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Inflammatory bowel disease & the liver
- 1. Inflammatory Bowel Disease& Liver Samir Haffar M.D. Assistant Professor of Gastroenterology
- 2. Liver & IBD ElevatedLTs reported in 10 to 50% of patients Rigorous search for causal mechanism necessary to avoid missing iatrogenic mechanism or conversely, wrongly accusing a useful treatment Nahona S et al. Gastroentérol Clin Biol 2009 ; 33 : 370 – 381. • In some patients Liver problem related to IBD itself • In others patients Cause attributed to IBD treatment • In still other patients Neither of these elements involved
- 3. Liver & inflammatorybowel disease Primary sclerosing cholangitis Gallbladder disease Diseases of the hepatic parenchyma Vascular diseases of the liver Anomalies of hepatic vascularization: NRH – SOS Drug hepatotoxicity Liver malignancies : HCC – HSTCL Amyloidosis
- 4. Primary sclerosingcholangitis PSC-IBD
- 5. Screening for PSCin patients with IBD Liver tests periodically • Patients with cholestatic presentation US and/or MRCP for initial evaluation of PSC • Patients with persistent cholestasis & normal US/MRCP ERCP for PSC Liver biopsy particularly for small-duct PSC • Patients with dominant strictures in ERCP Dilatation, biopsy & cytology, DIA, FISH • Mass lesions associated with PSC should be biopsied DIA: Digital Image Analysis FISH: Fluorescence In Situ Hybridization Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
- 6. ERCP in PSC Diffusemultifocal strictures involving medium-sized intrahepatic and/or large-sized extrahepatic ducts Gold standard for diagnosis
- 7. MRCP in PSC Retrospectivecase-control study 36 PSC & 51 controls – ERCP & MRCP in all Sensitivity: 81 – 91% & Specificity: 85 – 96% Slightly inferior to those obtained with ERCP MR cholangiography is now a first-intention exploration for PSC Moff SL. Gastrointest Endosc 2006 ; 64 : 219 – 23.
- 8. Liver biopsy inPSC Fibro-obliterative cholangitis Virtually pathognomonic 5 – 10% of patients Onion skin fibrosis Characteristic lesion Less than one half of patients Normal in 5 to 10% – Useful for small-duct PSC EASL Clinical Practice Guidelines. J Hepatol 2009 ; 51 : 237 – 267. Normal or nearly normal nonspecific liver biopsy cannot rule out PSC
- 9. Incidence of cholangiocarcinomain PSC Younossi ZM. Practical management of liver diseases. Cambridge University Press, Cambridge, UK, 2008.
- 10. Surveillance of PSC-associateddysplasia in PSC-IBD DIA: Digital Image Analysis FISH: Fluorescence In Situ Hybridization Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619. No formal guidelines • Annual follow up LTs – US – CA19-9 • Deterioration & ↑CA19-9 ERCP & biliary sampling Cytology DIA FISH Aberrant DNA methylation • Questionable cytology Surveillance Q 3 – 6 m • Liver mass on US CT or MRI – Biopsies
- 11. ERCP in PSC& cholangiocarcinoma Dominant stricture of proximal CHD should be considered suspicious for cholangiocarcinoma
- 12. Cholangiocarcinoma in apatient with PSC after colectomy for UC Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
- 13. Screening for IBDin patients with PSC • Screening performed even in absence of GI symptoms • Colonoscopy & biopsies of TE: Rectal sparing Pancolitis Minimally active disease Backwash ileitis Colorectal neoplasia • Colonoscopy in PSC-IBD: Q year with multiple biopsies • Patients with initial normal colonoscopy: Q 3 years Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
- 14. Cumulative probability ofCRC or dysplasia p = 0.057 Log rank test Loftus Jr E V et al. Gut 2005 ; 54 : 91 – 96
- 15. Overall survival ofCRC or dysplasia P = 0.001 Log rank test Loftus Jr E V et al. Gut 2005 ; 54 : 91 – 96.
- 16. Navaneethan U etal. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619. Surveillance of colonic dysplasia in IBD-PSC Annual surveillance colonoscopy Flat DAML Multifocal LG High grade cancer Colectomy dysplasia colonoscopy in 3 – 6 months indefinite for dysplasiano dysplasia colonoscopy every year adenoma-like unifocal LG
- 17. Small-duct PSC “formally pericholangitis” •Diagnosis Biological cholestasis Normal cholangiography Histology compatible with PSC • Frequency 10% in high-quality ERCP • Evolution to PSC 25% after 10 years follow-up • Prognosis Better than ‘‘classical’’ PSC • Cholangiocarcinoma Never been described Specific disease of BD with different natural history
- 18. Liver transplantation freein small & large-duct PSC Björnsson E et al. Gastroenterology 2008 ; 134 : 975 – 980. 83 pts with small-duct PSC from Europe & US 157 pts with large-duct PSC matched for age, gender, & institution HR: 3.04 95% CI: 1.82-5.06 P < .0001
- 19. IgG4 associated cholangitis(IAC) • Increased serum levels of IgG4 • IgG4 plasma cell infiltration of bile ducts • Preferential involvement of extrahepatic ducts • Frequent association with another fibrosing condition Autoimmune pancreatitis (> 50%) • Regression of biliary stenosis with corticosteroid therapy Björnsson E et al. Hepatology 2007 ; 45 : 1547 – 1554. Dastis SN et al. J Hepatol. 2009 ; 51: 601 – 605. Atypical form of PSC or different entity
- 20. IgG4 associated cholangitis& UC IgG4 stain showing many positive cells around duct > 10 cells / hpf Björnsson E et al. Hepatology 2007 ; 45 : 1547 – 1554. Dastis SN et al. J Hepatol 2009 ; 51 : 601 – 605.
