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. 2023 Feb 6;5(1):otad005.
doi: 10.1093/crocol/otad005. eCollection 2023 Jan.

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Thiopurine Hepatotoxicity in Crohn's Disease

Alvin T George  1 , Matthew Glover  1 , Quazim Alayo  2 , Maria Zulfiqar  3 , Daniel R Ludwig  3 , Matthew A Ciorba  1 , Scott McHenry  1 , Parakkal Deepak  1
Affiliations

Nonalcoholic Fatty Liver Disease Is a Risk Factor for Thiopurine Hepatotoxicity in Crohn's Disease

Alvin T George et al. Crohns Colitis 360. .

Abstract

Background: Patients with Crohn's disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD.

Methods: In this prospective cohort analysis, CD patients at a single center were recruited 6/2017-5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF >5.5%. Statistical analysis was performed using a Cox-proportional hazards model.

Results: Of the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2-7.3, P = .018) independent of age, body mass index, hypertension, and type 2 diabetes. Steatosis severity by PDFF positively correlated with peak alanine aminotransferase (ALT) at follow-up. Kaplan-Meier analysis demonstrated poorer complication-free survival (log-rank 13.1, P < .001).

Conclusions: NAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy.

Keywords: Crohn’s disease; hepatotoxicity; nonalcoholic fatty liver disease; proton density fat fraction; thiopurine.

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Conflict of interest statement

A.T.G., M.G., Q.A., M.Z., D.R.L., and S.M.: nothing to disclose. M.A.C. participated in consulting, advisory board, or speaker’s bureau for AbbVie, Pfizer, Bristol Myers Squibb, and Theravance, and received funding under a sponsored research agreement unrelated to the data in the paper from Incyte, Pfizer, Janssen, and the Crohn’s and Colitis Foundation. P.D. holds the position of Associate Editor for Crohn’s & Colitis 360 and has been recused from reviewing or making decisions for the manuscript. Research support under a sponsored research agreement unrelated to the data in the paper and/or consulting from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Scipher Medicine, and CorEvitas, LLC. Writing assistance: none.

Figures

Figure 1.
Figure 1.
Patient selection. Abbreviations: MRE, magnetic resonance enterography; NAFLD, nonalcoholic fatty liver disease.
Figure 2.
Figure 2.
NAFLD and liver injury in patients taking thiopurines. NAFLD was significantly associated with elevated liver enzymes at follow-up in patients taking thiopurines (A, P = .002), and this remained true for those with persistent elevations (B, P < .001). This trend remained suggestive at greater magnitudes of ALT elevation (C, P = .051). The peak ALT level at follow-up was significantly greater in the NAFLD group than those without NAFLD (D, 43 vs 28 units L−1, P < .001). * indicates P < .05. Abbreviations: ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; ULN, upper limit of normal.
Figure 3.
Figure 3.
Peak ALT at follow-up or baseline CPN-CD as a function of baseline severity of hepatic steatosis in patients with Crohn’s disease. There was a direct association between peak ALT at follow-up (A) or baseline CPN-CD score (B) with baseline severity of hepatic steatosis. Abbreviations: ALT, alanine aminotransferase; CPN-CD, clinical prediction tool for nonalcoholic fatty liver disease in Crohn’s disease; PDFF, proton density fat fraction.
Figure 4.
Figure 4.
Baseline azathioprine dose and peak 6-methylmercaptopurine levels in patients with elevated liver enzymes at follow-up. Patients with elevated liver enzymes at follow-up were found to have similar baseline doses of azathioprine (A, P = .711) and peak 6-methylmercaptopurine (B, P = .486) levels. Mean denoted as “X.” Abbreviation: NAFLD, nonalcoholic fatty liver disease.
Figure 5.
Figure 5.
Complication-free survival on thiopurine therapy in patients with CD as a function of NAFLD (P < .001). Abbreviations: CD, Crohn’s disease; NAFLD, nonalcoholic fatty liver disease.
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