Hepatobiliary manifestations of inflammatory bowel disease.

REVIEW ARTICLE

Hepatobiliary Manifestations of Inflammatory Bowel Disease Andres J. Yarur, MD,* Frank Czul, MD,* and Cynthia Levy, MD†

Abstract: Patients with inflammatory bowel diseases (IBDs) may present with several hepatic abnormalities. Some of these liver diseases are benign and only require observation, whereas others may cause liver failure and require liver transplantation. The aim of this review was to present and summarize the latest evidence on the most common liver diseases seen in patients with IBD. These manifestations can be divided in to 3 groups: those that are seen in association with IBD, those that are due to metabolic and physiologic changes induced by the IBD and those that are secondary to the drugs used in the treatment of IBD. Primary sclerosing cholangitis is one of the most common hepatobiliary manifestations of IBD that is more prevalent in patients with ulcerative colitis. There is no approved medical treatment for primary sclerosing cholangitis and about 50% of patients will require liver transplantation within 10 to 15 years from the time of diagnosis. Among the drugs that are commonly used in the treatment of IBD, thiopurines and methotrexate impose the higher risk of hepatotoxicity. In most cases, dose adjustment and avoidance of hepatotoxins will normalize the liver tests and discontinuation of the drug is required in a minority of cases. Reactivation of hepatitis B virus during immunosuppressive therapy is a major concern and adequate screening and vaccination is warranted. The approach to a patient with IBD who presents with abnormal liver chemistries can be challenging not only because 2 or more conditions can co-exist but also because management must be individualized. (Inflamm Bowel Dis 2014;20:1655–1667) Key Words: inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, liver diseases, primary sclerosing cholangitis, drug-induced liver disease, methotrexate, azathioprine, mercaptopurine, infliximab, hepatitis B

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atients with inflammatory bowel diseases (IBDs) may experience multiple complications outside the gastrointestinal tract. Diseases of the liver and biliary ducts stand as some of the most common extraintestinal manifestations of IBD and can be either primary or induced by one of the multiple drugs used for IBD treatment. This association is seen with both Crohn’s disease (CD) and ulcerative colitis (UC). The range of hepatic complications is wide with biliary diseases and adverse events secondary to therapy, including reactivation of hepatitis B and drug-induced liver injury (DILI), being the most common. Other described conditions include metabolic diseases (nonalcoholic steatohepatitis and amyloidosis), granulomatous hepatitis, liver abscesses, and hepatic vascular complications (portal vein thrombosis). Recognizing such hepatobiliary conditions is of utmost importance because they may preclude the use of specific drugs to treat IBD and may eventually lead to severe complications such as end-stage liver disease.

Received for publication March 13, 2014; Accepted April 3, 2014. From the *Division of Gastroenterology, and †Division of Hepatology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida. The authors have no conflicts of interest to disclose. Reprints: Cynthia Levy, MD, Division of Hepatology, Department of Medicine, University of Miami, Jackson Medical Towers, 1500 NW, 12th Avenue, Suite 1101, Miami, FL 33136 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000065 Published online 28 May 2014.

Inflamm Bowel Dis Volume 20, Number 9, September 2014

HEPATOBILIARY DISORDERS ASSOCIATED WITH IBD Primary Sclerosing Cholangitis Epidemiology and Natural History Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease characterized by gradual inflammation and fibrosis of intrahepatic and/or extrahepatic bile ducts, potentially leading to end-stage liver disease. The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 person/year and 0 to 16.2 per 100,000 people, respectively.1 Both genders are affected, but two thirds of patients with PSC are men.1 The median age at onset is between 30 and 40 years even though women are diagnosed at a later age.1,2 The association between IBD and PSC has been well documented and is the most common hepatobiliary disease seen in these patients.3 Among those with PSC, about 70% to 80% have UC and 15% to 20% have CD.4,5 Those IBD patients with PSC are more likely to develop malignant complications and to require liver transplantation.6 Conversely, only about 0.4% to 7.5% of patients with IBD will develop PSC.2,3 The natural history of PSC is variable and studies have not been concordant. The median reported survival free of transplantation ranges between 12 and 18 years from diagnosis.7,8 Some predictive models such as the Mayo risk score, which includes patient’s age, laboratory tests, and presence of variceal bleeding, have been proposed. However, it is difficult to extrapolate its predictive value to the entire PSC population, even when www.ibdjournal.org |

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accounting for histologic stage.8,9 Other studies have used cholangiographic findings to predict prognosis, concluding that higher grade and multiple strictures indicate poor prognosis.8,10 When compared with the general population, patients with PSC have a significantly higher mortality rate and risk of developing a malignancy, especially a primary hepatobiliary cancer.11 In a population-based Swedish study, 199 patients with PSC were identified between 1992 and 2005. They identified a 4-fold increase in mortality risk compared with the general population. Older age, female gender, jaundice, cholangitis, and higher bilirubin levels were significantly associated with the risk of liver-related death or orthotopic liver transplantation (OLT).12 More than half of all cholangiocarcinomas are diagnosed within the first year of diagnosis of PSC, and thereafter, the annual risk is about 0.6%.12 Even though that study failed to demonstrate an increased risk for other malignancies, previous studies have found that patients with PSC are also at a higher risk of developing colon and pancreatic cancers.5

