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1.  Inflammatory bowel disease and thromboembolism 
World Journal of Gastroenterology : WJG  2014;20(38):13863-13878.
Patients with inflammatory bowel disease (IBD) have an increased risk of vascular complications. Thromboembolic complications, both venous and arterial, are serious extraintestinal manifestations complicating the course of IBD and can lead to significant morbidity and mortality. Patients with IBD are more prone to thromboembolic complications and IBD per se is a risk factor for thromboembolic disease. Data suggest that thrombosis is a specific feature of IBD that can be involved in both the occurrence of thromboembolic events and the pathogenesis of the disease. The exact etiology for this special association between IBD and thromboembolism is as yet unknown, but it is thought that multiple acquired and inherited factors are interacting and producing the increased tendency for thrombosis in the local intestinal microvasculature, as well as in the systemic circulation. Clinicians’ awareness of the risks, and their ability to promptly diagnose and manage tromboembolic complications are of vital importance. In this review we discuss how thromboembolic disease is related to IBD, specifically focusing on: (1) the epidemiology and clinical features of thromboembolic complications in IBD; (2) the pathophysiology of thrombosis in IBD; and (3) strategies for the prevention and management of thromboembolic complications in IBD patients.
doi:10.3748/wjg.v20.i38.13863
PMCID: PMC4194568  PMID: 25320522
Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Thrombosis; Thromboembolism; Hypercoagulability; Epidemiology; Endothelial dysfunction; Treatment
2.  Inflammatory bowel disease register: Steps towards Crohn’s & colitis foundation of Saudi Arabia (CCFSA) 
Inflammatory bowel diseases (IBD) are among the leading cause of financial burden, morbidity and employee absenteeism in developed countries because of their chronic remitting and relapsing courses. IBD is estimated to affect the Canadian economy to the tune of 100 million dollars per year. The data regarding exact prevalence in Asian countries, including Saudi Arabia, is still incomplete as there is underreporting and lack of proper registry of the diagnosed cases. The prevalence of inflammatory bowel disease (Ulcerative colitis, Crohn’s disease) has increased over the last decade in Saudi Arabia due to increased IBD awareness among population, as more patients seek medical help and also due to unknown reasons. There is a need of proper registration of IBD patients and establishment of Crohn’s & colitis foundation of Saudi Arabia (CCFSA) as in other parts of the world. The Crohn’s & colitis foundation of Saudi Arabia will be a forum which will co ordinate IBD treatment and research in the country in addition to health education among IBD population.
PMCID: PMC3616950  PMID: 23580900
3.  Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways 
PLoS Medicine  2008;5(12):e239.
Background
Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis.
Methods and Findings
Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C→G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09–1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1+/lacZ mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1+/lacZ mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model.
Conclusions
HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.
Charlie Lees and colleagues identify a reduced-function variant of the hedgehog signaling pathway protein GLI1 that associates with inflammatory bowel disease, and investigate its role in a mouse model of colitis.
Editors' Summary
Background.
Inflammatory bowel diseases (IBDs) are common disorders in which parts of the digestive tract become repeatedly or continuously inflamed. The immune system normally protects the body from entities it identifies as foreign, but in IBD it mistakenly recognizes gut tissue, and immune system cells accumulate in the lining of the bowel, which causes inflammation. There are two main types of IBD—Crohn's disease (CD), which mainly affects the small bowel, and ulcerative colitis (UC), which affects only the large bowel (colon). Both types tend to run in families and usually develop between the ages of 15 and 35 years. Symptoms—including diarrhea, abdominal cramps, and unexplained weight loss—can be mild or severe and the disease can develop slowly or suddenly. There is no cure for IBD except surgical removal of the affected part of the digestive tract. However, drugs that modulate the immune system (for example, corticosteroids) or that specifically inhibit “proinflammatory cytokines” (proteins made by the immune system that stimulate inflammation) are often helpful in reducing symptoms.
Why Was This Study Done?
Why the immune system becomes unbalanced in people with IBD is not clear but it is known that IBD is “polygenic,” that is, a disease caused by the combined actions of two or more inherited gene variants. Although UC and CD are clinically different diseases, they share several “susceptibility loci” (regions of the genome that harbor disease-associated gene variants), including the IBD2 locus. The identification of the actual gene within the IBD2 locus that is altered in people who are susceptible to IBD might provide new insights into what causes the immune imbalance in IBD and into how to treat the disease. In this study, the researchers test the hypothesis that a variant of a gene called GLI1, which lies in the IBD2 locus, is associated with IBD susceptibility. GLI1 encodes a transcription factor (a protein that regulates the production of proteins) that is a central component in the signaling pathway named for a protein called “hedgehog.” This pathway is involved in the development of many organs, including the digestive tract.
What Did the Researchers Do and Find?
The researchers used a technique called gene-wide haplotype tagging to look for inherited GLl1 variants in patients with IBD and in healthy people living in Scotland, England, and Sweden. A specific variant of the GLI1 gene, resulting in alteration of a single amino acid component of the GLI1 protein, was associated with IBD (particularly with UC) in both Scotland and England; the same variant was weakly associated with IBD in the Swedish population. The variant GLI1 protein was only half as active as the normal protein in a laboratory assay, and, consistent with this result, the expression of several components of the hedgehog signaling pathway was lower in colon samples taken from patients with UC than in samples taken from healthy individuals. Finally, Gli1+/lacZ mice (which express half the normal amount of Gli1 protein) developed severe intestinal inflammation more rapidly than wild-type mice when they were treated with dextran sodium sulfate (DSS), a chemical that induces acute (sudden) colitis. Cellular analysis revealed that myeloid cells (cells that sense and modify the inflammatory response) are direct targets of the hedgehog signaling pathway. Furthermore, the expression of several pro-inflammatory cytokines (in particular, one called IL-23) increased more markedly in the Gli1+/lacZ mice than in the wild-type mice after DSS treatment.
What Do These Findings Mean?