- 21. Gallbladder disease inpatients with PSC Said K et al. J Hepatol 2008 ; 48 : 598 – 605. Dysplasia & carcinoma common in GB epithelium Regular examination of GB in PSC patients Cholecystectomy regardless of GB lesion size One or more GB abnormalities 41% Gallstones 25% Cholecystitis 25% GB mass (size 21, 9 mm) 6% (56% carcinoma) 286 PSC patients, liver unit, Karolinska, Swedeen
- 22. Gallbladder carcinoma ina patient with PSC Said K et al. J Hepatol 2008 ; 48 : 598 – 605. Ultrasound Histology
- 23.
- 24. Ulcerative colitis No gallstones Gallstones 172 13 93.0% 7.0 % 175 10 94.6 % 5.4 % Gallstones in patients with IBD Case-control study – followed 7.2 years (range 5 – 11) Disease Cases with IBD Controls N % N % OR (95% CI) Crohn’s disease No gallstones Gallstones 374 41 90.1 % 9.9 % 394 21 94.9 5.1 Parente F et al. Hepatology 2007 ; 45 : 1267 – 1274. Only CD pts have significantly higher risk of developing gallstones Risks: ileal involvement, extent of ileal resection & TPN 2.09 (1.20 – 3.64) 1.33 (0.56 – 3.16)
- 25. Prophylactic cholecystectomy during ileocolicresection in Crohn’ disease • Patients 191 patients with Crohn's ileitis Medical treatment – ileocolic resection Matched control group for age & gender • Retrospective Questionnaire – telephone interviews • CholecystetomyCrohn ileitis 17/134 Control group 15/150 • Conclusion Prophylactic cholecystectomy not justified Chew SS et al. Dis Colon Rectum 2003 ; 46 : 1484 – 8. P = not significant
- 26. Diseases ofthe hepatic parenchyma
- 27. Diseases of hepaticparenchyma • Autoimmune hepatitis1 Exceptional • Primary biliary cirrhosis2 20 cases reported • Granulomatous hepatitis3 Crohn – Sulfasalazine • Hepatic steatosis4 40% in Crohn’s disease 35% in ulcerative colitis • Liver abscesses5 Generally single germ Steroids, AZA, anti-TNF 1 Ahmad J et al. Gastroenterol Clin N Am 2002 ; 31 : 329 – 45. 2 Xiao WB et al. World J Gastroenterol 2003 ; 9 : 878 – 80. McCluggage WG et al. Histopathology 1994 ; 25 : 219 – 28. 4Bargiggia S et al. J Clin Gastroenterol 2003 ; 36 : 417 – 20. 5Navot-Mintzer D et al. Inflamm Bowel Dis 2006 ; 12 : 666 – 7.
- 28. Vascular diseasesof the liver
- 29. Vascular liver diseases& IBD Clinical case reports • Portal vein thrombosis1 Surgery – UC following IPAA & ↑ risk of pouchitis • Pylephlebitis with portal vein gas2 High mortality (11%) • Peliosis hepatis & sinusoidal dilatation3 Generally asymptomatic – PHT – anicteric cholestasis • Budd-Chiari syndrome4 UC more often than Crohn’s disease 1 Irving PM et al. Clin Gastroenterol Hepatol 2005 ; 3 : 617 – 28. 2 Ng SS et al. World J Gastroenterol 2006 ; 12 : 5582 – 6. 3 Launay D et al. Rev Med Interne 2002 ; 23 : 198 – 202. 4 Chesner IM et al. Gut 1986 ; 27 : 1096 – 100.
- 30. PV gas &PV thrombosis in fulminant Crohn’s colitis PV gas & PV thrombosis Gross ascites Pneumoperitoneum World J Gastroenterol 2006 ; 14 : 5582 – 5586.
- 31. Peliosis hepatis &Crohn’s disease Rare association Launay D et al. Rev Méd Interne 2002 ; 23 : 198-202 Sinusoidal & Disse space dilatation around atrophied hepatocytes
- 32. Conditions associated withpeliosis hepatis Azathioprine 6-Thioguanine AIDS/Bartonella infection Tuberculosis Myeloproliferative diseases Leukemia Lymphoma Multiple myeloma Macroglobulinemia Anabolic steroids Oral contraceptives Arsenic Thoratrast Vinyl chloride Yamada’s textbook of gastroenterology, Blackwell Publishing, fifth Edition, 2009.
- 33. UC complicated byBudd-Chiari syndrome Portal tract with rim of viable hepatocytes Central veins occluded by fibrin thrombi with surrounding haemorrhage & necrosis (H & E x 68) Chesner I M et al. Gut, 1986 , 27 , 1096 – 1100.
- 34. Anomalies ofhepatic vascularization: NRH – SOS
- 35. Nodular regenerative hyperplasia R.Lencioni et al. Focal Liver Lesions. Springer-Verlag Berlin Heidelberg 2005. NRH may resemble cirrhosis grossly Gross appearance Nodules less well defined Parenchyma softer than in cirrhosis Fibrous septa are lacking At cut surface
- 36. Kaplan-Meier estimate ofcumulative risk of NRH 1888 consecutive IBD pts treated with AZA Seksik P et al. Inflamm Bowel Dis 2010 in press. 2 variables associated with NRH occurrence Male gender: P = 0.0001, HR 8.5 (95% CI 1.9 - 37.9) Small bowel resection ≥ 50 cm: P < 0.0001, HR 6.6 (95% CI: 2.2-20.0) 15 patients developed NRH Median treatment duration: 52.4 months Cumulative incidence: 1.28 0.45% at 10 y
- 37. MRI in NRH 45patients tt with 6-TG – MRI & liver biopsy in all cases Seiderer J et al. J Hepatol 2005 ; 43 : 303 – 309. Speckled enhancement in a patient with NRH Fine-nodular aspect of enhancement Normal appearance of liver in a patient without NRH Arterial phase after injection of gadolinium Sen: 77% – Sp: 72% (Promising non-invasive diagnosis)
- 38. Nodular regenerative hyperplasiaof the liver Seiderer J et al. J Hepatol 2005 ; 43 : 303 – 309. Hepatocyte hyperplasia Sinusoidal dilatation Compression zones Hematoxylin-eosin staining (x 20) Characteristics of NRH best seen in silver reticulin staining Silver reticulin (x 20)
- 39. Drugs implicated inSOS Azathioprine 6-mercaptopurine 6-thioguanine Actinomycin D Busulfan Cytosine arabinoside Cyclophosphamide Dacarbazine Gemtuzumab-ozogamicin Melphalan Oxaliplatin Urethane DeLeve LD et al. Hepatology 2009 ; 49 : 1729 – 1764.
