Inflammatory bowel disease & the liver

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  • 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
  • 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
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • histological study of liver biopsy showing hyperplasticparenchymatous nodules without extensive fibrosis on silver reticulin staining, with compressed and atrophic internodular parenchyma.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • Le seuil de 1500 mg de méthotrexate en dose cumulée ne repose que sur un consensus d’experts.
  • 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.
  • 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
  • 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 …
  • 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.
  • Inflammatory bowel disease & the liver

    1. 1. Inflammatory Bowel Disease & LiverSamir Haffar M.D.Assistant Professor of Gastroenterology
    2. 2. Liver & IBDElevated LTs reported in 10 to 50% of patientsRigorous search for causal mechanism necessary toavoid missing iatrogenic mechanism or conversely,wrongly accusing a useful treatmentNahona 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. 3. Liver & inflammatory bowel 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. 4.  Primary sclerosing cholangitisPSC-IBD
    5. 5. Screening for PSC in patients with IBDLiver tests periodically• Patients with cholestatic presentationUS and/or MRCP for initial evaluation of PSC• Patients with persistent cholestasis & normal US/MRCPERCP for PSCLiver biopsy particularly for small-duct PSC• Patients with dominant strictures in ERCPDilatation, biopsy & cytology, DIA, FISH• Mass lesions associated with PSC should be biopsiedDIA: Digital Image AnalysisFISH: Fluorescence In Situ HybridizationNavaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
    6. 6. ERCP in PSCDiffuse multifocal strictures involving medium-sized intrahepaticand/or large-sized extrahepatic ductsGold standard for diagnosis
    7. 7. MRCP in PSCRetrospective case-control study36 PSC & 51 controls – ERCP & MRCP in allSensitivity: 81 – 91% & Specificity: 85 – 96%Slightly inferior to those obtained with ERCPMR cholangiography is now a first-intention exploration for PSCMoff SL. Gastrointest Endosc 2006 ; 64 : 219 – 23.
    8. 8. Liver biopsy in PSCFibro-obliterative cholangitisVirtually pathognomonic5 – 10% of patientsOnion skin fibrosisCharacteristic lesionLess than one half of patientsNormal in 5 to 10% – Useful for small-duct PSCEASL Clinical Practice Guidelines. J Hepatol 2009 ; 51 : 237 – 267.Normal or nearly normal nonspecific liver biopsy cannot rule out PSC
    9. 9. Incidence of cholangiocarcinoma in PSCYounossi ZM. Practical management of liver diseases.Cambridge University Press, Cambridge, UK, 2008.
    10. 10. Surveillance of PSC-associated dysplasia in PSC-IBDDIA: Digital Image AnalysisFISH: Fluorescence In Situ HybridizationNavaneethan 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 samplingCytologyDIAFISHAberrant DNA methylation• Questionable cytology Surveillance Q 3 – 6 m• Liver mass on US CT or MRI – Biopsies
    11. 11. ERCP in PSC & cholangiocarcinomaDominant stricture of proximal CHD should beconsidered suspicious for cholangiocarcinoma
    12. 12. Cholangiocarcinoma in a patient withPSC after colectomy for UCNavaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
    13. 13. Screening for IBD in patients with PSC• Screening performed even in absence of GI symptoms• Colonoscopy & biopsies of TE: Rectal sparingPancolitisMinimally active diseaseBackwash ileitisColorectal neoplasia• Colonoscopy in PSC-IBD: Q year with multiple biopsies• Patients with initial normal colonoscopy: Q 3 yearsNavaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
    14. 14. Cumulative probability of CRC or dysplasiap = 0.057Log rank testLoftus Jr E V et al. Gut 2005 ; 54 : 91 – 96
    15. 15. Overall survival of CRC or dysplasiaP = 0.001Log rank testLoftus Jr E V et al. Gut 2005 ; 54 : 91 – 96.
    16. 16. Navaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.Surveillance of colonic dysplasia in IBD-PSCAnnual surveillance colonoscopyFlatDAMLMultifocal LGHigh gradecancerColectomydysplasiacolonoscopyin 3 – 6 monthsindefinite for dysplasiano dysplasiacolonoscopyevery yearadenoma-likeunifocal LG
    17. 17. Small-duct PSC“formally pericholangitis”• Diagnosis Biological cholestasisNormal cholangiographyHistology 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 describedSpecific disease of BD with different natural history
    18. 18. Liver transplantation free in small & large-duct PSCBjörnsson E et al. Gastroenterology 2008 ; 134 : 975 – 980.83 pts with small-duct PSC from Europe & US157 pts with large-duct PSC matched for age, gender, & institutionHR: 3.0495% CI: 1.82-5.06P < .0001
    19. 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 conditionAutoimmune pancreatitis (> 50%)• Regression of biliary stenosis with corticosteroid therapyBjörnsson E et al. Hepatology 2007 ; 45 : 1547 – 1554.Dastis SN et al. J Hepatol. 2009 ; 51: 601 – 605.Atypical form of PSCor different entity
    20. 20. IgG4 associated cholangitis & UCIgG4 stain showing many positive cells around duct> 10 cells / hpfBjörnsson E et al. Hepatology 2007 ; 45 : 1547 – 1554.Dastis SN et al. J Hepatol 2009 ; 51 : 601 – 605.
