Alimentary Pharmacology and Therapeutics

Systematic review: the epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease E. Gizard*, A. C. Ford†, J.-P. Bronowicki* & L. Peyrin-Biroulet*

*Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Universit
e de Lorraine, Vandoeuvre-les-Nancy, France. † Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK.

Correspondence to: Prof. L. Peyrin-Biroulet, Inserm U954 and Department of HepatoGastroenterology, University Hospital of Nancy, All
ee du Morvan, 54511 Vandoeuvre-les-Nancy, France. E-mail: [email protected]

Publication data Submitted 12 December 2013 First decision 31 December 2013 Resubmitted 21 April 2014 Accepted 22 April 2014 EV Pub Online 11 May 2014 This uncommissioned systematic review was subject to full peer-review.

SUMMARY Background Extraintestinal manifestations are frequent in inflammatory bowel diseases (IBD). Most studies published so far focused on viral hepatitis and liver toxicity of IBD-related drugs. Aim To conduct a systematic review of hepatobiliary manifestations associated with IBD. We excluded viral hepatitis and liver toxicity of IBD-related drugs. Methods Studies were identified through the electronic database of MEDLINE, EMBASE and the annual meetings of Digestive Disease Week, the American College of Gastroenterology, the United European Gastroenterology Week and the European Crohn’s and Colitis Organization. Results One hundred and forty six articles were included in this systematic review. Cholelithiasis is more frequent in Crohn’s disease (CD) than in general population. Prevalence of cholelithiasis in CD ranged from 11% to 34%, whereas it ranges from 5.5% to 15% in non-IBD patients. PSC is more frequent in UC than in CD. Prevalence of PSC ranges from 0.76% to 5.4% in UC and from 1.2% to 3.4% in CD. There is a male predominance when PSC is associated with UC, with a male/female ratio ranging from 65/35 to 70/30. No conclusion can be made on a possible increased risk of gall-bladder carcinoma. Mean prevalence of fatty liver is 23% (range, 1.5–55%). Hepatic amyloidosis occurs in less than 1% of IBD. Liver abscess is encountered mainly in CD. Portal vein thrombosis occurs in 39% to 45% of IBD patients undergoing proctocolectomy. Conclusions Hepatobiliary manifestations associated with inflammatory bowel diseases are frequent and probably underdiagnosed. Aliment Pharmacol Ther 2014; 40: 3–15

ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12794

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E. Gizard et al. INTRODUCTION Inflammatory bowel diseases (IBD) are chronic disabling conditions.1 Numerous studies have been published so far concerning hepatobiliary manifestations associated with IBD.2, 3 However, most of them focused on viral hepatitis4–6 and liver toxicity of IBD-related medications.7–13 These topics will not be developed in this systematic review. We refer the reader to previous well-conducted literature reviews.2–13 Other hepatobiliary manifestations have been reported in IBD such as cholelithiasis, primary sclerosing cholangitis (PSC), steatosis, autoimmune hepatitis (AIH), hepatic amyloidosis, liver abscess, IgG4-associated cholangitis (IAC), portal vein thrombosis (PVT), granulomatous hepatitis and primary biliary cirrhosis (PBC).6, 7 The increase in obesity14–16 as well as changes in diagnostic modalities, with an increasing use of MR,17 made such manifestations more prevalent in IBD. We conducted a systematic review of their epidemiology and risk factors. A better knowledge of these manifestations in IBD is necessary to improve their management. LITERATURE SEARCH We conducted a computerised search of English language publications listed in the electronic databases of MEDLINE from 1874 to August, 2013. Studies were identified using the following search terms : “inflammatory bowel disease”, “cholelithiasis”, “primary sclerosing cholangitis”, “fatty liver”, “autoimmune hepatitis”, “amyloidosis”, “liver abscess”, “Immunoglobulin G”, “cholangitis”, “portal vein”, “thrombosis”, “granulomatous disease, chronic”, “primary biliary cirrhosis” [MeSH term] and “IGG4 cholangitis” as free text term. We also searched publications available in EMBASE, Cochrane library version 5.0.2 and the annual meetings of Digestive Disease Week, the American College of Gastroenterology, the United European Gastroenterology Week and the European Crohn’s and Colitis Organization. Manual searches of reference lists from potentially relevant articles were used to identify any additional studies that may have been missed using the electronic search. All case reports and case series of hepatobiliary manifestations associated with IBD were also reviewed. We included both adult and paediatric IBD. Articles on viral hepatitis and liver toxicity of IBD-related medications were excluded. The presence of IBD could be defined according to clinical symptoms, a physician’s diagnosis, endoscopy and/or radiological findings. Gallstone disease was defined using ultrasonography and oral cholecysto4