- 40. Acute SOS after6-TG therapy for Crohn’s Disease Reticulin staining Near total occlusion of a central vein Kane S et al. Inflamm Bowel Dis 2004 ; 10 : 652 – 654.
- 41.
- 42. Council for InternationalOrganizations of Medical Sciences (CIOMS) Benichou C. J Hepatol 1990 ;11 : 272 – 6. International consensus meeting • Liver tests (LTs) Instead of liver function tests • Abnormality of LTs ↑ AST, ALT, AP, or TB between N – 2 N • Liver injury > 2 ULN in ALT, AST, AP or TB • Acute liver injury Increases lasted < 3 months - Hepatocellular ALT > 2 N or ALT/AP ≥ 5 - Cholestatic AP > 2 N or ALT/AP ≤ 2 - Mixed ALT/AP between 2 – 5 • Chronic liver injury Increases lasted > 3 months
- 43. Biour M etal. Gastroentérol Clin Biol 2004 ; 28 : 720 – 759.
- 44. Drug-induced liver injury& IBD AZA +++ +++ +++ ++ + + SOS – NRH D – Y 6-MP ++ +++ ++ + SOS – NRH D – Y 6-TG + + + + SOS – NRH D – Y MTX ++ + ++ +++ NASH D – Y Sulfasalazine ++ ++ ++ + Granuloma W – M Mésalazine + + + D – Y Cyc A + ++ D – Y Tacrolimus + + + SOS W Infliximab ++ ++ ++ ++ W MFM + + + D D: days – W: weeks – M: months – Y: years SOS: sinusoidal obstruction syndrome – NRH: nodular regenerative hyperplasia Larrey D. Gastroentérol Clin Biol 2008 ; 32 : S194 – S204. Acute hepatitis Chronic hepatitis Cirrhosis Other Delay HC Chol Mixed Fulminant
- 45. Thiopurine-induced liver injuryin IBD Systematic review • Frequency 3.3% (95% CI: 2.7 – 3.9%) 1% per patient & year of treatment • Chronology First months after treatment (1.5 – 5 m) R/O other causes if delayed liver injury • Liver injury Hypersensitivity Idiosyncratic cholestatic reaction Endothelial injury: NRH – SOS – Peliosis • AZA vs MP Unknown if there is any difference Gisbert JP et al. Am J Gastroenterol 2007 ;102:1518–1527
- 46. Management of thiopurine-inducedliver injury Gisbert JP et al. Am J Gastroenterol 2007 ;102:1518–1527 Mild abnormality of LTs Asymptomatic Continue AZA/MP Frequent control Moderate-severe No jaundice 50% dose reduction Frequent control AZA/MP withdrawal Severe cholestatic jaundice Normal LTs Initial AZA/MP dose Abnormal LTs AZA/MP withdrawal MP instead of AZA
- 47. Liver & methotrexate Mostfeared long-term side effect is liver fibrosis • Studies from the 80’s Cirrhosis: 0 – 26% Cumulative dose ≥ 1.5 g Liver biopsy at 1.5 g & repeated every 1 – 1.5 g • Recent studies* Characterization of HCV & NASH Cirrhosis: 0 – 6% vs 0.8% in general population** No association between high dose & liver fibrosis * Laharie D et al. J Hepatol 2010 (in press). ** Fleming KM et al. J Hepatol 2008 ; 49 : 732 – 738. (based on expert opinion)
- 48. Cumulative probability ofadvanced fibrosis (Ishak score ≥4) whilst on MTX therapy Aithal GP et al. Aliment Pharmacol Ther 2004 ; 19 : 391 – 399. 1500 mg 0% 3000 mg 2.6% 4500 mg 2.6% 5000 mg 8.2% 6000 mg 8.2% 66 patients treated with methotrexate for psoriasis – 121 liver biopsies
- 49. Non-invasive diagnosis ofliver fibrosis due to MTX Case-control study – 518 pts (390 MTX – 128 controls) Laharie D et al. J Hepatol 2010 ; 53 : 1035 – 1040. Severe liver fibrosis rare in pts treated with MTX (8.5%) Risk factors: BMI >28 kg/m2 & high alcohol consumption 7.9 kPs 0.48
- 50. Monitoring patients treatedwith MTX • Non-invasive tests (FibroScan &/or Fibrotest) Before starting methotrexate Regular tests during treatment course Especially in viral hepatitis, steatosis & alcoholism • Liver biopsy Case-by case indication For example: prolonged transaminase elevation
- 51. Hepatic malignancies: HepatosplenicT-cell lymphoma & HCC
- 52. Hepatosplenic T-cell lymphoma Majorityof reported cases rapidly fatal • Most patients Young males (5 – 20 years) Crohn’s disease (90%) Combined thiopurine/anti-TNF • Usual presentation Hepatosplenomegaly Fever –↑ LFTs – pancytopenia • No effective therapy Chemotherapy-SC transplantation • Role of anti-TNF in development of HSTCL uncertain Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
- 53. Hepatocellular carcinoma • 3patients with Crohn’s disease • 1 patient with ulcerative colitis • 4 patients treated with AZA or AZA-infliximab • 2 patients were young (22 and 28 years) & exposed to AZA for 3 – 6 years Four cases of hepatocellular carcinoma reported Nahona S et al. Gastroentérol Clin Biol 2009 ; 33 : 370 – 381.
