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Liver abnormalities in bowel diseases
Best Practice & Research Clinical Gastroenterology 27 (2013) 531–542
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Best Practice & Research Clinical Gastroenterology
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Liver abnormalities in bowel diseases Martin Kummen, MD, Research Fellow a, b,1, Erik Schrumpf, MD, PhD, Prof. em. a, b, 2, Kirsten Muri Boberg, MD, PhD, Prof. a, b, c, * a
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway c Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway b
a b s t r a c t Keywords: Biliary tract disease Celiac disease Inflammatory bowel disease Liver disease Primary sclerosing cholangitis
Liver abnormalities are often seen in bowel diseases. Whether these represent aspects of two separate diseases, or if one is causing the other, is not always easy to decide. Extraintestinal manifestations of inflammatory bowel disease (IBD) or coeliac disease are frequently observed. Of these extraintestinal manifestations, hepatic disorders are among the most common. Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis are the most frequent hepatic disorders in IBD and coeliac disease, respectively. Genetic studies have lately elucidated the associations between IBD and PSC, but there is still a long way until we have complete understanding of the molecular aetiology and pathophysiology of these conditions. There is no curative treatment available for PSC, besides liver transplantation. Steatosis and cholelithiasis are also common in IBD, as are signs of hepatic injury due to IBD treatment. Less common liver abnormalities include liver abscesses, hepatic thromboembolic events, granulomatous liver disease and hepatic amyloidosis. Ó 2013 Elsevier Ltd. All rights reserved.
* Corresponding author. Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway. Tel.: þ47 23 07 00 00; fax: þ47 23 07 39 28. E-mail addresses: [email protected] (M. Kummen), [email protected] (E. Schrumpf), kboberg@ ous-hf.no, [email protected] (K.M. Boberg). 1 Tel.: þ47 23 07 36 82; fax: þ47 23 07 39 28. 2 Tel.: þ47 23 07 36 42; fax: þ47 23 07 39 28. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.013
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Introduction It has been known for almost 150 years that bowel disease can be accompanied by abnormalities in other organs, in particular the liver [1]. Depending upon the population studied, as many as 40% of patients with inflammatory bowel disease (IBD) show signs of extraintestinal manifestations [2,3]. Hepatobiliary abnormalities have been described in 4.7%–29% of IBD patients [4,5]. A true estimate of the frequency of hepatobiliary disorders associated with IBD is, however, difficult to produce since studies of unselected patients with a complete workup, including liver biopsy and endoscopic retrograde cholangiography (ERC), cannot be justified due to ethical reasons. Liver abnormalities are also often seen in coeliac disease. When the patients convert to a gluten free diet, most abnormal liver biochemistry tests normalize [6]. Kaukinen et al reported on four patients with end stage liver failure, of which three were referred for liver transplantation. All four patients subsequently proved to have coeliac disease, and they all recovered after starting gluten free diet [7]. This observation underscores the importance of having bowel diseases in mind when evaluating liver pathology. In this review, we present the clinically most important hepatic manifestations and complications seen in patients with bowel disease, with main focus on ulcerative colitis (UC), Crohn’s disease (CD) and coeliac disease (Table 1). Liver abnormalities seen in malignant bowel diseases and their treatment are beyond the scope of this review. Primary sclerosing cholangitis In UC, primary sclerosing cholangitis (PSC) is the most important associated hepatic disorder, affecting 2.9%–7.6% of patients [8–10]. The prevalence of PSC in CD patients is lower, with estimates varying between 0.7% and 3.4% [5,8,11]. Regarding patients with PSC, the association with IBD is striking. Up to 80% of PSC patients have concomitant IBD, although there is a considerable geographical variation [12]. PSC is also seen in coeliac disease, but the association is much weaker than with IBD [12– 15]. There is a male predominance in PSC, with a male:female-ratio of 2:1. PSC patients often suffer from other autoimmune diseases, apart from IBD [16–18]. Patients are relatively young at diagnosis of PSC, with a mean age between 30 and 40 years [16,19]. Aetiology and pathogenesis Although the aetiology and pathogenesis of PSC are not completely understood, advances in the elucidation of disease mechanisms have been made during recent years [18,20]. PSC is generally considered an immune-mediated, rather than an autoimmune disease, for several reasons. First, there is no proof of a disease-specific autoantibody like anti-transglutaminase 2 (anti-TG2) in coeliac disease
Table 1 Liver abnormalities associated with IBD and coeliac disease. Liver abnormality
Primary sclerosing cholangitis (PSC) Small-duct PSC IgG4-associated cholangitis Autoimmune hepatitis Primary biliary cirrhosis Fatty liver Cholelithiasis Less common abnormalities Thromboembolic complications Liver abscess Hepatic amyloidosis Granulomatous liver disease
Associated with Ulcerative colitis
Crohn’s disease
Coeliac disease
þþ þþ (þ) þ (þ) þ
þ þ (þ)
(þ)
þ
þ þ þ þ þ þ
þ þþ þ
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and the antimitochondrial antibody directed against the dihydrolipoyl transacetylase (PDC-E2) in primary biliary cirrhosis (PBC). Second, there is a predominance of male patients in PSC, in contrast to the female predominance seen in most auto-immune diseases [18]. Last, immunosuppressive treatment has not been successful in treating PSC patients. Three complimentary pathways have been described in an effort to explain PSC aetiology and pathogenesis. (1) A number of studies have supported the existence of a genetic susceptibility. (2) The hypothesis of the ‘leaky-gut’, which is compatible with the close relationship between PSC and IBD [18,21,22]. This hypothesis also involves the possibility of ‘aberrant lymphocyte homing’. (3) The hypothesis on the possible role of ‘toxic bile’ causing bile duct injury [12,23]. Studies on environmental factors in PSC are scarce, although a protective effect of smoking has been suggested [12,24]. Genetic susceptibility Siblings of PSC patients have 9–39 times increased risk of acquiring PSC compared to the general population, supporting the concept that heritable factors are involved [25]. In a series of studies, 16 highly robust and several additional suggestive genetic risk loci have been associated with PSC [20,26,27]. It is of interest that almost half of these overlap with susceptibility loci for IBD [20,27]. About half also overlap with susceptibility loci for autoimmune diseases, e.g. type one diabetes, thyroid disease, psoriasis and coeliac disease. Most of the genetic loci found to be associated with PSC are related to inflammatory pathways. The strongest association is located within the major histocompability complex (MHC) at chromosome 6p21 and peaks near the classical HLA class I genes that are involved in presentation of molecules to T-cells and NK-cells [28]. It is also of interest that genetic risk variants for disease, like FUT2 which is a susceptibility gene in both CD and PSC, have been shown to influence the composition of the gut microbiota [20,29]. The ‘leaky gut’ hypothesis Gut microbiota may influence metabolic and inflammatory pathways within the bile ducts and the liver. These effects are thought to occur by ‘leakage’ of bacterial products from the gut in the setting of prolonged and active intestinal inflammation, disturbing the gut mucosal barrier function and leading to increased intestinal permeability, followed by portal inflammation [20,30]. T-cells activated in the intestine in IBD can further contribute to this portal inflammation by so called ‘aberrant homing’ of lymphocytes: T-cells are recruited to the liver by means of adhesion molecules and chemokines that normally are restricted to the intestine, but which under certain conditions are expressed in the liver [18,20,31]. The ‘toxic bile’ hypothesis The third important hypothesis regarding the pathogenesis of PSC suggests that an altered (‘toxic’) bile composition along with defective protection systems in the biliary epithelium, could contribute to bile duct injury and cholangitis [12,18,20]. The cholangitis phenotype due to toxic bile observed in mice and humans with defects in the phospholipid transporter ABCB4 supports this hypothesis [23].
Clinical presentation and diagnosis Disease development in PSC is usually insidious, and as many as 44% of the patients have no liver related symptoms at the time of diagnosis. The onset of pathology is thought to precede that of clinical onset by several years [16,30]. The ‘typical’ clinical scenario for PSC is a patient with IBD, usually male, who presents with signs of clinical and/or biochemical cholestasis. Alkaline phosphatase activity is often elevated two to three times the upper limit of normal [16,32]. Presenting symptoms include jaundice, abdominal pain, fever and fatigue, sometimes in the setting of bacterial cholangitis. Rarely, patients present with sign of portal hypertension, like variceal bleeding or ascites [16,19,30]. Most
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patients have already been diagnosed with IBD, but in 20%–40% of cases the diagnosis of PSC precedes that of IBD [18]. One has to pursue and exclude aetiologies of secondary cholangitis first, since PSC is a diagnosis of exclusion [18,33]. A complete medical history with occupational and drug history should be obtained [18,33]. Ultrasonography is often the first imaging modality used, sometimes with computed tomography (CT) as a useful supplement, to diagnose extra-hepatic obstruction. If these examinations and serological tests (the most important being anti-mitochondrial antibodies (AMA)) are negative, cholangiography is the next step, by means of magnetic resonance cholangiography (MRC) or ERC. MRC is a safe option with far less complications compared to ERC, with good accuracy in detecting obstruction of the biliary tree [33]. The advantages of ERC include the possibility to perform interventions if indicated. The cholangiogram is characterized by diffusely distributed, multifocal, short strictures, alternating with normal or slightly dilated segments producing a ‘beaded’ pattern [18,33]. If the cholangiogram is normal, a liver biopsy is required for detection of possible small-duct PSC, further elaborated upon below [33]. A schematic overview of the diagnostic process in PSC and related cholestatic disorders associated with IBD, is shown in Fig. 1.
Fig. 1. A schematic overview of the diagnostic process in PSC and related cholestatic disorders associated with IBD [33,34]. IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiography; ERC, endoscopic retrograde cholangiography; PSC, primary sclerosing cholangitis; IAC, IgG4-associated cholangitis; >IgG4, elevated IgG4.