gram in older studies. Diagnosis of PSC was made based on endoscopic retrograde cholangiography or magnetic resonance cholangiography. Fatty liver disease was defined on histological findings or ultrasonography. AIH diagnosis was made based on biological and histological criteria, according to international recommendations. Diagnosis of hepatic amyloidosis and granulomatous hepatitis was based on histological findings. Diagnosis of liver abscess was made using clinical, biological and radiological findings. IAC was screened using biological measures. Histological confirmation was not systematic. The presence of portal vein thrombosis could be defined according to ultrasonography and/or CT scan findings. PBC was diagnosed using biological criteria; histological confirmation was not systematically done. We collected prevalence and/or incidence of each hepatobiliary manifestation of interest in IBD, and their associated risk factors. We finally performed a manual selection of studies. Eligible articles were reviewed in a blind manner by two different investigators (EG and LPB). Agreement between investigators was >95% and disagreement in data extraction was resolved by consensus between authors (EG and LPB). We reviewed a total of 532 eligible articles, and 99 were included in this systematic review (Table 1).

CHOLELITHIASIS Epidemiology The relationship between IBD, especially CD, and cholelithiasis is known since the 1970s.18 Fourteen studies reported prevalence and/or incidence of cholelithiasis in IBD.19–32 We excluded four studies due to insufficient data.26, 27, 29, 31 Crohn’s disease. Eight studies that included 1450 patients (one population-based and seven referral centre-based) evaluated the prevalence of cholelithiasis in

Table 1 | Articles included in this systematic review

Cholelithiasis Primary sclerosing cholangitis Fatty liver Hepatic amyloidosis Abscess Portal vein thrombosis

Eligible articles

Included articles

122 109 65 165 10 82

35 35 29 5 6 7

Aliment Pharmacol Ther 2014; 40: 3-15 ª 2014 John Wiley & Sons Ltd

Systematic review: hepatobiliary manifestations in IBD CD.21–25, 28, 30, 32 One study that included 429 patients was referral centre-based and evaluated the incidence of cholelithiasis in CD patients.19 Diagnostic modality was ultrasonography in eight studies19, 21–25, 28, 32 and oral cholecystogram in one study.30 Five studies assessed the prevalence of cholelithiasis in a control population.21– 23, 25, 28 The only population-based study that included 131 CD patients and 556 control subjects, found a significant increase in prevalence of cholelithiasis in CD patients, with a standardised relative risk of 1.8 [95% CI, 1.2–2.7].22 The largest referral centre-based studies that compared prevalence of cholelithiasis in CD and general population, including 311 CD, also found a significant increase in prevalence of cholelithias. The prevalence of gallstones among CD was 11% and was higher than in UC patients (7.5%) and controls (5.5%) (P = 0.0016).23 Overall, prevalence of cholelithiasis in CD ranged from 11% to 34%, whereas it ranged from 5.5% to 15% in control groups. Results are summarised in Table 2. The only study assessing incidence of cholelithiasis in CD was conducted by Parente et al. in 2007 and included 429 CD and 634 matched controls. They were followed for a mean of 7.2 years. Investigation method was ultrasonography. The incidence rates of gallstones disease were 14.35 [95% CI, 10.01–18.69]/1000 persons/ year in CD as compared with 7.75 [95% CI, 4.51–10.99] in matched controls (P = 0.012). The estimated risk of gallstone disease for CD was 2.09 [95% CI, 1.20–3.64].19