Pathogenesis In PSC, the injury occurs in small, medium, and large bile ducts, with an inflammatory response that involves lymphocytes, plasma cells, and neutrophils progressively inducing concentric periductal fibrosis, which eventually leads to biliary strictures.13 The exact etiology of PSC is unknown, but multiple possible underlying mechanisms have been proposed. The known association with IBD, the increased risk of autoimmune diseases, and the association with several different human leukocyte antigen (HLA) haplotypes suggest that immunity plays a major role in the pathogenesis of PSC.14,15 As with IBD, there is probably an underlying genetic predisposition. PSC has a complex genetic phenotype, and the role of environmental factors is key. Although the bile duct injury is likely immunologically mediated, the antigens that trigger this aberrant response have not been identified. Population-based studies have shown that first-degree relatives of patients with PSC run an increased risk of PSC when compared with the general population.5 Many of these genes code important factors of the innate and adaptive immune systems while the role of others is unclear. Multiple HLA haplotypes have been linked to PSC; HLA-B8 and HLA-DRB1*0301(DR3) have the strongest association, even though HLA-DRB3*0101(DRw52a) and HLA-DRB1*0401 (DR4) have also been linked with PSC.15 The HLA-associated susceptibility is different when comparing patients with UC with and without PSC, which has supported the hypothesis that UC with PSC is a different phenotypic entity.16 Even though about 16 risk loci have been identified in PSC at genome-wide significance level, they account for only 7.3% of the overall PSC liability.17 Furthermore, many of the genome-wide significant risk loci for PSC are also risk loci for UC and/or CD (Table 1).18 Abnormalities in the adaptive and innate immune responses, which involve memory T cells, B cells, natural killer cells, and macrophages, have been proposed as well.19 Although in most liver diseases, T helpers (Th2) initiate and perpetuate hepatic fibrosis, in patients with PSC, Th1 are dominant.20 The

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TABLE 1. Risk Loci Shared by PSC, UC, and CD Locus Risk loci shared by PSC and UC 01p36.32 02q37.3 Risk loci shared by PSC and CD 06q15 10p15.1 Risk loci shared by PSC, UC, and CD 03p21.31 04q27 12q13 21q22

Gene

TNFRSF14 GPR35 BACH2 IL2RA MST1 L2, IL21 HDAC7 PSMG1

interleukin 12 family also plays a very important role in the disease, including the differentiation of naive T cells into Th1.20 An imbalance between Th17 and Treg cells has also been observed, with high Th17 and low Treg expression.21 The role of natural killer cells in PSC is not completely understood, but natural killer cells are overexpressed in hepatic tissue and peripheral blood of patients with PSC.20 Still with respect to immunologic mechanisms, it is thought that memory T lymphocytes that were primed in the intestine persist as memory cells and undergo enterohepatic circulation, triggering portal inflammation through aberrantly expressed adhesion molecules in both the liver and the gut.22 Studies have shown that patients with PSC have an ectopic expression of mucosal addressin cell adhesion molecule 1, which is usually only seen in the intestine.23 Nevertheless, ectopic hepatic expression of mucosal addressin cell adhesion molecule 1 is not only seen in PSC but can also be expressed in the liver of other hepatic inflammatory diseases.22 Increased intestinal permeability is also thought to play a role in the pathogenesis of PSC. Bacteria and bacterial products reaching the portal system can subsequently lead to biliary inflammation and recurrent cholangitis, probably through activation of the innate immune response.24,25 The impact of gut microbiota on the pathogenesis and course of PSC needs to be further examined. Finally, some animal models support the toxic bile hypothesis, in which dysfunction of specific transporters in the cannalicular membrane would lead to accumulation of cytotoxic hydrophobic bile acids in bile. This mechanism may be more important in later stages of PSC and may affect progression as opposed to initiation of the disease. Other etiologic mechanisms such as ischemia and chronic viral infections have been postulated, but lack consistent evidence.

Clinical Manifestations and Diagnosis Almost 50% of patients with PSC can be asymptomatic at the time of diagnosis and the disease is identified after routine hepatic chemistries are performed.7,26 This is commonly seen in


Hepatobiliary Manifestations of IBD

patients with IBD who undergo laboratory testing as part of their standard clinical care.27 When present, the most common symptoms are pruritus, right upper quadrant abdominal pain, jaundice, weight loss, and/or fatigue. On examination, it is possible to find icterus, hepatomegaly, splenomegaly, and excoriation marks from scratching. Although laboratory tests may help, the diagnosis cannot be made based on liver biochemistries alone and requires confirmatory imaging. Laboratory tests usually demonstrate a cholestatic pattern with elevation of the serum alkaline phosphatase (AP) and gamma-glutamyl transpeptidase, whereas aminotransferases can also be elevated. Importantly, a normal AP level does not rule out PSC.28 Multiple autoantibodies have been associated with PSC, although their use and interpretation in clinical practice is unclear and they probably do not play a role in the disease pathogenesis. Angulo et al29 found that anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies (particularly those with perinuclear staining), anti-cardiolipin antibodies (hypergammaglobulinemia), rheumatoid factor, and thyroperoxidase antibody were found in a significantly higher proportion of patients with PSC when compared with controls. These autoantibodies were present regardless of the presence of IBD and with the exception of anticardiolipin antibodies, they did not correlate with disease severity.29 Cholangiography showing the distinctive multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts with irregular annular strictures yielding a “beaded” pattern is needed to establish the diagnosis and can be performed through endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography (MRCP), or percutaneous transhepatic cholangiography. Because MRCP is the least invasive of the 3 and offers a high sensitivity and specificity, it has become the test of choice to initiate the evaluation (Fig. 1).30 Indeed, a recent study identified MRCP as the most cost-effective strategy for initial diagnosis of PSC.31 Nonetheless, MRCP can miss early changes of PSC and endoscopic retrograde cholangiopancreatography can be valuable in ruling out large duct PSC when MRCP imaging is suboptimal.28 Liver biopsy has a limited role in the assessment of PSC. The classical finding of periductal fibrosis is only present in a small number of cases32 and is not really pathognomonic because it can also be seen in secondary forms of sclerosing cholangitis. Liver biopsy should be considered in patients who (1) are suspected to have an overlap syndrome of PSC and autoimmune hepatitis (AIH) or (2) may have small duct PSC. The fibrosis staging can be made through histology, but newer noninvasive tests like elastography can also be a reliable tool.33