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It is recommended that all PSC patients without a previous diagnosis of IBD undergo a colonoscopy with biopsies, since colitis in PSC tends to be clinically mild and sometimes asymptomatic [33,34]. Colonoscopy with biopsies should also be performed during surveillance and follow-up of PSC [33–35]. The majority (approximately 80%) of PSC patients with IBD are diagnosed with UC, but there are several features of the colitis in PSC that deviates from the ‘classical’ UC. The PSC patients typically present with increased incidence of pancolitis, rectal spearing, ileal involvement, right-sided colitis and a higher frequency of colorectal malignancy [20,35,36]. Data also suggest that there is a predominantly rightsided inflammation increasing towards the ileum, contrasting UC patients without liver disease [20,35]. On this basis, the IBD in PSC has been proposed to represent a distinct sub-entity of IBD, (‘PSCIBD’), but as of today, this denomination has not been implemented in clinical practice [20,35,36]. Disease course, treatment and transplantation The disease course in PSC is often quiescent regarding clinical signs and symptoms. In some patients, the course is characterized by intermittent fluctuations. In most cases, the disease will ultimately progress, with increasing signs of cholestasis and cirrhosis, until liver failure arises [19]. On a histopathological level, four discrete stages of the disease have been defined, ranging from mild portal inflammation to established cirrhosis [33,37]. There is no disease specific medical treatment available for PSC that has impact on endpoints like transplant free survival or mortality [18]. Treatment with ursodeoxycholic acid (UDCA) is debated. A follow-up of a previous randomized controlled trial of high-dose (28–30 mg/kg/day) UDCA versus placebo [38] revealed an increased risk of colorectal neoplasia in UDCA treated patients with PSC and UC. A recent metaanalysis found no effect of UDCA on the risk of colorectal neoplasia, but sub-group analysis showed a significant 65% reduction in the risk of advanced neoplasia (colorectal cancer and/ or high grade dysplasia) [39]. The recommendations regarding UDCA treatment in PSC differ somewhat between the recent European [33] and American [34] practice guidelines. The European guidelines state that the limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC, while the American guidelines recommend against the prescription of UDCA in adult patients with PSC [20,33,34]. Dominant strictures (stenosis <1.5 mm in diameter in the common bile duct and <1 mm in the left and right hepatic ducts) should be treated with dilatation in symptomatic patients [33,34]. Biliary stents can also be used if dilatation has unsatisfactory effect, and should be followed by antibiotic prophylaxis [33]. Median survival after diagnosis of PSC is 10–12 years [18]. The only curative option for patients with end stage liver disease in PSC is liver transplantation. Prognosis after liver transplantation is good with 5- and 10-year survival rates up to 85% [18]. PSC relapse is possible, but its frequency is a matter of debate [18,20,30]. Cholangiocarcinoma Cholangiocarcinoma is the most feared complication in PSC. This malignancy affects 10–15% of patients, representing a 160-fold increased risk compared to the general population [33,40]. About half of the cholangiocarcinoma cases are diagnosed within the first year after diagnosis of PSC [18,20]. The carbohydrate antigen 19-9 (CA 19-9) is the most frequently used serological biomarker for cholangiocarcinoma, but the test is hampered by limited sensitivity and specificity [33,34,41]. MRC and CT may be useful radiological modalities. ERC with brush cytology of the biliary tree has a good specificity but variable sensitivity that may be improved by molecular techniques [33,34,42]. Liver transplantation can be a treatment option in highly selected cases [18,20,43]. Prognosis of cholangiocarcinoma in PSC is very poor, with two year survival being very unusual [18,34,41]. Small-duct PSC The condition that originally was designated pericholangitis, is now commonly referred to as smallduct PSC [44]. Small-duct PSC clinically resembles large-duct PSC, both regarding a cholestatic
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biochemical pattern and histopathological findings of bile duct injury on liver biopsy, but is characterized by a normal cholangiogram [12,44]. Up to 100% of the patients have IBD, depending on the definition of small-duct PSC, with a UC:CD ratio of about 4:1 [12,36,45,46]. Patients with small-duct PSC and CD have a female predominance, as opposed to patients with large-duct PSC and UC [9,11]. In contrast to the case in large-duct PSC, the incidence of cholangiocarcinoma in small-duct PSC seems negligible [12,45]. Several studies have shown that small-duct PSC has a better prognosis than largeduct PSC, with a longer median survival free of liver transplantation and other major clinical events [45,47]. IgG4-associated cholangitis IgG4-associated cholangitis (IAC) is a newly defined entity that was first described in 2006 [48]. According to clinical practice guidelines [20,33,34], IAC is considered a secondary sclerosing cholangitis. Some data suggest that the immunopathogenesis of IAC differs from that of other immunemediated cholestatic liver diseases like PSC and PBC [18,20]. IAC is also seen in patients with IBD, although this association is far less pronounced than that of PSC and IBD [33]. It is important to consider IAC in the differential diagnosis of PSC because of its remarkable responsiveness to corticosteroid therapy [18,20]. A positive response to steroids is part of the diagnostic criteria of IAC [20,33]. Besides this, the patient must fulfil two or more of the four main manifestations: (1) Elevated serum levels of IgG4. PSC patients can have minor elevations of serum IgG4, and a distinct cut-off level for discrimination between PSC and IAC based on IgG4 serum levels alone has not been established. The relevance of elevated IgG4 in PSC patients is so far unknown. (2) Imaging modalities showing suggestive pancreatic findings. (3) Biopsies of the papilla Vateri and the common bile duct with more than ten IgG4-positive cells per high power field. (4) Involvement of other organs [18,20,33]. IAC can also be diagnosed on one of the following criteria alone: (A) Biopsy of pancreas or pancreatic/biliary resection shows diagnostic features of autoimmune pancreatitis (AIP) or IAC, or (B) classical imaging findings of AIP and elevated serum IgG4 [20,33]. Autoimmune hepatitis and overlap syndromes Autoimmune hepatitis (AIH) has been linked to IBD, especially to CD, as well as to coeliac disease [8,13]. Of patients with AIH and IBD, a significant proportion of patients turns out to have PSC if cholangiography is performed [8,49]. These patients have often been classified as PSC/AIH-overlap patients. It is, however, very difficult to compare and draw conclusions from earlier studies because the overlap syndromes are poorly defined [8,33]. The International Autoimmune Hepatitis Group has therefore proposed that patients with autoimmune liver disease should be categorized as AIH, PBC and PSC/small-duct PSC, respectively [50]. Patients with PBC or PSC that develop features of AIH should be considered for immunosuppressive treatment [8,50]. Primary biliary cirrhosis The link between coeliac disease and PBC is well established, and the increased risk of PBC in coeliac disease compared to controls varies between studies from 3- to 20-fold [6,14,51]. PBC is the most common liver disease in coeliac disease. PBC and coeliac disease share several pathophysiological and clinical features. Both are regarded as autoimmune disorders with a female predominance, autoimmune comorbidity and an immune response against autoantigens (TG2 and PDC-E2 in coeliac disease and PBC, respectively) [51,52]. Increased intestinal permeability is seen early in coeliac disease and can cause increased exposure of gut microbial antigens to the immune system, especially in the liver [6,51,53]. The theory of microbial mediated molecular mimicry as a trigger of PBC and findings in several studies showing association between the gut microbiota and coeliac disease, support the possibility of a common pathogenic link between coeliac disease and PBC [6,51,52,54]. Patients with coeliac disease and PBC often present with similar symptoms, like malabsorption, weight loss, osteopenia, steatorrhoea, anaemia and fatigue as well as with abnormal liver biochemistry tests [13,51].
