Version May 2024
INTRODUCTION — Inflammatory bowel disease (IBD) is characterized by chronic or recurring inflammation of the gastrointestinal (GI) tract and is comprised of two major disorders: ulcerative colitis and Crohn disease. Ulcerative colitis affects the colon, whereas Crohn disease can involve any part of the GI tract. Patients with IBD may also have extraintestinal manifestations, and diseases of the liver and biliary tract are common in IBD. This topic is an overview of hepatobiliary disorders that occur in patients with IBD, including drug-induced hepatoxicity associated with IBD-related treatments.
The clinical manifestations, diagnosis, and treatment of ulcerative colitis are discussed separately:
●(See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults".)
●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)
●(See "Management of moderate to severe ulcerative colitis in adults".)
●(See "Management of the hospitalized adult patient with severe ulcerative colitis".)
The clinical manifestations, diagnosis, and treatment of Crohn disease are discussed separately:
●(See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)
●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)
●(See "Medical management of moderate to severe Crohn disease in adults".)
The dermatologic and ocular manifestations of IBD are presented separately. (See "Dermatologic and ocular manifestations of inflammatory bowel disease".)
EPIDEMIOLOGY AND PATHOGENESIS — Abnormal liver biochemical tests are present in up to 30 percent of patients with IBD and do not correlate with bowel disease activity, while chronic liver disease affects approximately 5 percent of patients with IBD [1].
The pathogenesis of IBD-associated hepatobiliary disorders is unclear and may involve immunologic, genetic, and environmental factors [2]. (See "Genetic factors in inflammatory bowel disease" and "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)
INITIAL EVALUATION — Hepatobiliary disease may be suspected in patients with IBD who have symptoms (eg, jaundice, pruritus, nausea, vomiting) or who are asymptomatic but have abnormal liver biochemical and/or function tests.
The initial evaluation includes obtaining a history to identify potential risk factors for liver disease (eg, alcohol use) and performing a physical examination to look for signs of chronic liver disease (eg, jaundice, ascites, spider telangiectasias). The clinical manifestations and diagnosis of chronic liver disease are discussed separately. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
Subsequent testing is determined based on the information gathered from the history and physical examination as well as the pattern of test abnormalities. Elevations of liver enzymes often reflect hepatocellular injury to the liver (alanine aminotransferase, aspartate aminotransferase) or biliary obstruction (alkaline phosphatase). While an abnormal serum albumin or prothrombin time may reflect malnutrition in a patient with active IBD, these may be seen in the setting of impaired hepatic synthetic function (algorithm 1). The serum bilirubin in part measures the liver's ability to detoxify metabolites and transport organic anions into bile.
The evaluation of patients with IBD and abnormal liver tests (with or without symptoms) is similar to the evaluation for patients without IBD, and this is discussed separately. (See "Approach to the patient with abnormal liver biochemical and function tests".)
DRUG-INDUCED LIVER INJURY — Multiple drugs used for treating IBD have been associated with liver injury; however, dose adjustment or drug discontinuation typically results in improvement [3,4]. The clinical manifestations, diagnosis, and general management of drug-induced liver injury are discussed separately. (See "Drug-induced liver injury".)
Immunomodulators
●Thiopurines – The clinical presentation of thiopurine hepatotoxicity varies from asymptomatic aminotransferase elevations to cholestatic hepatitis to rarely reported conditions such as hepatic sinusoidal obstruction syndrome or peliosis hepatis. (See "Peliosis hepatis" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Introduction'.)
Patients treated with thiopurines (azathioprine, 6-mercaptopurine) are routinely monitored with liver biochemical testing, and this is discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dosing and monitoring'.)
●Methotrexate – Mild elevations in aminotransferases are common in patients on methotrexate, while hepatic steatosis and fibrosis develop infrequently [2]. Hepatotoxicity due to methotrexate may result from direct damage to the hepatocytes through a dose-dependent mechanism [5,6].
Patients treated with methotrexate are advised to avoid alcohol, and folate supplementation is given [7]. The approach to monitoring and drug dose adjustments for patients on methotrexate are discussed in more detail separately. (See "Major side effects of low-dose methotrexate", section on 'Hepatotoxicity' and "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)
Liver biopsy is not routinely indicated for all patients on methotrexate maintenance therapy; however, identifying patients at risk for hepatotoxicity who may require liver biopsy is discussed separately.
Biologic agents
●Anti-tumor necrosis factor (anti-TNF) agents – Therapeutic antibodies against TNF alpha (eg, infliximab, adalimumab) infrequently cause liver injury; however, possible effects range from mildly elevated transaminases (less than twice the upper limit of normal ) to acute hepatitis, or rarely, severe cholestatic liver disease [8-13]. Monitoring patients on anti-TNF therapy is discussed separately. (See "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Tumor necrosis factor inhibitors' and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Monitoring'.)
