Critical Review of Gaps in the Diagnosis and Management of Drug-Induced Liver Injury Associated with Severe Cutaneous Adverse Reactions

Abstract

Drug-induced liver injury (DILI) encompasses the unexpected damage that drugs can cause to the liver. DILI may develop in the context of an immunoallergic syndrome with cutaneous manifestations, which are sometimes severe (SCARs). Nevirapine, allopurinol, anti-epileptics, sulfonamides, and antibiotics are the most frequent culprit drugs for DILI associated with SCARs. Interestingly, alleles HLA-B*58:01 and HLA-A*31:01 are associated with both adverse reactions. However, there is no consensus about the criteria used for the characterization of liver injury in this context, and the different thresholds for DILI definition make it difficult to gain insight into this complex disorder. Moreover, current limitations when evaluating causality in patients with DILI associated with SCARs are related to the plethora of causality assessment methods and the lack of consensual complementary tools. Finally, the management of this condition encompasses the treatment of liver and skin injury. Although the use of immunomodulant agents is accepted for SCARs, their role in treating liver injury remains controversial. Further randomized clinical trials are needed to test their efficacy and safety to address this complex entity. Therefore, this review aims to identify the current gaps in the definition, diagnosis, prognosis, and management of DILI associated with SCARs, proposing different strategies to fill in these gaps.

A diagnostic challenge: Life-threatening drug reaction with eosinophilia and systemic symptoms in the setting of a SARS-CoV-2 and human herpesvirus-6 reactivation in a patient with severe hepatic injury on bupropion

“… 5 Case reports of bupropion-induced liver injury have been documented, and liver injury in DRESS might be one variant of DILI as evidenced by our patient’s course. 6 , 7 …”

Hepatic Safety of Febuxostat and Allopurinol for Gout Patients: A Systematic Review of Randomized Controlled Trial

“…These reactions are commonly seen in cases of allopurinol liver injury accompanied by drug reaction with eosinophilia and systematic symptoms (DRESS syndrome) or Stevens Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN). 19,20,[39][40][41][42][43] An included study showed hepatobiliary disorders were experienced in allopurinol groups only for cholestasis (0.6%) and hepatotoxicity (0.6%) and assessed as severe in intensity. These liver abnormalities did not appear in the febuxostat groups.…”

Drug-Induced Severe Cutaneous Adverse Reactions: Insights Into Clinical Presentation, Immunopathogenesis, Diagnostic Methods, Treatment, and Pharmacogenomics

“…Similarly, aside from the causality assessment tools, there are no specific or collective tools available to evaluate SCARs in relation to liver injury. Because of this, less effective treatment for SCARs with systemic involvement may be chosen ( Villanueva-Paz et al, 2021 ).…”