Colorectal cancer in patients with inflammatory bowel disease:Can we predict risk?

The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), may be complicated by colorectal cancer (CRC). In a recent population-based cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed CRC during 30 years of observation. The overall risk of CRC among patients with UC and CD was comparable with that of the general population. However, patients diagnosed with UC during childhood or as adolescents, patients with long duration of disease and those with concomitant primary sclerosing cholangitis were at increased risk. In this commentary, we discuss the mechanisms underlying carcinogenesis in IBD and current investigations of genetic susceptibility in IBD patients. Further advances will depend on the cooperative work by epidemiologist and molecular geneticists in order to identify genetic polymorphisms involved in IBD-associated CRC. The ultimate goal is to incorporate genotypes and clinical parameters into a predictive model that will refine the prediction of risk for CRC in colonic IBD. The challenge will be to translate these new findings into clinical practice and to determine appropriate preventive strategies in order to avoid CRC in IBD patients. The achieved knowledge may also be relevant for other inflammation-associated cancers.     

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.     

Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature

Ulcerative colitis(UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammationrelated genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.     

The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease

BACKGROUND & AIMS: The pregnane X receptor (PXR) regulates an array of genes involved in the response to xenobiotics. Evidence from several studies suggests that xenobiotic metabolism may play a role in inflammatory bowel disease (IBD) and that low levels of PXR may be associated with disease expression. The aim of this study was to investigate the association of functional polymorphisms of the PXR encoding gene (NR1I2) with disease in IBD populations. METHODS: This was a case-control study examining 8 NR1I2 single nucleotide polymorphisms (SNPs) previously associated with altered activity of PXR-regulated genes in an Irish cohort including 422 patients with IBD and 350 ethnically matched controls. RESULTS: We showed significant associations of NR1I2 with IBD, Crohn's disease (CD), and ulcerative colitis (UC) groups compared with a control population for SNPs -23585 (IBD: P = .000008; odds ratio [OR], 1.62; 95% confidence interval [CI], 1.31-2.00) and -24381 (IBD: P = .0002; OR, 1.50; 95% CI, 1.21-1.84). SNPs 7635 (P = .0008) and 8055 (P = .007) were found to be associated with IBD and CD but not UC. Risk of IBD is strongly correlated to genotype at these sites, especially for the -25385CC genotype (P = .00001; OR, 2.92; 95% CI, 1.87-4.66). We also show specific correlations of IBD phenotype with genotypes and haplotypes in the patient group. CONCLUSIONS: These results show that genetic variation in the PXR encoding gene, which has been associated with altered activity of PXR, is strongly associated with susceptibility to IBD, CD, and UC.     

Influence of environmental factors in the development of inflammatory bowel diseases

Idiopathic inflammatory bowel diseases(IBD), Crohn's disease(CD) and ulcerative colitis(UC), are multifactorial diseases that are manifested after disruption of a genetic predisposed individual and its intestinal microflora through an environmental stimulus. Urbanization and industrialization are associated with IBD. Epidemiological data, clinical observations and family/immigrants studies indicate the significance of environmental influence in the development of IBD. Some environmental factors have a different effect on the subtypes of IBD. Smoking and appendectomy is negatively associated with UC, but they are aggravating factors for CD. A westernized high fat diet, full of refined carbohydrates is strongly associated with the development of IBD, contrary to a high in fruit, vegetables and polyunsaturated fatty acid-3 diet that is protective against these diseases. High intake of nonsteroidal antiinflammatory drug and oral contraceptive pills as well as the inadequacy of vitamin D leads to an increased risk for IBD and a more malignant course of disease. Moreover, other factors such as air pollution, psychological factors, sleep disturbances and exercise influence the development and the course of IBD. Epigenetic mechanism like DNA methylation, histone modification and altered expression of miR NAS could explain the connection between genes and environmental factors in triggering the development of IBD.     