cirrhosis. In PSC, however, UDCA has not been shown to slow disease progression, improve histology, or reduce the risk of mortality or need for OLT.35,36 Higher doses of UDCA were used in a large U.S.-based randomized controlled trial but the study had to be terminated early as patients receiving UDCA at high doses (28–30 mg/kg per day) were 2-fold more likely to reach the primary endpoint of death, need for liver transplant, or development of varices.37 In fact, patients on high-dose UDCA also had a significantly higher risk of colorectal neoplasia compared with patients receiving placebo. Thus, the American Association for the Study of Liver Diseases recommends against the use of UDCA in patients with PSC.28 However, the European society does not make specific recommendations and states that low-dose UDCA may be considered as chemoprevention for colorectal cancer in high-risk groups.38 Based on the concept that patients with PSC have abnormal humoral and cellular immune systems, the efficacy of corticosteroids has been studied, without success.36 Other immunosupressors, including thiopurines, tacrolimus, methotrexate (MTX), and anti–tumor necrosis factor (anti-TNF) agents, have also been tested, showing no clinical benefit in PSC even though they may have a role for patients with overlapping features of AIH.28,39–43 Antibiotics have also been used in the treatment of PSC. A randomized controlled trial comparing the use of metronidazole and UDCA with placebo and UDCA showed that the former group improved their serum levels of AP but there was no change in disease progression (evaluated by liver histology and cholangiography).44 More recently, a randomized controlled trial compared low and high doses of metronidazole to low and high doses of vancomycin in a total of 35 patients with PSC. The primary endpoint was a drop in AP at 12 weeks. Only patients in the vancomycin arms reached primary endpoint (mean drop 40%). Secondary endpoints were Mayo risk score, total bilirubin, pruritus, and adverse events. The Mayo risk score improved for patients on both metronidazole and vancomycin at a low dose, but the total bilirubin only improved in the low-dose metronidazole arm and pruritus in the group that received high-dose metronidazole. Adverse events were common, especially in the high-dose subgroups.45 Other antibiotics have also been tried in small studies but further research is needed. Ongoing trials are currently investigating the role of antibiotics, anti-fibrotic agents (LOXL2 antibodies), retinoic acid, and FXR agonists in the treatment of PSC.

Treatment

Endoscopic Therapy

Management of PSC aims to halt disease progression and to treat its complications. Currently, no medical treatment has been proven to decrease the progression of PSC. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that promotes hepatobiliary secretion, protects cholangiocytes against cytotoxic hydrophobic bile acids, and protects hepatocytes from bile acid-induced apoptosis.34 It is Food and Drug Administration approved for the treatment of another cholestatic liver disease, primary biliary

Approximately 45% to 63% of patients with PSC can present with high-grade dominant strictures in the biliary system, which may develop de novo or in areas with previous stenosis.46,47 These strictures can cause symptoms and elevation of the bilirubin, even though previous studies have not found a relation between the presence of dominant strictures and cholestasis.47 Most importantly, cholangiocarcinoma needs to be considered and ruled out. A recent study found that after a mean follow-up www.ibdjournal.org |

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FIGURE 1. MRCP of a patient with PSC, showing the characteristic “beading” appearance in the intrahepatic ducts.

time of almost 10 years, 26% of patients with dominant strictures developed cholangiocarcinoma.46 Patients with dominant strictures benefit from endoscopic intervention. Performing balloon dilation and/or placing a stent can provide adequate biliary drainage, even though the best modality on how to approach these lesions has not been well established.48 A retrospective study found that stenting was not better than dilation alone and carried an increased risk of complications, even though a subgroup of patients did not respond to balloon dilation.49 For those patients requiring stenting, removal or exchange needs to be done promptly to reduce the risk of cholangitis.49 When cannulation of the common bile duct cannot be accomplished, performing a percutaneous transhepatic cholangiogram is a viable option to decompress the biliary obstruction and provide cytology and tissue samples.49 Newer technologies such as confocal laser endomicroscopy and intraductal optical coherence tomography may have a role in determining the nature of the stricture (benign versus malignant), but they are not readily available and further studies are needed before they become the standard of care.50,51

Cholangiocarcinoma in PSC The diagnosis of cholangiocarcinoma can be challenging due to the abnormal baseline radiologic findings and the highly desmoplastic nature of this tumor. Brush cytology and/or biopsy samples should be obtained.52 The use of fluorescence in situ

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hybridization (FISH) may aid in the diagnosis of cholangiocarcinoma. However, although highly specific, FISH has limited sensitivity.53 To overcome this limitation, use of serial FISH testing for dominant strictures may be of benefit because about 75% of patients with more than 1 positive FISH test for polysomy will be diagnosed with cholangiocarcinoma within 3 years.54 Combination of these tests with annual measurement of tumor markers (CA 19-9) may offer a benefit and is recommended in suggested surveillance algorithms.55,56 Screening recommendations for cholangiocarcinoma are shown in Table 2.

