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Review
. 2021 Nov 15;10(22):5317.
doi: 10.3390/jcm10225317.

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

Marina Villanueva-Paz  1 , Hao Niu  1   2 , Antonio Segovia-Zafra  1   2 , Inmaculada Medina-Caliz  1 , Judith Sanabria-Cabrera  1   2   3 , M Isabel Lucena  1   2   3 , Raúl J Andrade  1   2 , Ismael Alvarez-Alvarez  1   2
Affiliations
Review

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

Marina Villanueva-Paz et al. J Clin Med. .

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.

Keywords: causality assessment; clinical trial; diagnosis; drug-induced liver injury; gaps; hypersensitivity; immune response; management; severe cutaneous adverse reactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immune system association in DILI with SCARs: The three main hypotheses regarding the immunological mechanisms involved in ADRs are: (1) The hapten hypothesis, (2) The pharmacological interaction (p-i) hypothesis, and (3) The altered peptide repertoire hypothesis.
Figure 2
Figure 2
Different GWAS-determined HLA alleles linked to the risk of developing ADRs. There are three main types of associations: Some overlap in HLA associations, where the same allele is linked to the risk of developing ADR due to different drugs (green boxes); HLA alleles that are shared by both SCARs and DILI and trigger both ADRs (pink boxes); and HLA alleles not shared by SCARs and DILI, where different ADRs due to the same drugs are linked to different HLA alleles (orange boxes). DILI, Drug-Induced Liver Injury; SCAR, Severe Adverse Cutaneous Reaction; ADR, Adverse Drug Reaction; GWAS, Genome-Wide Association Studies; HLA, Human Leukocyte Antigen; DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms; SJS, Stevens–Johnson Syndrome; TEN, Toxic Epidermal Necrosis.
Figure 3
Figure 3
Identified gaps in the pathway of diagnosis and management of DILI associated with SCARS. DILI, Drug-Induced Liver Injury; SCAR, Severe Adverse Cutaneous Reaction.
See this image and copyright information in PMC

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