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Elevated aminotransferases are commonly found in untreated coeliac disease patients, and the possibility of liver disease must be evaluated if they do not normalize after initiation of gluten free diet [6,55,56]. In patients with persisting liver abnormalities after introduction of a gluten free diet, the diagnosis of PBC should be looked for by the analysis of AMA [51]. There is a possible link between PBC and IBD, but this is not well established. Males with UC seem to be more prone to PBC than their female counterparts. UC patients with PBC tend to have a more limited bowel disease, with a predominance of left sided colitis and proctitis [46]. Fatty liver Patients with IBD as well as patients with coeliac disease have been reported to have an increased risk of fatty liver changes [14,46,57]. Liver steatosis has been found in as many as 35% of patients with IBD by ultrasound screening [46,58]. Fatty changes have been shown to correlate with colitis severity, but are also found in asymptomatic patients [46,57]. Corticosteroid therapy, parenteral nutrition, small bowel surgery and malnutrition may be contributing factors for the development of fatty liver changes in IBD patients. Likewise, malnutrition may be a predisposing factor in coeliac disease [13,57,59]. Treatment focuses on induction of remission of the bowel disease and improving nutritional status. Cholelithiasis There is a well-documented increased risk of gallstones in CD, particularly when the disease affects the terminal ileum, or if this segment has been surgically removed [60–62]. However, the prevalence varies significantly between studies [62]. Bile supersaturated with cholesterol and increased bilirubin content has been suggested to increase the risk of gallstones in CD, though the former seems only to be the case when the disease involves the ileum [63,64]. Some studies have also found reduced motility and emptying of the gallbladder in patients with CD and suggest these as possible contributing factors to gallstone formation, but this hypothesis is controversial [65,66]. Interestingly, reduced gallbladder motility has also been shown in coeliac disease, explained by reduced secretion of cholecystokinin [67]. There is, however, no epidemiological evidence of increased risk of gallstones in coeliac disease. UC patients seem to carry the same risk of cholelithiasis as controls [60,61]. Less common liver abnormalities Liver abscess Liver abscesses are rare in IBD patients. They may occur, however, and are then more often seen in CD than in UC. Streptococcus species are the most common pathogens and are isolated in a high percentage of liver abscesses in IBD patients, in contrast to the combination of several gram-negative strains often seen in liver abscesses in the general population [68]. Prolonged treatment with intravenous antibiotics, with or without percutaneous drainage, is the treatment of choice [69]. If antibiotic therapy does not have the expected effect and cultures are negative, it is important to consider the differential diagnosis of an aseptic abscess. Aseptic abscesses are characterized by deep, sterile, round lesions consisting of neutrophils and involving the liver in 40% of cases. They are thought to represent a non-infectious inflammatory disorder [70,71], and treatment with corticosteroids has a striking effect. An amoebic liver abscess is the most common extraintestinal manifestation in intestinal amoebiasis [72]. It is noteworthy that some patients presenting with a liver abscess can have synchronous amoebic colitis without bowel symptoms, and that microscopy of stool is often negative for trophozoites and cysts [72]. Liver abscesses have also been reported in other infectious bowel diseases, like those caused by Clostridium difficile and Edwardsiella tarda [73,74]. Thromboembolic complications IBD patients carry a 2–3 fold risk of thromboembolic events, and approximately half of the patients have no other identifiable risk factor [75–77]. Patients with coeliac disease do not seem to have an
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increased risk, but cases have been reported [13]. Thrombosis of the portal or liver veins, the latter causing Budd–Chiari syndrome, are rare but potentially critical complications in IBD patients [78–80]. The acute thromboembolic episode may be asymptomatic or produce non-specific symptoms, which makes it easy to overlook. It is nevertheless important to bear this possibility in mind, especially in patients with an active phase of inflammation where the risk increases substantially [79,81,82]. Hepatic amyloidosis Secondary amyloidosis in IBD is rare, affecting <1% of patients. This complication is seen about ten times more often in CD than in UC [83,84]. Hepatic amyloidosis seldom causes elevation of hepatic biochemistry or hepatomegaly. Treatment with colchicine has been used, and recent case reports have described successful response to treatment with both budesonide and infliximab [84–86]. Granulomatous liver diseases Granulomatous liver diseases have been observed in up to 15% of liver biopsies, and occur both in IBD and in several infectious bowel diseases. Patients using tumour necrosis factor antagonists (TNF-a inhibitors) have an increased risk of infectious granulomatous complications [87]. Liver abnormalities associated with treatment of bowel diseases Hepatic injuries due to standard medications used in the treatment of IBD are common. It can be a challenge for the clinician to distinguish between potential side effects of drugs and other hepatic involvement when confronted with signs of hepatic injury in an IBD patient. Thiopurines Three thiopurines are used in the treatment of IBD, including azathioprine, mercaptopurine and thioguanine. Up to 39% of patients receiving these compounds experience side effects, most of these occurring within the first three months. Hepatotoxicity is not uncommon [88–91]. The overall risk of drug-induced liver injury per patient-treatment-year seems to be just above 1% [90]. Surveillance of liver biochemistry is warranted in patients using thiopurines, and asymptomatic elevated transaminases often respond to dose reduction [89,92]. The other hepatological side effects include hepatocellular necrosis, cholestasis, sinusoidal dilatation, veno-occlusive disease, peliosis hepatis, nodular regenerative hyperplasia and hepatosplenic T-cell lymphoma [92–95]. Sulfasalazine and mesalazine Sulfasalazine can cause acute hepatocellular damage as part of hypersensitivity reaction, which is relatively infrequent [96]. It usually occurs within the first two months of treatment. Cholestasis and acute granulomatous hepatitis have also been reported [93]. Acute liver failure is uncommon, and occurs in 1.4 in 1000 persons treated [96]. Mesalazine has less hepatological side affects than sulfasalazine, often reported at the level of placebo [93,97]. A report from the UK in 2003 calculated a frequency of drug induced liver injury of mesalazine of 3.2 per million prescriptions [97]. TNF-a inhibitors The TNF-a inhibitors infliximab and adalimumab are both used in UC and CD. Minor elevation of transaminases are reported in up to 18% of patients [98]. Infliximab-induced hepatitis and hepatosplenic T-cell lymphoma have also been reported, although the latter is controversial [46,93,95]. Other drugs that can cause hepatic side effects, but are not further evaluated here, include ciclosporin, other 5-aminosalicylates (balsalazide and olsalazine), other biological agents (certolizumab and
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natalizumab), methotrexate, quinolones and other antibiotics used in infectious bowel disorders and sometimes in IBD. Total parenteral nutrition Total parenteral nutrition is administrated to IBD patients with intestinal failure of various causes. Parenteral nutrition is known to be associated with biochemical and histological hepatic dysfunction like steatosis, cholestasis and cirrhosis [99]. The duration of the total parenteral nutrition and the length of bowel resection are risk factors for cholestasis, which can be reversible [99,100]. Summary Bowel diseases may be associated with liver abnormalities. PSC is the most important hepatobiliary disorder in IBD, and PBC is the most frequently observed hepatic abnormality in coeliac disease. There is still no medical treatment available for PSC, making this condition one of the most common indications for liver transplantation in western counties. It is important to differentiate PSC from AIC and to identify features of AIH in PSC, in order to diagnose conditions that may be available to immunosuppressive therapy. Abnormal liver biochemistry is common at diagnosis of coeliac disease, and secondary causes should be sought if they do not normalize within six months of starting a gluten free diet. The pathophysiological link between PSC and IBD and PBC and coeliac disease, respectively, are still not fully understood, although, recent advances in genetic studies have given some clues. Other, complimentary pathophysiological pathways, must be elucidated if we are to find new treatment possibilities of the hepatobiliary disorders that are associated with bowel diseases.
Practice points Primary sclerosing cholangitis is the most common and most important liver disease in IBD patients. Colonoscopy screening with biopsies should be performed in all PSC patients. Primary biliary cirrhosis is the most common liver disease in coeliac disease. The possible presence of coeliac disease should be investigated in patients with severe liver disease.
Research agenda
Further explore aetiology and pathogenesis in PSC and its relationship to IBD. Search for medical treatment in PSC. Provide better tools for diagnosing IgG4-accociated cholangitis. The role of the gut microbiota in the relationship between bowel disease and liver abnormalities should be further investigated.
Conflicts of interest None. Acknowledgements Financial support: This study was supported by the Norwegian PSC Research Center (http://ousresearch.no/nopsc/).
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References [1] Hoffman CEE. Versehluss der Gallenwege durch Verdiekang der Wandungen. Arch Pathol Anat Physiol Klin Med 1867;39: 206–15. [2] Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005;129:827–36. [3] Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study. Inflamm Bowel Dis 2004;10:207–14. [4] Mendes FD, Levy C, Enders FB, Loftus EV, Angulo P, Lindor KD. Abnormal hepatic biochemistries in patients with inflammatory bowel disease. Am J Gastroenterol 2007;102:344–50. [5] Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96:1116–22. [6] Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology 2007;46:1650–8. [7] Kaukinen K, Halme L, Collin P, Färkkilä M, Mäki M, Vehmanen P, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002;122:881–8. [8] Saich R, Chapman R. Primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes in inflammatory bowel disease. World J Gastroenterol 2008;14:331–7. [9] Olsson R, Danielsson A, Järnerot G, Lindström E, Lööf L, Rolny P, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991;100:1319–23. [10] Schrumpf E, Fausa O, Kolmannskog F, Elgjo K, Ritland S, Gjone E. Sclerosing cholangitis in ulcerative colitis. A follow-up study. Scand J Gastroenterol 1982;17:33–9. [11] Rasmussen HH, Fallingborg JF, Mortensen PB, Vyberg M, Tage-Jensen U, Rasmussen SN. Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn’s disease. Scand J Gastroenterol 1997;32:604–10. [12] Karlsen TH, Schrumpf E, Boberg KM. Update on primary sclerosing cholangitis. Dig Liver Dis 2010;42:390–400. [13] Freeman HJ. Hepatic manifestations of celiac disease. Clin Exp Gastroenterol 2010;3:33–9. [14] Ludvigsson JF, Elfström P, Broomé U, Ekbom A, Montgomery SM. Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol 2007;5:63–9. [15] Lawson A, West J, Aithal GP, Logan RFA. Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther 2005;21:401–5. [16] Bergquist A, Said K, Broomé U. Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol 2007;42:88–93. [17] Sinakos E, Samuel S, Enders F, Loftus EV, Sandborn WJ, Lindor KD. Inflammatory bowel disease in primary sclerosing cholangitis: a robust yet changing relationship. Inflamm Bowel Dis 2013;19:1004–9. [18] Krones E, Graziadei I, Trauner M, Fickert P. Evolving concepts in primary sclerosing cholangitis. Liver Int 2012;32: 352–69. [19] Karlsen TH, Schrumpf E, Boberg KM. Primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2010;24:655–66. [20] Karlsen TH, Boberg KM. Update on primary sclerosing cholangitis. J Hepatol 2013;59:571–82. [21] Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hübscher SG, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9þ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med 2004;200: 1511–7. [22] Hillan KJ, Hagler KE, MacSween RN, Ryan AM, Renz ME, Chiu HH, et al. Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease. Liver 1999;19:509–18. [23] Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 2007;27:77–98. [24] Loftus EV, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR, Offord KP, et al. Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology 1996;110:1496–502. [25] Bergquist A, Lindberg G, Saarinen S, Broomé U. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol 2005;42:252–6. [26] Janse M, Lamberts LE, Franke L, Raychaudhuri S, Ellinghaus E, Boberg KM, et al. Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. Hepatology 2011;53: 1977–85. [27] Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 2013;45:670–5. [28] Næss S, Shiryaev A, Hov JR, Franke A, Karlsen TH. Genetics in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2012;36:325–33. [29] Rausch P, Rehman A, Künzel S, Häsler R, Ott SJ, Schreiber S, et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci U S A 2011;108: 19030–5. [30] Weismüller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP. The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 2008;48(Suppl. 1):S38–57. [31] Adams DH, Eksteen B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat Rev Immunol 2006;6:244–51. [32] Broomé U, Olsson R, Lööf L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–5. [33] European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. [34] Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–78.
