Risk for colorectal cancer in ulcerative colitis:Changes,causes and management strategies

The risk of colorectal cancer for any patient with ulcer-ative colitis is known to be elevated, and is estimated to be 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. Risk factors for cancer in-clude extent and duration of ulcerative colitis, primary sclerosing cholangitis, a family history of sporadic colorectal cancer, severity of histologic bowel inflam-mation, and in some studies, young age at onset of colitis. In this review, the authors discuss recent epide-miological trends and causes for the observed chang-es. Population-based studies published within the past 5 years suggest that this risk has decreased over time, despite the low frequency of colectomies. The crude annual incidence rate of colorectal cancer in ulcerative colitis ranges from approximately 0.06% to 0.16% with a relative risk of 1.0-2.75. The exact mechanism for this change is unknown; it may partly be explained by the more widespread use of maintenance therapy and surveillance colonoscopy.

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors:Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take"toll"?

煽动性的肠疾病(IBD ) 的致病仅仅部分被理解。各种各样环境并且主人(例如基因 -- ，上皮 -- ，有免疫力、非有免疫力) 因素被包含。它是有可能的基因异质的多因素的复合基因疾病。一些基因自己与 IBD 被联系，当其它增加 ulcerative (UC ) 或 Crohn 的疾病(CD ) 的风险或与疾病地点或行为被联系时。这评论在 IBD 的遗传探讨最近的进展。文章在在微生物引起、基因的因素之间的串音上讨论当前的信息(例如 NOD2/CARD15， SLC22A46A5 和 DLG5 ) 。在理解 IBD 和罐头的致病在最近的年帮助获得的基因数据为治疗学的干预识别很多个潜在的目标。以后，遗传可以更精确地帮助在 IBD 诊断并且预言疾病路线。

Perianal disease,small bowel disease,smoking,prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease

AIM:To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine(AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease(CD).METHODS:Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed(M/F:155/185, duration:9.4 ± 7.5 years) with a complete clinical follow-up.Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively.Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits.RESULTS:A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean diseaseduration of 9.0 ± 7.2 years.In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/ biological therapy use were independent predictors of disease behavior change.In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location(P = 0.001), presence of perianal disease(P < 0.001), prior steroid use(P = 0.006), early AZA(P = 0.005) or AZA/biological therapy(P = 0.002), or smoking(P = 0.032) were independent predictors of disease behavior change.CONCLUSION:Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

Association of extraintestinal manifestations of inflammatory bowel disease in a province of western Hungary with disease phenotype:Results of a 25-year follow-up study

IBD is a systemic disease associated with a large number of extraintestinal manifestations (EIMs). Our aim was to determine the prevalence of EIMs in a large IBD cohort in Veszprem Province in a 25-year follow-up study.METHODS: Eight hundred and seventy-three IBD patients were enrolled (ulcerative colitis/UC/: 619, m/f: 317/302,mean age at presentation: 38.3 years, average disease duration: 11.2 years; Crohn's disease/CD/: 254, m/f: 125/129,mean age at presentation: 32.5 years, average disease duration: 9.2 years). Intestinal, extraintestinal signs and laboratory tests were monitored regularly. Any alteration suggesting an EIMs was investigated by a specialist.RESULTS: A total of 21.3% of patients with IBD had EIM (UC: 15.0%, CD: 36.6%). Age at presentation did not affect the likelihood of EIM. Prevalence of EIMs was higher in women and in CD, ocular complications and primary sclerosing cholangitis (PSC) were more frequent in UC. In UC there was an increased tendency of EIM in patients with a more extensive disease.Joint complications were more frequent in CD (22.4% VS UC 10.2%, P＜0.01). In UC positive family history increased the risk of joint complications (OR:3.63). In CD the frequency of type-1 peripheral arthritis was increased in patients with penetrating disease (P=0.028). PSC was present in 1.6% in UC and 0.8% in CD. Dermatological complications were present in 3.8% in UC and 10.2% in CD, the rate of ocular complications was around 3% in both diseases. Rare complications were glomerulonephritis, autoimmune hemolytic anaemia and celiac disease.CONCLUSION: Prevalence of EIM in Hungarian IBD patients is in concordance with data from Western countries. The high number of EIM supports a role for complex follow-up in these patients.ACKNOWLEDGEMENTDr. Zsuzsanna Erdelyi, Dr. Agnes Horvath, Dr Gabor Mester (Veszprem), Dr. Sandor Meszaros (Ajka), Dr. Csaba Molnar help in data collection and to Gabriella Demenyi for technical assistance.