PSC and IBD At the time of diagnosis of PSC, IBD must be ruled out and a complete colonoscopy with multiple segmental biopsies of the mucosa needs to be performed. This procedure is recommended because in patients with PSC–IBD, rectal sparing is a common phenotypic feature, the intestinal disease is frequently asymptomatic, and a highly active histologic activity may be masked by a low-grade endoscopic activity.57,58 If the initial endoscopic and histologic assessment is negative, we suggest repeating the colonoscopy in 5 years. Additionally, PSC–IBD patients are at higher risk of developing a colonic neoplasia and a more intensive colonoscopic surveillance is needed.59 Thus, annual surveillance colonoscopy is recommended for this population (Table 2). The duration and severity of PSC does not seem to be associated with a higher risk of colonic neoplasia in patients with UC.60



TABLE 2. Surveillance Recommendations for Patients with PSC and IBD Malignancy

Strategy

Cholangiocarcinoma MRI/MRCP or ultrasound plus CA 19-9 annually Colorectal cancer For patients with PSC–IBD: colonoscopy with biopsies at the time of PSC diagnosis and repeated every 1–2 yrs Gallbladder neoplasia Annual imaging study to detect polyps. If polyp $0.8 cm, perform cholecystectomy; if ,0.8 cm and good liver function, consider cholecystectomy if not repeat imaging study every 3–6 mo Hepatocellular The same imaging modality used for cholangiocarcinoma surveillance is enough to screen for hepatocellular carcinoma as well carcinoma MRI, magnetic resonance imaging.

IBD may be diagnosed at any time during the course of PSC and can even develop after OLT, but in most cases, the diagnosis of IBD precedes that of PSC.61 Conversely, PSC can develop in patients with UC after total proctocolectomy (TPC).28 Interestingly, a recent study comparing 2 cohorts of patients (one group diagnosed with IBD between 1993 and 1997 and another between 2003 and 2007) showed that those with a recent diagnosis of IBD (2003–2007) were more likely to be diagnosed with PSC before IBD, whereas those with a early IBD diagnosis (1993–1997) were more likely to be diagnosed with IBD first.62 The authors propose that the findings could be explained by the widespread availability of newer, noninvasive imaging studies available to work up patients with abnormal liver enzymes (like MRCP). Patients with PSC–IBD have a characteristic phenotype: the disease usually affects the entire colon, they are more likely to have rectal sparing and “backwash ileitis,” and have a significantly higher risk of developing colorectal dysplasia and cancer.57,59 A meta-analysis found that PSC–UC patients have a 5-fold increased risk for colorectal dysplasia and carcinoma when compared with those UC patients without PSC.59 Also, they have an increased risk of developing pouchitis after an ileal pouch–anal anastomosis (IPAA) or peristomal varices after a colectomy with end-ileostomy, which is not associated with the severity of liver disease.57,63 Table 3 summarizes the distinct phenotypic characteristic of patients with IBD and PSC. Disease activity of both conditions is inversely proportional: those patients with aggressive PSC that progresses to endstage liver disease and require liver transplantation are more likely to have quiescent UC, require less courses of corticosteroids, have fewer UC flare-ups, and have a lower rate of colectomy.53,64

Conversely, those patients with a less aggressive PSC (not requiring OLT) have been found to have higher level of intestinal inflammation at histology and a higher frequency of colon carcinoma and dysplasia.64 In PSC–UC patients, TPC has no favorable effect on the disease course of PSC.65

Liver Transplant in Patients with PSC–IBD The indications for OLT in patients with PSC are similar to those with end-stage liver disease due to other etiologies. Some specific indications to prioritize patient with PSC include recurrent ascending cholangitis, intractable pruritus, and limited stage cholangiocarcinoma.28 PSC can recur after OLT in 12% to 37% of the cases and can be diagnosed within months after OLT, but in most cases, it does not seem to affect survival.66–68 Interestingly, studies have shown that colectomy pre-OLT or peri-OLT decreases the risk of PSC recurrence when compared with those with an intact colon or those who undergo colectomy after OLT.68 Patients who receive a graft meeting extended donor criteria are also at higher risk of PSC recurrence.68 In patients who underwent OLT for PSC, the cumulative risk for developing IBD after the transplant is 15% after 1 year and 54% after 10 years.61 That same study found that in patients with IBD pre-OLT, symptoms at the time of the transplant, short interval of IBD before OLT, and use of tacrolimus were risk factors for developing a flare-up, and patients in whom a 5-aminosalicylate was started immediately after the OLT had a reduced risk of IBD recurrence.61 The authors also reported that patients with PSC without IBD that undergo OLT and who are cytomegalovirus negative and receive a liver from a cytomegalovirus-positive donor are at a higher risk of developing IBD

TABLE 3. Key Differences in Presentation of IBD with PSC PSC–UC Higher prevalence of pan-colitis with rectal sparing and backwash ileitis Higher rate of pouchitis after protcocolectomy with IPAA Further increase in risk of colon cancer

PSC–CD Higher rate of colonic disease compared with patients with CD and without PSC

