Treatment of Drug-Induced Liver Injury

Abstract

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.

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

“…Finally, and in support of the immune involvement, DIAIH responds well to the immune modulatory action of glucocorticoid treatment without relapse after treatment cessation, whereas relapse in genuine AIP is common in and characteristic for this disease [ 130 , 134 ]. Interesting is the fact that that glucocorticoids are only partially effective in treating unselected idiosyncratic DILI caused by various drugs as a whole DILI cohort, suggesting that not all DILI cases are triggered by immune mechanisms [ 141 ] in line with previous proposals [ 70 ].…”

“…In this context, there is also uncertainty how inflammatory mediators interact with parenchymal and non-parenchymal cells of the liver and how immunological processes affect the liver histology, function and integrity of liver mitochondria and bile salt export pumps (BSEP) [ 70 ]. There are no evidence-based data on the possible role of ferroptosis and pyroptosis [ 141 ] for the hepatic immune system in idiosyncratic DILI with established diagnosis using RUCAM.…”

Analysis of medical malpractice liability disputes related to novel antineoplastic drugs and research on risk prevention and control strategies

“…The two HBVr cases cited above have been confirmed by judicial institutions as HBVr, but given that a large number of DILI cases are attributed erroneously to nondrug alternative causes, the lack of RUCAM evaluation results should not be disregarded [ 46 ]. We recommend conducting RUCAM assessments on patients with liver function injury.…”

“…Case 10 was unable to be re-evaluated with RUCAM because liver function data was not published in the court documents. Current pharmacotherapy options of DILI remain under discussion, but the use of the offending drug must be stopped as soon as DILI is suspected [ 46 ]. Therefore, it is important to clarify the DILI diagnosis.…”

Lansoprazole Ameliorates Isoniazid-Induced Liver Injury

“…Drug-induced liver injury (DILI) is the most common cause of acute liver failure in developed countries [ 1 ]. The diagnosis, treatment, and prevention of DILI remain a challenge [ 2 , 3 , 4 ].…”