- 54.
- 55. Secondary amyloidosis (AAtype) Rare but serious complication • Incidence: < 1 % – Crohn’s/UC: 10/1 • M/F ratio: 3/1 • More common in ileocolitis than in ileitis or colitis • Two-thirds of patients have fistulas & abscesses • Effective treatment remains controversial: Surgery – Colchicine – immunosuppressive drugs anti-TNFα : targets deterioration of further damage Oikonomou K et al. Inflamm Bowel Dis 2010 in press.
- 56.
Editor's Notes
- #5 Patients with PSC and IBD may demonstrate a distinct pattern of clinical behavior compared with IBD patients without concomitant PSC, leading to the coined term of PSC-IBD as a separate clinical entity by the Mayo group
- #6 Prevalence of PSC in patients with IBD:1.5%–7.5% of patients with IBD will develop PSC during their disease course.DIA:Digital Image Analysis of cell samplesFISH:Fluorescence In Situ Hybridization of cell samples
- #8 MR cholangiography is now a first-intention exploration, ERCP being performed only for therapeutic purposes, or rarely when complementary diagnostic information is needed.GastrointestEndosc 2006;64:219-23.Background: We hypothesized that magnetic resonance cholangiography (MRC) may have less accuracy for the diagnosis and the assessment of the severity of primary sclerosingcholangitis (PSC) than endoscopic retrograde cholangiography (ERC).Objective: The aim of this study was to determine the diagnostic accuracy and interobserver agreement of both ERC and MRC in PSC.Design: A case-control study.Setting: University Hospital.Patients: ERCs and MRCs of 36 patients with PSC and 51 controls (normal/other biliary tract diseases) were read in an independent, blinded, and random fashion by 2 magnetic resonance radiologists and 2 interventional endoscopists by using a previously validated classification system. Readers had no access to clinical history, laboratory results, or patient mix.Results: Extrahepaticductal (EHD) and intrahepaticductal (IHD) visualization was excellent in 64% of 66% of MRCs and 86% of 74% of ERCs. Sensitivity and specificity for diagnosis of PSC for readers 1 to 4 were 91% and 85%, 88% and 90%, 81% and 96%, and 83% and 96%. respectively. Receiver operating curve values were excellent for all readers (all > 0.9). Interobserver agreement (k statistics) for the diagnosis of PSC (MRC, 0.83; ERC, 0.73) and for identifying the presence of IHD strictures (MRC, 0.64; ERC, 0.86) was good for both modalities, but only ERC (ERC, 0.55; MRC, 0.36) was good for the presence and the severity of EHD strictures. When assessment ofdisease severity was limited to the 36 patients with PSC, interobserver agreement was very poor for both MRC (0.23 and 0.07 for EHD and IHD, respectively) and ERC (0.24 and 0.34 for EHD and IHD, respectively).Limitations: The retrospective case–control study made it difficult to assess the impact of the diagnosis on patient management.Conclusions: ERC and MRC were comparable for diagnosing PSC, with very good interobserver agreement for the diagnosis of PSC and IHD strictures. Only ERC had good agreement for EHD strictures. Interobserver agreement was very poor for both MRC and ERC when disease severity of PSC was assessed.
- #9 The most common histological feature, the fibrous obliterating cholangitis, is absent in more than two thirds of the biopsy specimens due to the heterogeneous distribution of lesions within the liver. Periductal concentric (“onion-skin”) fibrosis is a classic histopathologic finding of PSC, but this observation is infrequent in PSC liver biopsy specimens and may also be observed in SSC.The histology report thus generally mentions lesions ‘‘compatible’’ with the diagnosis of bile duct disease: peribiliary portal inflammation, discrete atrophy of the bile ducts without periductal fibrosis, proliferative ductal reaction or ductopenia. The biopsy is found normal in 5-10% of cases. Consequently, when the context is suggestive, a normal or nearly normal nonspecific liver biopsy cannot rule out the diagnosis of primary sclerosingcholangitis.
- #11 A combination of cytology, FISH, and DIA was shown to have a sensitivity of 50%–64%, but with a specificity and a positive predictive value of 100%.
- #14 Prevalence of IBD during primary sclerosingcholangitis: Two thirds of cases.Ulcerative colitis is the main IBD involved.Prevalence of Crohn’s disease during PSC varies from 1 to 17%: always involves the colon.Ulcerative colitis is diagnosed before primary sclerosingcholangitis in about two thirds of patients but the inverse is also possible; the colitis may even begin after liver transplantation. There is no correlation between the severity of ulcerative colitis and the severity of primary sclerosingcholangitis; colectomy does not appear to modify the course of the primary sclerosingcholangitis.