These findings suggest that the normal response of the mammalian gut to challenge with inflammatory substances involves hedgehog signaling through GLI1 and that reduced GLI1 function might be one trigger for IBD. More specifically, the human genetic studies identify a GLI1 variant that is associated with IBD (at least in certain north European populations), the laboratory experiments indicate that this GLI1 variant encodes a protein with reduced activity, and the animal studies show that a similar reduction in Gli1 activity is sufficient to heighten intestinal inflammatory responses. Although this last result needs to be confirmed in animal models of chronic colitis that more closely resemble human IBD, these findings suggest that drugs that modulate hedgehog signaling might be useful in the treatment of IBD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050239.
The MedlinePlus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish)
MedlinePlus provides links to other information Crohn's disease and ulcerative colitis (in English and Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis
The UK National Health Service Direct Encyclopedia also provides information on Crohn's disease and on ulcerative colitis
Wikipedia has a page on the hedgehog signaling pathway (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050239
PMCID: PMC2596854  PMID: 19071955
4.  Emerging Inflammatory Bowel Disease in Saudi Outpatients: A Report of 693 Cases 
Background/Aim:
Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology and considered traditionally as a disease of the western world. Recently, rising trends have been observed in countries previously known to have a low prevalence and incidence. The aim of this study is to collect epidemiological data on IBD outpatients and to add data from the Kingdom of Saudi Arabia (KSA) to the available IBD literature.
Patients and Methods:
The medical records of 693 Saudi patients with IBD over a period of 17 years, between 1993 and 2009, were reviewed. The demographic and clinical data and methods of diagnosis were retrieved.
Results:
The total number of patients in this cohort was 693. It constituted 238 (34.3%) ulcerative colitis (UC) and 455 (65.7%) Crohn's disease (CD) patients. UC was steady throughout the years, whereas only 1.2 CD patients were diagnosed per year in the first 11 years, and 73.7 per year in the last six years. The median age of UC patients was 34 years, ranging from 10 to 80 years with a peak between 21 and 40 years and in CD it was 27 years, ranging from 11 to 73 years with a peak between 11 and 30 years. There was a male preponderance of 1.5:1 and 2:1, respectively. The rest of the data is discussed in this study.
Conclusion:
IBD is no longer a rare disease in KSA. UC is in a steady state, whereas CD is increasing significantly and far outnumbering UC.
doi:10.4103/1319-3767.105915
PMCID: PMC3603484  PMID: 23319033
Crohn's disease; rising trend; Saudi Arabia; ulcerative colitis
5.  Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications 
Gut  1999;45(3):389-394.
BACKGROUND—Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD.
AIMS—To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD.
METHODS—Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC).
RESULTS—Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B12 levels were lower in patients with IBD irrespective of MTHFR genotype.
CONCLUSIONS—There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B12 therapy to protect against the thromboembolic complications of raised tHcy.


Keywords: methylenetetrahydrofolate reductase; C677T variant; inflammatory bowel disease
PMCID: PMC1727640  PMID: 10446107
6.  Inflammatory Bowel Disease: An Expanding Global Health Problem 
This review provides a summary of the global epidemiology of inflammatory bowel diseases (IBD). It is now clear that IBD is increasing worldwide and has become a global emergence disease. IBD, which includes Crohn’s disease (CD) and ulcerative colitis (UC), has been considered a problem in industrial-urbanized societies and attributed largely to a Westernized lifestyle and other associated environmental factors. Its incidence and prevalence in developing countries is steadily rising and has been attributed to the rapid modernization and Westernization of the population. There is a need to reconcile the most appropriate treatment for these patient populations from the perspectives of both disease presentation and cost. In the West, biological agents are the fastest-growing segment of the prescription drug market. These agents cost thousands of dollars per patient per year. The healthcare systems, and certainly the patients, in developing countries will struggle to afford such expensive treatments. The need for biological therapy will inevitably increase dramatically, and the pharmaceutical industry, healthcare providers, patient advocate groups, governments and non-governmental organizations should come to a consensus on how to handle this problem. The evidence that IBD is now affecting a much younger population presents an additional concern. Meta-analyses conducted in patients acquiring IBD at a young age also reveals a trend for their increased risk of developing colorectal cancer (CRC), since the cumulative incidence rates of CRC in IBD-patients diagnosed in childhood are higher than those observed in adults. In addition, IBD-associated CRC has a worse prognosis than sporadic CRC, even when the stage at diagnosis is taken into account. This is consistent with additional evidence that IBD negatively impacts CRC survival. A continuing increase in IBD incidence worldwide associated with childhood-onset of IBD coupled with the diseases’ longevity and an increase in oncologic transformation suggest a rising disease burden, morbidity, and healthcare costs. IBD and its associated neoplastic transformation appear inevitable, which may significantly impact pediatric gastroenterology and adult CRC care. Due to an infrastructure gap in terms of access to care between developed vs. developing nations and the uneven representation of IBD across socioeconomic strata, a plan is needed in the developing world regarding how to address this emerging problem.
doi:10.4137/CGast.S12731
PMCID: PMC4020403  PMID: 24833941
Inflammatory bowel disease; industrial-urbanized-societies; colorectal cancer
7.  An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis  
PLoS Medicine  2008;5(3):e41.
Background
The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease.
Methods and Findings
We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics.
Conclusions
Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease.
Paul Allen and colleagues describe the development of a mouse model of fulminant ulcerative colitis with multiple genetic hits in immune regulation which can be moderated by anti-cytokine therapy and broad-spectrum antibiotics.
Editors' Summary
Background.
Inflammatory bowel disease (IBD), a group of disorders characterized by inflammation (swelling) of the digestive tract (the tube that runs from the mouth to the anus), affects about 1.4 million people in the US. There are two main types of IBD. In Crohn's disease, which can affect any area of the digestive tract but most commonly involves the lower part of the small intestine (small bowel), all the layers of the intestine become inflamed. In ulcerative colitis, which primarily affects the colon (large bowel) and the rectum (the part of the bowel closest to the anus), only the lining of the bowel becomes inflamed, the cells in this lining die, and sores or ulcers form. Both types of IBD most commonly develop between the ages of 15 and 35 years, often run in families, and carry an increased risk of cancer. Symptoms—usually diarrhea and abdominal cramps—can be mild or severe and the disorder can develop slowly or suddenly. There is no medical cure for IBD, but drugs that modulate the immune system (for example, corticosteroids) can help some people. Some people benefit from treatment with drugs that specifically inhibit “proinflammatory cytokines,” proteins made by the immune system that stimulate inflammation (for example, TNFα and INFγ). When medical therapy fails, surgery to remove the affected part of the bowel may be necessary.