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when compared with those who receive a liver from a cytomegalovirus-negative donor.61 Even though it has been hypothesized that TPC and IPAA may increase the risk for post-OLT infectious complications and graft survival, in a recent study evaluating a total of 79 transplants for PSC (30 with PSC alone, 27 PSC/UC, and 22 PSC/UC who also had an IPAA) followed for a mean period of 85 to 118 months, patients with TPC and IPAA who underwent OLT did not have a higher rate of infectious complications when compared with those with an intact colon.69 Although colectomy for UC does not seem to affect the severity of coexisting PSC, it has been suggested that the use of steroids and other immunosuppressive agents given to patients after OLT for PSC should also treat the coexisting UC.70 Remarkably, the current trend in the management of immunosuppression post-OLT is to minimize the use of steroids, which can potentially adversely affect control of the concomitant UC despite the use of other immunosupressors.71 Another concern is whether the immunosuppression used in patients who underwent OLT can accelerate the development of dysplasia or malignancy that can develop in the setting of UC, especially when considering that PSC alone may increase the likelihood of dysplasia or malignancy. A multiinstitutional report concluded that TPC and IPAA can be performed safely after OLT and emphasized that management strategies should include the optimization of small bowel length during the pouch and ileostomy construction, vigorous postoperative hydration, early ileostomy closure, and careful monitoring for pouchitis.72 Inflammation of the ileal reservoir made as part of the IPAA (pouchitis) is the most common long-term complication of this procedure, and patients with PSC are at a higher risk of developing pouchitis.63 The cumulative risk of pouchitis in the patients without PSC at 10 years is 46% compared with 79% for the patients with PSC and 71% on those who underwent OLT for PSC.63,73 These findings indicate that OLT and post-OLT immunosuppressive therapy have no significant impact on the incidence or the disease course of pouchitis.73

Overlap Between AIH and PSC An overlap syndrome between AIH and PSC has been reported in up to 6% of patients with PSC and also has a strong association with IBD.74–77 Patients with PSC–AIH present at a younger age and have a worse prognosis when compared with those with PSC alone.74 AIH is frequently diagnosed before PSC, and determining whether a patient has an overlap syndrome is challenging.78 About 10% of adult patients with a diagnosis of AIH have radiologic findings consistent with PSC79; younger age at diagnosis, higher baseline AP and bilirubin, and greater lobular activity on initial liver biopsy were significantly associated with the detection of PSC–AIH overlap.79 One study found that 16% of patients with AIH had UC and of those, 42% had imaging compatible with PSC.80 Generally speaking, overlap should be considered in the differential diagnosis of a patient with either AIH or PSC when

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the phenotype of disease differs from the common clinical course and anticipated response to treatment. PSC–AIH should be considered in patients with imaging consistent with PSC who also present serologic work-up compatible with AIH and have lymphoplasmacytic portal-based infiltrates with at least moderate interface hepatitis on liver biopsy.81 Patients with an established diagnosis of AIH who also have IBD should be evaluated for concomitant PSC.

Small Duct PSC Some patients with IBD may present with biochemical features of chronic cholestasis and hepatic histology consistent with PSC, even though they have normal cholangiographic findings.82 This entity was first known as pericholangitis and was though to be always associated with IBD.83 Further studies reported that about 81% of patients with small duct PSC have IBD, and among these, 78% had UC and 21% had Crohn’s colitis.84 Interestingly, small duct PSC with IBD resembles large duct PSC in its HLA association, which is not the case in small duct PSC without IBD.85 Patients with IBD and abnormal liver tests who have normal MRCP or endoscopic retrograde cholangiopancreatography, and with otherwise unrevealing work-up, should undergo liver biopsy to exclude small duct disease. Small duct PSC has a better prognosis when compared with regular PSC and patients do not seem to be at a higher risk of developing cholangiocarcinoma.82,84 Nevertheless, after a mean follow-up of 13 years, almost 30% of the patients developed large duct PSC.84 These patients with progression to large duct should undergo surveillance for cholangiocarcinoma. No therapeutic clinical trials have been conducted for small duct PSC.

Cholelithiasis Gallstones are reported in 13% to 24% of all patients with CD.86–89 An Italian prospective cohort study followed up 634 patients with IBD for a mean of 7 years and found that in those with CD, the incidence of developing gallstone disease was 14/ 1000 person-years.90 The site of CD involvement may influence the risk of gallstones.86,88,89 When compared with those with only ileal involvement, patients with ileo-colonic disease are at higher risk of having gallstone disease.89 History of previous intestinal resections and number of resections have been reliably identified as risk factors for cholelithiasis, whereas older age and female gender have been only inconsistently reported as risk factors.86–90 Multiple mechanisms may explain these observations. One of the most accepted is the disturbance of the enterohepatic circulation of bile salts. Due to damage and/or resection of the ileum, decreased reabsorption of bile salts leads to the excretion of supersaturated bile and the subsequent formation of cholesterol gallstones.91,92 Another proposed mechanism is gallbladder hypomotility with stasis and biliary sludge formation, which in the setting of bilirubin supersaturation may contribute to the process.88,93 Prolonged fasting and the use of total parenteral nutrition are commonly seen in patients with CD and contribute to such gall bladder dysmotility and stasis.94 In UC, the risk of cholelithiasis


does not seem to be increased.87,90 The lack of small bowel (ileal) involvement in patients with UC may explain this observation.

DRUG-INDUCED LIVER DISEASE IN IBD Currently, multiple drugs are used in the treatment of IBD. Although some offer a clear therapeutic benefit, their use carries a potential risk of hepatotoxicity. With some drugs, the reaction is idiosyncratic (immune or metabolic) and with others is due to intrinsic hepatotoxins. Also, each drug can induce 1 or more types of liver disease (acute versus chronic, cholestasic versus hepatocellular, steatosis, granulomas, etc.). We will review the most frequent drugs used in patients with IBD that can potentially cause DILI.