M. Kummen et al. / Best Practice & Research Clinical Gastroenterology 27 (2013) 531–542
541
[35] Jørgensen KK, Grzyb K, Lundin KEA, Clausen OPF, Aamodt G, Schrumpf E, et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis 2012;18:536–45. [36] Loftus EV, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54:91–6. [37] Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1981;1:632–40. [38] Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VAC, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011;106:1638–45. [39] Singh S, Khanna S, Pardi DS, Loftus EV, Talwalkar JA. Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2013;19:1631–8. [40] Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321–7. [41] Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011; 54:1842–52. [42] Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2006;45:568–74. [43] Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8. [44] Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts? Ann Intern Med 1985;102:581–7. [45] Björnsson E, Olsson R, Bergquist A, Lindgren S, Braden B, Chapman RW, et al. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology 2008;134:975–80. [46] Navaneethan U, Shen B. Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. Inflamm Bowel Dis 2010;16:1598–619. [47] Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, et al. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn’s disease. J Crohns Colitis 2012;6:174–81. [48] Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070–5. [49] Perdigoto R, Carpenter HA, Czaja AJ. Frequency and significance of chronic ulcerative colitis in severe corticosteroidtreated autoimmune hepatitis. J Hepatol 1992;14:325–31. [50] Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374–85. [51] Volta U, Caio G, Tovoli F, de Giorgio R. Gut-liver axis: an immune link between celiac disease and primary biliary cirrhosis. Expert Rev Gastroenterol Hepatol 2013;7:253–61. [52] Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 2013;13:294–302. [53] Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012;590:447–58. [54] Wacklin P, Kaukinen K, Tuovinen E, Collin P, Lindfors K, Partanen J, et al. The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease. Inflamm Bowel Dis 2013;19:934–41. [55] Casella G, Antonelli E, Bella CD, Villanacci V, Fanini L, Baldini V, et al. Prevalence and causes of abnormal liver function in patients with coeliac disease. Liver Int 2013;33:1128–31. [56] Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–76. [57] McGowan CE, Jones P, Long MD, Barritt AS. Changing shape of disease: nonalcoholic fatty liver disease in Crohn’s diseaseA case series and review of the literature. Inflamm Bowel Dis 2012;18:49–54. [58] Gisbert JP, Luna M, González-Lama Y, Pousa ID, Velasco M, Moreno-Otero R, et al. Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients. Inflamm Bowel Dis 2007;13:1106–14. [59] Sourianarayanane A, Garg G, Smith TH, Butt MI, McCullough AJ, Shen B. Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease. J Crohns Colitis 2013;7:e279–85. [60] Lapidus A, Bångstad M, Aström M, Muhrbeck O. The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol 1999;94:1261–6. [61] Parente F, Pastore L, Bargiggia S, Cucino C, Greco S, Molteni M, et al. Incidence and risk factors for gallstones in patients with inflammatory bowel disease: a large case-control study. Hepatology 2007;45:1267–74. [62] Masclee AA, Vu MK. Gallbladder motility in inflammatory bowel diseases. Dig Liver Dis 2003;35(Suppl. 3):S35–8. [63] Lapidus A, Akerlund JE, Einarsson C. Gallbladder bile composition in patients with Crohn’s disease. World J Gastroenterol 2006;12:70–4. [64] Dowling RH, Bell GD, White J. Lithogenic bile in patients with ileal dysfunction. Gut 1972;13:415–20. [65] Damião AO, Sipahi AM, Vezozzo DP, Gonçalves PL, Fukui P, Laudanna AA. Gallbladder hypokinesia in Crohn’s disease. Digestion 1997;58:458–63. [66] Vu MK, Gielkens HA, van Hogezand RA, van Oostayen JA, Lamers CB, Masclee AA. Gallbladder motility in Crohn disease: influence of disease localization and bowel resection. Scand J Gastroenterol 2000;35:1157–62. [67] Fraquelli M, Bardella MT, Peracchi M, Cesana BM, Bianchi PA, Conte D. Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac disease. Am J Gastroenterol 1999;94:1866–70. [68] Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscess in inflammatory bowel disease: report of two cases and review of the literature. J Gastroenterol Hepatol 2004;19:1338–42. [69] Albuquerque A, Magro F, Rodrigues S, Lopes S, Pereira P, Melo RB, et al. Liver abscess of the caudate lobe due to Staphylococcus aureus in an ulcerative colitis patient: first case report. J Crohns Colitis 2011;5:360–3.
542
M. Kummen et al. / Best Practice & Research Clinical Gastroenterology 27 (2013) 531–542
[70] André MFJ, Piette JC, Kémény JL, Ninet J, Jego P, Delèvaux I, et al. Aseptic abscesses: a study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore) 2007;86:145–61. [71] Zakout R, Fonseca M, Santos JM, Marques A, Távora I, Oliveira E, et al. Multiple aseptic liver abscesses as the initial manifestation of Crohn’s disease: report of a case. Dis Colon Rectum 2009;52:343–5. [72] Stanley SL. Amoebiasis. Lancet 2003;361:1025–34. [73] Sakurai T, Hajiro K, Takakuwa H, Nishi A, Aihara M, Chiba T. Liver abscess caused by Clostridium difficile. Scand J Infect Dis 2001;33:69–70. [74] Ohara Y, Kikuchi O, Goto T, Yoshida T, Mori H, Matsueda K, et al. Successful treatment of a patient with sepsis and liver abscess caused by Edwardsiella tarda. Intern Med 2012;51:2813–7. [75] Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:657–63. [76] Kappelman MD, Horvath-Puho E, Sandler RS, Rubin DT, Ullman TA, Pedersen L, et al. Thromboembolic risk among danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011;60:937–43. [77] Jackson LM, O’Gorman PJ, O’Connell J, Cronin CC, Cotter KP, Shanahan F. Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden. QJM 1997;90:183–8. [78] Jackson CS, Fryer J, Danese S, Vanagunas A, Polensky S, Buchman AL. Mesenteric vascular thromboembolism in inflammatory bowel disease: a single center experience. J Gastrointest Surg 2011;15:97–100. [79] Maconi G, Bolzacchini E, Dell’Era A, Russo U, Ardizzone S, de Franchis R. Portal vein thrombosis in inflammatory bowel diseases: a single-center case series. J Crohns Colitis 2012;6:362–7. [80] Dacha S, Devidi M, Osmundson E. Budd-Chiari syndrome in a patient with ulcerative colitis and no inherited coagulopathy. World J Hepatol 2011;3:164–9. [81] Spina L, Saibeni S, Battaglioli T, Peyvandi F, de Franchis R, Vecchi M. Thrombosis in inflammatory bowel diseases: role of inherited thrombophilia. Am J Gastroenterol 2005;100:2036–41. [82] Landman C, Nahon S, Cosnes J, Bouhnik Y, Brixi-Benmansour H, Bouguen G, et al. Portomesenteric vein thrombosis in patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:582–9. [83] Wester AL, Vatn MH, Fausa O. Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998. Inflamm Bowel Dis 2001;7:295–300. [84] Sattianayagam PT, Gillmore JD, Pinney JH, Gibbs SDJ, Wechalekar AD, Gilbertson J a, et al. Inflammatory bowel disease and systemic AA amyloidosis. Dig Dis Sci 2013;58:1689–97. [85] Cabezuelo JB, Egea JP, Ramos F, Torrella E, Muray S, Alcázar C. Infliximab in the treatment of amyloidosis secondary to Crohn’s disease. Nefrologia 2012;32:385–8. [86] Wang Y, Lee H, Shen B. Systemic secondary amyloidosis in a 70-year-old patient with Crohn’s disease: treatment with oral budesonide. Inflamm Bowel Dis 2013;19:E74–5. [87] Coash M, Forouhar F, Wu CH, Wu GY. Granulomatous liver diseases: a review. J Formos Med Assoc 2012;111:3–13. [88] Jharap B, Seinen ML, de Boer NKH, van Ginkel JR, Linskens RK, Kneppelhout JC, et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010;16:1541–9. [89] Frei P, Biedermann L, Nielsen OH, Rogler G. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol 2013;19:1040–8. [90] Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007;102:1518–27. [91] Nielsen OH, Bjerrum JT, Herfarth H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol 2013;53:575–88. [92] Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013;19:1699– 706. [93] Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis 2010;28: 508–18. [94] Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, et al. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007;56:1404–9. [95] Kotlyar DS, Osterman MT, Diamond RH, Porter D, Blonski WC, Wasik M, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9:36–41. [96] Jobanputra P, Amarasena R, Maggs F, Homer D, Bowman S, Rankin E, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: a case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008; 9:48. [97] Logan RF, van Staa TP. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the committee on safety of medicines. Gut 2003;52:536–9. [98] Coffin CS, Fraser HF, Panaccione R, Ghosh S. Liver diseases associated with anti-tumor necrosis factor-alpha (TNF-a) use for inflammatory bowel disease. Inflamm Bowel Dis 2011;17:479–84. [99] Gura KM, Lee S, Valim C, Zhou J, Kim S, Modi BP, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008;121:e678–86. [100] Raphael BP, Duggan C. Prevention and treatment of intestinal failure-associated liver disease in children. Semin Liver Dis 2012;32:341–7.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
5
Liver abnormalities in bowel diseases Martin Kummen, MD, Research Fellow a, b,1, Erik Schrumpf, MD, PhD, Prof. em. a, b, 2, Kirsten Muri Boberg, MD, PhD, Prof. a, b, c, * a
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway Institute of Clinical Medicine, University of Oslo, Oslo, Norway c Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway b
a b s t r a c t Keywords: Biliary tract disease Celiac disease Inflammatory bowel disease Liver disease Primary sclerosing cholangitis
Liver abnormalities are often seen in bowel diseases. Whether these represent aspects of two separate diseases, or if one is causing the other, is not always easy to decide. Extraintestinal manifestations of inflammatory bowel disease (IBD) or coeliac disease are frequently observed. Of these extraintestinal manifestations, hepatic disorders are among the most common. Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis are the most frequent hepatic disorders in IBD and coeliac disease, respectively. Genetic studies have lately elucidated the associations between IBD and PSC, but there is still a long way until we have complete understanding of the molecular aetiology and pathophysiology of these conditions. There is no curative treatment available for PSC, besides liver transplantation. Steatosis and cholelithiasis are also common in IBD, as are signs of hepatic injury due to IBD treatment. Less common liver abnormalities include liver abscesses, hepatic thromboembolic events, granulomatous liver disease and hepatic amyloidosis. Ó 2013 Elsevier Ltd. All rights reserved.