Why Was This Study Done?
Exactly what causes IBD is not clear, but people with IBD seem to have an overactive immune system. The immune system normally protects the body from harmful substances but in IBD it mistakenly recognizes the food substances and “good” bacteria that are normally present in the human gut as foreign and hence reacts against them. As a result, immune system cells accumulate in the lining of the bowel and cause inflammation. Several different pathways usually prevent inappropriate immune activation, so could IBD be caused by alterations in one or several of these immune regulatory pathways? In previous studies, mice with a defect in just one pathway have developed mild intestinal abnormalities but not the problems seen in the most severe forms of IBD. In this study, therefore, the researchers have generated and characterized a new mouse line with defects in two immune regulatory pathways to see whether this might be a better animal model of human IBD.
What Did the Researchers Do and Find?
To make their new mouse line, the researchers mated mice that had a defective TGFβ signaling pathway in their T lymphocytes with mice that had a defective IL-10 signaling pathway. Both these pathways are anti-inflammatory, and mice with defects in either pathway develop mild and variable inflammation of the colon (colitis) by age 3–4 months. By contrast, the doubly defective mice (dnKO mice) failed to thrive, lost weight, and died by 4–6 weeks of age. The colons of 4- to 5-week old dnKO mice were inflamed and ulcerated (some changes were visible in 3-week-old mice) and contained many immune system cells. Mice with a single defective signaling pathway had no gut abnormalities at this age. The dnKO mice, just like people with IBD, had higher than normal blood levels of IFNγ, TNFα, and other proinflammatory cytokines; these raised levels were the result of abnormal lymphocyte activation. Treatment of the dnKO mice with a combination of agents that neutralize IFNγ and TNFα (anti-cytokine therapy) greatly reduced the colitis seen in these mice; neutralization of IFNγ alone had some beneficial effects, but neutralization of TNFα alone had no effect. Finally, early treatment of the dnKO mice with broad-spectrum antibiotics completely inhibited colitis.
What Do These Findings Mean?
These findings suggest that dnKO mice are a good model for fulminant (severe and rapidly progressing) ulcerative colitis and support the idea that IBD involves multiple genetic defects in immune regulation. They also indicate that the IL-10 and the TGFβ signaling pathways normally cooperate to inhibit the inappropriate immune responses to intestinal bacteria seen in IBD. This new mouse model should help researchers unravel what goes wrong in IBD and should also help them develop new treatments for ulcerative colitis. More immediately, these findings suggest that combined anti-cytokine therapy may be a better treatment for ulcerative colitis than single therapy. In addition, they suggest that clinical studies should be started to test whether broad-spectrum antibiotics can ameliorate ulcerative colitis in people.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050041.
The Medline Plus Encyclopedia has pages on Crohn's disease and on ulcerative colitis (in English and Spanish)
Information is available from the UK National Health Service Direct Health Encyclopedia about Crohn's disease and ulcerative colitis
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on Crohn's disease and ulcerative colitis
Information and support for patients with inflammatory bowel disease and their caregivers is provided by the Crohn's and Colitis Foundation of America and by the UK National Association for Colitis and Crohn's Disease
doi:10.1371/journal.pmed.0050041
PMCID: PMC2270287  PMID: 18318596
8.  Survey of perceptions and practices among Canadian gastroenterologists regarding the prevention of venous thromboembolism for hospitalized inflammatory bowel disease patients 
BACKGROUND:
Patients with inflammatory bowel disease (IBD) who are hospitalized with disease flares are known to be at an increased risk of venous thromboembolism (VTE). This is a preventable complication; however, there is currently no standardized approach to the prevention and management of VTE.
OBJECTIVES:
To characterize the opinions and general prophylaxis patterns of Canadian gastroenterologists and IBD experts.
METHODS:
A survey questionnaire was sent to Canadian gastroenterologists affiliated with a medical school or IBD referral centre. Participants were required to be practicing physicians who had completed all of their training and had been involved in the care of IBD patients within the previous 12 months. Various clinical scenarios were presented and demographic data were solicited.
RESULTS:
The majority of respondents were practicing in an academic setting (95%) and considered themselves to be IBD experts or subspecialists (71%). Eighty-three per cent reported providing VTE prophylaxis most, if not all of the time, and most (96%) used pharmacological prophylaxis alone, usually heparin or one of its analogues. There was less consistency among respondents with respect to whether IBD patients in remission, but admitted for another condition, should be given prophylaxis. There was also less agreement regarding the duration of anticoagulation in patients with confirmed VTE.
CONCLUSION:
There was a general consensus among academic gastroenterologists that IBD inpatients are at an increased risk for VTE and would benefit from VTE prophylaxis. However, areas of uncertainty still exist and the IBD community would benefit from evidence-based clinical practice guidelines to standardize the management of this important problem.
PMCID: PMC3495696  PMID: 23166902
Hospitalization; Inflammatory bowel disease; Prophylaxis; Venous thromboembolism
9.  Hepatobiliary manifestations in inflammatory bowel disease: The gut, the drugs and the liver 
Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.
doi:10.3748/wjg.v19.i42.7327
PMCID: PMC3831215  PMID: 24259964
Inflammatory bowel disease; Hepatobiliary disorders; Extraintestinal manifestations; Primary sclerosing cholangitis; Drug-induced liver injury; Hepatotoxicity; Hepatitis B; Hepatitis C
10.  Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis 
AIM: To review the current literature for the specific clinical characteristics of inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC).
