Letter to the Editor: Hepatocellular pattern is compatible with fenbendazole-associated drug-induced liver injury

Abstract

We respond to Supple’s proposal, published in the World Journal of Clinical Cases, that liver injury following fenbendazole dose escalation in a patient receiving nivolumab/relatlimab represented immunogenic tumor-cell death. Marked aminotransferase elevation with modest alkaline phosphatase elevation is compatible with hepatocellular injury; neither this pattern nor an aspartate aminotransferase: alanine aminotransferase ratio near unity identifies its cause. The exposure history, improvement after withdrawal without corticosteroids, and subsequent tolerance of immunotherapy supported our original clinical interpretation of fenbendazole-associated drug-induced liver injury. Concurrent nosode exposure and possible immune-mediated or combination effects limit single-agent attribution. The reported R ratio and Roussel Uclaf Causality Assessment Method score cannot be independently verified from the available information; neither is presented here as an established error or a newly adjudicated result. Tumor necrosis was not demonstrated, although the reported investigations cannot exclude microscopic necrosis. These limitations do not establish anticancer benefit. The clinical priority remains evaluation of potentially serious liver injury and avoidance of deliberate diagnostic fenbendazole rechallenge.

Key Words: Fenbendazole; Drug-induced liver injury; Hepatocellular injury; Immune checkpoint inhibitor; Roussel Uclaf Causality Assessment Method; Tumor onconecrosis

Core Tip: Modest alkaline phosphatase elevation does not contradict hepatocellular drug-induced liver injury, and the aspartate aminotransferase:alanine aminotransferase ratio cannot establish tumor onconecrosis. Our original clinical assessment favored fenbendazole-associated injury on the overall course, with residual uncertainty from co-exposures. The reported R ratio and Roussel Uclaf Causality Assessment Method score remain unresolved verification needs rather than established errors; this limitation does not validate an alternative mechanism. Severe liver injury should prompt clinical evaluation and should not be interpreted as evidence of anticancer efficacy.

TO THE EDITOR

Our published case described severe liver injury following self-administration and dose escalation of fenbendazole during nivolumab/relatlimab therapy[1]. We thank Supple[2] for proposing an alternative explanation involving potentiated immunogenic tumor-cell death. Our clinical interpretation continues to favor fenbendazole-associated drug-induced liver injury (DILI) over that proposed explanation. Hence, this response aimed to clarify the distinction between a compatible injury phenotype, a probabilistic clinical attribution, and proof of a specific mechanism.

Hepatocellular biochemical pattern

At presentation, aspartate aminotransferase (AST) was 2435 U/L, alanine aminotransferase (ALT) 2407 U/L, alkaline phosphatase (ALP) 215 U/L (reported ULN 120 U/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) 1.52[1]. ALP was therefore approximately 1.79 times its ULN. Marked aminotransferase elevation with a relatively modest ALP elevation is compatible with hepatocellular injury[3]. Accordingly, the limited ALP elevation cannot be used to argue that hepatocellular DILI is biochemically implausible.

The normalized R ratio is calculated as (ALT/ALT ULN)/(ALP/ALP ULN), rather than the unnormalized ALT:ALP ratio. For the reported values, the expression is R = (2407/ALT ULN)/(215/120). The laboratory-specific ALT ULN is not provided in the material available for this correspondence; therefore, the reported R value of 11.2 cannot be independently verified. We do not conclude that this value is necessarily incorrect, substitute an assumed reference limit, or assign a revised numerical R value. This limitation does not establish that an AST:ALT ratio near unity distinguishes DILI from tumor necrosis. The biochemical findings are compatible with hepatocellular injury but do not, by themselves, identify fenbendazole as the responsible agent.

Clinical course and causality assessment

Symptoms began approximately seven weeks after fenbendazole initiation and one week after escalation from 222 mg three times weekly to 222 mg daily. ALT decreased from 2407 U/L to 527 U/L within approximately 10 days after withdrawal, without corticosteroids. Immunotherapy was subsequently reintroduced without recurrent liver injury. This observation contributed to our clinical interpretation but does not, by itself, exclude an immune-mediated contribution[4]. The exposure timing and improvement after withdrawal support the clinical suspicion of drug-associated injury but are components of the causality assessment rather than independent confirmation beyond the Roussel Uclaf Causality Assessment Method (RUCAM).

The original report assigned a RUCAM score of 8. The available information does not permit independent verification of the complete assessment, including the dechallenge and previous-hepatotoxicity components. These remain unresolved verification needs rather than established scoring errors. The 2016 updated RUCAM provides a framework for reviewing the reported allocations, but the version originally used requires confirmation[5]. We therefore report the historical score without assigning a revised total or causality category.

Evidence concerning tumor onconecrosis

Published fenbendazole-associated DILI includes a case with histologic findings of centrilobular hepatocyte injury and necrosis[6]. Its enzyme profile and recovery interval cannot define a mandatory signature for every subsequent case. The original report in our patient described computed tomography findings as largely similar to the preceding month[1]. The reported imaging does not demonstrate a major interval tumor response, but it cannot exclude focal or microscopic necrosis. Lactate dehydrogenase, uric acid, serial tumor markers, lesion-level necrosis assessment, and histology were not reported. We therefore make no claim of a negative metabolic or pathological evaluation. Missing investigations leave uncertainty; they do not supply affirmative evidence that immunogenic tumor-cell death caused this episode.

The checkpoint-related examples discussed by Supple concern albendazole, flubendazole, and mebendazole[2]. Dogra et al. did study fenbendazole directly and reported anticancer activity in experimental systems, including xenografts[7]. These findings align with our original distinction between preclinical activity and demonstrated clinical benefit. Neither these experiments nor an ivermectin analogy establishes fenbendazole–nivolumab/relatlimab efficacy or treatment-induced hepatic tumor necrosis in this patient. A hypothesis merits testing without being adopted as the explanation for the observed injury.

Patient safety

The reported bilirubin elevation and INR, together with marked aminotransferase elevation, establish a clinically concerning presentation[1,3]. We did not use Hy’s law to identify a specific culprit or to estimate individual mortality. Formal assessment requires the relevant laboratory reference limits and adequate consideration of competing causes. Regardless of the final causality score, deliberate fenbendazole re-exposure solely to resolve this diagnostic debate is not justified after clinically significant suspected DILI. Rechallenge can cause serious recurrent injury[8]. Fenbendazole is a veterinary anthelmintic not approved for human use[6].

Conclusion

Fenbendazole-associated DILI remains our favored clinical interpretation of the reported course, while co-exposure limits single-agent attribution and the reported R ratio and RUCAM score remain unverified. The available findings do not demonstrate fenbendazole-potentiated tumor onconecrosis or anticancer benefit. Clarifying limitations in causal attribution does not justify continuing or deliberately restarting a suspected nonessential exposure after serious liver injury.