Aminosalicylates: Sulfasalazine and Mesalamine Sulfasalazine was commonly used to treat IBD before the new generation of drugs was introduced. It gets metabolized in the bowel where it is cleaved into sulfapyridine and 5-aminosalicylic acid by colonic bacteria. The sulfapyridine is then absorbed, acetylated, and eliminated in the urine.95 Most patients with acute liver injury due to sulfasalazine are slow acetylators.96 In patients with IBD, the rate of hepatotoxicity has been low even though studies performed in patients with rheumatoid arthritis have reported significant liver injury in 4 per 1000 users.97 The reaction usually occurs within the first month of treatment, is often related to hypersensitivity, and can cause elevation of both hepatocellular and cholestasic enzymes.98 Formulations based on mesalamine deliver the 5-aminosalicylic acid directly in the bowel and DILI is rare.

Thiopurines The thiopurine analogs effective in the maintenance of remission in patients with IBD include mercaptopurine (MP) and its pro-drug azathioprine (AZA). These medications antagonize endogenous purines, interfering with synthesis ofDNA. After getting absorbed from the gastrointestinal tract, 88% of AZA is converted to MP, which can then be metabolized through 3 competing pathways: conversion to 6-thiouric acid by xanthine oxidase, conversion to thioinosine monophosphate by hypoxanthine phosphoribosyltransferase, or methylation by thiopurine methyltransferase into 6-methyl mercaptopurine (6-MMP).99 Thiopurine hepatotoxicity has been well described and is one of the most common reasons for AZA/MP discontinuation.100,101 Thiopurine-induced liver injury occurred more frequently within the first month, with 50% of cases being diagnosed within the first 3 months.102 A wide range of possible manifestations has been described and most are reversible. The most commonly reported findings are cholestatic hepatitis, peliosis hepatis, hepatic sinusoidal dilatation, veno-occlusive disease, perisinusoidal and portal fibrosis, and nodular regenerative hyperplasia of the liver.103 Higher levels of 6-MMP have been found to be associated with a higher risk of hepatotoxicity but it is important to note that having low levels of 6-MMP does not preclude the development


of hepatotoxicity and liver enzymes need to be monitored regularly. Even though 6-MMP levels $5700 pmol/8 · 108 erythrocytes have been associated with hepatotoxicity, a study found that almost 40% of patients who develop DILI with thiopurines have a 6-MMP level ,5300 pmol/8 · 108 erythrocytes.100,104 A subgroup of patients has metabolic pathways favoring an augmented conversion of MP into 6-MMP rather than the metabolite associated with a therapeutic effect (6-thioguanine nucleotide).105 This phenomenon can be confirmed by checking metabolite levels when increasing thiopurine dose in patients who are clinically not responding.105 A study from Spain found that the incidence of hepatotoxicity is higher when thiopurines are used in combination with corticosteroids.102 An algorithm suggesting how to monitor patients receiving thiopurines is presented in Figure 2. Because some patients present with resistance to AZA/MP, investigators attempted to use 6-thioguanine in the treatment of CD with promising results.106,107 Unfortunately, its use is highly associated with liver toxicity, including the development of nodular regenerative hyperplasia, early fibrosis, and venous outflow disease (Budd–Chiari).108,109

Methotrexate MTX inhibits dihydrofolate reductase, blocking the synthesis of nucleoside thymidine, required for DNA synthesis. It also inhibits enzymes involved in purine metabolism, blocking T-cell activation and suppressing intercellular adhesion molecule expression.110 Available literature supports the efficacy of intramuscular MTX for the induction and maintenance of remission in patients with CD.111 MTX has several side effects and its hepatotoxicity is well known. A meta-analysis of clinical trials evaluating the effect of MTX in IBD reported that of 373 patients, 39 (10.5%) had elevation of aminotransferases.112 The incidence of hepatotoxicity, which the authors defined as .2-fold increase over the upper limit of the normal, was 0.9 per 100 personmonths, whereas the rate of an elevation of liver enzymes, ,2fold the upper limit, was 1.4 per 100 person-months.112 Of the 39 patients who developed an enzyme elevation, 3 were controlled with drug dose reduction, and 26 resolved without any intervention, and only 10 discontinued the medication. The main risk factor for MTX-induced hepatotoxicity is concomitant use of alcohol, even though infection with hepatitis B or C, diabetes mellitus, exposure to other liver toxins, and persistently elevated liver enzymes have also been implicated.112 Supplementation with folic acid or folinic acid decreases the risk of hepatic adverse events and should be recommended.113 An important point of debate has been the need for routine liver biopsy while on treatment with MTX. Originally, a liver biopsy was recommended after 1.5 g of cumulative MTX dose.114 Latest rheumatology guidelines suggest monitoring for toxicity by measuring aminotransferases and albumin every 4 to 8 weeks and then every 8 to 12 weeks once the patient is on a stable dose of the drug and enzymes have been within normal limits.115 They suggest performing a liver biopsy if 6 of 12 tests are abnormal within a year. A study looking at the long-term effect of MTX in patients www.ibdjournal.org |

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FIGURE 2. Suggested surveillance and management of patients who develop abnormal liver enzymes while on thiopurines. 6-TGN, 6-thioguanine nucleotide. (1) levels $5700 pmol/8 · 108 erythrocytes.

