title: Severe villus atrophy and chronic malabsorption induced by azathioprine.
abstract: Azathioprine is commonly prescribed for autoimmune hepatitis and inflammatory bowel disease. An acute gastroenteritis-like syndrome has been ascribed to azathioprine use, but chronic diarrhea has not. We report a patient with autoimmune hepatitis who developed severe small-bowel villus atrophy and chronic diarrhea after azathioprine was initiated (50 mg/day). We present a case report of a patient followed up prospectively. Duodenal mucosal histology and expression of brush border enzyme dipeptidyl peptidase IV and peptide transporter PepT1 messenger RNA levels were determined before and after azathioprine discontinuation. Chronic diarrhea developed several weeks after the initiation of azathioprine and resulted in micronutrient depletion and severe protein-calorie malnutrition, which was unresponsive to oral pancreatic enzyme therapy or a gluten-free diet. Severe malabsorption required parenteral nutrition support for longer than 1.5 years; this was complicated by unstable blood glucose control, acute calculous cholecystitis, catheter sepsis, and severe venous thrombosis. When the temporal association between azathioprine and diarrhea was identified, the drug was tapered while the patient consumed an unrestricted diet. Within 2 weeks after azathioprine was discontinued, diarrhea had completely resolved, and parenteral nutrition was discontinued. Mucosal biopsies obtained before and 4 months after azathioprine discontinuation showed complete reversal of severe duodenal villus atrophy and marked up-regulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient has subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for longer than 4 years. Azathioprine can induce severe small-bowel villus atrophy, diarrhea, and malabsorption that is reversible with drug discontinuation.
authors.affiliation: Department of Medicine, Center for Clinical and Molecular Nutrition, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA. tzieg01@emory.edu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ziegler
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández-Estívariz
authors.forename: Li H
authors.initials: LH
authors.lastname: Gu
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Leader
mesh_terms: D000328:Adult; D001284:Atrophy; D001379:Azathioprine / Q000009:adverse effects*; D002352:Carrier Proteins / Q000235:genetics; D002908:Chronic Disease; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D004386:Duodenum / Q000473:pathology*; D006801:Humans; D008286:Malabsorption Syndromes / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000074011:Peptide Transporter 1; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; C082186:SLC15A1 protein, human; D027981:Symporters; D018819:Dipeptidyl Peptidase 4; D001379:Azathioprine