* Corresponding author. Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, N-0424 Oslo, Norway. Tel.: þ47 23 07 00 00; fax: þ47 23 07 39 28. E-mail addresses: [email protected] (M. Kummen), [email protected] (E. Schrumpf), kboberg@ ous-hf.no, [email protected] (K.M. Boberg). 1 Tel.: þ47 23 07 36 82; fax: þ47 23 07 39 28. 2 Tel.: þ47 23 07 36 42; fax: þ47 23 07 39 28. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.013
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Introduction It has been known for almost 150 years that bowel disease can be accompanied by abnormalities in other organs, in particular the liver [1]. Depending upon the population studied, as many as 40% of patients with inflammatory bowel disease (IBD) show signs of extraintestinal manifestations [2,3]. Hepatobiliary abnormalities have been described in 4.7%–29% of IBD patients [4,5]. A true estimate of the frequency of hepatobiliary disorders associated with IBD is, however, difficult to produce since studies of unselected patients with a complete workup, including liver biopsy and endoscopic retrograde cholangiography (ERC), cannot be justified due to ethical reasons. Liver abnormalities are also often seen in coeliac disease. When the patients convert to a gluten free diet, most abnormal liver biochemistry tests normalize [6]. Kaukinen et al reported on four patients with end stage liver failure, of which three were referred for liver transplantation. All four patients subsequently proved to have coeliac disease, and they all recovered after starting gluten free diet [7]. This observation underscores the importance of having bowel diseases in mind when evaluating liver pathology. In this review, we present the clinically most important hepatic manifestations and complications seen in patients with bowel disease, with main focus on ulcerative colitis (UC), Crohn’s disease (CD) and coeliac disease (Table 1). Liver abnormalities seen in malignant bowel diseases and their treatment are beyond the scope of this review. Primary sclerosing cholangitis In UC, primary sclerosing cholangitis (PSC) is the most important associated hepatic disorder, affecting 2.9%–7.6% of patients [8–10]. The prevalence of PSC in CD patients is lower, with estimates varying between 0.7% and 3.4% [5,8,11]. Regarding patients with PSC, the association with IBD is striking. Up to 80% of PSC patients have concomitant IBD, although there is a considerable geographical variation [12]. PSC is also seen in coeliac disease, but the association is much weaker than with IBD [12– 15]. There is a male predominance in PSC, with a male:female-ratio of 2:1. PSC patients often suffer from other autoimmune diseases, apart from IBD [16–18]. Patients are relatively young at diagnosis of PSC, with a mean age between 30 and 40 years [16,19]. Aetiology and pathogenesis Although the aetiology and pathogenesis of PSC are not completely understood, advances in the elucidation of disease mechanisms have been made during recent years [18,20]. PSC is generally considered an immune-mediated, rather than an autoimmune disease, for several reasons. First, there is no proof of a disease-specific autoantibody like anti-transglutaminase 2 (anti-TG2) in coeliac disease
Table 1 Liver abnormalities associated with IBD and coeliac disease. Liver abnormality
Primary sclerosing cholangitis (PSC) Small-duct PSC IgG4-associated cholangitis Autoimmune hepatitis Primary biliary cirrhosis Fatty liver Cholelithiasis Less common abnormalities Thromboembolic complications Liver abscess Hepatic amyloidosis Granulomatous liver disease
Associated with Ulcerative colitis
Crohn’s disease
Coeliac disease
þþ þþ (þ) þ (þ) þ
þ þ (þ)
(þ)
þ
þ þ þ þ þ þ
þ þþ þ
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and the antimitochondrial antibody directed against the dihydrolipoyl transacetylase (PDC-E2) in primary biliary cirrhosis (PBC). Second, there is a predominance of male patients in PSC, in contrast to the female predominance seen in most auto-immune diseases [18]. Last, immunosuppressive treatment has not been successful in treating PSC patients. Three complimentary pathways have been described in an effort to explain PSC aetiology and pathogenesis. (1) A number of studies have supported the existence of a genetic susceptibility. (2) The hypothesis of the ‘leaky-gut’, which is compatible with the close relationship between PSC and IBD [18,21,22]. This hypothesis also involves the possibility of ‘aberrant lymphocyte homing’. (3) The hypothesis on the possible role of ‘toxic bile’ causing bile duct injury [12,23]. Studies on environmental factors in PSC are scarce, although a protective effect of smoking has been suggested [12,24]. Genetic susceptibility Siblings of PSC patients have 9–39 times increased risk of acquiring PSC compared to the general population, supporting the concept that heritable factors are involved [25]. In a series of studies, 16 highly robust and several additional suggestive genetic risk loci have been associated with PSC [20,26,27]. It is of interest that almost half of these overlap with susceptibility loci for IBD [20,27]. About half also overlap with susceptibility loci for autoimmune diseases, e.g. type one diabetes, thyroid disease, psoriasis and coeliac disease. Most of the genetic loci found to be associated with PSC are related to inflammatory pathways. The strongest association is located within the major histocompability complex (MHC) at chromosome 6p21 and peaks near the classical HLA class I genes that are involved in presentation of molecules to T-cells and NK-cells [28]. It is also of interest that genetic risk variants for disease, like FUT2 which is a susceptibility gene in both CD and PSC, have been shown to influence the composition of the gut microbiota [20,29]. The ‘leaky gut’ hypothesis Gut microbiota may influence metabolic and inflammatory pathways within the bile ducts and the liver. These effects are thought to occur by ‘leakage’ of bacterial products from the gut in the setting of prolonged and active intestinal inflammation, disturbing the gut mucosal barrier function and leading to increased intestinal permeability, followed by portal inflammation [20,30]. T-cells activated in the intestine in IBD can further contribute to this portal inflammation by so called ‘aberrant homing’ of lymphocytes: T-cells are recruited to the liver by means of adhesion molecules and chemokines that normally are restricted to the intestine, but which under certain conditions are expressed in the liver [18,20,31]. The ‘toxic bile’ hypothesis The third important hypothesis regarding the pathogenesis of PSC suggests that an altered (‘toxic’) bile composition along with defective protection systems in the biliary epithelium, could contribute to bile duct injury and cholangitis [12,18,20]. The cholangitis phenotype due to toxic bile observed in mice and humans with defects in the phospholipid transporter ABCB4 supports this hypothesis [23].
Clinical presentation and diagnosis Disease development in PSC is usually insidious, and as many as 44% of the patients have no liver related symptoms at the time of diagnosis. The onset of pathology is thought to precede that of clinical onset by several years [16,30]. The ‘typical’ clinical scenario for PSC is a patient with IBD, usually male, who presents with signs of clinical and/or biochemical cholestasis. Alkaline phosphatase activity is often elevated two to three times the upper limit of normal [16,32]. Presenting symptoms include jaundice, abdominal pain, fever and fatigue, sometimes in the setting of bacterial cholangitis. Rarely, patients present with sign of portal hypertension, like variceal bleeding or ascites [16,19,30]. Most
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patients have already been diagnosed with IBD, but in 20%–40% of cases the diagnosis of PSC precedes that of IBD [18]. One has to pursue and exclude aetiologies of secondary cholangitis first, since PSC is a diagnosis of exclusion [18,33]. A complete medical history with occupational and drug history should be obtained [18,33]. Ultrasonography is often the first imaging modality used, sometimes with computed tomography (CT) as a useful supplement, to diagnose extra-hepatic obstruction. If these examinations and serological tests (the most important being anti-mitochondrial antibodies (AMA)) are negative, cholangiography is the next step, by means of magnetic resonance cholangiography (MRC) or ERC. MRC is a safe option with far less complications compared to ERC, with good accuracy in detecting obstruction of the biliary tree [33]. The advantages of ERC include the possibility to perform interventions if indicated. The cholangiogram is characterized by diffusely distributed, multifocal, short strictures, alternating with normal or slightly dilated segments producing a ‘beaded’ pattern [18,33]. If the cholangiogram is normal, a liver biopsy is required for detection of possible small-duct PSC, further elaborated upon below [33]. A schematic overview of the diagnostic process in PSC and related cholestatic disorders associated with IBD, is shown in Fig. 1.
Fig. 1. A schematic overview of the diagnostic process in PSC and related cholestatic disorders associated with IBD [33,34]. IBD, inflammatory bowel disease; MRC, magnetic resonance cholangiography; ERC, endoscopic retrograde cholangiography; PSC, primary sclerosing cholangitis; IAC, IgG4-associated cholangitis; >IgG4, elevated IgG4.
