Bad Medicine: New Data Aim to Limit Drug Hepatotoxicity

Hepatotoxicity Due to ICIs

Immune checkpoint inhibitors (ICIs) are commonly used, effective anticancer drugs; however, they have the potential to cause liver injury, which may limit their use. Although patients treated with ICIs may be reluctant to halt treatment, liver failure is rarely reported. Is it possible to predict, characterize, and manage hepatotoxicity associated with ICIs to derive maximum therapeutic benefits while minimizing liver injury?

To address this question, Abu-Sbeih and colleagues^[2] conducted a study to characterize the clinical features and outcomes of patients with ICI-related hepatotoxicity at a tertiary cancer center. Adult patients (n = 5762) who received ICIs (cytotoxic T lymphocyte-associated protein-4 [CTLA-4], programmed death protein-1 and its ligand [PD-1/L1], or their combination) were identified.

One hundred participants exhibited either moderate (n = 85) or severe (n = 15) ICI hepatotoxicity, defined as an elevation in alanine aminotransferase (ALT) after ICI initiation in the absence of a competing etiology. Only 5% of affected patients had concurrent jaundice. The median number of ICI infusions before the onset of hepatotoxicity was three, and the mean interval from ICI initiation to hepatotoxicity was 57 days for CTLA-4, 85 days for PD-1/L1, and 56 days for combination therapy. The investigators found no association between the severity of hepatotoxicity and ICI class or the presence of preexisting liver disease.

Hepatotoxicity in 67 patients was treated with steroids, with or without mycophenolate mofetil. Mean duration from the recognition of hepatotoxicity to improvement of ALT to less than three times the upper limit of normal was 29 days for patients who received immunosuppression and 24 days for those who did not. ICI hepatotoxicity, although rarely clinically significant, led to permanent discontinuation of ICI treatment in 69 patients, and 31 patients received ICI therapy after hepatotoxicity had resolved. Seven of 25 patients who received anti–PD-1/L1 redeveloped hepatotoxicity, as did one of six who received anti–CTLA-4.

The investigators conclude that prompt recognition and drug withdrawal may be key to minimizing liver injury resulting from ICIs.

Genetic Risk Factors for Idiosyncratic DILI

Watkins and colleagues^[3] set out to identify susceptibility variants associated with idiosyncratic DILI. To do so, they used the largest existing multiethnic cohort of patients registered with DILI due to a variety of drugs or herbal and dietary supplements.

The investigators identified and replicated a genome-wide significant association with rs2476601, a nonsynonymous polymorphism (Trp620Arg) in the gene PTPN22. The minor allele frequency of this variant differed by ethnicity but showed the same effect size across ethnic groups. The strongest association was in European persons whose DILI was associated with amoxicillin-clavulanate. In this cohort, rs2476601 doubled the DILI risk in persons carrying the known HLA risk alleles A*02:01 and DRB1*15:01, but was not a risk factor in those not carrying the HLA risk alleles. In addition, the HLA-C*04:01 allele was identified as a potential DILI risk factor across ethnicities and agents.

The investigators state that this single-nucleotide polymorphism in the gene PTPN22 is the first confirmed non-HLA, genome-wide association study-significant variant associated with DILI risk due to many drugs. Because this variant has also been associated with increased risk for numerous autoimmune diseases, these findings further support the importance of immune mechanisms in idiosyncratic DILI.

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