- #15 PSC-IBD: a unique form of IBD associated with PSCGut 2005 ; 54 : 91 – 96.Background: Inflammatory bowel disease associated with primary sclerosingcholangitis (PSC-IBD) may have a high prevalence of rectal sparing, backwash ileitis, and colorectal neoplasia.Aims: To describe the clinical features and outcomes of PSC-IBD and compare these to a group of chronic ulcerative colitis (CUC) patients.Methods: The medical records of all patients with PSC-IBD evaluated at the Mayo Clinic Rochester between 1987 and 1992 were abstracted for information on endoscopic and histological features, colorectal neoplasia, surgery, and other clinical outcomes. Patients referred for colorectal neoplasia and those who did not undergo colonoscopy with biopsies were excluded. A control group of CUC patients matched for sex, duration of IBD at first clinic visit, and calendar year of first clinic visit was identified, and similar information was abstracted.Results: Seventy one PSC-IBD patients and 142 CUC patients without PSC were identified. Rectal sparing and backwash ileitis were more common in the PSC-IBD group (52% and 51%, respectively) than in controls (6% and 7%, respectively). Overall, colorectal neoplasia developed in 18 cases and 15 controls, including 11 cancers (seven cases and four controls). An increased risk of colorectal neoplasia or death was not detected in a matched analysis. Although the cumulative incidence of colorectal neoplasia was higher in cases (33%) than in controls (13%) at five years, this was of borderline statistical significance (p = 0.054, unmatched log rank test). Overall survival from first clinic visit was significantly worse among cases (79% v 97%) at five years (p,0.001, unmatched log rank test).Conclusion: PSC-IBD is frequently characterised by rectal sparing and backwash ileitis. Colorectal neoplasia develops in a substantial fraction and overall survival is worse. PSC-IBD may represent a distinct IBD phenotype.
- #16 PSC-IBD: a unique form of IBD associated with PSCGut 2005 ; 54 : 91 – 96.Background: Inflammatory bowel disease associated with primary sclerosingcholangitis (PSC-IBD) may have a high prevalence of rectal sparing, backwash ileitis, and colorectal neoplasia.Aims: To describe the clinical features and outcomes of PSC-IBD and compare these to a group of chronic ulcerative colitis (CUC) patients.Methods: The medical records of all patients with PSC-IBD evaluated at the Mayo Clinic Rochester between 1987 and 1992 were abstracted for information on endoscopic and histological features, colorectal neoplasia, surgery, and other clinical outcomes. Patients referred for colorectal neoplasia and those who did not undergo colonoscopy with biopsies were excluded. A control group of CUC patients matched for sex, duration of IBD at first clinic visit, and calendar year of first clinic visit was identified, and similar information was abstracted.Results: Seventy one PSC-IBD patients and 142 CUC patients without PSC were identified. Rectal sparing and backwash ileitis were more common in the PSC-IBD group (52% and 51%, respectively) than in controls (6% and 7%, respectively). Overall, colorectal neoplasia developed in 18 cases and 15 controls, including 11 cancers (seven cases and four controls). An increased risk of colorectal neoplasia or death was not detected in a matched analysis. Although the cumulative incidence of colorectal neoplasia was higher in cases (33%) than in controls (13%) at five years, this was of borderline statistical significance (p = 0.054, unmatched log rank test). Overall survival from first clinic visit was significantly worse among cases (79% v 97%) at five years (p,0.001, unmatched log rank test).Conclusion: PSC-IBD is frequently characterised by rectal sparing and backwash ileitis. Colorectal neoplasia develops in a substantial fraction and overall survival is worse. PSC-IBD may represent a distinct IBD phenotype.
- #18 Thus, in IBD patients presenting with elevation of alkaline phosphatase and a normal cholangiogram by ERCP/MRCP, and being excluded for other liver and biliary diseases, liver biopsy may be needed to rule out small-duct PSC.
- #20 Although an increased serum IgG4 level was observed in 9% of patients with PSCIAC appears to be a histologically and pathogenetically distinct entity with dramatic response to corticosteroid therapy in contrast to the progressive and refractory nature in PSC.IAC was described in 2 patients with concurrent IBD. The 2 patients were HLA-identical siblings and both had UC with coexisting IAC responsive to low-dose corticosteroid therapy.the question whether PSC, IAC, and AIP share a common pathogenesis or are variations of the same disease spectrum need to be further explored.IgG4 related systemic diseaseDiagnosis of IAC:Diagnosis is confirmed if biliary or other organ histology shows marked infiltration with IgG4 positive cells (> 10 cells/ hpf) or the stricture responds/resolves with steroid treatment.
- #21 Diagnosis of IAC is confirmed if biliary or other organ histology shows marked infiltration with IgG4 positive cells (10 cells/hpf) or the stricture responds/resolves with steroid treatment.
- #22 Gallbladder disease in patients with primary sclerosingcholangitisSaid K et al. J Hepatol 2008 ; 48 : 598 – 605.Background/Aims: Gallbladder abnormalities may be part of the spectrum in primary sclerosingcholangitis (PSC). The aim of the present study was to evaluate the occurrence and prognostic importance of gallbladder abnormalities in patients with PSC.Methods: Presence of gallbladder abnormalities was assessed in 286 patients with PSC treated at the Liver Unit, Karolinska University Hospital, Huddinge, between 1970 and 2005.Results: One or more gallbladder abnormalities were found in 41% of the patients. Gallstones were found in 25% and cholecystitis in 25%. Cholecystitis among patients with extrahepatic involvement of PSC (30% (65/214)) was significantly higher than among those with intrahepatic involvement (9% (6/70)) (P < 0.0001). A gallbladder mass lesion with a mean size of 21 (±9) mm (S.D.) was found in 18 (6%) patients, in 56% (10/18) of whom it constituted gallbladder carcinoma. In 9 patients without a gallbladder mass lesion, histological re-evaluation disclosed epithelial dysplasia of the gallbladder.Conclusions: Gallbladder disease is common in patients with PSC. Dysplasia and carcinoma are commonly found in gallbladder epithelium, suggesting that regular examination of the gallbladder in PSC patients could be of value for early detection of a gallbladder mass lesion. Cholecystectomy is recommended when such a lesion is detected, regardless of its size.