炎症性肠病患者抑制性杀伤细胞免疫球蛋白样受体基因多态性分析

目的 分析炎症性肠病(inflammatory bowel disease,IBD)患者抑制性杀伤细胞免疫球蛋白样受体(killer cell immunoglobulin-like receptor,iKIR)基因多态性,探讨iKIR基因多态性与IBD的关联性.方法 收集100例溃疡性结肠炎(UC)、52例克罗恩病(CD)患者和106名种族匹配的健康对照者外周血DNA标本,采用序列特异性引物聚合酶链反应(PCR-SSP)方法,分析上述对象iKIR基因位点的多态性,计算iKIR基因表型频率和基因频率,比较IBD患者与健康对照者间的差异.结果 iKIR基因(包括KIR2DL1、KIR2DL2、KIR2DL3、KIR2DL4、KIR2DL5、KIR3DL1、KIR3DL2、KIR3DL3)在IBD患者和健康对照组均有不同程度的表达.UC患者KIR2DL1和KIR2DL3表现型频率比健康对照组显著降低(P=0.001),而KIR2DL2、KIR2DL4、KIR2DL5、KIR3DL1、KIR3DL2和KIR3DL3表现型频率与健康对照组比较差异无统计学意义(P＞0.05).CD患者KIR2DL1表现型频率比健康对照组显著降低(P=0.007),而其余iKIR基因表现型频率与健康对照组比较差异无统计学意义(P＞0.05).结论 KIR2DL1和KIR2DL3表现型频率在UC患者中显著下降,提示其与UC的易感性有密切关系; 而KIR2DL1基因可能与CD易感性密切相关.     

TNF-α在IBD发病机制中的调节

炎症性肠病（inflammatory bowel disease,IBD）是一种病因不明的肠道非特异性炎症性疾病,包括溃疡性结肠炎和克罗恩病,它们有各自的临床特征,内镜表现和组织学可区分;有学者认为它们是同一疾病的两个不同的阶段。在免疫应答中,TNF-α（TNF核心家族成员之一）作为细胞增殖和凋亡的主要促炎因子,在IBD的发病机制中起重要的调节作用。     

Associations between CD24 gene polymorphisms and inflammatory bowel disease:A meta-analysis

AIM: To evaluate the relationships between CD24 gene polymorphisms and the risk of inflammatory bowel disease(IBD), including ulcerative colitis(UC)and Crohn's disease(CD).METHODS: The PubMed, Web of Science and Cochrane Library databases were searched(up to May30, 2014). The search terms "CD24", "inflammatory bowel disease", "Crohn's disease", "Ulcerative colitis","IBD", "CD" or "UC"; and "polymorphism", "mutation"or "variant" were used. Association studies were limited to the English language, but no limitations in terms of race, ethnicity or geographic area were employed.Stata SE12 software was used to calculate the pooled odds ratios(ORs) with 95% confidence intervals(CIs).P 0.05 was considered statistically significant. The information was independently extracted from each eligible study by two investigators. Two common polymorphisms, C170T(rs8734) and TG1527del(rs3838646), in the CD24 gene were assessed.RESULTS: A total of three case-control studies including 2342 IBD patients and 1965 healthy controls were involved in this meta-analysis. The patients and controls were from Caucasian cohorts. The three articles included in this meta-analysis all conformed to Hardy-Weinberg equilibrium. This meta-analysis revealed that there were no significant associations between the two CD24 polymorphisms and the risk for IBD(all P 0.05). However, in a disease subgroup analysis, we found that the CD24 C170 T polymorphism was associated with an increased risk of UC in a dominant model(OR = 1.79, 95%CI: 1.15-2.77, P =0.009) and an additive model(OR = 1.87, 95%CI:1.19-2.93, P = 0.007), but this relationship was not present for CD. The CD24 TG1570 del polymorphism was significantly associated with CD in the additive model(OR = 1.24, 95%CI: 1.01-1.52, P = 0.037).CONCLUSION: Our findings provide evidence that the CD24 C170 T polymorphism might contribute to the susceptibility to UC, and the CD24 TG1527 del polymorphism might be associated with the risk of CD.     

Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

INTRODUCTIONUlcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel diseases (IBD) of the intestine. UC and CD are both debilitating chronic disorders that afflict millions of individuals throughout the world…     

Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult- and pediatric-onset inflammatory bowel disease in Italy

AIM： To investigate gene variants in a large Italian inflammatory bowel disease （IBD） cohort, and to analyze the correlation of sub-phenotypes （including age at diagnosis） and epistatic interaction with other IBD genes. METHODS： Total of 763 patients with Crohn＇s disease （CD, 189 diagnosed at age 〈 19 years）, 843 with ulcerative colitis （UC, 179 diagnosed 〈19 years）, 749 healthy controls, and 546 healthy parents （273 trios） were included in the study. The rs2241880 [autophagy-related 16-like 1 （ATG16L1）], rs11209026 and rs7517847 [interleukin 23 receptor （IL23R）], rs2066844, rs2066845, rs2066847 （CARD15）, rs1050152 （OCTN1）, and rs2631367 （OCTN2） gene variants were genotyped. RESULTS： The frequency of G allele of ATG16L1 SNP （Ala197Thr） was increased in patients with CD compared with controls （59% vs 54% respectively） （OR = 1.25, CI = 1.08-1.45, P = 0.003）, but not in UC （55%）. The frequency of A and G （minor） alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD （4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P 〈 0.01）, compared with controls （6% and 38%, respectively）. The A allele （but not G） was also reduced signifi cantly in UC （4%, OR = 0.69, CI = 0.5-0.94, P = 0.019）. No association was demonstrated with sub-phenotypes and interaction with CARD15 , and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION： The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.     

江苏汉族人群白细胞介素-23受体基因多态性与炎症性肠病及其表型的关系

目的 探讨江苏汉族人群中IL-23受体基因多态性与炎症性肠病及其表型的关系.方法 选取178例炎症性肠病患者[溃疡性结肠炎(UC) 135例,克罗恩病(CD)43例]和134例健康对照,检测IL-23受体基因的6个单核苷酸多态性位点(rs1 1805303、rs1343151、rs11465804、rs11209032、rs17375018、rs11465788)的基因多态性,分析其与UC、CD各临床表型的关联性.结果 rs 11805303的T等位基因频率在UC中为60.4％,高于对照组(50.4％),P=0.020.UC的基因-表型分析显示,rs17375018位点的基因多态性与结肠炎活动性指数(UCDAI)即UC的严重程度相关,携带等位基因G的患者倾向于发生轻度UC.CD的基因-表型分析显示,rs17375018位点的A等位基因频率在诊断年龄≤25岁的CD患者中明显高于诊断年龄＞25岁的患者(41.7％比22.0％,P=0.050,OR=2.532,95％ CI0.988～6.494);rs11805303位点的基因型与CD的诊断年龄、病变范围有关联性(P值分别为0.039和0.044);rs 17375018位点的A等位基因携带者发生肠外表现的几率较等位基因G携带者低(23.1％比46.7％,P=0.040,OR =2.917,95％ CI1.027～8.283).结论 在江苏汉族人群中,rs11805303是UC的易感基因位点,同时rs11805303、rs17375018位点的基因多态性与UC、CD的临床表型有关联性.     

Combined therapeutic approach： Inflammatory bowel diseases and peripheral or axial arthritis

Inflammatory bowel diseases （IBDs）, particularly Crohn＇s disease （CD） and ulcerative colitis （UC）, are associated with a variety of extra-intestinal manifestations （EIMs）. About 36% of IBD patients have at least one EIM, which most frequently affect the joints, skin, eyes and the biliary tract. The EIMs associated with IBD have a negative impact on patients with UC and CD, and the resolution of most of them parallels that of the active IBD in terms of timing and required therapy; however, the clinical course of EIMs such as axial arthritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis is independent of IBD activity. The peripheral and axial arthritis associated with IBD have traditionally been treated with simple analgesics, non-steroidal anti-inflammatory drugs, steroids, sulfasalazine, methotrexate, local steroid injections and physiotherapy, but the introduction of biological response modifiers such as tumor necrosis factor-α blockers, has led to further improvements.     