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It is recommended that all PSC patients without a previous diagnosis of IBD undergo a colonoscopy with biopsies, since colitis in PSC tends to be clinically mild and sometimes asymptomatic [33,34]. Colonoscopy with biopsies should also be performed during surveillance and follow-up of PSC [33–35]. The majority (approximately 80%) of PSC patients with IBD are diagnosed with UC, but there are several features of the colitis in PSC that deviates from the ‘classical’ UC. The PSC patients typically present with increased incidence of pancolitis, rectal spearing, ileal involvement, right-sided colitis and a higher frequency of colorectal malignancy [20,35,36]. Data also suggest that there is a predominantly rightsided inflammation increasing towards the ileum, contrasting UC patients without liver disease [20,35]. On this basis, the IBD in PSC has been proposed to represent a distinct sub-entity of IBD, (‘PSCIBD’), but as of today, this denomination has not been implemented in clinical practice [20,35,36]. Disease course, treatment and transplantation The disease course in PSC is often quiescent regarding clinical signs and symptoms. In some patients, the course is characterized by intermittent fluctuations. In most cases, the disease will ultimately progress, with increasing signs of cholestasis and cirrhosis, until liver failure arises [19]. On a histopathological level, four discrete stages of the disease have been defined, ranging from mild portal inflammation to established cirrhosis [33,37]. There is no disease specific medical treatment available for PSC that has impact on endpoints like transplant free survival or mortality [18]. Treatment with ursodeoxycholic acid (UDCA) is debated. A follow-up of a previous randomized controlled trial of high-dose (28–30 mg/kg/day) UDCA versus placebo [38] revealed an increased risk of colorectal neoplasia in UDCA treated patients with PSC and UC. A recent metaanalysis found no effect of UDCA on the risk of colorectal neoplasia, but sub-group analysis showed a significant 65% reduction in the risk of advanced neoplasia (colorectal cancer and/ or high grade dysplasia) [39]. The recommendations regarding UDCA treatment in PSC differ somewhat between the recent European [33] and American [34] practice guidelines. The European guidelines state that the limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC, while the American guidelines recommend against the prescription of UDCA in adult patients with PSC [20,33,34]. Dominant strictures (stenosis <1.5 mm in diameter in the common bile duct and <1 mm in the left and right hepatic ducts) should be treated with dilatation in symptomatic patients [33,34]. Biliary stents can also be used if dilatation has unsatisfactory effect, and should be followed by antibiotic prophylaxis [33]. Median survival after diagnosis of PSC is 10–12 years [18]. The only curative option for patients with end stage liver disease in PSC is liver transplantation. Prognosis after liver transplantation is good with 5- and 10-year survival rates up to 85% [18]. PSC relapse is possible, but its frequency is a matter of debate [18,20,30]. Cholangiocarcinoma Cholangiocarcinoma is the most feared complication in PSC. This malignancy affects 10–15% of patients, representing a 160-fold increased risk compared to the general population [33,40]. About half of the cholangiocarcinoma cases are diagnosed within the first year after diagnosis of PSC [18,20]. The carbohydrate antigen 19-9 (CA 19-9) is the most frequently used serological biomarker for cholangiocarcinoma, but the test is hampered by limited sensitivity and specificity [33,34,41]. MRC and CT may be useful radiological modalities. ERC with brush cytology of the biliary tree has a good specificity but variable sensitivity that may be improved by molecular techniques [33,34,42]. Liver transplantation can be a treatment option in highly selected cases [18,20,43]. Prognosis of cholangiocarcinoma in PSC is very poor, with two year survival being very unusual [18,34,41]. Small-duct PSC The condition that originally was designated pericholangitis, is now commonly referred to as smallduct PSC [44]. Small-duct PSC clinically resembles large-duct PSC, both regarding a cholestatic
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biochemical pattern and histopathological findings of bile duct injury on liver biopsy, but is characterized by a normal cholangiogram [12,44]. Up to 100% of the patients have IBD, depending on the definition of small-duct PSC, with a UC:CD ratio of about 4:1 [12,36,45,46]. Patients with small-duct PSC and CD have a female predominance, as opposed to patients with large-duct PSC and UC [9,11]. In contrast to the case in large-duct PSC, the incidence of cholangiocarcinoma in small-duct PSC seems negligible [12,45]. Several studies have shown that small-duct PSC has a better prognosis than largeduct PSC, with a longer median survival free of liver transplantation and other major clinical events [45,47]. IgG4-associated cholangitis IgG4-associated cholangitis (IAC) is a newly defined entity that was first described in 2006 [48]. According to clinical practice guidelines [20,33,34], IAC is considered a secondary sclerosing cholangitis. Some data suggest that the immunopathogenesis of IAC differs from that of other immunemediated cholestatic liver diseases like PSC and PBC [18,20]. IAC is also seen in patients with IBD, although this association is far less pronounced than that of PSC and IBD [33]. It is important to consider IAC in the differential diagnosis of PSC because of its remarkable responsiveness to corticosteroid therapy [18,20]. A positive response to steroids is part of the diagnostic criteria of IAC [20,33]. Besides this, the patient must fulfil two or more of the four main manifestations: (1) Elevated serum levels of IgG4. PSC patients can have minor elevations of serum IgG4, and a distinct cut-off level for discrimination between PSC and IAC based on IgG4 serum levels alone has not been established. The relevance of elevated IgG4 in PSC patients is so far unknown. (2) Imaging modalities showing suggestive pancreatic findings. (3) Biopsies of the papilla Vateri and the common bile duct with more than ten IgG4-positive cells per high power field. (4) Involvement of other organs [18,20,33]. IAC can also be diagnosed on one of the following criteria alone: (A) Biopsy of pancreas or pancreatic/biliary resection shows diagnostic features of autoimmune pancreatitis (AIP) or IAC, or (B) classical imaging findings of AIP and elevated serum IgG4 [20,33]. Autoimmune hepatitis and overlap syndromes Autoimmune hepatitis (AIH) has been linked to IBD, especially to CD, as well as to coeliac disease [8,13]. Of patients with AIH and IBD, a significant proportion of patients turns out to have PSC if cholangiography is performed [8,49]. These patients have often been classified as PSC/AIH-overlap patients. It is, however, very difficult to compare and draw conclusions from earlier studies because the overlap syndromes are poorly defined [8,33]. The International Autoimmune Hepatitis Group has therefore proposed that patients with autoimmune liver disease should be categorized as AIH, PBC and PSC/small-duct PSC, respectively [50]. Patients with PBC or PSC that develop features of AIH should be considered for immunosuppressive treatment [8,50]. Primary biliary cirrhosis The link between coeliac disease and PBC is well established, and the increased risk of PBC in coeliac disease compared to controls varies between studies from 3- to 20-fold [6,14,51]. PBC is the most common liver disease in coeliac disease. PBC and coeliac disease share several pathophysiological and clinical features. Both are regarded as autoimmune disorders with a female predominance, autoimmune comorbidity and an immune response against autoantigens (TG2 and PDC-E2 in coeliac disease and PBC, respectively) [51,52]. Increased intestinal permeability is seen early in coeliac disease and can cause increased exposure of gut microbial antigens to the immune system, especially in the liver [6,51,53]. The theory of microbial mediated molecular mimicry as a trigger of PBC and findings in several studies showing association between the gut microbiota and coeliac disease, support the possibility of a common pathogenic link between coeliac disease and PBC [6,51,52,54]. Patients with coeliac disease and PBC often present with similar symptoms, like malabsorption, weight loss, osteopenia, steatorrhoea, anaemia and fatigue as well as with abnormal liver biochemistry tests [13,51].
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Elevated aminotransferases are commonly found in untreated coeliac disease patients, and the possibility of liver disease must be evaluated if they do not normalize after initiation of gluten free diet [6,55,56]. In patients with persisting liver abnormalities after introduction of a gluten free diet, the diagnosis of PBC should be looked for by the analysis of AMA [51]. There is a possible link between PBC and IBD, but this is not well established. Males with UC seem to be more prone to PBC than their female counterparts. UC patients with PBC tend to have a more limited bowel disease, with a predominance of left sided colitis and proctitis [46]. Fatty liver Patients with IBD as well as patients with coeliac disease have been reported to have an increased risk of fatty liver changes [14,46,57]. Liver steatosis has been found in as many as 35% of patients with IBD by ultrasound screening [46,58]. Fatty changes have been shown to correlate with colitis severity, but are also found in asymptomatic patients [46,57]. Corticosteroid therapy, parenteral nutrition, small bowel surgery and malnutrition may be contributing factors for the development of fatty liver changes in IBD patients. Likewise, malnutrition may be a predisposing factor in coeliac disease [13,57,59]. Treatment focuses on induction of remission of the bowel disease and improving nutritional status. Cholelithiasis There is a well-documented increased risk of gallstones in CD, particularly when the disease affects the terminal ileum, or if this segment has been surgically removed [60–62]. However, the prevalence varies significantly between studies [62]. Bile supersaturated with cholesterol and increased bilirubin content has been suggested to increase the risk of gallstones in CD, though the former seems only to be the case when the disease involves the ileum [63,64]. Some studies have also found reduced motility and emptying of the gallbladder in patients with CD and suggest these as possible contributing factors to gallstone formation, but this hypothesis is controversial [65,66]. Interestingly, reduced gallbladder motility has also been shown in coeliac disease, explained by reduced secretion of cholecystokinin [67]. There is, however, no epidemiological evidence of increased risk of gallstones in coeliac disease. UC patients seem to carry the same risk of cholelithiasis as controls [60,61]. Less common liver abnormalities Liver abscess Liver abscesses are rare in IBD patients. They may occur, however, and are then more often seen in CD than in UC. Streptococcus species are the most common pathogens and are isolated in a high percentage of liver abscesses in IBD patients, in contrast to the combination of several gram-negative strains often seen in liver abscesses in the general population [68]. Prolonged treatment with intravenous antibiotics, with or without percutaneous drainage, is the treatment of choice [69]. If antibiotic therapy does not have the expected effect and cultures are negative, it is important to consider the differential diagnosis of an aseptic abscess. Aseptic abscesses are characterized by deep, sterile, round lesions consisting of neutrophils and involving the liver in 40% of cases. They are thought to represent a non-infectious inflammatory disorder [70,71], and treatment with corticosteroids has a striking effect. An amoebic liver abscess is the most common extraintestinal manifestation in intestinal amoebiasis [72]. It is noteworthy that some patients presenting with a liver abscess can have synchronous amoebic colitis without bowel symptoms, and that microscopy of stool is often negative for trophozoites and cysts [72]. Liver abscesses have also been reported in other infectious bowel diseases, like those caused by Clostridium difficile and Edwardsiella tarda [73,74]. Thromboembolic complications IBD patients carry a 2–3 fold risk of thromboembolic events, and approximately half of the patients have no other identifiable risk factor [75–77]. Patients with coeliac disease do not seem to have an