with IBD found that even with higher cumulative doses (mean cumulative dose of 2.6 g for a mean of 132 wk) were associated with little hepatotoxicity.116 The current consensus is that routine liver biopsy is not warranted. We suggest re-testing abnormal liver enzymes: if confirmed, our management will depend on the cumulative dose of MTX the patient has received. If it is less than 1.5 g, a work-up to rule out other liver diseases should be performed first. If the studies are unrevealing, then proceed with liver biopsy. Alternatively, if the liver enzymes are abnormal in a patient who has received a cumulative dose of 1.5 g or more, then a liver biopsy is warranted. Transient elastography may have a role in the monitoring of these patients but further studies are needed.117

aminotransferase elevation. Nevertheless, patients on MTX/infliximab who had enzyme elevation did not develop liver-related symptoms.118 The Food and Drug Administration has received multiple reports of DILI from patients on infliximab and even though most of them had other risk factors for liver disease, it was concluded that infliximab may induce hepatotoxicity.119 Natalizumab is an IgG4 monoclonal antibody that blocks the adhesion and subsequent migration of leukocytes into the gut by binding alpha-4 integrin. A postmarketing study reported 6 cases of DILI associated with natalizumab use, with 4 developing such reaction after the first infusion; 3 patients developed features of AIH.120

Biologic Agents

Viral Hepatitis in Patients Receiving Immunosuppression for IBD

Multiple biologic agents have been approved for the treatment of CD and UC. All but one of them (natalizumab) are anti-TNF. Case reports of hepatotoxicity due to anti-TNF agents are scattered and may be biased by the fact that these drugs are commonly used in combination with known hepatotoxic medications (thiopurines and MTX). Nevertheless, they are recognized as drugs that can potentially be toxic to the liver. In a study comparing patients receiving MTX/infliximab to MTX/placebo, those on placebo had significantly lower rate of

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Reactivation of hepatitis B virus (HBV) is an important concern for patients on immunosuppressive therapy even though the actual incidence among IBD patients is unknown. Several case reports describe HBV reactivation after use of infliximab in combination with prednisone and/or AZA.121–123 Until further studies on the safety of IBD medications and risk of HBV reactivation in IBD patients are performed, it is recommended to screen all IBD patients for previous HBV exposure.


Current guidelines by the American Association for the Study of Liver Diseases recommend HBV screening on those requiring immunosuppression, including anti-TNF drugs.124 Screening for HBV should be performed at the time of diagnosis of IBD rather than delaying until treatment with an immunomodulator or anti-TNF is considered. Hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody are recommended screening tests. The utility of hepatitis B core antibody (antiHBc) is controversial; however, it is recommended screening all IBD patients for anti-HBc. Even though anti-HBc may be falsely elevated in a low prevalence population, a positive anti-HBc (in the setting of undetectable HBsAg) can represent occult HBV in immunosuppressed patients and in patients co-infected with hepatitis C virus (HCV) or HIV.125 Patients with HBsAg should be given prophylaxis before undergoing treatment with any immunosuppressive medication, including steroids, immunomodulators, or biologics, to prevent HBV reactivation. Lamivudine, the only medication used in randomized trials for HBV reactivation prophylaxis, is associated with a high rate of drug resistance.124 Although lamivudine may be appropriate for a short-duration prophylaxis during chemotherapy, immunosuppressive medications for IBD may be required indefinitely. Other antiviral medications for HBV, such as tenofovir, adefovir, telbivudine, and entecavir, have not been evaluated for the prophylaxis of HBV reactivation in immunosuppressed patients. Tenofovir and entecavir have the lowest rates of resistance with long-term use and may be the preferred agents for treatment of chronic HBV infection (in case patients actually have viremia) and for prophylaxis of reactivation (HBsAg positive, HBVDNA negative) when length of therapy is unknown.124 For


patients with isolated hepatitis B core antibody positivity, close monitoring of liver biochemistries is recommended, and HBV DNA should be checked if liver enzymes become elevated during treatment. Vaccination to prevent infection should also be performed in patients with IBD. The timing of HBV vaccination is important and preferably given before initiating therapy with immunomodulators or biologics. Hepatitis B surface antibody titers should be checked after HBV vaccination, particularly in older patients or patients previously or currently treated with immunosuppressive medications. Patients with an inadequate response should receive a second full series of HBV vaccine. Patients who fail a second series are unlikely to develop adequate immunologic response to HBV vaccine.125 An algorithm presenting the screening and management of patients with latent HBV is presented in Figure 3. Infection with HCV does not seem to be higher in patients with IBD, even though a study found that patients with CD (but not UC) younger than 50 years had a higher prevalence of the infection.125 Because patients with IBD with HCV are excluded from clinical trials, it becomes difficult to draw strong conclusions regarding the effects of IBD therapy on progression of HCV. Corticosteroids have a negative effect on HCV infection and can increase viral replication. Although this is seen in patients after OLT for HCV, no studies have been performed in patients with IBD. The experience with anti-TNF use in patients with chronic HCV is limited mainly to those with rheumatoid arthritis. A randomized controlled trial evaluating use of etanercept as adjuvant therapy to interferon and ribavirin found significant improvement in rates of virological response. Although this drug is not efficacious in controlling IBD, these results suggest that

FIGURE 3. Screening and management of latent hepatitis B in patients with IBD. Anti-HBs, hepatitis B surface antibody. www.ibdjournal.org |

