Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use

Abstract

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.

Idiosyncratic DILI: Immunology in Cases with Evidence Based on RUCAM

“…Additional strong evidence for the involvement of the immune system in the development of iDILI was provided byantibodies against CYP isoformsfound in the serum of patients with RUCAM based iDILI due to a limited number of drugs: sevoflurane and deflurane (Table 2) [44][45][46].…”

“…Nicoll, 2012 45] Bishop, 2019 [46] This table is derived from a previous open access article [44]. Abbreviations: CYP, Cytochrome P450; DILI, drug-induced liver injury; RUCAM, Roussel Uclaf Causality Assessment Method; TFA, Trifluoroacetyl.…”

“…obtained for sevoflurane and desflurane, another modern volatile anesthetic, whereby sevoflurane was used mostly alone and rarely combined with desflurane [46]. Five patients with iDILI reached a RUCAM score of ≥6, and serum anti-CYP 2E1 antibodies were found in three patients with RUCAM scores of 12, 7, and 6, whereas in two patients with RUCAM scores of 12 and 7, anti-CYP 2E1 antibodies were not detected in the serum [44][45][46].As a result, only part of the RUCAM based iDILI cases were associated with these antibodies, while additional analysis revealed that anti-CYP 2E1 antibodies were detected unexpectedly in patients, who were exposed to the anesthetics but did not fulfill the RUCAM criteria of iDILI, thereby not providing a homogenous antibody picture [44,46]. Besides, the data of this analysis are highly appreciated as of robust quality andsince the evaluating group published an excellent external interrater performance for their use of RUCAM [46] confirming previous reports on external interrater qualification in favor of RUCAM [49,50] and on internal interrater performance [6].…”

“…For reasons of completeness, other drugs are to be mentioned, because they function as known substrates of hepatic microsomal CYP isoforms, are metabolized by CYPs, and can trigger suspected iDILI, but none of these iDILI cases received the benefit of causality assessment by RUCAM [44], a major flaw in face of many alternative causes not related to drug treatment (Table 1) [37,38]. Among the drugs under critical discussion are halothane (causing serum anti-CYP 2E1 antibodies) [51][52][53][54][55][56][57], isoflurane (anti-CYP 2E1) [57], isoniazid (anti-CYP 2C9) [48], dihydralazine (anti-CYP 1A2), tienilic acid (anti-CYP 2C9), and antiepileptics (anti-CYP 3A) [51].…”

“…The association of serum anti-CYP isoforms with iDILI by sevoflurane and desflurane suggests an immunological involvement in this process but not necessarily a causal immune relationship between CYP and the liver injury [44]. In fact, liver injury by drugs such as sevoflurane and desflurane is also associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates [45,46] that form protein adducts and may generate free radicals, known as reactive oxygen species (ROS) [45,[57][58][59].…”