Ulcerative colitis. Five studies that included 502 patients, all referral centre-based, evaluated prevalence of cholelithiasis in UC patients.20, 21, 23, 25, 30 Diagnostic modality was ultrasonography in four studies,20, 21, 23, 25 and oral cholecystogram in one study.30 Three studies also assessed prevalence of cholelithiasis in a control population.21, 23, 25 One study that included 429 patients, referral centre-based, evaluated incidence of cholelithiasis in

UC.19 Prevalence of cholelithiasis in UC ranged from 4.6% to 36.4%. One study including 114 UC found a significant higher risk of cholelithiasis in UC compared to a control population, with a prevalence of 9.6% and an odd ratio of 2.5 [95% CI, 1.2–5.2].25 Other studies did not find such increased risk.21, 23 Results are summarised in Table 3. The only study assessing incidence of cholelithiasis in UC was conducted by Parente et al. in 2007. It included 205 UC and 634 matched controls. They were followed for a mean of 7.2 years. Investigation method was ultrasonography. The incidence rate of gallstone disease was 7.48 [95% CI, 3.41–11.55]/1000 persons/year in UC patients as compared with 6.06 [95% CI, 2.30–9.81]/1000 persons/year in matched controls (P = 0.38).19

Type of gallstones associated with IBD. Eight studies analysed bile composition in IBD patients.33–40 Two studies analysed bile composition of UC patients, providing conflicting results.33, 34 In a first study, bile composition of patients undergoing colectomy was similar to control patients without gallstones.33 After colectomy, cholesterol concentrations were high, with saturated biles and presence of cholesterol crystals in bile.33 In a second study, UC patients with previous colectomy had normal biliary lipid composition, normal cholesterol saturation and normal nucleation time.34 Six studies analysed bile composition of CD patients.35–40 Bile samples of 14 CD who had an ileal resection and 10 healthy subjects were compared. Cholesterol saturation was significantly lower in CD patients who had a long or short ileal resection compared with healthy subjects.35 The bilirubin concentrations were 45– 50% higher in patients who had a long or a short ileal resection compared with healthy controls.35 These results suggesting an increased risk of developing pigment

Table 2 | Prevalence of gallstone disease in CD and control population Author 21

Kratzer Lapidus22 Bargiggia23 Fraquelli24 Lorusso25 Whorwell28 Baker30 Hutchinson32

Year

Country

Number of patients with CD included

Crohn’s disease %

2005 1999 2003 2001 1990 1984 1974 1994

Germany Sweden Italy Italy Italy UK USA UK

222 131 311 330 45 38 122 251

13% 26.4% 11% 24% 13.3% 34% 25.4% 28%

Aliment Pharmacol Ther 2014; 40: 3-15 ª 2014 John Wiley & Sons Ltd

General population % 7–8% (adult population) 15% (age-matched controls) 5.5% (adult population) 9.7% (adult population) 8% (age-matched controls)

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E. Gizard et al. Table 3 | Prevalence of gallstone disease in UC and control population Author

Year

Country

Number of patients with UC included

Ulcerative colitis %

Morsy20 Kratzer21 Bargiggia23 Lorusso25 Baker30

2012 2005 2003 1990 1974

Egypt Germany Italy Italy USA

33 88 200 114 67

36.4% 4.6% 7.5% 9.6% 7.5%

stones.35 Similar results were found in a study including 10 patients with operated ileal CD compared to 50 healthy subjects, finding a significant decrease in cholesterol saturation in bile of CD patients,36 and in another study, comparing gall-bladder bile samples from 29 patients with CD and 19 with UC, finding higher bilirubin concentration in bile of patients with ileal disease and/or resection.40 Other studies showed that CD patients should be prone to develop both cholesterol and pigments gallstones, with increased cholesterol saturated bile, faster nucleation time, concomitant with an increased bile concentration of bilirubin.37–39

