title: Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.
abstract: BACKGROUND
  Although tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study.
  
  
  METHODS
  We reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH.
  
  
  RESULTS
  We identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS).
  
  
  CONCLUSIONS
  Our findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.
authors.affiliation: aDivision of Gastroenterology and Hepatology bDivision of Rheumatology cDepartment of Pathology, VA North Texas Healthcare System dDivision of Digestive and Liver Diseases eDivision of Rheumatology fDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Feagins
authors.forename: Avegail
authors.initials: A
authors.lastname: Flores
authors.forename: Cristina
authors.initials: C
authors.lastname: Arriens
authors.forename: Christina
authors.initials: C
authors.lastname: Park
authors.forename: Terri
authors.initials: T
authors.lastname: Crook
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimold
authors.forename: Geri
authors.initials: G
authors.lastname: Brown
mesh_terms: D001685:Biological Factors / Q000627:therapeutic use*; D001706:Biopsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D000637:Transaminases / Q000097:blood; D016896:Treatment Outcome; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000097:blood
chemical_list: D001685:Biological Factors; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D000637:Transaminases