- #25 Chew SS, Ngo TQ, Douglas PR, Newstead GL, Selby W, Solomon MJ. Cholecystectomy in patients with Crohn’s ileitis. Dis Colon Rectum 2003;46:1484-8.Because of the higher prevalence of gallstone disease, prophylactic cholecystectomy could be warranted in patients undergoing ileal resection. An Australian team compared a group of patients with operated ilealCrohn’s disease (n = 89) with a group of patients with ilealCrohn’s disease treated medically (n = 45). Patients were contacted by phone; 20 had symptomatic gallstones (18/89 with ileal resection and 2/45 with medical treatment). In this work, the prevalence of cholecystectomy was the same in the two groups. Thus cholecystectomy would not appear to be warranted during ileal resection for Crohn’s disease.
- #26 Chew SS, Ngo TQ, Douglas PR, Newstead GL, Selby W, Solomon MJ. Cholecystectomy in patients with Crohn’s ileitis. Dis Colon Rectum 2003;46:1484-8.PURPOSE: Gallstone disease is reported to be higher in patients with Crohn's disease than in the general population. This study was designed to determine the prevalence of cholecystectomy in patients with Crohn's ileitis, attempt to identify any associated risk factors, and determine whether it is justified to perform prophylactic cholecystectomy during ileocolic resection.METHODS: A total of 191 patients with Crohn's ileitis who were treated medically or who had an ileocolic resection were retrospective reviewed. A questionnaire survey was performed. Telephone interviews were conducted for the nonrespondents. Further review of medical records was performed to determine the details of admissions for any gallstone disease and/or subsequent cholecystectomy. A.RESULTS: A total of 191 questionnaires were mailed, and the overall response rate was 70.2 percent (134/191) after telephone interview follow-up. There were 2 of 45 medical and 18 of 89 surgical patients with symptomatic cholelithiasis, i.e., 14.9 percent (20/134) of respondents. As a result, 2 patients (1.5 percent) required endoscopic sphincterotomy, 17 patients (12.7 percent) needed cholecystectomy, and 1 patient (0.7 percent) did not have any intervention. Only five patients had a cholecystectomy after their ileal resections. In the control group of 150 patients, 15 patients (14 females; mean age, 51.9 years; range, 34-78 years) had previous cholecystectomy. There was no significant difference with prevalence of cholecystectomy in Crohn's patients compared with controls (17/134 vs. 15/150; P = not significant). Furthermore, the number of ileal resections did not affect the cholecystectomy rate, but patients who had >30 cm of ileum resected were more likely to have cholecystectomy (P = 0.056).CONCLUSIONS: The prevalence of gallstone disease in Crohn's ileitis requiring cholecystectomy is similar to that of the general population with a female predominance. In addition, the number of patients requiring cholecystectomy after ileal resection was low. Thus, synchronous prophylactic cholecystectomy during ileocolic resection for Crohn's ileitis is not justified.
- #28 Bargiggia S, Maconi G, Elli M, Molteni P, Ardizzone S, Parente F, et al. Sonographic prevalence of liver steatosis and biliary tract stones in patients with inflammatory bowel disease: study of 511 subjects at a single center. J ClinGastroenterol 2003;36:417—20.An ultrasound study in 511 patients with IBD found hepatomegaly in 25.7% and moderate to severe hepatic steatosis (defined by the intensity gradient between the liver and the kidney) in 39.5% of patients with Crohn’s disease and 35% of those with ulcerative colitis.
- #32 RésuméIntroduction. – Les maladies inflammatoires chroniques de l’intestin se compliquent dans 10 à 30 % des cas d’anomalies hépatobiliaires. Parmi celles-ci, la stéatose hépatique et les lithiases biliaires sont les plus fréquentes dans la maladie de Crohn. À l’inverse, la péliose hépatique n’est qu’exceptionnellement décrite en association avec les maladies inflammatoires chroniques de l’intestin. Nousdécrivons un cas de péliose hépatique compliquant une maladie de Crohn jusqu’alors méconnue.Exégèse. – Une jeune femme âgée de 24 ans consultait pour une hépatomégalie et une altération de l’état général. L’interrogatoire retrouvait une diarrhée depuis trois mois et un épisode de rectorragie. Il existait une lésion aphtoïde de la langue. Le transit du grêle mettait en évidence un aspect typique d’iléite terminale évocateur de maladie de Crohn. Le foie était morphologiquement hétérogène. La ponction–biopsie hépatique permettait de poser le diagnostic de péliose hépatique pour laquelle les autres causes étaient écartées. Il s’agissait donc d’une péliose hépatique découverte devant une hépatomégalie et associée à une maladie de Crohn méconnue.Conclusion. – L’association entre une maladie de Crohn et une péliose hépatique n’a été qu‘exceptionnellement décrite. Il ne s’agit pas a priori d’un facteur de gravité des maladies inflammatoires chroniques de l’intestin. La signification physiopathologique de cette association est inconnue. La péliose hépatique est définie dans sa forme macrokystiquepar la présence de cavités multiples remplies d’hématies dans le parenchyme hépatique et souvent accompagnées par une dilatation des sinusoïdes. Dans les formes plus modérées, il existe une distension des sinusoïdes sans cavité mais avec un décollement endothélial ou des hématies. Causes de la péliose hépatique:Contraception orale - insuffisance cardiaque droite – tuberculose - infection par le virus de l’immunodéficience humaine- cancers – hémopathies - prise de vitamine A – azathioprine - dérivés C-17 α-alkyl de la testostérone.
- #36 Nodular regenerative hyperplasia is arare disorder defined by the presence of diffuse nodules of the hepatic parenchyma without annular fibrosis and may lead to severe portal hypertension.Diagnosis of NRH was suspected on acquired thrombocytopenia (i.e., platelet count under 150,000 per mm3), splenomegaly, or clinical signs of portal hypertension and proven by liver biopsy.