Asian perspectives in the management of inflammatory bowel disease: Findings from a recent survey

Background and Aim:  The prevalence and incidence of inflammatory bowel disease (IBD) differs worldwide. While the prevalence of IBD has stabilized in Europe, the USA and Japan, an increasing trend has been observed in Asia. However, there are no data on the current clinical practice for the management of IBD in the region. The present study aims to investigate the number of existing and new cases of IBD and to understand the current practice of diagnosis and treatment of IBD in different Asian countries.
Methods:  A self-administered questionnaire, designed according to European and US guidelines, was distributed to IBD specialists throughout Asia. The questionnaire estimated the annual incidence of existing and new IBD cases in physicians' clinical practices and evaluated their procedures of diagnosis and preference for therapeutic treatment and maintenance treatment.
Results:  Eighty-seven questionnaires were received out of the 107 distributed. In the clinical practices of these 87 respondents, there were 502 existing and 73 new cases per year for ulcerative colitis (UC) and 202 existing and 32 new cases per year for Crohn's disease (CD). Colonoscopy and histology were the most commonly used methods for the diagnosis of UC and CD, but clinical practice regarding the diagnosis of IBD varied. The treatment of choice for mild-to-moderate UC and CD was 5-aminosalicylic acid (5-ASA), which is also the preferred choice for the maintenance treatment of UC and CD.
Conclusion:  Clinical practice with regards to IBD diagnosis and management varies within Asia.5-ASA is the preferred treatment and maintenance therapy for mild-to-moderate IBD.     

New serological markers in pediatric patients with inflammatory bowel disease

The spectrum of serological markers associated with inflammatory bowel disease(IBD)is rapidly growing.Due to frequently delayed or missed diagnoses,the application of non-invasive diagnostic tests for IBD,as well as differentiation between ulcerative colitis(UC)and Crohn’s disease(CD),would be useful in the pediatric population.In addition,the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody(pANCA)improved the sensitivity of serological markers in pediatric patients with CD and UC.Some studies suggested that age-associated differences in the patterns of antibodies may be present,particularly in the youngest children.In CD,most patients develop stricturing or perforating complications,and a significant numberof patients undergo surgery during the disease course.Based on recent knowledge,serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery.Pediatric UC is characterized by extensive colitis and a high rate of colectomy.In patients with UC,high levels of antiCBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis.Thus,serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression.In conclusion,identification of patients at an increased risk of rapid disease progression is of great interest,as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD,and reduce complications and hospitalizations.     

Inflammatory bowel disease in pediatric and adolescent patients:A biomolecular and histopathological review

Crohn’s disease(CD)and ulcerative colitis(UC)are the two main forms of inflammatory bowel disease(IBD)with both overlapping and distinct clinical,pathological and biomolecular features.It has been suggested that pediatric IBD is a distinct disease entity,with probably different disease subtypes.The aim of this study is to review and summarize the evolution of the current concept of pediatric IBD.The results of this review reinforce the idea that pediatric CD and UC may be further classified in various clinicopathologic entities.For clinicians and pathologists convenience,practical algorithms for the distinction of the various subphenotypes of pediatric IBD are also provided.     

The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease

BACKGROUND & AIMS: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C-->T), and OCTN2 variant (SLC22A5 -207G-->C) was performed using the TaqMan system. RESULTS: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D', >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. CONCLUSIONS: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.     

Atypical, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies in patients with inflammatory bowel disease

Atypical, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies (x-, c- and pANCA, respectively) are associated with a variety of inflammatory diseases, including inflammatory bowel disease (IBD). Anti-neutrophil cytoplasmic antibodies are more common in patients with ulcerative colitis (UC) than in patients with Crohn's disease (CD). Most publications only refer to p- and cANCA in relation to IBD. We have prospectively evaluated the reactivity of sera from 58 patients with IBD and 10 healthy controls against human neutrophils with emphasis on the distinction of the ANCA types. The sera were incubated with ethanol- and formaldehyde-fixed granulocytes to differentiate between c-, p- and xANCA. The results showed that 10 of 24 patients with UC were positive for ANCA, whereas only one of 34 patients with CD was ANCA positive. These results correspond to a sensitivity of 42%, a specificity of 97%, a negative predictive value of 91% and a positive predictive value of 75% in UC. Of the 11 ANCA-positive sera, two showed a cytoplasmic staining pattern, three showed a perinuclear and six an atypical staining pattern. The disease activity was not correlated to either the ANCA titre or to the presence of ANCA in the serum. In conclusion, ANCA are of limited value in differentiating between UC and CD. Because the majority of ANCA in patients with IBD are xANCA, these ANCA should be explored by not only incubating on ethanol-fixed granulocytes, but also on formaldehyde-fixed granulocytes.