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increased risk, but cases have been reported [13]. Thrombosis of the portal or liver veins, the latter causing Budd–Chiari syndrome, are rare but potentially critical complications in IBD patients [78–80]. The acute thromboembolic episode may be asymptomatic or produce non-specific symptoms, which makes it easy to overlook. It is nevertheless important to bear this possibility in mind, especially in patients with an active phase of inflammation where the risk increases substantially [79,81,82]. Hepatic amyloidosis Secondary amyloidosis in IBD is rare, affecting <1% of patients. This complication is seen about ten times more often in CD than in UC [83,84]. Hepatic amyloidosis seldom causes elevation of hepatic biochemistry or hepatomegaly. Treatment with colchicine has been used, and recent case reports have described successful response to treatment with both budesonide and infliximab [84–86]. Granulomatous liver diseases Granulomatous liver diseases have been observed in up to 15% of liver biopsies, and occur both in IBD and in several infectious bowel diseases. Patients using tumour necrosis factor antagonists (TNF-a inhibitors) have an increased risk of infectious granulomatous complications [87]. Liver abnormalities associated with treatment of bowel diseases Hepatic injuries due to standard medications used in the treatment of IBD are common. It can be a challenge for the clinician to distinguish between potential side effects of drugs and other hepatic involvement when confronted with signs of hepatic injury in an IBD patient. Thiopurines Three thiopurines are used in the treatment of IBD, including azathioprine, mercaptopurine and thioguanine. Up to 39% of patients receiving these compounds experience side effects, most of these occurring within the first three months. Hepatotoxicity is not uncommon [88–91]. The overall risk of drug-induced liver injury per patient-treatment-year seems to be just above 1% [90]. Surveillance of liver biochemistry is warranted in patients using thiopurines, and asymptomatic elevated transaminases often respond to dose reduction [89,92]. The other hepatological side effects include hepatocellular necrosis, cholestasis, sinusoidal dilatation, veno-occlusive disease, peliosis hepatis, nodular regenerative hyperplasia and hepatosplenic T-cell lymphoma [92–95]. Sulfasalazine and mesalazine Sulfasalazine can cause acute hepatocellular damage as part of hypersensitivity reaction, which is relatively infrequent [96]. It usually occurs within the first two months of treatment. Cholestasis and acute granulomatous hepatitis have also been reported [93]. Acute liver failure is uncommon, and occurs in 1.4 in 1000 persons treated [96]. Mesalazine has less hepatological side affects than sulfasalazine, often reported at the level of placebo [93,97]. A report from the UK in 2003 calculated a frequency of drug induced liver injury of mesalazine of 3.2 per million prescriptions [97]. TNF-a inhibitors The TNF-a inhibitors infliximab and adalimumab are both used in UC and CD. Minor elevation of transaminases are reported in up to 18% of patients [98]. Infliximab-induced hepatitis and hepatosplenic T-cell lymphoma have also been reported, although the latter is controversial [46,93,95]. Other drugs that can cause hepatic side effects, but are not further evaluated here, include ciclosporin, other 5-aminosalicylates (balsalazide and olsalazine), other biological agents (certolizumab and
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natalizumab), methotrexate, quinolones and other antibiotics used in infectious bowel disorders and sometimes in IBD. Total parenteral nutrition Total parenteral nutrition is administrated to IBD patients with intestinal failure of various causes. Parenteral nutrition is known to be associated with biochemical and histological hepatic dysfunction like steatosis, cholestasis and cirrhosis [99]. The duration of the total parenteral nutrition and the length of bowel resection are risk factors for cholestasis, which can be reversible [99,100]. Summary Bowel diseases may be associated with liver abnormalities. PSC is the most important hepatobiliary disorder in IBD, and PBC is the most frequently observed hepatic abnormality in coeliac disease. There is still no medical treatment available for PSC, making this condition one of the most common indications for liver transplantation in western counties. It is important to differentiate PSC from AIC and to identify features of AIH in PSC, in order to diagnose conditions that may be available to immunosuppressive therapy. Abnormal liver biochemistry is common at diagnosis of coeliac disease, and secondary causes should be sought if they do not normalize within six months of starting a gluten free diet. The pathophysiological link between PSC and IBD and PBC and coeliac disease, respectively, are still not fully understood, although, recent advances in genetic studies have given some clues. Other, complimentary pathophysiological pathways, must be elucidated if we are to find new treatment possibilities of the hepatobiliary disorders that are associated with bowel diseases.
Practice points Primary sclerosing cholangitis is the most common and most important liver disease in IBD patients. Colonoscopy screening with biopsies should be performed in all PSC patients. Primary biliary cirrhosis is the most common liver disease in coeliac disease. The possible presence of coeliac disease should be investigated in patients with severe liver disease.
Research agenda
Further explore aetiology and pathogenesis in PSC and its relationship to IBD. Search for medical treatment in PSC. Provide better tools for diagnosing IgG4-accociated cholangitis. The role of the gut microbiota in the relationship between bowel disease and liver abnormalities should be further investigated.
Conflicts of interest None. Acknowledgements Financial support: This study was supported by the Norwegian PSC Research Center (http://ousresearch.no/nopsc/).
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References [1] Hoffman CEE. Versehluss der Gallenwege durch Verdiekang der Wandungen. Arch Pathol Anat Physiol Klin Med 1867;39: 206–15. [2] Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005;129:827–36. [3] Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. Autoimmune disorders and extraintestinal manifestations in first-degree familial and sporadic inflammatory bowel disease: a case-control study. Inflamm Bowel Dis 2004;10:207–14. [4] Mendes FD, Levy C, Enders FB, Loftus EV, Angulo P, Lindor KD. Abnormal hepatic biochemistries in patients with inflammatory bowel disease. Am J Gastroenterol 2007;102:344–50. [5] Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96:1116–22. [6] Rubio-Tapia A, Murray JA. The liver in celiac disease. Hepatology 2007;46:1650–8. [7] Kaukinen K, Halme L, Collin P, Färkkilä M, Mäki M, Vehmanen P, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002;122:881–8. [8] Saich R, Chapman R. Primary sclerosing cholangitis, autoimmune hepatitis and overlap syndromes in inflammatory bowel disease. World J Gastroenterol 2008;14:331–7. [9] Olsson R, Danielsson A, Järnerot G, Lindström E, Lööf L, Rolny P, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991;100:1319–23. [10] Schrumpf E, Fausa O, Kolmannskog F, Elgjo K, Ritland S, Gjone E. Sclerosing cholangitis in ulcerative colitis. A follow-up study. Scand J Gastroenterol 1982;17:33–9. [11] Rasmussen HH, Fallingborg JF, Mortensen PB, Vyberg M, Tage-Jensen U, Rasmussen SN. Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn’s disease. Scand J Gastroenterol 1997;32:604–10. [12] Karlsen TH, Schrumpf E, Boberg KM. Update on primary sclerosing cholangitis. Dig Liver Dis 2010;42:390–400. [13] Freeman HJ. Hepatic manifestations of celiac disease. Clin Exp Gastroenterol 2010;3:33–9. [14] Ludvigsson JF, Elfström P, Broomé U, Ekbom A, Montgomery SM. Celiac disease and risk of liver disease: a general population-based study. Clin Gastroenterol Hepatol 2007;5:63–9. [15] Lawson A, West J, Aithal GP, Logan RFA. Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther 2005;21:401–5. [16] Bergquist A, Said K, Broomé U. Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol 2007;42:88–93. [17] Sinakos E, Samuel S, Enders F, Loftus EV, Sandborn WJ, Lindor KD. Inflammatory bowel disease in primary sclerosing cholangitis: a robust yet changing relationship. Inflamm Bowel Dis 2013;19:1004–9. [18] Krones E, Graziadei I, Trauner M, Fickert P. Evolving concepts in primary sclerosing cholangitis. Liver Int 2012;32: 352–69. [19] Karlsen TH, Schrumpf E, Boberg KM. Primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2010;24:655–66. [20] Karlsen TH, Boberg KM. Update on primary sclerosing cholangitis. J Hepatol 2013;59:571–82. [21] Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hübscher SG, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9þ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med 2004;200: 1511–7. [22] Hillan KJ, Hagler KE, MacSween RN, Ryan AM, Renz ME, Chiu HH, et al. Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease. Liver 1999;19:509–18. [23] Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 2007;27:77–98. [24] Loftus EV, Sandborn WJ, Tremaine WJ, Mahoney DW, Zinsmeister AR, Offord KP, et al. Primary sclerosing cholangitis is associated with nonsmoking: a case-control study. Gastroenterology 1996;110:1496–502. [25] Bergquist A, Lindberg G, Saarinen S, Broomé U. Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol 2005;42:252–6. [26] Janse M, Lamberts LE, Franke L, Raychaudhuri S, Ellinghaus E, Boberg KM, et al. Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. Hepatology 2011;53: 1977–85. [27] Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet 2013;45:670–5. [28] Næss S, Shiryaev A, Hov JR, Franke A, Karlsen TH. Genetics in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2012;36:325–33. [29] Rausch P, Rehman A, Künzel S, Häsler R, Ott SJ, Schreiber S, et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc Natl Acad Sci U S A 2011;108: 19030–5. [30] Weismüller TJ, Wedemeyer J, Kubicka S, Strassburg CP, Manns MP. The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 2008;48(Suppl. 1):S38–57. [31] Adams DH, Eksteen B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease. Nat Rev Immunol 2006;6:244–51. [32] Broomé U, Olsson R, Lööf L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 1996;38:610–5. [33] European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–67. [34] Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–78.