Striking elevation in incidence and prevalence of inflammatory bowel disease in a province of western Hungary between 1977-2001

AIM:An investigation into inflammatory bowel disease and colorectal cancer in Veszprem Province was conducted from 1977 to 2001.METHODS: Both hospital and outpatient records were collected and reviewed comprehensively. The majority of patients were followed up regularly.RESULTS:The population of the province was decreased from 386000 to 376000 during the period. Five hundred sixty new cases of ulcerative colitis (UC), 212 of Crohn's disease (CD), and 40 of indeterminate colitis (IC) were diagnosed. The incidence rates increased from 1.66 to 11.01 cases per 100 000 persons for UC, from 0.41 to 4.68 for CD and from 0.26 to 0.74 for IC. The prevalence rate at the end of 2001 was 142.6 for UC and 52.9 cases per 100 000 persons for CD. The peak onset age in UC patients was between 30 and 40 years, in CD between 20 and 30 years. A family history of IBD was present in 3.4% in UC and 9.9% in CD patients.Smoking increased the risk for CD (OR=1.94) while it decreased the risk for UC (OR=0.25). Twelve colorectal carcinomas were observed in this cohort, the cumulative colorectal cancer risk after 10 years in UC was 2%, after 20 years 8.8%, after 30 years 13.3%.CONCLUSION:The incidence and prevalence rates of IBD have increased steadily in Veszprem Province, now equivalent to that in Western European countries. Rapid increase in incidence rates supports a probable role for environmental factors. The rate of colorectal cancers in IBD is similar to that observed in Western countries.

Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: Phenotype-genotype correlations

AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD.METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing highperformance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP.RESULTS: NOD2/CARD15 mutations were found in 185patients (35.1%) and in 33 controls (16.5%, P＜0.0001).SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P＜0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vscontrols: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (ORhet = 1.71,95%CI = 1.12-2.6, P= 0.0001, ORtwo-riskalleles = 25.2,95%CI = 4.37- , P＜0.0001), early disease onset (carrier:26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95%CI = 1.29-3.08,P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs64.8%), stricturing behavior (OR = 1.69, 95%CI = 1.13-2.55,P = 0.026) and increased need for resection (OR=1.71,95%CI: 1.13-2.62, P= 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P= 0.06), in NOD2mut/wt: 26.7 years.CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease,stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4mutation carriers tended to present at earlier age.

Selection criteria for preoperative endoscopic retrograde cholangiopancreatography before laparoscopic cholecystectomy and endoscopic treatment of bile duct stones:Results of a retrospective,single center study between 1996-2002

AIM: The optimal treatment for bile duct stones (in terms of cost, complications and accuracy) is unclear. The aim of our study was to determine the predictive factors for preoperative endoscopic retrograde cholangiopancreatography (ERCP).METHODS: Patients undergoing preoperative ERCP (≤90 d before laparoscopic cholecystectomy) were evaluated in this retrospective study from the 1^st of January 1996 to the 31^st of December 2002. The indications for ERCP were elevated serum bilirubin, elevated liver function tests (LFT), dilated bile duct (≥8 mm) and/or stone at US examination, coexisting acute pancreatitis and/or acute pancreatitis or jaundice in patient's history. Suspected prognostic factors and the combination of factors were compared to the result of ERCRRESULTS: Two hundred and six preoperative ERCPs were performed during the observed period. The rate of successful cannulation for ERC was (97.1%). Bile duct stones were detected in 81 patients (39.3%), and successfully removed in 79 (97.5%). The number of prognostic factors correlated with the presence of bile duct stones. The positive predictive value for one prognostic factor was 1.2%, for two 43%,for three 72.5%, for four or more 91.4%.CONCLUSION: Based on our data preoperative ERCP is highly recommended in patients with three or more positive factors (high risk patients). In contrast, ERCP is not indicated in patients with zero or one factor (low risk patients).Preoperative ERCP should be offered to patients with two positive factors (moderate risk patients), however the practice should also be based on the local conditions (e.g.skill of the endoscopist, other diagnostic tools).