Risk factors Nine studies investigated risk factors for gallstone disease in CD.19, 21–25, 28, 30, 32 Previous intestinal resection was the most frequent risk factor for gallstone disease, assessed in six studies.19, 22–24, 30, 32 An ileal resection >30 cm was associated with formation of gallstone disease with an odd ratio of 7.03 [95% CI, 2.56–19.3] in Parente study.19 The risk tends to increase with the number of intestinal resection. In Lapidus and colleagues study, 48% (10/21) of the patients having had at least three intestinal resections had gallstone disease, compared with 20.7% (6/29) of the non-operated patients (P < 0.005).22 Other identified risk factors were location of the disease in three studies,19, 24, 25 duration of the disease in three studies,19, 30, 32 age in three studies,21, 23, 24 number of clinical recurrence, number of hospitalisations, total parenteral nutrition treatment and long hospital stay in one study19 and female sex in one study.23 There were no significant differences between CD patients with and without gallstones in terms of activity, extent, or duration of disease or anthropometric measurements in Whorwell et al. 1984 study.28 Three studies reported abnormalities in gall-bladder motility in CD.41–43 Patients with CD have been found to have impaired gall-bladder emptying.41, 43 Gastrointestinal motility was studied during fasting and after a meal in CD and compared to healthy subject. 6

General population % 7–8% (adult population) 5.5% (adult population) 9.7% (adult population)

The incidence of phase III of the migrating motor complex in the antroduodenal area was considerably reduced in CD. Thus, could lead to a reduction in cyclic phasic contractions of gall-bladder.42 Of note, six cases of gallstone ileus were reported in patients with CD.44–49 Few studies reported the risk to develop gall-bladder cancer in IBD.50–56 The largest one found two gall-bladder carcinomas among 67 patients with IBD and dominant stenosis PSC, whereas no cases of cancer were observed among 53 patients with IBD and no dominant stenosis PSC.50 Of note, six studies reported cases of gall-bladder carcinomas associated with IBD.51–56

PRIMARY SCLEROSING CHOLANGITIS Epidemiology The relationship between PSC and IBD has been first described in the 1960s.57, 58 Fourteen studies assessed so far the prevalence of PSC in IBD.59–72 There is a male predominance when PSC is associated with UC, with a male/female ratio ranging from 65/35 to 70/30 in the largest studies.50, 61, 73–75 No conclusions can be made on the male/female ratio in PSC-CD as data are scarce.59, 69, 73 Ulcerative colitis. Twelve studies that included a total of 10 169 patients reported prevalence of PSC in UC.60– 69, 71, 72 Diagnosis was made using cholangiography or magnetic resonance cholangiography. Prevalence of PSC in UC ranged from 0.76% to 5.4%. The largest population-based study included 4454 Canadian IBD patients, with a known diagnosis of IBD for at least 10 years.69 Prevalence of PSC in UC was 1% in women and 3% in men. PSC was significantly more frequent in men than in women (P = 0.03). Odds ratio of developing PSC in UC compared to a population-based age, gender- and geography-matched cohort was 30.3 [95% CI, 11.0–83.0] (P < 0.0001) for men and 9.5 [95% CI, 2.7–32.] (P < 0.0001) for women.69 Aliment Pharmacol Ther 2014; 40: 3-15 ª 2014 John Wiley & Sons Ltd

Systematic review: hepatobiliary manifestations in IBD Most of the studies reported prevalence of PSC among patients with abnormal liver function test, especially elevated serum alkaline phosphatase values.60, 61, 63, 65– 68, 71, 72 In a Swedish population of 1500 UC patients, PSC was screened in patients with abnormal serum alkaline phosphatase values.64 The prevalence of PSC was 3.7% (55/1500).64 Of note, the lowest prevalence (3/396, 0.75%) was found in the study by Wewer et al. study, where patients were screened for PSC only if they had biochemical values more than twice the upper normal limit in two consecutive blood tests within a fortnight.72 One study assessed prevalence of PSC in patients with UC and normal liver function test. Among 68 patients, no PSC was found.62 Other results are summarised in Table 4.