M. Kummen et al. / Best Practice & Research Clinical Gastroenterology 27 (2013) 531–542
541
[35] Jørgensen KK, Grzyb K, Lundin KEA, Clausen OPF, Aamodt G, Schrumpf E, et al. Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients. Inflamm Bowel Dis 2012;18:536–45. [36] Loftus EV, Harewood GC, Loftus CG, Tremaine WJ, Harmsen WS, Zinsmeister AR, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54:91–6. [37] Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1981;1:632–40. [38] Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VAC, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011;106:1638–45. [39] Singh S, Khanna S, Pardi DS, Loftus EV, Talwalkar JA. Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2013;19:1631–8. [40] Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321–7. [41] Razumilava N, Gores GJ, Lindor KD. Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011; 54:1842–52. [42] Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E. Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2006;45:568–74. [43] Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, et al. Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8. [44] Wee A, Ludwig J. Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts? Ann Intern Med 1985;102:581–7. [45] Björnsson E, Olsson R, Bergquist A, Lindgren S, Braden B, Chapman RW, et al. The natural history of small-duct primary sclerosing cholangitis. Gastroenterology 2008;134:975–80. [46] Navaneethan U, Shen B. Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. Inflamm Bowel Dis 2010;16:1598–619. [47] Halliday JS, Djordjevic J, Lust M, Culver EL, Braden B, Travis SPL, et al. A unique clinical phenotype of primary sclerosing cholangitis associated with Crohn’s disease. J Crohns Colitis 2012;6:174–81. [48] Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, et al. Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol 2006;101:2070–5. [49] Perdigoto R, Carpenter HA, Czaja AJ. Frequency and significance of chronic ulcerative colitis in severe corticosteroidtreated autoimmune hepatitis. J Hepatol 1992;14:325–31. [50] Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E. Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011;54:374–85. [51] Volta U, Caio G, Tovoli F, de Giorgio R. Gut-liver axis: an immune link between celiac disease and primary biliary cirrhosis. Expert Rev Gastroenterol Hepatol 2013;7:253–61. [52] Sollid LM, Jabri B. Triggers and drivers of autoimmunity: lessons from coeliac disease. Nat Rev Immunol 2013;13:294–302. [53] Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012;590:447–58. [54] Wacklin P, Kaukinen K, Tuovinen E, Collin P, Lindfors K, Partanen J, et al. The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease. Inflamm Bowel Dis 2013;19:934–41. [55] Casella G, Antonelli E, Bella CD, Villanacci V, Fanini L, Baldini V, et al. Prevalence and causes of abnormal liver function in patients with coeliac disease. Liver Int 2013;33:1128–31. [56] Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656–76. [57] McGowan CE, Jones P, Long MD, Barritt AS. Changing shape of disease: nonalcoholic fatty liver disease in Crohn’s diseaseA case series and review of the literature. Inflamm Bowel Dis 2012;18:49–54. [58] Gisbert JP, Luna M, González-Lama Y, Pousa ID, Velasco M, Moreno-Otero R, et al. Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients. Inflamm Bowel Dis 2007;13:1106–14. [59] Sourianarayanane A, Garg G, Smith TH, Butt MI, McCullough AJ, Shen B. Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease. J Crohns Colitis 2013;7:e279–85. [60] Lapidus A, Bångstad M, Aström M, Muhrbeck O. The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol 1999;94:1261–6. [61] Parente F, Pastore L, Bargiggia S, Cucino C, Greco S, Molteni M, et al. Incidence and risk factors for gallstones in patients with inflammatory bowel disease: a large case-control study. Hepatology 2007;45:1267–74. [62] Masclee AA, Vu MK. Gallbladder motility in inflammatory bowel diseases. Dig Liver Dis 2003;35(Suppl. 3):S35–8. [63] Lapidus A, Akerlund JE, Einarsson C. Gallbladder bile composition in patients with Crohn’s disease. World J Gastroenterol 2006;12:70–4. [64] Dowling RH, Bell GD, White J. Lithogenic bile in patients with ileal dysfunction. Gut 1972;13:415–20. [65] Damião AO, Sipahi AM, Vezozzo DP, Gonçalves PL, Fukui P, Laudanna AA. Gallbladder hypokinesia in Crohn’s disease. Digestion 1997;58:458–63. [66] Vu MK, Gielkens HA, van Hogezand RA, van Oostayen JA, Lamers CB, Masclee AA. Gallbladder motility in Crohn disease: influence of disease localization and bowel resection. Scand J Gastroenterol 2000;35:1157–62. [67] Fraquelli M, Bardella MT, Peracchi M, Cesana BM, Bianchi PA, Conte D. Gallbladder emptying and somatostatin and cholecystokinin plasma levels in celiac disease. Am J Gastroenterol 1999;94:1866–70. [68] Margalit M, Elinav H, Ilan Y, Shalit M. Liver abscess in inflammatory bowel disease: report of two cases and review of the literature. J Gastroenterol Hepatol 2004;19:1338–42. [69] Albuquerque A, Magro F, Rodrigues S, Lopes S, Pereira P, Melo RB, et al. Liver abscess of the caudate lobe due to Staphylococcus aureus in an ulcerative colitis patient: first case report. J Crohns Colitis 2011;5:360–3.
542
M. Kummen et al. / Best Practice & Research Clinical Gastroenterology 27 (2013) 531–542
[70] André MFJ, Piette JC, Kémény JL, Ninet J, Jego P, Delèvaux I, et al. Aseptic abscesses: a study of 30 patients with or without inflammatory bowel disease and review of the literature. Medicine (Baltimore) 2007;86:145–61. [71] Zakout R, Fonseca M, Santos JM, Marques A, Távora I, Oliveira E, et al. Multiple aseptic liver abscesses as the initial manifestation of Crohn’s disease: report of a case. Dis Colon Rectum 2009;52:343–5. [72] Stanley SL. Amoebiasis. Lancet 2003;361:1025–34. [73] Sakurai T, Hajiro K, Takakuwa H, Nishi A, Aihara M, Chiba T. Liver abscess caused by Clostridium difficile. Scand J Infect Dis 2001;33:69–70. [74] Ohara Y, Kikuchi O, Goto T, Yoshida T, Mori H, Matsueda K, et al. Successful treatment of a patient with sepsis and liver abscess caused by Edwardsiella tarda. Intern Med 2012;51:2813–7. [75] Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:657–63. [76] Kappelman MD, Horvath-Puho E, Sandler RS, Rubin DT, Ullman TA, Pedersen L, et al. Thromboembolic risk among danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011;60:937–43. [77] Jackson LM, O’Gorman PJ, O’Connell J, Cronin CC, Cotter KP, Shanahan F. Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V Leiden. QJM 1997;90:183–8. [78] Jackson CS, Fryer J, Danese S, Vanagunas A, Polensky S, Buchman AL. Mesenteric vascular thromboembolism in inflammatory bowel disease: a single center experience. J Gastrointest Surg 2011;15:97–100. [79] Maconi G, Bolzacchini E, Dell’Era A, Russo U, Ardizzone S, de Franchis R. Portal vein thrombosis in inflammatory bowel diseases: a single-center case series. J Crohns Colitis 2012;6:362–7. [80] Dacha S, Devidi M, Osmundson E. Budd-Chiari syndrome in a patient with ulcerative colitis and no inherited coagulopathy. World J Hepatol 2011;3:164–9. [81] Spina L, Saibeni S, Battaglioli T, Peyvandi F, de Franchis R, Vecchi M. Thrombosis in inflammatory bowel diseases: role of inherited thrombophilia. Am J Gastroenterol 2005;100:2036–41. [82] Landman C, Nahon S, Cosnes J, Bouhnik Y, Brixi-Benmansour H, Bouguen G, et al. Portomesenteric vein thrombosis in patients with inflammatory bowel disease. Inflamm Bowel Dis 2013;19:582–9. [83] Wester AL, Vatn MH, Fausa O. Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998. Inflamm Bowel Dis 2001;7:295–300. [84] Sattianayagam PT, Gillmore JD, Pinney JH, Gibbs SDJ, Wechalekar AD, Gilbertson J a, et al. Inflammatory bowel disease and systemic AA amyloidosis. Dig Dis Sci 2013;58:1689–97. [85] Cabezuelo JB, Egea JP, Ramos F, Torrella E, Muray S, Alcázar C. Infliximab in the treatment of amyloidosis secondary to Crohn’s disease. Nefrologia 2012;32:385–8. [86] Wang Y, Lee H, Shen B. Systemic secondary amyloidosis in a 70-year-old patient with Crohn’s disease: treatment with oral budesonide. Inflamm Bowel Dis 2013;19:E74–5. [87] Coash M, Forouhar F, Wu CH, Wu GY. Granulomatous liver diseases: a review. J Formos Med Assoc 2012;111:3–13. [88] Jharap B, Seinen ML, de Boer NKH, van Ginkel JR, Linskens RK, Kneppelhout JC, et al. Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts. Inflamm Bowel Dis 2010;16:1541–9. [89] Frei P, Biedermann L, Nielsen OH, Rogler G. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol 2013;19:1040–8. [90] Gisbert JP, González-Lama Y, Maté J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol 2007;102:1518–27. [91] Nielsen OH, Bjerrum JT, Herfarth H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol 2013;53:575–88. [92] Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013;19:1699– 706. [93] Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis 2010;28: 508–18. [94] Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, et al. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007;56:1404–9. [95] Kotlyar DS, Osterman MT, Diamond RH, Porter D, Blonski WC, Wasik M, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9:36–41. [96] Jobanputra P, Amarasena R, Maggs F, Homer D, Bowman S, Rankin E, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: a case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008; 9:48. [97] Logan RF, van Staa TP. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the committee on safety of medicines. Gut 2003;52:536–9. [98] Coffin CS, Fraser HF, Panaccione R, Ghosh S. Liver diseases associated with anti-tumor necrosis factor-alpha (TNF-a) use for inflammatory bowel disease. Inflamm Bowel Dis 2011;17:479–84. [99] Gura KM, Lee S, Valim C, Zhou J, Kim S, Modi BP, et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008;121:e678–86. [100] Raphael BP, Duggan C. Prevention and treatment of intestinal failure-associated liver disease in children. Semin Liver Dis 2012;32:341–7.