Adverse effects of anti-TNF agents are discussed in more detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
●Anti-interleukin (anti-IL) 12/23 antibody – Ustekinumab, an anti-IL 12/23 antibody, has been infrequently associated with transient mild-to-moderate aminotransferase elevations (less than five times the upper limit of normal) that resolved despite continuing therapy [14]. The adverse effects of ustekinumab are discussed in more detail separately. (See "Treatment selection for moderate to severe plaque psoriasis in special populations", section on 'Ustekinumab' and "Treatment of peripheral psoriatic arthritis" and "Treatment of peripheral psoriatic arthritis", section on 'Ustekinumab'.)
●Anti-integrin antibodies – Vedolizumab, an alpha-4-beta-7 integrin inhibitor, has been rarely associated with hepatic steatosis. Less than 2 percent of patients experience mild to moderate elevations in aminotransferases and/or bilirubin (≥3 times the upper limit of normal). In general, these abnormalities do not lead to discontinuation of the medication [15]. The adverse effects of vedolizumab are discussed in more detail separately. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Anti-integrin antibody therapy'.)
Other drugs
●Tofacitinib – Tofacitinib is an orally administered nonselective Janus kinase (JAK) inhibitor that is used for treating moderate to severe ulcerative colitis. Tofacitinib has been associated with serum aminotransferase elevations that are typically transient and mild (less than twice the upper limit of normal) [16]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)
Laboratory monitoring for patients on maintenance therapy for moderate to severe ulcerative colitis is discussed separately. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Monitoring'.)
●Sulfasalazine – Sulfasalazine may infrequently cause hepatocellular (elevated aminotransferases) or cholestatic enzyme (alkaline phosphatase) abnormalities, often related to a hypersensitivity reaction. Sulfasalazine is a prodrug of 5-aminosalicylic acid, which is used more commonly than sulfasalazine and does not have side effects that have been associated with sulfasalazine. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease", section on 'Side effects'.)
●Ozanimod – Ozanimod is an oral sphingosine-1-phosphate (S1P) receptor modulator that is used for treating moderate to severe ulcerative colitis. Ozanimod has been associated with transient liver enzyme elevations during therapy but has not been linked to severe liver injury [17]. (See "Management of moderate to severe ulcerative colitis in adults".)
INFECTION
Pyogenic liver abscess — Pyogenic liver abscess is a rare extraintestinal manifestation of Crohn disease; however, the clinical and laboratory findings (eg, fever, abdominal pain, diarrhea, leukocytosis) can mimic a disease flare. The diagnosis is confirmed by obtaining a purulent aspirate of a liver lesion identified by imaging [18]. The treatment of pyogenic liver abscess includes antibiotics and abscess drainage, and this is discussed separately. (See "Pyogenic liver abscess".)
The mechanism of abscess formation in patients with IBD is unclear. It may be due to direct extension of an intra-abdominal abscess or possibly due to portal pyemia with secondary seeding in the liver parenchyma. Additional factors that may contribute to abscess formation include chronic glucocorticoid use, fistulizing disease phenotype, and abdominal surgery [18]. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Features of transmural inflammation'.)
Reactivation of viral hepatitis — Individuals with a history of hepatitis B virus (HBV) infection who receive immunosuppressive therapy (eg, biologic agents) are at risk for HBV reactivation and a flare of their HBV disease. This can occur upon drug withdrawal or between treatment courses. Prior to initiating biologic therapy, patients with IBD are screened for HBV infection, and pretreatment screening and vaccination for HBV are discussed in more detail separately:
●(See "Hepatitis B virus immunization in adults".)
Prevention, diagnosis, and management of HBV reactivation among patients receiving immunosuppressive therapy are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
NONALCOHOLIC FATTY LIVER DISEASE — Nonalcoholic fatty liver disease (NAFLD) is liver steatosis with no other cause of fat accumulation, and the prevalence of NAFLD in patients with IBD ranges from 33 to 50 percent [19-22]. Risk factors for NAFLD in patients with IBD include glucocorticoid use, older age, higher body mass index, and higher triglyceride levels [19,20]. The diagnosis and management of NAFLD are presented separately. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Management of nonalcoholic fatty liver disease in adults".)
CHOLESTATIC LIVER DISEASE
Primary sclerosing cholangitis — Primary sclerosing cholangitis (PSC) is a chronic, cholestatic disease of the liver and bile ducts that is often progressive and characterized by inflammation, fibrosis, and stricturing of the intra- and extrahepatic bile ducts. PSC is closely associated with IBD (primarily ulcerative colitis), and patients with concurrent PSC and IBD have an increased risk of colorectal cancer. The epidemiology, clinical features, diagnosis, and management of IBD in patients with PSC are presented separately. (See "Primary sclerosing cholangitis: Epidemiology and pathogenesis" and "Primary sclerosing cholangitis: Inflammatory bowel disease and colorectal cancer".)