Smoking in inflammatory bowel diseases:Good,bad or ugly?

吸烟是在煽动性的肠疾病(IBD ) 的一个重要环境因素，有在 ulcerative (UC ) 和 Crohn'disease (CD ) 的不同效果。最近的元分析部分证实了那支吸烟被发现对 ulcerative 保护的以前的调查结果，减少并且在疾病的发作以后，可能改进它的功课对结肠切除术的需要。然而，吸烟增加开发 CD 的风险并且变得更坏它的功课，为类固醇，抑制免疫力的药和重新操作增加需要。吸烟停止加重 ulcerative 并且改进 CD。数据是不管多么，象涉及这种双关系的潜在的机制一样大部分矛盾仍然是未知的。在这篇评论文章，作者考察在煽动性的肠疾病吸烟的角色。

Mucocele of the appendix: An unusual cause of lower abdominal pain in a patient with ulcerative colitis-. A case report and review of literature

The authors report the case of a 60-year-old male patient.In November 2001 he developed intestinal symptoms of bloody diarrhea and abdominal pain. Colononoscopy and biopsy established the diagnosis of ulcerative colitis (proctosigmoiditis). The disease activity was moderate at the beginning.No significant laboratory alterations were found (including CEA, CA19-9),and mesalazine was started orally.He was in remission until November 2003, when he was admitted to our Outpatient Clinic for upper and right lower abdominal pain and bloody diarrhea. Colonoscopy found proctosigmoiditis with a moderate activity, gastroscopy revealed chronic gastritis,laboratory data was normal. Treatment was amended with mesalazine clysma and methylprednisolone (16 mg) orally. Symptoms ameliorated;however, right lower abdominal pain persisted. US and CT examination demonstrated a pericecal cystic mass (11 cmx3.5 cm). At first pericecal abscess was suspected, as the previous US examination (6 mo earlier) had revealed normal findings. Fine needle aspiration was performed. Cytology confirmed the diagnosis of mucocele.The patient underwent partial cecum resection and extirpation of the mucocele. He recovered well and the final histology revealed a cystadenoma of the appendix. Follow up was started. The patient is now free of symptoms.Although primary adenocarcinoma of the appendix is uncommon, the authors emphasize that preoperative diagnosis of an underlying malignancy in a mucocele is important for patient management; however, it is difficult on imaging studies.

Is early limited surgery associated with a more benign disease course in Crohn's disease?

AIM:To analyze the difference in disease course and need for surgery in patients with Crohn’s disease(CD).METHODS:Data of 506 patients with incident CD were analyzed(age at diagnosis:31.5±13.8 years).Both hospital and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database,which includes incident CD patients diagnosed between January 1,1977 and December 31,2008.Follow-up data were collected until December 31,2009.All patients included had at least 1year of follow-up available.Patients with indeterminate colitis at diagnosis were excluded from the analysis.RESULTS:Overall,73 patients(14.4%)required resective surgery within 1 year of diagnosis.Steroid exposure and need for biological therapy were lower in patients with early limited surgery(P<0.001 and P=0.09).In addition,surgery rates during follow-up in patients with and without early surgery differed significantly after matching on propensity scores(P<0.001,HR=0.23).The need for reoperation was also lower in patients with early limited resective surgery(P=0.038,HR=0.42)in a Kaplan-Meier and multivariate Cox regression(P=0.04)analysis.However,this advantage was not observed after matching on propensity scores(PLogrank=0.656,PBreslow=0.498).CONCLUSION:Long-term surgery rates and overall exposure to steroids and biological agents were lower in patients with early limited resective surgery,but reoperation rates did not differ.

NKX2-3 and IRGM variants are associated with diseasesu sceptibility to IBD in Eastern European patients