- #37 Incidence of NRH in IBD treatede with AZAInflamm Bowel Dis 2010;000:000–000Background: Nodular regenerative hyperplasia (NRH) is a rare hepatic disorder that may lead to severe portal hypertension. Cases of NRH have been reported in patients receiving thiopurines for inflammatory bowel disease (IBD). Since azathioprine (AZA) is used more and more frequently as a maintenance treatment in IBD, the risk of NRH must be known. The objective of this study was to evaluate the prevalence of NRH and its predictive factors in IBD patients treated with AZA.Materials and Methods: From the same tertiary referral center, 1888 consecutive IBD patients treated with AZA were studied. Clinical diagnosis of NRH was proven by liver biopsy in all cases except one. The cumulative risk of NRH was estimated with the Kaplan–Meier method. Factors associated with NRH were tested independently with the log-rank method and multivariate proportional hazards model with time-dependent covariates.Results: Fifteen patients developed NRH in a median treatment duration of 52.4 months (SE 1.6). The cumulative incidence of NRH was 1.28 6 0.45% at 10 years. Only two variables were independently associated with NRH occurrence: male gender (P = 0.0001, hazard ratio [HR] 8.5, 95% confidence interval [CI] 1.9– 37.9) and small bowel resection 50 cm (P < 0.0001, HR 6.6, 95% CI 2.2–20.0), either prior to or after AZA initiation. Conclusions: The risk of developing NRH during AZA treatment is low. This study suggests that male patients with small bowel resection 50 cm constitute the group with the higher risk of developing NRH while treated with AZA.
- #38 Background/Aims:Although 6-thioguanine (6-TG) has been suggested as an effective treatment option for patients with inflammatory bowel disease (IBD), the recent description of its hepatotoxicity has led to the recommendation not to consider this drug. We initiated a multicenter safety study in IBD-patients treated with 6-TG to investigate hepatic changes by liver biopsy and magnetic resonance imaging (MRI).Methods: Forty-five patients from three European centers treated with 6-TG (40–80 mg/d) at least for 8 weeks were enrolled. In all patients liver biopsy and MRI were performed. Slides and MR images were independently read by two pathologists and radiologists, respectively, and interpreted according to predefined criteria by consent.Results: In 8 patients nodular regenerative hyperplasia (NRH) was diagnosed by liver biopsy, in 8 additional patients NRH could not be excluded due to equivocal pathological findings. MRI demonstrated a sensitivity of 77% and a specificity of 72% in the detection of pathohistological findings consistent with and/or possibly related to NRH.Conclusions: Our study suggests that 6-TG therapy in IBD patients is associated with NRH of the liver. Based on a special MRI protocol, non-invasive diagnosis of NRH with promising sensitivity and specificity was demonstrated.
- #39 histological study of liver biopsy showing hyperplasticparenchymatous nodules without extensive fibrosis on silver reticulin staining, with compressed and atrophic internodular parenchyma.
- #40 Previously known as hepatic veno-occlusive disease.Partial or total non-thromboticfibrous obstruction of centrolobular veins.Manifestation: anictericcholestasis – ascites – PHT Few published cases in patients treated for 1- 2 years for UC or CD.
- #41 Acute Sinusoidal Obstruction Syndrome After 6-TG Therapy for Crohn’s DiseaseAbstract: 6-Thioguanine (6-TG), the active metabolite of 6-mercaptopurine and its prodrugazathioprine, are thought to be responsiblefor clinical efficacy in the treatment of active Crohn’s disease. Its use as a therapeutic agent for inflammatory bowel disease (IBD)has been limited to patients who are resistant to or intolerant of other antimetabolites. Short-term experience with this agent has not demonstrated an increased incidence of hematologic or hepatic toxicity; however long-term safety data are scarce. We herein report a patient who developed acute sinusoidal obstruction syndrome after 14 months of successful thioguanine treatment. This is the first report of such a complication in an adult treated with 6-TG for active Crohn’s disease.SOS: Partial or total non-thrombotic fibrous obstruction of CVManifestation: PHT – Ascites – AnictericcholestasisThere have been a few published cases of sinusoidal obstruction in patients treated for one or two years for ulcerative colitis or Crohn’s disease.
- #45 The term “liver tests” (LTs) should be used instead of “liver function tests.” “acute” liver injury was considered present when these increases had lasted less than 3 months“chronic” liver injury was used when these increases had lasted more than 3 monthsAcute drug-induced liver injury1- Drug-induced cholestatic injury: has been defined by an international consensus panel by an isolated elevation of serum alkaline phosphatase (AP) >2 ULN or an alanineaminotransferase (ALT)/AP ratio (both elevated above ULN) ≤ 2. 2- Drug-induced hepatocellular injury as the predominant form of DILI is defined by isolated ALT >2 ULN or an ALT/AP ratio (bothelevated above ULN) ≥ 5. 3- Mixed type injury is defined by an ALT/AP ratio of 2–5. Drug-induced cholestatic injury has a better prognosis than hepatocellular injury.For many drugs, the reported prevalence of DILI is between 1 in 10,000 and 1 in 100,000 patients, and about 30% of cases with DILI are cholestatic. However, these estimates are weakened by considerable underreporting of DILI. Both environmental and genetic factors may determine susceptibility. Genetically determined variations of hepatobiliary transporter and biotransformation enzyme expressionand function may be important risk factors for an individual’s susceptibility to cholestasis under conditions of xenobiotic stress by drugs.Cholestasis:By convention, cholestasis is considered chronic if it lasts >6 months.Isolated serum GGT elevation has little specificity for cholestasis, and may also result from enzyme induction in response to alcohol or drug intake.The cut-off levels of serum AP and GGT requiring diagnostic work-up are debated: AP levels higher than 1.5 times the upper limitof normal (ULN) and GGT levels >3 ULN have been proposed.