Among 126 patients with IBD, including 22 with concomitant PSC, pANCA were found in 88% of PSC-IBD patients.76 In another study including 50 patients with PSC-UC and six with PSC-CD, pANCA were positive in 54% and 50% of patients respectively.77 Prevalence was 60% for PSC-IBD in a study including 124 IBD patients and 27 PSC patients.78

Crohn’s disease. Three studies that included a total of 4880 patients reported prevalence of PSC in CD.59, 69, 71 Prevalence ranged from 1.2% to 3.4%. The largest population-based study included 4454 Canadian IBD patients, with a known diagnosis of IBD for at least 10 years. Prevalence of PSC in CD was 0.3% in women and 0.4% in men. No over risk to develop PSC was found in CD compared to a population-based age, gender- and geography-matched cohort.69 Among 262 consecutive patients with CD, 38 had long-standing increased ALP values. Nine of them were diagnosed with PSC (3.4%). The prevalence of PSC was 9% when considering large bowel CD.59 In Cape Town, three of 164 patients followed for CD had a persistently raised alkaline phosphatase level of hepatic origin. Investigations revealed the presence of PSC in two patients (1.2%).71

Risk factors A population-based study including 4454 Canadian IBD patients found a significant higher prevalence of PSC in UC (2%) than in CD (0.4%) (P = 0.0002). In UC, PSC was significantly more common in men (3%) than in women (1%) (P = 0.03).69 Several studies found a milder course of IBD patients with PSC66, 74, 75, 79–82 and a more extensive disease.66, 74 In the study by Olsson et al., where the overall prevalence of PSC in UC was 3.7%, the prevalence of PSC was 5.5% in patients with substantial colitis and 0.5% in patients with distal colitis.64 In 80 patients with PSC-IBD, 50 (97%) PSC-UC patients had pancolitis compared with 32 (62%) matched UC patients (P < 0.001).83 CD associated with PSC has a more frequent large bowel involvement.59, 73 In 74 PSC-CD patients, 95% had a colitis and four 5% ileitis only.83 PSC requiring liver transplantation is associated with a milder course of UC.84, 85 Rectal sparing and backwash ileitis are inconstant findings.74, 75, 83, 86 Proctocolectomy has no beneficial effect on PSC.87 The absence of colon after liver transplantation (LT) protects the patient from recurrent PSC.88, 89 In a study enrolling 230 consecutive adult patients who underwent LT for PSC, 162 had IBD.88 The recurrence-free patient survival was significantly better in patients who underwent pre-/peri-LT colectomy.88, 89

Prevalence of pANCA positivity. Three studies reported prevalence of pANCA positivity in PSC-IBD.76–78 Table 4 | Overall prevalence of PSC in UC patients Country

Number of patients

Author

Year

Aitola60 Broome61 Lupinetti63 Olsson64 Rasmussen65 Schrumpf66 Shepherd67 Hashimoto68 Bernstein69

1994 1994 1980 1991 1992 1982 1983 1993 2001

Tobias71 Wewer72

1983 South Africa 250 1991 Denmark 396

Finland Sweden USA Sweden Denmark Norway UK Japan Canada

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534 1274 202 1500 305 336 681 163 4454

PSC % 2% 2.3% 1% 3.7% 3.6% 5.4% 2.4% 3.1% Men: 3% Women: 1% 3.2% 0.75%

Small duct or large duct PSC. Two studies reported the type of PSC associated with IBD.50, 73 In a study enrolling 170 PSC-IBD, large duct involvement was present in 78% of patients with PSC-CD and in 94% of patients with PSC-UC.73 Among 120 patients with PSC-IBD, 53 had no dominant stenosis and 67 had dominant stenosis.50

FATTY LIVER Epidemiology A relationship between IBD and fatty liver has been suspected for a very long time. Thomas CH in 1873 published an article entitled « Ulceration of the colon with a much enlarged fatty liver ».90 Fourteen studies assessed prevalence of fatty liver in IBD. We excluded 13 7

