SOCIETY STATEMENT Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees ÃLawrence J. Saubermann, yMark Deneau, zRichard A. Falcone, §Karen F. Murray, jjSabina Ali, ôRohit Kohli, #Udeme D. Ekong, ÃÃPamela L. Valentino, yyAndrew B. Grossman, yyzzElizabeth B. Rand, ÃÃMaureen M. Jonas, ôShehzad A. Saeed, and §§Binita M. Kamath ABSTRACT Hepatobiliary disorders are common in patients with inflammatory bowel epatobiliary disorders are common in patients with inflamma- disease (IBD), and persistent abnormal liver function tests are found in H tory bowel disease (IBD), and persistent abnormal liver enzyme approximately 20% to 30% of individuals with IBD. In most cases, the cause tests are found in approximately 20% to 30% of individuals with IBD of these elevations will fall into 1 of 3 main categories. They can be as a (1–4). In most cases, the cause of these elevations will fall into 1 of 3 result of extraintestinal manifestations of the disease process, related to main categories. They can be a result of extraintestinal manifestations medication toxicity, or the result of an underlying primary hepatic disorder of the disease process, related to medication toxicity, or the result of an unrelated to IBD. This latter possibility is beyond the scope of this review underlying primary hepatic disorder unrelated to IBD (Table 1). This article, but does need to be considered in anyone with elevated liver function latter possibility is beyond the scope of this clinical report, but does tests. This review is provided as a clinical summary of some of the major need to be considered in anyone with elevated liver enzyme levels. This hepatic issues that may occur in patients with IBD. report is provided as a clinical summary of some of the major hepatic issues that may manifest in patients with IBD. Key Words: autoimmune hepatitis, Crohn disease, hepatitis, inflammatory bowel disease, primary sclerosing cholangitis, ulcerative colitis Extraintestinal Associations of Inflammatory (JPGN 2017;64: 639–652) Bowel Disease Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is a chronic, progress- Received October 21, 2016; accepted December 8, 2016. ive, cholestatic liver disease. It is characterized by inflammation From the ÃDivision of Pediatric Gastroenterology and Nutrition, Golisano and fibrosis of the entire biliary tree, with multifocal bile duct Children’s Hospital, University of Rochester, Rochester, NY, the strictures. PSC is rare in the general pediatric population, with an y Division of Pediatric Gastroenterology, University of Utah, Salt Lake incidence and prevalence of 0.2 and 1.5 cases per 100,000 children, City, the zDivision of Pediatric General and Thoracic Surgery, Cincin- nati Children’s Hospital Medical Center, Cincinnati, OH, the §Division respectively (5). The majority of PSC cases appear concurrently of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hos- with IBD, particularly ulcerative colitis (UC) (6,7). The proportion pital, Seattle, WA, the jjDivision of Pediatric Gastroenterology, Stanford of patients with IBD with PSC varies and is most often reported to Children’s Health, Palo Alto, CA, the ôDivision of Pediatric Gastro- be 4% or less (6,8,9). Study designs vary greatly and may under- enterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital estimate the true prevalence, however. Rates of PSC in IBD are 10% Medical Center, Cincinnati, OH, the #Section of Pediatric Gastroenter- to 25% in series that are population based, that have longer follow- ology and Hepatology, Yale University School of Medicine, New Haven, up (10), or where groups of patients are screened with liver biopsy CT, the ÃÃDivision of Gastroenterology, Hepatology, and Nutrition, and/or cholangiography regardless of symptoms (11,12). Boston Children’s Hospital, Harvard Medical School, Boston, MA, the Intestinal inflammation in a patient with PSC may represent a yyDivision of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, the zzPerelman School of Medicine, University unique phenotype of IBD, termed PSC-IBD (7). PSC-IBD is charac- of Pennsylvania, Philadelphia, PA, and the §§Division of Gastroenter- terized by more frequent pancolitis with rectal sparing, and a higher ology, Hepatology, and Nutrition, The Hospital for Sick Children, incidence of backwash ileitis compared with UC (7). Patients with University of Toronto, Toronto, Canada. Crohn disease (CD) and PSC are more likely to have Crohn colitis Address correspondence and reprint requests to Lawrence J. Saubermann, (7,13–15). The IBD activity of PSC-IBD may be less severe (15,16), MD, FACG, AGAF, Chief, Division of Pediatric Gastroenterology