AIM: To investigate variants of immunity-related GT-Pase family M (IRGM) and NKX2-3 genes and genotype-phenotype in Eastern European patients with inflammatory bowel disease (IBD).METHODS: We analyzed 1707 Hungarian and Czech subjects with Crohn’s disease (CD) (n = 810, age: 37.1 ± 12.6 years, duration: 10.7 ± 8.4 years) and ulcerative colitis (UC) (n = 428, age: 43.7 ± 15.0 years, duration: 12.6 ± 9.9 years), as well as 469 healthy controls. IRGM rs13361189, NKX2-3 rs10883365 and ECM1 rs13294 polymorphisms were tested by LightCy-cler allele discrimination. Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: NKX2-3 rs10883365 variant allele was as-sociated with increased risk for CD (P = 0.009, OR = 1.24, 95% CI = 1.06-1.48) and UC (P = 0.001, OR = 1.36, 95% CI = 1.13-1.63), whereas variant IRGM allele increased risk for CD (P = 0.029, OR = 1.36, 95% CI = 1.03-1.79). In contrast, ECM1 rs13294 was not associat-ed with either CD or UC. In CD, the variant IRGM allele was associated with a colon-only location (P = 0.02, OR = 1.62, 95% CI = 1.07-2.44), whereas in UC, the ECM1 variant was associated with cutaneous manifestations (P = 0.002, OR = 3.36, 95% CI = 1.48-7.63). Variant alleles did not predict resistance to steroids or azathio-prine, efficacy of infliximab, or need for surgery. CONCLUSION: NKX2-3 and IRGM are susceptibility locifor IBD in Eastern European patients. Further studies are needed to confirm the reported phenotype-genotype associations.

Prevalence and predictors of hospitalization in Crohn's disease in a prospective population-based inception cohort from 2000-2012

AIM: To analyze the prevalence, length and predictors of hospitalization in the biological era in the populationbased inception cohort from Veszprem province.METHODS: Data of 331 incident Crohn's disease(CD) patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed(median age at diagnosis: 28; IQR: 21-40 years). Both in- and outpatient records were collected and comprehensively reviewed.RESULTS: Probabilities of first CD-related hospitalization and re-hospitalization were 32.3%, 45.5%,53.7% and 13.6%, 23.9%, 29.8%, respectively after one, three and five years of follow-up in Kaplan-Meier analysis. First-year hospitalizations were related to diagnostic procedures(37%), surgery or disease activity(27% and 21%). Non-inflammatory disease behavior at diagnosis(HR = 1.32, P = 0.001) and perianal disease(HR = 1.47, P = 0.04) were associated with time to first CD-related hospitalization, while disease behavior change(HR = 2.38, P = 0.002) and need for steroids(HR = 3.14, P = 0.003) were associated with time to first re-hospitalization in multivariate analyses.Early CD-related hospitalization(within the year of diagnosis) was independently associated with need for immunosuppressives(OR = 2.08, P = 0.001) and need for surgeries(OR = 7.25, P < 0.001) during the disease course.CONCLUSION: Hospitalization and re-hospitalization rates are still high in this cohort, especially during the first-year after the diagnosis. Non-inflammatory disease behavior at diagnosis was identified as the pivotal predictive factor of both hospitalization and rehospitalization.

Evolution of disease phenotype in adult and pediatric onset Crohn's disease in a population-based cohort

AIM:To investigate the evolution of disease phenotypein adult and pediatric onset Crohn's disease(CD) populations,diagnosed between 1977 and 2008.METHODS:Data of 506 incident CD patients were analyzed(age at diagnosis:28.5 years,interquartile range:22-38 years).Both in-and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database,which included incident patients diagnosed between January 1,1977 and December 31,2008 in adult and pediatric onset CD populations.Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis.RESULTS:Among this population-based cohort,seventy-four(12.8%) pediatric-onset CD patients were identified(diagnosed ≤ 17 years of age).There was no significant difference in the distribution of disease behavior between pediatric(B1:62%,B2:15%,B3:23%) and adult-onset CD patients(B1:56%,B2:21%,B3:23%) at diagnosis,or during follow-up.Overall,the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5-and 10-years of follow-up.Similarly,time to change in disease behaviour from non stricturing,non penetrating(B1) to complicated,stricturing or penetrating(B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis.Calendar year of diagnosis(P = 0.04),ileal location(P < 0.001),perianal disease(P < 0.001),smoking(P = 0.038) and need for steroids(P < 0.001) were associated with presence of,or progression to,complicated disease behavior at diagnosis and during follow-up.A change in disease location was observed in 8.9% of patients and it was associated with smoking status(P = 0.01),but not with age at diagnosis.CONCLUSION:Long-term evolution of disease behavior was not different in pediatric-and adult-onset CD patients in this population-based cohort but was associated to location,perianal disease and smoking status.