via a nasogastric tube in patients intoxicated with APAP is effective remains to be established [112].…”

Section: Magnesium Isoglycyrrhizinatementioning

confidence: 99%

Treatment of Drug-Induced Liver Injury

Teschke

2022

Biomedicines

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Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

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Severe DILI in a Patient under Polypharmacy Including Rosuvastatin: Diagnostic Challenges and Lessons from a Case Report Assessed Using the Updated RUCAM Algorithm

Díaz-Orozco

Quiroz-Compean

Aquino-Matus

et al. 2022

IJGHD

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Background: Drug-induced liver injury (DILI) and the causative drug in patients under polypharmacy medication represent a challenging diagnosis. Case reporT: A 73 years old multimorbid man receiving polypharmacy, including rosuvastatin among other drugs, presented with high values of alanine aminotransferase (950 U/L) and aspartate aminotransferase (702 U/L), associated with a normal value of alkaline phosphatase (46 U/L), which turned out as DILI due to the hepatocellular injury type with an R-value of 29.8 as calculated from liver test values. Causality for each drug was assessed using the updated RUCAM (Roussel Uclaf Causality Assessment Method) prospectively. Causality for rosuvastatin and diltiazem was highly probable based on a RUCAM score of 9, but no reports of DILI caused by diltiazem were found. In addition, the causality grade for other drugs included in the patient’s medication was “probable” based on a RUCAM score of 6 to 8. The patient experienced a favorable outcome after discontinuation of all medication. Discussion: The medication history, as well as the prospective and proactive causality evaluation by the updated RUCAM, helped establish the diagnosis of severe DILI by two highly suspected causative drugs, considering also several drugs with a “probable” causality grade in this case. Statins may cause direct damage to the liver, interact with other drugs, and enhance the susceptibility to DILI caused by commonly safe drugs. Conclusion: In this case, the DILI was caused by rosuvastatin as evidenced by a high score in the updated RUCAM, but a large number of comedications may have a co-triggering effect.

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Acetaminophen syn. Paracetamol: Acute Liver Injury and Acute on Chronic Liver Failure with Case Analysis and Causality Assessment Using RUCAM

Cited by 4 publications

References 73 publications

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

Treatment of Drug-Induced Liver Injury

Severe DILI in a Patient under Polypharmacy Including Rosuvastatin: Diagnostic Challenges and Lessons from a Case Report Assessed Using the Updated RUCAM Algorithm

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