E. Gizard et al. studies whose methodology was poor and/or with missing data. It was mainly old studies.91–103

Ulcerative colitis. A total of 13 studies that included 1471 patients evaluated prevalence of fatty liver disease in UC.20, 23, 61, 62, 104–112 Diagnosis modality was necropsy in three studies,104–106 liver biopsy during colectomy in three studies,107–109 liver biopsy in subjects with normal liver function tests in one study,62 ultrasonography in five studies20, 23, 61, 110, 111 and it was not specified in one study.112 Mean prevalence of fatty liver disease in UC was 23% (range, 1.5–55%). Results are summarised in Table 5. The largest study was an Italian multicentre study that included 317 UC patients, who were evaluated by ultrasonography and compared to a control group. They found a significant increase in fatty liver disease in UC.

Table 5 | Prevalence of fatty liver disease in UC (US = ultrasonography)

Author

Year

Kimmelstiel104 Warren105 Parker106 Eade107

1952 1949 1954 1970

Broome62

1990

Mattila

108

1994

Broome61

1994

Scalone109

2003

YamamotoFurusho110 Morsy20 Riegler111 Bargiggia23 Mendes112

2010

8

2012 1998 2003 2007

Diagnostic modality Necropsy Necropsy Necropsy Biopsy at colectomy Liver biopsy, normal liver function tests Biopsy at colectomy US  liver biopsy, abnormal liver function tests Biopsy at colectomy US US US US Not specified. Abnormal liver function tests

Number of patients

Number of fatty liver disease (%)

93 60 73 132

14 (15%) 33 (55%) 14 (19%) (45%)

74

3 (4%)

59

9 (15.2%)

142

11 (7.7%)

21

4 (19%)

200 33 317 200 67

Bright liver on ultrasonography was significantly more frequent in patients with UC (13.6%) than in controls (7.3%) (P = 0.014).111 The only study assessing prevalence of fatty liver disease in patients with UC and normal liver function test gathered 74 UC patients in a Swedish centre. Liver biopsy was performed. Twenty three patients showed fatty infiltration, and three showed fatty liver (4%).62 Two studies included patients with UC and abnormal liver function tests. The largest included 142 UC that showed signs of hepatobiliary disease. Among them, 74 patients had persistent abnormal liver function tests at follow-up with 11 patients diagnosed with fatty liver. Diagnosis was made using ultrasonography, and biopsy in some cases.61

Crohn’s disease. Four studies that included 604 patients, evaluated prevalence of fatty liver disease in CD. Diagnosis modality was ultrasonography in three studies,23, 28, 111 and was not specified in one study.112 Prevalence of fatty liver disease in CD ranged from 1.5% to 39.5%. Results are summarised in Table 6. The largest study included 311 CD patients that were investigated clinically and with ultrasonography. Prevalence of mild-to-moderate to severe liver steatosis in CD was 39.5%, significantly higher than among healthy controls.23 In comparison, prevalence of Non fatty liver disease (NAFLD) in the general population ranges from 6.3% to 33% with a median of 20%.113 Risk factors Four studies assessed risk factors for fatty liver in IBD.62, 106, 107, 114 Fatty liver was correlated with extent of colitis in the study by Eade et al.107 Neither Parker et al.106 nor Broome et al. enrolling 68 UC with normal liver function tests could identify risk factors for fatty liver Table 6 | Prevalence of fatty liver disease in CD (US = ultrasonography)

50 (25%) 15 43 71 1

(45.4%) (13.6%) (35.5%) (1.5%)

Author 111

Riegler Bargiggia23 Mendes112

Whorwell28

Year

Diagnostic modality

1998 US 2003 US 2007 Not specified. Abnormal liver function tests 1984 US

Number of fatty liver Number of patients disease 167 311 88

15 (8.9%) 123 (39.5%) 1 (1.5%)

38

4 (11%)

Aliment Pharmacol Ther 2014; 40: 3-15 ª 2014 John Wiley & Sons Ltd

Systematic review: hepatobiliary manifestations in IBD in UC.62 Mc Gowan et al. reported seven cases of non-alcoholic fatty liver disease associated with CD. Five of them were obese; they all had been treated with corticosteroids in the course of their CD, only one patient received some within the preceding 12 months.114 AASLD does not recognise IBD as a risk factor for NAFLD.113