METHODS: A systematical review for clinical characteristics of IBD in PSC was performed by conducting a broad search for “primary sclerosing cholangitis” in Pubmed. “Clinical characteristics” were specified into five predefined subthemes: epidemiology of IBD in PSC, characteristics of IBD in PSC (i.e., location, disease behavior), risk of colorectal cancer development, IBD recurrence and de novo disease after liver transplantation for PSC, and safety and complications after proctocolectomy with ileal pouch-anal anastomosis. Papers were selected for inclusion based on their relevance to the subthemes, and were reviewed by two independent reviewers. Only full papers relevant to PSC-IBD were included. Additionally the references of recent reviews for PSC (< 5 years old) were scrutinized for relevant articles.
RESULTS: Initial literature search for PSC yielded 4704 results. After careful review 65 papers, comprising a total of 11406 PSC-IBD patients, were selected and divided according to subtheme. Four manuscripts overlapped and were included in two subthemes. Prevalence of IBD in PSC shows a large variance, ranging from 46.5% to 98.7% with ulcerative colitis (UC) being the most common type (> 75%). The highest IBD rates in PSC are found in papers reviewing both endoscopic and histological data for IBD diagnosis. Although IBD in PSC is found to be a quiescent disease, pancolitis occurs often, with rates varying from 35% to 95%. Both backwash ileitis and rectal sparing are observed infrequently. The development of dysplasia or colorectal carcinoma is increased in PSC-IBD; the cumulative 10 years risk varying between 0% and 11%. Exacerbation of IBD is common after liver transplantation for PSC and de novo disease is seen in 1.3% to 31.3% of PSC-IBD patients. The risk for development of pouchitis in PSC-IBD is found to be significant, affecting 13.8% to 90% of the patients after proctocolectomy with ileo anal-pouch anastomosis.
CONCLUSION: IBD in primary sclerosing cholangitis represents a distinct phenotype that differs from UC and Crohn’s disease and therefore requires specialized management.
doi:10.3748/wjg.v21.i6.1956
PMCID: PMC4323476
Primary sclerosing cholangitis; Inflammatory bowel disease; Incidence; Clinical characteristics; Risk of colorectal carcinoma; Liver transplantation; Pouchitis
11.  Highlights in IBD Epidemiology and Its Natural History in the Paediatric Age 
Background. The number of patients of all age brackets diagnosed with Inflammatory Bowel Disease (IBD) has risen dramatically worldwide over the past 50 years. IBD's changing epidemiology suggests that environmental factors play a major role in modifying disease expression. Aim. To review studies carried out worldwide analyzing IBD epidemiology. Methods. A Medline search indicating as keywords “Inflammatory Bowel Disease,” “epidemiology,” “natural history,” “Crohn's Disease,” “Ulcerative Colitis,” and “IBD Unclassified” was performed. A selection of clinical cohort and systematic review studies that were carried out between 2002 and 2013 was reviewed. Studies referring to an earlier date were also considered whenever the data were relevant to our review. Results. The current mean prevalence of IBD in the total population of Western countries is estimated at 1/1,000. The highest prevalence and incidence rates of IBD worldwide are reported from Canada. Just as urbanization and socioeconomic development, the incidence of IBD is rising in China. Conclusions. Multicenter national registers and international networks can provide information on IBD epidemiology and lead to hypotheses about its causes and possible management strategies. The rising trend in the disease's incidence in developing nations suggests that its epidemiological evolution is linked to industrialization and modern Westernized lifestyles.
doi:10.1155/2013/829040
PMCID: PMC3884601  PMID: 24454343
12.  Prospective study of immunological factors in non-inflammatory bowel disease enterocutaneous fistulas 
BMC Surgery  2011;11:12.
Background
Enterocutaneous fistulas (ECF) are debilitating and usually result following complex abdominal surgery. While there is an association with inflammatory bowel disease (IBD), a large number of fistulas occur after surgery not related to IBD. The consequences of ECF include short bowel syndrome and the need for long term parenteral nutrition.
ECF can heal spontaneously and in the case of IBD can be cured by medical therapy in some instances. Those that do not resolve spontaneously have to be cured by surgery which is complex and associated with a high morbidity. It is not considered traditional treatment to use the same medical therapy as in IBD to cure ECF caused by other conditions.
A small case series has reported three patients with persistent ECF not related to IBD to have healed following use of Infliximab which is the treatment commonly used for ECF caused by IBD. Infliximab acts by inhibiting the activity of the inflammatory cytokine TNF- alpha. It is not known if this cytokine is present in ECF tissue in the absence of IBD.
The aim of this study is to demonstrate the presence of inflammatory markers in tissue surrounding non-IBD ECF and in particular to quantify the presence of the cytokine TNF- alpha. We hypothesise that TNF - alpha levels are raised in non-IBD ECF.
Methods/Design
Tissue and serum from ECF of IBD and non-IBD patients will be prospectively collected at St. Mark's Hospital Intestinal Failure Unit. The control group will consist of patients undergoing colonoscopy for bowel cancer screening, with normal findings. Biopsies of the terminal ileum will be obtained from this group during colonoscopy. The fistula tract and serum cytokine profiles of interleukins (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, TNF- alpha, IFN-y, MCP-1, EGF and VEGF will be assessed.
Discussion
This study aims to assess the presence or absence of TNF- alpha expression in the ECF tissue in non-IBD origin. If our hypothesis is correct we would then be able to study the use of the TNF- alpha inhibitor Infliximab as a therapeutic option in the treatment of non-IBD ECF. Secondary aims include assessing the spectrum of inflammatory cytokines and markers present in tissue and serum of non-IBD ECF when compared with IBD ECF and normal controls.
Trial registration
ISRCTN44000447
doi:10.1186/1471-2482-11-12
PMCID: PMC3116454  PMID: 21619579
13.  Establishment of a Population–based Registry of Inflammatory Bowel Diseases in Fars Province, Iran 
BACKGROUND
Inflammatory bowel diseases (IBD) are debilitating diseases that lead to a variety of problems in a patient’s daily life and are a huge burden for the health care system. Since this group of diseases are multifactorial and complex, long-term longitudinal studies are clearly needed to understand them better. A population–based registry (IBD-FaR) has been established in Fars, a southern Iranian province, with the intent to create a reliable data source. This registry will be of considerable help in future planning of health care resources necessary to deal with IBD and to enable investigators to test their theories on the origin and/or treatment of IBD.