    21. 21. Gallbladder disease in patients with PSCSaid K et al. J Hepatol 2008 ; 48 : 598 – 605.Dysplasia & carcinoma common in GB epitheliumRegular examination of GB in PSC patientsCholecystectomy regardless of GB lesion sizeOne 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. 22. Gallbladder carcinoma in a patient with PSCSaid K et al. J Hepatol 2008 ; 48 : 598 – 605.Ultrasound Histology
    23. 23.  Gallbladder disease
    24. 24. Ulcerative colitisNo gallstonesGallstones1721393.0 %7.0 %1751094.6 %5.4 %Gallstones in patients with IBDCase-control study – followed 7.2 years (range 5 – 11)Disease Cases with IBD ControlsN % N % OR (95% CI)Crohn’s diseaseNo gallstonesGallstones3744190.1 %9.9 %3942194.95.1Parente F et al. Hepatology 2007 ; 45 : 1267 – 1274.Only CD pts have significantly higher risk of developing gallstonesRisks: ileal involvement, extent of ileal resection & TPN2.09 (1.20 – 3.64)1.33 (0.56 – 3.16)
    25. 25. Prophylactic cholecystectomy duringileocolic resection in Crohn’ disease• Patients 191 patients with Crohns ileitisMedical treatment – ileocolic resectionMatched control group for age & gender• Retrospective Questionnaire – telephone interviews• CholecystetomyCrohn ileitis 17/134Control group 15/150• Conclusion Prophylactic cholecystectomy not justifiedChew SS et al. Dis Colon Rectum 2003 ; 46 : 1484 – 8.P = not significant
    26. 26.  Diseases of the hepatic parenchyma
    27. 27. Diseases of hepatic parenchyma• Autoimmune hepatitis1 Exceptional• Primary biliary cirrhosis2 20 cases reported• Granulomatous hepatitis3 Crohn – Sulfasalazine• Hepatic steatosis4 40% in Crohn’s disease35% in ulcerative colitis• Liver abscesses5 Generally single germSteroids, AZA, anti-TNF1 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. 28.  Vascular diseases of the liver
    29. 29. Vascular liver diseases & IBDClinical case reports• Portal vein thrombosis1Surgery – UC following IPAA & ↑ risk of pouchitis• Pylephlebitis with portal vein gas2High mortality (11%)• Peliosis hepatis & sinusoidal dilatation3Generally asymptomatic – PHT – anicteric cholestasis• Budd-Chiari syndrome4UC more often than Crohn’s disease1 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. 30. PV gas & PV thrombosisin fulminant Crohn’s colitisPV gas & PV thrombosisGross ascitesPneumoperitoneumWorld J Gastroenterol 2006 ; 14 : 5582 – 5586.
    31. 31. Peliosis hepatis & Crohn’s diseaseRare associationLaunay D et al. Rev Méd Interne 2002 ; 23 : 198-202Sinusoidal & Disse space dilatation around atrophied hepatocytes
    32. 32. Conditions associated with peliosis hepatisAzathioprine6-ThioguanineAIDS/Bartonella infectionTuberculosisMyeloproliferative diseasesLeukemiaLymphomaMultiple myelomaMacroglobulinemiaAnabolic steroidsOral contraceptivesArsenicThoratrastVinyl chlorideYamada’s textbook of gastroenterology, Blackwell Publishing, fifth Edition, 2009.
    33. 33. UC complicated by Budd-Chiari syndromePortal tract with rim of viable hepatocytesCentral veins occluded by fibrin thrombiwith surrounding haemorrhage & necrosis(H & E x 68)Chesner I M et al. Gut, 1986 , 27 , 1096 – 1100.