Confounding factors. Assessment of prevalence of fatty liver disease in IBD is difficult because of many possible confounding factors. Corticosteroid therapy is known to induce bright focal area in the liver, particularly liver hilus.115 It may also induce staetaohepatitis.116 Prevalence of obesity is increasing worldwide.14, 15, 113, 117, 118 IBD population is also concerned. For instance in Tayside, Scotland, in 2009, the increase of obesity in the general population was also observed in the IBD subgroup:16 18% of the IBD population were obese, 38% were overweight. This is also found in children. In the US, approximately one in five children with CD and one in three with UC are overweight or obese.119 HEPATIC AMYLOIDOSIS Epidemiology Systemic amyloidosis is a rare complication of IBD, with a prevalence of about 0.5%. There is a predominance of CD where prevalence ranges from 0.9% to 3%.120–122 It mostly involves kidney, but some cases of hepatic localisations are described: in a series of 18 IBD patients with amyloidosis, 11 had hepatic localisation.121 Concerning systemic amyloidosis associated with IBD, patients are mostly male, often have extraintestinal inflammatory manifestations, and more severe intestinal disease.121 The pathogenesis remains unclear. Amyloidosis can appear early in the history of CD, sometimes before diagnosis of CD is made,123 or years after initial digestive symptoms.124 Mortality is almost related to renal failure, Wester et al. reported a 5-year survival rate of 89% and a 15-year survival rate of 60% in cases of secondary amyloidosis associated with IBD.121

quent in CD. Margalit et al. conducted in 2004 a literature review on the subject. They reported about 60 cases of liver abscess in IBD, only seven occurring in patients with UC.125 CD in these patients is usually an active disease. It is rarely an initial manifestation. Abscesses tend to be multiple, and are mostly in the right lobe of the liver with occasional additional involvement of the left lobe. Clinical manifestations are similar to those in patients without CD. Abscess cultures are positive in most cases and blood cultures are positive in 50% of patients.125–127

Risk factors Several risk factors were identified, including intra-abdominal abscesses, fistulising disease, intestinal perforation, abdominal surgery, corticosteroids and malnutrition.125 PORTAL VEIN THROMBOSIS Epidemiology PVT is a rare complication of IBD, occurring more frequently in the setting of recent abdominal surgery.128 Three studies that included 298 patients reported prevalence of PVT in IBD undergoing proctocolectomy.128–130 Its prevalence ranged from 39% to 45% after surgery. Portal vein thrombi were seen in 41 (45%) of 92 IBD patients having CT after total proctocolectomy with ileal pouch anal anastomosis (IPAA).129 It was 39% of 112 patients undergoing IPAA in another study, with all patients having received prophylaxis with subcutaneous unfragmented heparin.130 CT was performed for hyperleukocytosis, fever, abdominal pain, ileus, abdominal distension or tenderness and decreased stoma output. Of 94 patients, 45% undergoing restorative proctocolectomy were found to have PVT.128

LIVER ABSCESS

Risk factors Proposed causes are mobilisation of the small bowel to the root of the mesentery, tension of the pouch anastomosis and manipulation of the mesenteric vessels with high ligation of ileocolonic vessels.107–109 Post-operative pouchitis seems more frequent in patients suffering from PVT. Ball et al. found, after a mean follow-up of 36.2 months, that 15.4% of patients without PVT had pouchitis compared to 45.5% of those with PVT.130

Epidemiology Liver abscess is a rare complication of IBD. Its prevalence has never been assessed. They seem to be more fre-

CONCLUSION Hepatobiliary manifestations associated with IBD are frequent and underdiagnosed.

Risk factors No studies assessed risk factors of hepatic amyloidosis in IBD patients.