and with a lower rate of colectomy (17). Patients with PSC-IBD are, Nutrition, Director, Pediatric Clinical Research Office, Golisano however, at much greater risk of colorectal carcinoma (18), and have Children’s Hospital, University of Rochester Medical Center, 601 a worsened overall survival compared with patients with traditional Elmwood Ave, Box 667, Rochester, NY 14642 UC (7). In addition, pouchitis is more common in PSC-IBD after (e-mail: [email protected]). colectomy with ileal pouch-anal anastomosis surgery (19,20). The authors report no conflicts of interest. Copyright # 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Diagnosis Gastroenterology, Hepatology, and Nutrition. The diagnosis of PSC is based on a cholestatic serum DOI: 10.1097/MPG.0000000000001492 biochemical profile with characteristic changes on liver histology JPGN Volume 64, Number 4, April 2017 639 Copyright © ESPGHAL and NASPGHAN. All rights reserved. Saubermann et al JPGN Volume 64, Number 4, April 2017 TABLE 1. Hepatobiliary issues to consider in patients with inflamma- years of PSC diagnosis (3). The 5-year survival with the native liver tory bowel disease is approximately 80% (5,25,26). PSC is one of the most important sources of morbidity and mortality for pediatric patients with IBD. Extraintestinal manifestations: In a population-based study of more than 600 pediatric patients with Immune-related: IBD followed for a median of approximately 6 years, 8 deaths or Primary sclerosing cholangitis liver transplants were related to PSC, 2 deaths were from hema- Autoimmune hepatitis tologic malignancy, and only 1 death was secondary to compli- Autoimmune sclerosing cholangitis cations of intestinal disease (colorectal cancer [CRC]) (5). Thrombotic disorders: Portal vein thrombosis Treatment Venous thromboembolism Treatment of PSC is mainly supportive and palliative. Bile Hepatic vein thrombosis acids and antimicrobials have received the most attention and Medication Toxicity: clinical use, and are discussed below. Several medicines have been Glucocorticoids shown to improve liver biochemistry with prolonged therapy, but no Sulfasalazine drug has been proven to alter the natural history of the disease. Liver Thiopurines transplantation (LT) remains the only option for progressive PSC. Methotrexate Pediatric data on ursodeoxycholic acid (ursodiol) are limited. Anti-TNFs Small series have shown improvement in liver biochemistries, but Underlying disorder: data are lacking on histology, cholangiography, and survival out- Cholelithiasis comes (25–27). Currently a prospective trial of ursodiol treatment Viral Hepatitis for PSC in children is underway and is recruiting subjects (Clin- Transplant issues icalTrials.gov NCT01088607). Ursodiol has been extensively stu- IgG4 cholangiopathy died in adult PSC, and doses of 17 to 23 mg Á kgÀ1 Á dayÀ1 will Granulomatous hepatitis generally lead to improvement in liver biochemistries, but patient Primary biliary cirrhosis survival has not improved (25–27). Conversely, concerns over Hepatic amyloidosis adverse effects from high-dose ursodiol have been raised. A Nonalcoholic fatty liver disease/steatohepatitis randomized trial of ursodiol (28–30 mg Á kgÀ1 Á dayÀ1) for adults with PSC was terminated early due to clinical deterioration of TNF ¼ tumor necrosis factor. patients in the treatment arm (28). Ursodiol use was associated with a 2-fold risk of death or transplant and a 4-fold risk of CRC (28). One expert group now specifically recommends against the use of (fibro-obliterative cholangitis, periductal fibrosis), and/or cholan- ursodiol for PSC in adults in general, although it remains widely giography (multifocal bile duct strictures and segmental dilations) prescribed in moderate doses (21). Based on these adult data, high- typically initially imaged by magnetic resonance cholangiopan- dose ursodiol (28–30 mg Á kgÀ1 Á dayÀ1) should be avoided creatography (MRCP), and confirmed by endoscopic retrograde in children. cholangiopancreatography (ERCP) if needed (21). Liver involve- Limited anecdotal evidence supports the use of oral vanco- ment of PSC progresses independent of the bowel involvement in mycin as a potential treatment of pediatric PSC. A case series of 14 IBD (7,22). In fact, patients who undergo total colectomy for IBD pediatric patients treated with oral vancomycin described complete continue to have PSC activity. Immunosuppressive therapy for IBD normalization in ALT, GGT, and erythrocyte sedimentation rate in does not appear to affect the progression of PSC. Clinicians must all noncirrhotic PSC patients (4). In contrast, during prospective consider PSC even