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other anti-TNF agents may be safely used in patients with HCV.126 Other immunomodulators, including AZA and cyclosporine, are commonly used in post-OLT patients and do not seem to worsen the HCV.125

OTHER LIVER DISEASES SEEN IN PATIENTS WITH IBD


contributes to amyloid deposition in the vasculature and sinusoids of almost every organ, including the liver; in some cases, the diagnosis of amyloidosis precedes that of IBD.138 The association is higher in men and in CD when compared with UC.138,139 Suppression of the IBD activity can potentially lead to the control of amyloid.140 The disease can induce multiple complications, including proteinuric renal dysfunction, but survival is excellent in patients who undergo renal transplantation.141 Colchicine, budesonide, and infliximab can be effective in selected cases.142,143

Portal Vein Thrombosis Patients with IBD are at a higher risk of developing vascular complications.127,128 The portal and mesenteric veins can also be affected and thrombosis of these vessels have been found in 1% to 2% of patients with IBD.129 Most studies are limited to retrospective series and have been heterogeneous in terms of presentation and prognosis. A multicenter retrospective study found that portomesenteric vein thrombosis can occur even when the IBD is inactive and in about 40% of the cases this is an incidental finding.130 Another study found that venous thrombosis is usually seen in the setting of abdominal surgery.131 The clinical course is usually benign and use of anticoagulation remains controversial.132,133 There is currently no consensus on when to screen patients for congenital mutations (e.g., factor V Leiden, protein C deficiency) but we need to have in mind that IBD by itself is a potential precipitating factor, and studies have revealed that patients with CD or UC do not seem to have a higher prevalence of genetic clotting abnormalities. However, patients may develop an acquired prothrombotic disorder, which is usually related to disease activity.134,135

Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease has been described as a clinical and pathological syndrome that embraces a wide spectrum of histologic findings ranging from benign steatosis of the liver to nonalcoholic steatohepatitis and fibrosis. Nonalcoholic steatohepatitis refers to hepatic steatosis associated with hepatic inflammation, is histologically indistinguishable from alcoholic steatohepatitis, and can progress to cirrhosis. The reported prevalence of nonalcoholic fatty liver disease in patients with IBD has been variable. Autopsy series found that up to 88% of patients with IBD have steatosis, even though these studies have a selection bias.136 The prevalence in population studies has ranged between 2% and 8%.7,137 A recent study found that small bowel surgery, hypertension, obesity, and steroid use were significantly associated with nonalcoholic steatohepatitis.137 After excluding corticosteroids, the other drugs used in the treatment of IBD do not seem to induce hepatic steatosis with the exception of MTX, which can produce macrovesicular steatosis, inflammation, and fibrosis just as seen in nonalcoholic fatty liver disease.116

Secondary Amyloidosis Secondary amyloidosis is associated with chronic inflammatory and infectious diseases. In IBD, where the prevalence has been reported around 3%,138 chronic inflammation of the gut

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Hepatic Abscess Hepatic abscesses are a rare complication of IBD and are usually seen in patients with CD. These patients are typically young, more likely to present with multiple liver abscesses, usually with an intra-abdominal focus of infection (rather than biliary), and the abscesses are commonly secondary to a Streptococcus.144 The presence of intra-abdominal abscesses, a penetrating (fistulous) CD phenotype, and corticosteroid therapy are known risk factors.145 Although rare, this complication should be considered in patients with unexplained fever and dedicated imaging should be obtained.

CONCLUSIONS Multiple liver diseases can be seen in the setting of IBD; some are associated with IBD, whereas others are secondary to metabolic changes induced by the IBD or due to adverse effect of the medications. A significant number of patients with IBD present with abnormal liver chemistries and identifying the etiology can be challenging because the differential diagnosis is broad and 2 or more diseases can co-exist. Management of these conditions can range from careful monitoring up to liver transplantation. It is imperative to anticipate these complications, use appropriate screening tools, and identify those cases that warrant early and aggressive treatment.

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Systematic review: The epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease.

Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver.

Hepatopancreatobiliary manifestations of inflammatory bowel disease.

Extraintestinal Manifestations of Inflammatory Bowel Disease.

Pulmonary manifestations of inflammatory bowel disease.

Neurologic Manifestations of Inflammatory Bowel Disease.

Posterior segment manifestations of inflammatory bowel disease.

Rheumatological manifestations in inflammatory bowel disease.

Management of Musculoskeletal Manifestations in Inflammatory Bowel Disease.

Hepatic manifestations of non-steroidal inflammatory bowel disease therapy.

Mucocutaneous manifestations of inflammatory bowel disease in Turkey.

Polypoid and pseudopolypoid manifestations of inflammatory bowel disease.

Biological therapy for dermatological manifestations of inflammatory bowel disease.

Infliximab-induced skin manifestations in patients with inflammatory bowel disease.

Ophthalmic manifestations in patients with inflammatory bowel disease: A review.

Endocrine and metabolic manifestations in inflammatory bowel disease.

Ophthalmologic manifestations in patients with inflammatory bowel disease.

Neurologic manifestations of inflammatory bowel diseases.

Association of extraintestinal manifestations and anaemia with disease outcomes in patients with inflammatory bowel disease.

Manifestations of inflammatory bowel disease in patients of Haitian and Cape Verdean descent.

Oral Manifestations of Inflammatory Bowel Diseases: Two Case Reports.

Small bowel imaging of inflammatory bowel disease.

Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients.

Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch-anal anastomosis.