Early Hepatic Nodular Hyperplasia and Submicroscopic... : The American Journal of Surgical Pathology (original) (raw)

Original Article

Early Hepatic Nodular Hyperplasia and Submicroscopic Fibrosis Associated With 6-Thioguanine Therapy in Inflammatory Bowel Disease

Geller, Stephen A MD*; Dubinsky, Marla C MD†; Poordad, F Fred MD‡; Vasiliauskas, Eric A MD§; Cohen, Arthur H MD*; Abreu, Maria T MD§; Tran, Tram MD‡; Martin, Paul MD‡; Vierling, John M MD‡; Targan, Stephan R MD§

From the *Department of Pathology and Laboratory Medicine; †Division of Gastroenterology, Department of Pediatrics; ‡Section of Hepatology, Division of Gastroenterology, Department of Medicine; and §Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Reprints: Stephen A. Geller, MD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 (e-mail: [email protected]).

Abstract

Background

6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease.

Methods

We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson’s trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy.

Results

In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction.

Conclusions

6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.