Abstract:Background
Drug induced liver injury (DILI) is a rising morbidity amongst patients with COVID-19 clinical syndrome. The updated RUCAM causality assessment scale is validated for use in the general population, but its utility for causality determination in cohorts of patients with COVID-19 and DILI remains uncertain.
Methods
This retrospective study was comprised of COVID-19 patients presenting with suspected DILI to the emergency department of Weill Cornell medicine-affiliated Hamad General Hospital, Doha, Q… Show more
“…The top drugs causing RUCAM-based DILI worldwide have been assessed as to whether they were metabolized through CYP isoforms [62]. Literature provided highquality data on clinical features of DILI [1][2][3][4][5][6][7][8][9][10][16][17][18][19][20][21][22][23][24][25][26][27][28]39,64]. However, although most of the clinical features are well established, a variety of mechanistic steps remain unresolved in this complex disease.…”
Section: Basics Of Molecular and Mechanistic Toxicology In Dilimentioning
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.
“…The top drugs causing RUCAM-based DILI worldwide have been assessed as to whether they were metabolized through CYP isoforms [62]. Literature provided highquality data on clinical features of DILI [1][2][3][4][5][6][7][8][9][10][16][17][18][19][20][21][22][23][24][25][26][27][28]39,64]. However, although most of the clinical features are well established, a variety of mechanistic steps remain unresolved in this complex disease.…”
Section: Basics Of Molecular and Mechanistic Toxicology In Dilimentioning
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.
“…In a cohort of 72 patients, they found that RUCAM-based assessment had high inter-rater agreement and reliability, concluding that RUCAM was successful and useful in determining possible or probable cases of DILI in patients with COVID-19. 35 They also noted that 91.6% of these DILI cases were due to antimicrobial medications. 35 This risk of iatrogenic liver injury serves as a reminder of the risk which must be fully understood, and balanced against potential benefit, when it comes to selecting and utilizing medications in the setting of SARS-CoV-19 infection ( Figure 2 ).…”
Section: Dili and Covid-19mentioning
confidence: 99%
“… 35 They also noted that 91.6% of these DILI cases were due to antimicrobial medications. 35 This risk of iatrogenic liver injury serves as a reminder of the risk which must be fully understood, and balanced against potential benefit, when it comes to selecting and utilizing medications in the setting of SARS-CoV-19 infection ( Figure 2 ). Figure 2 Suspected etiologies of hepatobiliary injury.…”
Section: Dili and Covid-19mentioning
confidence: 99%
“…Naseralallah et al also delved into the uncertainty surrounding elevated liver enzymes in the setting of COVID-19, noting that many different combinations of medications were used to treat COVID-19 infection, especially early in the pandemic. 35 This recent study assessed the effectiveness of the updated RUCAM analysis in determining DILI in cases of CALI. In a cohort of 72 patients, they found that RUCAM-based assessment had high inter-rater agreement and reliability, concluding that RUCAM was successful and useful in determining possible or probable cases of DILI in patients with COVID-19.…”
This review analyzes data regarding liver injury associated with COVID-19 infection. We discuss reported effects on the liver from both COVID-19 and COVID-19 treatment as well as pathophysiology, review the potential role of drug-induced liver injury as an etiology of COVID-19-associated liver injury, and touch on other reports of significant outcomes including COVID-19 cholangiopathy and autoimmune hepatitis. Finally, we review the implications of COVID-19 infection in liver transplant recipients.
“…22 While the transaminitis may reflect direct liver injury other factors might also contribute including an associated immune-related inflammatory response, congestive hepatopathy, hepatic ischaemia, venous and arterial thrombosis, muscle breakdown, and drug-induced liver injury, including use of specific experimental COVID-19 treatments, such as lopinavir-ritonavir and tocilizumab, and complementary or alternative medicines. 3,[22][23][24][25]…”
Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, other organs, such as the liver, are also affected. In this overview, the effects of SARS-CoV-2 infection on the liver in both healthy people and in those with pre-existing liver disease are documented; the relationship between coronavirus disease 19 (COVID-19) vaccination and liver injury is examined; the mechanism of SARS-CoV-2-associated liver injury is explored; and the long-term consequences of COVID-19 are delineated, both in people with and without pre-existing liver disease.
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