METHODS
This registry is managed by both the Gastroenterohepatology Research Center and Health Policy Research Center at Shiraz University of Medical Sciences. A governing committee is responsible for decisions regarding budget allocations and use of data. The designed questionnaire includes a consent form, basic history data, risk factors, related procedures, medical therapy, and follow-up data. The establishment process has two parallel phases: in the first phase, data is collected from numerous sources, including annual hospital discharge data, referral from university affiliated physicians and private practices, pathologic reports, death certificates, self-referral, and insurance system data. In the interview, the questionnaire is completed and blood samples are taken. The gathered data are entered in a custom-designed, computerized data base. In the second phase, annual follow up interviews will be conducted. New IBD patients are also being registered. This phase will continue indefinitely, in order to include new incident cases.
RESULTS
Briefly, from May 2011 until December 2011, there were 188 patients [94 (50%) females and 94 (50%) males] diagnosed with IBD who were registered in IBD-FaR. Patients’ age range was between 15 and 80 years. A total of 164 (87.2%) patients out of 188 were registered as diagnosed with ulcerative colitis (UC) and 23 (12.2%) were registered as having Crohn’s disease (CD). Most patients 164 (87.2%) had negative family histories of IBD.
CONCLUSION
By retrospective and prospective data collection methods, this central database of IBD cases can determine the incidence, prevalence, and demographic characters of IBD in a defined population. It can facilitate future research to identify etiology, disease process, new treatment options, factors affecting prognosis, recurrences, optimal health care, morbidity and mortality of IBD, and at last but not least, provide educational and social support for patients by educational materials and organizing nongovermental organizations (NGOs).
PMCID: PMC4017688  PMID: 24829641
Inflammatory bowel disease; Registry; Population-based
14.  Development of Extraintestinal Manifestations in Pediatric Patients with Inflammatory Bowel Disease 
Inflammatory bowel diseases  2009;15(1):63-68.
Background
Extraintestinal manifestations (EIMs) in pediatric patients with inflammatory bowel disease (IBD) are poorly characterized. We examined the prevalence of EIMs at diagnosis, subsequent incidence, and risk factors for EIMs.
Methods
Data for 1649 patients from the PediIBD Consortium Registry, diagnosed with IBD before 18 years of age [1007(61%) with Crohn’s disease, 471(29%) with ulcerative colitis, and 171(10%) with indeterminate colitis], were analyzed using logistic regression, Kaplan-Meier, log rank tests and Cox models.
Results
EIMs were reported prior to IBD diagnosis in 97 of 1649 patients (6%). Older children at diagnosis had higher rates compared with younger children, and arthritis (26%) and aphthous stomatitis (21%) were most common. Among the 1552 patients without EIM at diagnosis, 290 developed at least one EIM. Kaplan-Meier estimates of cumulative incidence were 9% at 1 year, 19% at 5 years, and 29% at 15 years after diagnosis. Incidence did not differ by IBD type (p=0.20), age at diagnosis (p=0.22), or race/ethnicity (p=0.24). Arthritis (17%) and osteopenia/osteoporosis (15%) were the most common EIMs after IBD diagnosis.
Conclusions
In our large cohort of pediatric IBD patients, 6% had at least one EIM before diagnosis of IBD. At least one EIM will develop in 29% within 15 years of diagnosis. Incidence of EIMs both before and after diagnosis of IBD differs by type of EIM and may be slightly higher in girls, but is independent of the type of IBD, age at diagnosis, and race/ethnicity.
doi:10.1002/ibd.20604
PMCID: PMC2605161  PMID: 18626963
children; adolescents; ulcerative colitis; Crohn’s disease; arthritis; sclerosing cholangitis
15.  Clinical management of inflammatory bowel disease in the organ recipient 
There was estimated a higher incidence of de novo inflammatory bowel disease (IBD) after solid organ transplantation than in the general population. The onset of IBD in the organ transplant recipient population is an important clinical situation which is associated to higher morbidity and difficulty in the medical therapeutic management because of possible interaction between anti-reject therapy and IBD therapy. IBD course after liver transplantation (LT) is variable, but about one third of patients may worsen, needing an increase in medical therapy or a colectomy. Active IBD at the time of LT, discontinuation of 5-aminosalicylic acid or azathioprine at the time of LT and use of tacrolimus-based immunosuppression may be associated with an unfavorable outcome of IBD after LT. Anti-tumor necrosis factor alpha (TNFα) therapy for refractory IBD may be an effective and safe therapeutic option after LT. The little experience of the use of biological therapy in transplanted patients, with concomitant anti-rejection therapy, suggests there be a higher more careful surveillance regarding the risk of infectious diseases, autoimmune diseases, and neoplasms. An increased risk of colorectal cancer (CRC) is present also after LT in IBD patients with primary sclerosing cholangitis (PSC). An annual program of endoscopic surveillance with serial biopsies for CRC is recommended. A prophylactic colectomy in selected IBD/PSC patients with CRC risk factors could be a good management strategy in the CRC prevention, but it is used infrequently in the majority of LT centers. About 30% of patients develop multiple IBD recurrence and 20% of patients require a colectomy after renal transplantation. Like in the liver transplantation, anti-TNFα therapy could be an effective treatment in IBD patients with conventional refractory therapy after renal or heart transplantation. A large number of patients are needed to confirm the preliminary observations. Regarding the higher clinical complexity of this subgroup of IBD patients, a close multidisciplinary approach between an IBD dedicated gastroenterologist and surgeon and an organ transplantation specialist is necessary in order to have the best clinical management of IBD after transplantation.
doi:10.3748/wjg.v20.i13.3525
PMCID: PMC3974519  PMID: 24707135
Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Primary sclerosing cholangitis; Liver transplantation; Heart transplantation; Renal transplantation; Anti-tumor necrosis factor alpha therapy
16.  Pulmonary manifestations of inflammatory bowel disease 
World Journal of Gastroenterology : WJG  2014;20(37):13501-13511.