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E. Gizard et al. Cholelithiasis is twice more frequent in CD patients than in the general population.19, 24 This increased risk is not found in UC.19 The cause of this increase is multifactorial, probably secondary to abnormalities in bile composition leading to a faster nucleation time, and a reduced gall-bladder motility.24, 40, 41, 43 The impact of fasting and of total parenteral nutrition is also of particular interest.131–134 Primary sclerosing cholangitis is more frequent in UC than in CD.64, 71, 86 It must be screened among patients with IBD and abnormal liver function tests, using magnetic resonance cholangiography.135 An increased risk of fatty liver disease is suspected in IBD, even though data are inconclusive. Most of epidemiological studies are old and precede the obesity epidemic.114 Hence, data in the modern era are eagerly awaited. Hepatic amyloidosis is a rare complication of IBD, and its diagnosis is difficult. It must be screened in case of hepatomegaly associated with IBD, mostly CD, and must lead to liver biopsy.123, 124 Its impact on the evolution of IBD is not known. Liver abscess is a rare complication of IBD, and mainly concerns CD.126 It must be screened in case of abdominal pain, particularly of the right hypochondrium, with signs of general sepsis. Biology and ultrasonography or abdominal CT must be performed to confirm diagnosis and to look for a cause of the abscess.125 PVT is a frequent post-surgical complication, especially after IPAA. A post-surgical prophylactic anticoagulation should be systematic.130 PBC is a rare complication of IBD. Its prevalence seems to be higher in IBD than in general population.136 Concerning granulomatous hepatitis, only few cases related to IBD, both with UC and CD, have been reported.137 It seems to be idiopathic granulomatous hepatitis rather than CD metastasis, based on pathology reports and on the fact that it can affect both UC and CD patients.110, 138 It is usually related to medications, especially sulfasalazine139–142 and mesalazine (mesalamine).143 We did not find any study assessing prevalence of AIH in IBD. Most of the data concerning AIH in IBD come from studies focusing on PSC, with cases of AIH/ PSC overlap syndromes.144–155 A study that included 105 patients with severe AIH found 16% of concomitant UC.156 Five of them (42%) also had features of PSC on cholangiography.156 In a cohort of 55 paediatric patients with AIH, two different features of the disease were

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identified.157 It was called AIH and autoimmune sclerosing cholangitis (ASC) when radiological features of cholangiopathy were found. Twenty seven ASC and 28 AIH were identified. IBD was present in 12 (44%) of the ASC patients, with five UC, four indeterminate colitis and three CD. It was present in five (18%) of the AIH patients with two UC, one indeterminate colitis, one CD and one acute proctitis.157 In another group of 91 AIH patients, UC was diagnosed in five cases (5.5%).151 Serum IgG4 concentrations were measured in 127 PSC patients, 81% having concomitant IBD. Twelve patients had elevated IgG4. IBD was present in six of the 12 elevated IgG4 patients (50%) vs. 97 of the 115 normal IgG4 patients (90%), the difference reaching statistical significance.158 Four other cases of pancreatitis with PSC-like lesions were reported, none with IBD.159 Of note, Dastis et al. reported two UC patients with concomitant IAC.160 For some authors, presence of IBD argues against the diagnosis of IAC.161 No definite conclusions can be made on the possible association between IBD and IAC. Concerning PBC, about 30 cases were reported of association with IBD, both with CD and UC,136, 162–167 but with a predominance of UC. PBC prevalence seems to be higher in IBD than in the general population.166 PBC tends to affect more men when associated with IBD, with a sex ratio 2:1, while it is 10:1 in general population.136 The mean age also tends to be younger. When associated with UC, colitis tends to be milder and limited, with predominating proctitis.121–123 In conclusion, physicians managing IBD patients should be aware of the possibility of such hepatobiliary manifestations to improve their management and prognosis.

AUTHORSHIP Guarantor of the article: None. Author contributions: LPB takes responsibility for the integrity of the work as a whole, from inception to published article. EG, AF and LPB wrote the paper. EG collected the data. EG, AF and LPB contributed to the design of the study. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal and funding interests: None.

Aliment Pharmacol Ther 2014; 40: 3-15 ª 2014 John Wiley & Sons Ltd

Systematic review: hepatobiliary manifestations in IBD

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