    34. 34.  Anomalies of hepatic vascularization:NRH – SOS
    35. 35. Nodular regenerative hyperplasiaR. Lencioni et al. Focal Liver Lesions.Springer-Verlag Berlin Heidelberg 2005.NRH may resemble cirrhosisgrosslyGross appearanceNodules less well definedParenchyma softer than in cirrhosisFibrous septa are lackingAt cut surface
    36. 36. Kaplan-Meier estimate of cumulative risk of NRH1888 consecutive IBD pts treated with AZASeksik P et al. Inflamm Bowel Dis 2010 in press.2 variables associated with NRH occurrenceMale 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 NRHMedian treatment duration: 52.4 monthsCumulative incidence: 1.28 0.45% at 10 y
    37. 37. MRI in NRH45 patients tt with 6-TG – MRI & liver biopsy in all casesSeiderer J et al. J Hepatol 2005 ; 43 : 303 – 309.Speckled enhancement ina patient with NRHFine-nodular aspectof enhancementNormal appearance of liverin a patient without NRHArterial phase after injectionof gadoliniumSen: 77% – Sp: 72% (Promising non-invasive diagnosis)
    38. 38. Nodular regenerative hyperplasia of the liverSeiderer J et al. J Hepatol 2005 ; 43 : 303 – 309.Hepatocyte hyperplasiaSinusoidal dilatationCompression zonesHematoxylin-eosin staining (x 20)Characteristics of NRH bestseen in silver reticulin stainingSilver reticulin (x 20)
    39. 39. Drugs implicated in SOSAzathioprine6-mercaptopurine6-thioguanineActinomycin DBusulfanCytosine arabinosideCyclophosphamideDacarbazineGemtuzumab-ozogamicinMelphalanOxaliplatinUrethaneDeLeve LD et al. Hepatology 2009 ; 49 : 1729 – 1764.
    40. 40. Acute SOS after 6-TG therapy for Crohn’s DiseaseReticulin stainingNear total occlusion of a central veinKane S et al. Inflamm Bowel Dis 2004 ; 10 : 652 – 654.
    41. 41.  Drug hepatotoxicity
    42. 42. Council for International Organizationsof 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. 43. Biour M et al. Gastroentérol Clin Biol 2004 ; 28 : 720 – 759.
    44. 44. Drug-induced liver injury & IBDAZA +++ +++ +++ ++ + + SOS – NRH D – Y6-MP ++ +++ ++ + SOS – NRH D – Y6-TG + + + + SOS – NRH D – YMTX ++ + ++ +++ NASH D – YSulfasalazine ++ ++ ++ + Granuloma W – MMésalazine + + + D – YCyc A + ++ D – YTacrolimus + + + SOS WInfliximab ++ ++ ++ ++ WMFM + + + DD: days – W: weeks – M: months – Y: yearsSOS: sinusoidal obstruction syndrome – NRH: nodular regenerative hyperplasiaLarrey D. Gastroentérol Clin Biol 2008 ; 32 : S194 – S204.Acute hepatitis ChronichepatitisCirrhosis Other DelayHC Chol Mixed Fulminant
    45. 45. Thiopurine-induced liver injury in IBDSystematic 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 HypersensitivityIdiosyncratic cholestatic reactionEndothelial injury: NRH – SOS – Peliosis• AZA vs MP Unknown if there is any differenceGisbert JP et al. Am J Gastroenterol 2007 ;102:1518–1527
    46. 46. Management of thiopurine-induced liver injuryGisbert JP et al. Am J Gastroenterol 2007 ;102:1518–1527Mild abnormality of LTsAsymptomaticContinue AZA/MPFrequent controlModerate-severeNo jaundice50% dose reductionFrequent controlAZA/MP withdrawalSevere cholestaticjaundiceNormal LTsInitial AZA/MP doseAbnormal LTsAZA/MP withdrawal MP instead of AZA
    47. 47. Liver & methotrexateMost feared long-term side effect is liver fibrosis• Studies from the 80’sCirrhosis: 0 – 26%Cumulative dose ≥ 1.5 gLiver biopsy at 1.5 g & repeated every 1 – 1.5 g• Recent studies*Characterization of HCV & NASHCirrhosis: 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. 48. Cumulative probability of advanced fibrosis(Ishak score ≥4) whilst on MTX therapyAithal 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. 49. Non-invasive diagnosis of liver fibrosis due to MTXCase-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 consumption7.9 kPs0.48
    50. 50. Monitoring patients treated with MTX• Non-invasive tests (FibroScan &/or Fibrotest)Before starting methotrexateRegular tests during treatment courseEspecially in viral hepatitis, steatosis & alcoholism• Liver biopsyCase-by case indicationFor example: prolonged transaminase elevation
    51. 51.  Hepatic malignancies:Hepatosplenic T-cell lymphoma & HCC
    52. 52. Hepatosplenic T-cell lymphomaMajority of reported cases rapidly fatal• Most patients Young males (5 – 20 years)Crohn’s disease (90%)Combined thiopurine/anti-TNF• Usual presentation HepatosplenomegalyFever –↑ LFTs – pancytopenia• No effective therapy Chemotherapy-SC transplantation• Role of anti-TNF in development of HSTCL uncertainNavaneethan U et al. Inflamm Bowel Dis 2010 ; 16 : 1598 – 1619.
    53. 53. Hepatocellular carcinoma• 3 patients 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 yearsFour cases of hepatocellular carcinoma reportedNahona S et al. Gastroentérol Clin Biol 2009 ; 33 : 370 – 381.
    54. 54.  Secondary amyloidosis
    55. 55. Secondary amyloidosis (AA type)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 drugsanti-TNFα : targets deterioration of further damageOikonomou K et al. Inflamm Bowel Dis 2010 in press.
    56. 56. Thank You

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