- #46 6-TG:During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patientspresented data on the safety and efficacy of this drug. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting.
- #47 The term “liver tests” (LTs) should be used instead of “liver function tests.” “Abnormality of LTs” was defined as an increase in aspartatetransaminase (AST), alaninetransaminase (ALT), alkaline phosphatase (AP), or total bilirubin between N (upper limit of the normal range) and 2 N. An isolated increase even over 2 N in AST, AP, or total bilirubin should be considered only a biochemical abnormality and not necessarilya sign of liver injury. “Liver injury” (or “hepatotoxicity”) should be used if there is an increase of over 2 N in ALT or conjugated bilirubin (or a combined increase in AST, AP, and total bilirubin provided one of them is above 2 N).
- #48 Le seuil de 1500 mg de méthotrexate en dose cumulée ne repose que sur un consensus d’experts.
- #49 Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasisAithal GP et al. Aliment PharmacolTher 2004 ; 19 : 391 – 399.Background: Reports that up to 26% of subjects with psoriasis develop cirrhosis have led to a recommendation of serial liver biopsies after each cumulative dose of 1500 mg of methotrexate.Aim: To evaluate the progression of liver injury in patients with psoriasis and the impact of monitoring by liver biopsy on their management.Methods: One hundred and twenty-one liver biopsies from 66 subjects (aged 11–79 years) with psoriasis, receiving a median cumulative dose of 3206 mg of methotrexate over a period of 280.5 weeks, were evaluated.Results: The assessment of advanced fibrosis according to the Ishak system (≥ 4) correlated perfectly with that of the Scheuer system (≥ 3) and poorly with that of the Roenigk scale (≥ 3b) (r2 = 1.0 and 0.31, respectively). Two of 24 pre-treatment biopsies showed advanced fibrosis and both subjects were heavy drinkers. The cumulative probabilities of advanced fibrosis (Ishak≥ 4) were 0%, 2.6%, 2.6%, 8.2% and 8.2% at cumulative doses of 1500, 3000, 4500, 5000 and 6000 mg, respectively. None of the subjects developed cirrhosis during follow-up or discontinued therapy on the basis of liver biopsy findings.Conclusions: Advanced hepatic fibrosis with low-dose methotrexate therapy is much less frequent than previously reported. Pre-treatment or monitoring liver biopsies in accordance with the current guidelines have little impact on patient management.Ishak score system: 0 – 6 Scheuer scoring system: 0 – 4 Roenigk classification of methotrexate-associated liver damage: None – Mild – Moderate – Severe Le risque de fibrose hépatique sous méthotrexateestfaible.
- #50 Assessment of liver fibrosis with TE & FibroTest in pts treated with MTX for chronic inflammatory diseasesLaharie D et al. J Hepatol 2010 ; 53 : 1035 – 1040. Background & Aims: Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (Fibro-Scan) and FibroTest could be useful for monitoring MTX–livertoxicity. The aim of this case–control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX.Methods: Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and Fibro-Test when they were treated with MTX (cases) or before beginning treatment (controls).Results: Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28 kg/m2 and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results.Conclusions: Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.FibroScan >7.9 kPa suggesting severe liver fibrosis. > 12.5 kPa suggesting cirrhosisFibrotest > 0.48 suggesting severe liver fibrosis. > 0.74 suggesting cirrhosis
- #53 With wide use of biologics in IBD, there has been increasing reports of HSTCL in IBD patients.Usual presentation associated with HSTCL includes fever, fatigue, elevated LFTs, hepatosplenomegaly and pancytopenia. These symptoms may be seen in IBD patients and a high degree of suspicion, particularly in young patients on anti-TNF therapy, may be required todiagnose HSTCL. The FDA has issued a black box warning on the use of these drugs.The role of anti-TNF treatment in the development of HSTCL remains uncertain.Hepatosplenic T cell lymphoma in IBD – Leading article - Gut 2008;57:1639-1641 .The development of lymphoma in chronic inflammatory conditions has been a topic of great interest. Studies in inflammatory bowel disease (IBD) have demonstrated conflicting results, and it is often difficult to disassociate disease severity, disease duration and the risk attributable to drug exposure. Recently presented results from the very large French population-based CESAME study suggest a doubling of the risk of lymphoma in patients with IBD, with the majority of cases occurring in association with immunosuppressive therapy. Similarly, a meta-analysis of previous cohort studies concluded that the risk of lymphoma is increased fourfold in patients with IBD on thiopurine treatment (azathioprine and 6-mercaptopurine) compared with those not receiving such therapy. Such analyses cannot demonstrate causation, and it is possible that an increased lymphoma risk relates to more active underlying disease rather than thiopurine therapy, an interpretation supported by results from studies in IBD patients unexposed to such treatment. Whilst it is possible that thiopurine therapy carries a modestly increased relative risk of lymphoma, the absolute risk is still very small, and appears to be outweighed in the majority of patients by the benefits of better disease control. With the advent and success of antitumour necrosis factor (TNF) and other biological therapies, investigators have sought to define the place of concomitant immunomodulator therapy, and its effect on the risk–benefit equation. Early experience suggested that combination therapy was desirable to reduce the immunogenicity of infliximab, especially with episodic dosing. More recently, this approach has been challenged due to a lack of synergistic efficacy and the minimal reduction in immunogenicity when anti-TNF drugs are used …
- #56 Given the rarity, the asymptomatic nature in most presentations, and need for liver biopsy for diagnosis, the true incidence, natural history, and prognosis of hepatic amyloidosis in IBD remains unclear. Control of gut inflammation may reduce the severity of amyloiddeposition.