Extraintestinal manifestations of inflammatory bowel disease (IBD) are a systemic illness that may affect up to half of all patients. Among the extraintestinal manifestations of IBD, those involving the lungs are relatively rare and often overlooked. However, there is a wide array of such manifestations, spanning from airway disease to lung parenchymal disease, thromboembolic disease, pleural disease, enteric-pulmonary fistulas, pulmonary function test abnormalities, and adverse drug reactions. The spectrum of IBD manifestations in the chest is broad, and the manifestations may mimic other diseases. Although infrequent, physicians dealing with IBD must be aware of these conditions, which are sometimes life-threatening, to avoid further health impairment of the patients and to alleviate their symptoms by prompt recognition and treatment. Knowledge of these manifestations in conjunction with pertinent clinical data is essential for establishing the correct diagnosis and treatment. The treatment of IBD-related respiratory disorders depends on the specific pattern of involvement, and in most patients, steroids are required in the initial management. Corticosteroids, both systemic and aerosolized, are the mainstay therapeutic approach, while antibiotics must also be administered in the case of infectious and suppurative processes, whose sequelae sometimes require surgical intervention.
doi:10.3748/wjg.v20.i37.13501
PMCID: PMC4188901  PMID: 25309080
Inflammatory bowel diseases; Crohn’s disease; Ulcerative colitis; Lung diseases
17.  Epigenetic Regulation of WNT Signaling Pathway Genes in Inflammatory Bowel Disease (IBD) Associated Neoplasia 
Introduction
WNT signaling pathway dysregulation is an important event in the pathogenesis of colorectal cancer (CRC) with APC mutations seen in more than 80% of sporadic CRC. However, such mutations in the WNT signaling pathway genes are rare in inflammatory bowel disease (IBD) associated neoplasia (dysplasia and cancer). This study examined the role of epigenetic silencing of WNT signaling pathway genes in the pathogenesis of IBD-associated neoplasia.
Methods
Paraffin-embedded tissue samples were obtained and methylation of ten WNT signaling pathway genes, including APC1A, APC2, SFRP1, SFRP2, SFRP4, SFRP5, DKK1, DKK3, WIF1 and LKB1, was analyzed. Methylation analysis was performed on 41 IBD samples, 27 normal colon samples (NCs), and 24 sporadic CRC samples.
Results
Methylation of WNT signaling pathway genes is a frequent and early event in IBD and IBD-associated neoplasia. A progressive increase in the percentage of methylated genes in the WNT signaling pathway from NCs (4.2%) to IBD colitis (39.7%) to IBD-associated neoplasia (63.4%) was seen (NCs vs. IBD colitis, p<0.01; IBD colitis vs. IBD-associated neoplasia, p=0.01). In the univariate logistic regression model, methylation of APC2 (OR 4.7, 95% CI: 1.1–20.63, p=0.04), SFRP1 (OR 5.1, 95% CI: 1.1–31.9, p=0.04), and SFRP2 (OR 5.1, 95% CI: 1.1–32.3, p=0.04) was associated with progression from IBD colitis to IBD-associated neoplasia, while APC1A methylation was borderline significant (OR 4.1, 95% CI: 0.95–17.5, p=0.06). In the multivariate logistic regression model, methylation of APC1A and APC2 was more likely to be associated with IBD-associated neoplasia than IBD colitis. (OR APC1A: 6.4, 95% CI: 1.1–37.7 p=0.04; OR APC2 9.1, 95% CI: 1.3–61.7, p=0.02).
Summary
Methylation of the WNT signaling genes is an early event seen in patients with IBD colitis and there is a progressive increase in methylation of the WNT signaling genes during development of IBD-associated neoplasia. Moreover, methylation of APC1A, APC2, SFRP1, and SFRP2 appears to mark progression from IBD colitis to IBD-associated neoplasia, and these genes may serve as biomarkers for IBD-associated neoplasia.
doi:10.1007/s11605-008-0633-5
PMCID: PMC3976145  PMID: 18716850
IBD; Methylation; WNT signaling; Colorectal cancer
18.  Inflammatory bowel disease: Epidemiology, pathology and risk factors for hypercoagulability 
Hypercoagulability observed in patients with inflammatory bowel diseases (IBD) may lead to thromboembolic events (TE), which affect the venous and arterial systems alike and are an important factor in patients’ morbidity and mortality. The risk of TE in IBD patients has been demonstrated to be approximately three-fold higher as compared to the general population. The pathogenesis of thrombosis in IBD patients is multifactorial and not fully explained. The most commonly listed factors include genetic and immune abnormalities, disequilibrium between procoagulant and anticoagulant factors, although recently, the role of endothelial damage as an IBD-triggering factor is underlined. Several studies report that the levels of some coagulation enzymes, including fibrinogen, factors V, VII, VIII, active factor XI, tissue factor, prothrombin fragment 1 + 2 and the thrombin-antithrombin complex, are altered in IBD patients. It has been demonstrated that there is a significant decrease of tissue plasminogen activator level, a marked increase of plasminogen activator inhibitor type 1 and thrombin-activable fibrinolysis inhibitor, a significantly lower level of antithrombin III and tissue factor pathway inhibitor. IBD patients have been also observed to produce an increased amount of various anticoagulant antibodies. Hyperhomocysteinemia, which is a potential risk factor for TE was also observed in some IBD patients. Further studies are necessary to assess the role of coagulation abnormalities in IBD etiology and to determine indications for thromboprophylactic treatment in patients at high risk of developing TE.
doi:10.3748/wjg.v20.i1.53
PMCID: PMC3886032  PMID: 24415858
Crohn’s disease; Hypercoagulation; Risk factors; Thrombosis; Ulcerative colitis
19.  Epidemiology of Inflammatory Bowel Diseases in Iran and Asia; A Mini Review 
Iranian Journal of Medical Sciences  2013;38(2 Suppl):140-149.