Primary biliary cholangitis — Primary biliary cholangitis (PBC) is a disease characterized by progressive inflammatory destruction of interlobular bile ducts that results in cholestasis and cirrhosis with a strong association with antimitochondrial antibodies. There are multiple case reports of PBC in patients with ulcerative colitis [23-26]. The autoimmune features of both diseases and their common association with some HLA haplotypes suggest a similar genetic predisposition [24,27]. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis" and "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)".)
OTHER DISORDERS
Granulomatous hepatitis — Granulomatous hepatitis is a rare complication of Crohn disease that has also been associated with medications for IBD (mesalamine, sulfasalazine) (picture 1) [28,29]. Granulomas are generally asymptomatic, and prognosis is good. However, some patients with IBD and granulomatous hepatitis may have hepatomegaly and elevated alkaline phosphatase and/or aminotransferase levels. Diagnosis of and treatment (eg, glucocorticoids) for granulomatous hepatitis is presented separately. (See "Evaluation of the adult patient with hepatic granuloma".)
Hepatic amyloidosis — Secondary (reactive or AA) amyloidosis is an uncommon complication of chronic inflammatory diseases, and the prevalence in patients with ulcerative colitis and Crohn disease is less than 1 percent [30]. It is more common in men with colonic involvement. Amyloid deposits can involve almost any organ, including the liver, resulting in asymptomatic hepatomegaly. (See "Gastrointestinal amyloidosis: Clinical manifestations, diagnosis, and management".)
Therapy is directed primarily to achieve IBD remission and control intestinal inflammation, thereby decreasing the release of the acute phase reactant serum amyloid A, which is the precursor of the amyloid fibrils in this condition. (See "Pathogenesis of AA amyloidosis" and "Treatment of AA (secondary) amyloidosis".)
Case reports suggest clinical improvement with colchicine for patients with ulcerative colitis and with anti-TNF agents for patients with Crohn disease [31,32].
Portal vein thrombosis — Portal vein thrombosis is rarely associated with IBD; however, chronic inflammation, immobilization, and coagulation abnormalities seen in IBD may be risk factors [33-35]. (See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management" and "Epidemiology and pathogenesis of portal vein thrombosis in adults".)
GALLSTONES — The prevalence of gallstones is increased in patients with ileal Crohn disease (or those who have had ileal resection) [36]. Gallstones are probably caused by the malabsorption of bile acids, which interferes with their enterohepatic circulation. This leads to depletion of bile salts and the formation of lithogenic bile. (See "Gallstones: Epidemiology, risk factors and prevention".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Abnormal liver biochemical tests are common in patients with inflammatory bowel disease (IBD) and do not correlate with bowel disease activity, while chronic liver disease affects approximately 5 percent of patients with IBD. (See 'Epidemiology and pathogenesis' above.)
●Hepatobiliary disease may be suspected in patients with IBD who have symptoms (eg, jaundice, pruritus, nausea) or who are asymptomatic but have abnormal liver biochemical and/or function tests. The initial evaluation includes obtaining a history to identify potential risk factors for liver disease (eg, alcohol use) and performing a physical examination to look for signs of chronic liver disease (eg, ascites). Subsequent testing is determined based on the information gathered from the history and physical examination as well as the pattern of test abnormalities (table 1 and algorithm 1). (See 'Initial evaluation' above.)
●Multiple drugs used for treating IBD (eg, thiopurines) have been associated with hepatotoxicity; however, dose adjustment or drug discontinuation typically results in improvement. (See 'Drug-induced liver injury' above.)
●Pyogenic liver abscess is a rare extraintestinal manifestation of Crohn disease; however, the clinical and laboratory findings (eg, fever, abdominal pain, diarrhea, leukocytosis) can mimic a disease flare. The diagnosis and treatment of pyogenic liver abscess is discussed separately. (See "Pyogenic liver abscess".)
●Patients with IBD and a history of hepatitis B virus (HBV) infection who initiate immunosuppressive therapy are at risk for HBV reactivation. Prior to initiating biologic therapy, patients with IBD are screened for HBV infection. (See 'Reactivation of viral hepatitis' above.)
Prevention, diagnosis, and management of HBV reactivation among patients receiving immunosuppressive therapy are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Primary sclerosing cholangitis (PSC) is a chronic, cholestatic disease of the liver and bile ducts that is often progressive and characterized by inflammation, fibrosis, and stricturing of the intra- and extrahepatic bile ducts. PSC is closely associated with IBD (primarily ulcerative colitis), and this is discussed separately. (See "Primary sclerosing cholangitis: Epidemiology and pathogenesis", section on 'PSC and inflammatory bowel disease'.)
●Nonalcoholic fatty liver disease (NAFLD) is liver steatosis with no other cause of fat accumulation, and the prevalence of NAFLD in patients with IBD ranges from 33 to 50 percent. Risk factors for NAFLD in patients with IBD include glucocorticoid use, older age, higher body mass index, and higher triglyceride levels. (See 'Nonalcoholic fatty liver disease' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.
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