Tissue biopsies and response to steroids suggest an immune-mediated cause for hepatotoxicity. (A) Liver biopsy specimens taken from a normal patient, an otherwise healthy patient with CLL, and a subject with persistent transaminitis after discontinuation of idelalisib. Liver biopsy specimens from patients with CLL demonstrate lymphoid aggregates on hematoxylin and eosin staining (composed of CD20⁺ B cells, data not shown) as well as increased CD3⁺ T cells scattered throughout the parenchyma that are increased in number and activation (as assessed by perforin staining) in a subject on idelalisib. (B) A duodenal biopsy specimen from a subject with diarrhea on idelalisib reveals an activated (perforin-positive) CD8⁺ lymphocytic infiltrate, which is not present in a control sample taken from a subject without CLL. (C) Transaminase levels over time for a subject who, after an unsuccessful attempt at idelalisib reintroduction, was successfully reintroduced to the drug while on steroids.