The prevalence of inflammatory bowel diseases (IBDs) is set to stabilize in Western Europe and North America, as opposed to its increasing trend in developing countries in Asia. The epidemiology of IBDs in areas where the incidence and prevalence are relatively low provides an opportunity for researchers to determine the unknown aspects of them. In this review article, the PubMed and MEDLINE databases were searched from 1970 to 2012 and the epidemiological aspects assessed in Iranian articles were compared with identical subjects in other Asian countries. During this period, there were 21 documented articles on IBD epidemiology in Iran and 52 in Asia. According to the present review, CTLA-gene polymorphism and male/female ratio in ulcerative colitis (UC), incidence of extra-intestinal manifestations, extent of intestinal involvement, and family history in both UC and Crohn’s disease (CD) seemed to be different between Asia and Iran. In contrast, the incidence of primary sclerosing cholangitis in IBD patients and association between NO2/CARD15 mutation and CD as C3435-T allele and UC were nearly the same. The rate of IBD has increased significantly in Iran, as has that of other Asian countries during the last decade. A thorough, well-designed, population-based, multi-regional epidemiologic study seems mandatory due to the substantial demographic and characteristic variability in IBD patients in our region.
PMCID: PMC3771215  PMID: 24031103
Inflammatory bowel disease; Epidemiology; Prevalence; Iran
20.  Association of Secondhand Smoke Exposure with Pediatric Invasive Bacterial Disease and Bacterial Carriage: A Systematic Review and Meta-analysis 
PLoS Medicine  2010;7(12):e1000374.
Majid Ezzati and colleagues report the findings of a systematic review and meta-analysis that probes the association between environmental exposure to secondhand smoke and the epidemiology of pediatric invasive bacterial disease.
Background
A number of epidemiologic studies have observed an association between secondhand smoke (SHS) exposure and pediatric invasive bacterial disease (IBD) but the evidence has not been systematically reviewed. We carried out a systematic review and meta-analysis of SHS exposure and two outcomes, IBD and pharyngeal carriage of bacteria, for Neisseria meningitidis (N. meningitidis), Haemophilus influenzae type B (Hib), and Streptococcus pneumoniae (S. pneumoniae).
Methods and Findings
Two independent reviewers searched Medline, EMBASE, and selected other databases, and screened articles for inclusion and exclusion criteria. We identified 30 case-control studies on SHS and IBD, and 12 cross-sectional studies on SHS and bacterial carriage. Weighted summary odd ratios (ORs) were calculated for each outcome and for studies with specific design and quality characteristics. Tests for heterogeneity and publication bias were performed. Compared with those unexposed to SHS, summary OR for SHS exposure was 2.02 (95% confidence interval [CI] 1.52–2.69) for invasive meningococcal disease, 1.21 (95% CI 0.69–2.14) for invasive pneumococcal disease, and 1.22 (95% CI 0.93–1.62) for invasive Hib disease. For pharyngeal carriage, summary OR was 1.68 (95% CI, 1.19–2.36) for N. meningitidis, 1.66 (95% CI 1.33–2.07) for S. pneumoniae, and 0.96 (95% CI 0.48–1.95) for Hib. The association between SHS exposure and invasive meningococcal and Hib diseases was consistent regardless of outcome definitions, age groups, study designs, and publication year. The effect estimates were larger in studies among children younger than 6 years of age for all three IBDs, and in studies with the more rigorous laboratory-confirmed diagnosis for invasive meningococcal disease (summary OR 3.24; 95% CI 1.72–6.13).
Conclusions
When considered together with evidence from direct smoking and biological mechanisms, our systematic review and meta-analysis indicates that SHS exposure may be associated with invasive meningococcal disease. The epidemiologic evidence is currently insufficient to show an association between SHS and invasive Hib disease or pneumococcal disease. Because the burden of IBD is highest in developing countries where SHS is increasing, there is a need for high-quality studies to confirm these results, and for interventions to reduce exposure of children to SHS.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The deleterious health effects of smoking on smokers are well established, but smoking also seriously damages the health of nonsmokers. Secondhand smoke (SHS), which is released by burning cigarettes and exhaled by smokers, contains hundreds of toxic chemicals that increase the risk of adults developing lung cancer and heart disease. Children, however, are particularly vulnerable to the effects of SHS exposure (also known as passive smoking) because they are still developing physically. In addition, children have little control over their indoor environment and thus can be heavily exposed to SHS. Exposure to SHS increases the risk of ear infections, asthma, respiratory symptoms (coughing, sneezing, and breathlessness), and lung infections such as pneumonia and bronchitis in young children and the risk of sudden infant death syndrome during the first year of life.
Why Was This Study Done?
Several studies have also shown an association between SHS exposure (which damages the lining of the mouth, throat, and lungs and decreases immune defenses) and potentially fatal invasive bacterial disease (IBD) in children. In IBD, bacteria invade the body and grow in normally sterile sites such as the blood (bacteremia) and the covering of the brain (meningitis). Three organisms are mainly responsible for IBD in children—Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and Neisseria meningitidis. In 2000, S. pneumonia (pneumococcal disease) alone killed nearly one million children. Here, the researchers undertake a systematic review and meta-analysis of the association between SHS exposure in children and two outcomes—IBD and the presence of IBD-causing organisms in the nose and throat (bacterial carriage). A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method that combines the results of several studies. By combining data, it is possible to get a clearer view of the causes of a disease than is possible from individual studies.
What Did the Researchers Do and Find?
The researchers identified 30 case-control studies that compared the occurrence of IBD over time in children exposed to SHS with its occurrence in children not exposed to SHS. They also identified 12 cross-sectional studies that measured bacterial carriage at a single time point in children exposed and not exposed to SHS. The researchers used the data from these studies to calculate a “summary odds ratio” (OR) for each outcome—a measure of how SHS exposure affected the likelihood of each outcome. Compared with children unexposed to SHS, exposure to SHS doubled the likelihood of invasive meningococcal disease (a summary OR for SHS exposure of 2.02). Summary ORs for invasive pneumococcal disease and Hib diseases were 1.21 and 1.22, respectively. However, these small increases in the risk of developing these IBDs were not statistically significant unlike the increase in the risk of developing meningococcal disease. That is, they might have occurred by chance. For bacterial carriage, summary ORs for SHS exposure were 1.68 for N. meningitidis, 1.66 for S. pneumonia (both these ORs were statistically significant), and 0.96 for Hib (a nonsignificant decrease in risk).
What Do These Findings Mean?
These findings indicate that SHS exposure is significantly associated with invasive meningococcal disease among children. However, the evidence that SHS exposure is associated with invasive pneumococcal and Hib disease is only suggestive. These findings also indicate that exposure to SHS is associated with an increased carriage of N. meningitidis and S. pneumoniae. The accuracy and generalizability of these findings is limited by the small number of studies identified, by the lack of studies from developing countries where SHS exposure is increasing and the burden of IBD is high, and by large variations between the studies in how SHS exposure was measured and IBD diagnosed. Nevertheless, they suggest that, by reducing children's exposure to SHS (by, for example, persuading parents not to smoke at home), the illness and death caused by IBDs among children could be greatly reduced. Such a reduction would be particularly welcome in developing countries where vaccination against IBDs is low.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000374.
The US Centers for Disease Control and Prevention provides information on secondhand smoke, on children and secondhand smoke exposure, on meningitis, and on Hib infection
The US Environmental Protection Agency also provides information on the health effects of exposure to secondhand smoke (in English and Spanish) and a leaflet (also in English and Spanish) entitled Secondhand Tobacco Smoke and the Health of Your Family
The US Office of the Surgeon General provides information on the health consequences of involuntary exposure to tobacco smoke
The World Health Organization provides a range of information on the global tobacco epidemic
The World Health Organization has information on meningococcal disease (in English only) and on Hib (in several languages)
The US National Foundation for Infectious Diseases provides a fact sheet on pneumococcal disease
doi:10.1371/journal.pmed.1000374
PMCID: PMC2998445  PMID: 21151890
21.  Assessment of Thrombophilic Abnormalities During the Active State of Inflammatory Bowel Disease 
Background/Aims:
Thromboembolic disease has been recognized as a complication of inflammatory bowel disease (IBD). The relative contributions of inherited or acquired thrombophilia and the inflammatory response to the mechanism of this tendency are unclear. Thrombotic events are more common in active disease although significant numbers also occur spontaneously. The aim of this study was to investigate common thrombophilic markers in patients with active IBD.
Methods:
Twenty-six patients with IBD who had active disease, and 40 sex- and age-matched non-IBD patients were recruited into the study. For all the subjects, complete blood counts, C-reactive protein levels, erythrocyte sedimentation rate, International normalized ratio, activated partial thromboplastin time, and levels of lupus anticoagulant, anticardiolipin antibodies (ACA IgG), proteins C and S, antithrombin-III (AT-III), and factor V were measured.
Results:
The International normalized ratio, activated partial thromboplastin time, and levels of proteins C and S were comparable between the two groups. However, antithrombin-III levels were significantly lower in the IBD group as compared with that in the healthy control group (P < 0.001). ACA IgG was detected in one patient in the IBD group. Factor V Leiden mutation was present in 3.8% of the patients in the IBD group, whereas the prevalence was 2.5% in the control group. Significantly elevated platelet counts were observed in patients with active Crohn's disease compared with that in the control group (P < 0.001), but they were not significantly increased in active ulcerative colitis (P = 0.231).
Conclusions:
The present study failed to establish a strong association between the common thrombophilic markers and the active clinical course of IBD, with the exception of high platelet counts and lower levels of AT-III in the IBD group as compared with those in the control group. All other parameters of thrombophilia were comparable between the two groups.
doi:10.4103/1319-3767.41743
PMCID: PMC2702936  PMID: 19568537
Active state; inflammatory bowel disease; thrombophilic markers
22.  Prevalence of serum celiac antibody in patients with IBD in Japan 
Journal of Gastroenterology  2013;49(5):825-834.
Background
Although the incidence of inflammatory bowel diseases (IBD) in Japan has increased, the prevalence of celiac disease is considered very low with the lowest genetic disposition. IBD is reported as the most common comorbidity because of the high positive rate of serological celiac markers. The aim of this study was to examine the current incidence of celiac disease, especially in IBD patients in Japan, where both wheat consumption and incidence of IBD have increased.
Methods
A total of 172 patients with IBD and 190 controls in Japan were screened for serum antibody of tissue transglutaminase and deaminated gliadin peptide. In sero-positive patients, HLA testing and upper gastrointestinal endoscopy with duodenal biopsy was performed. Some of the sero-positive patients started a gluten-restricted or unrestricted diet, and serological change was determined.
Results
The positivity of both serum antibodies was significantly higher in IBD and correlated with disease activity. However, no biopsy-defined or HLA-defined true celiac disease was found. A decrease in serum antibody titers was observed with a gluten-restricted diet.
Conclusions
Despite the increased incidence of IBD and high positivity for serum celiac antibody in Japanese IBD patients, no true-positive celiac disease was noted, suggesting the presence of gluten intolerance in these populations.
doi:10.1007/s00535-013-0838-6
PMCID: PMC4019828  PMID: 23754511
Celiac disease; Japanese; Inflammatory bowel diseases; Gluten
23.  Inflammatory bowel disease: An increased risk factor for neurologic complications 
Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn’s disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity.
doi:10.3748/wjg.v20.i5.1228
PMCID: PMC3921505  PMID: 24574797
Extraintestinal manifestations; Inflammatory bowel disease; Multiple sclerosis; Neuropathy; Stroke; Tumor necrosis factor inhibitor
24.  Anemia in inflammatory bowel disease: A neglected issue with relevant effects 
Anemia, a common complication associated with inflammatory bowel disease (IBD), is frequently overlooked in the management of IBD patients. Unfortunately, it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population. Anemia in IBD is pathogenically complex, with several factors contributing to its development. While iron deficiency is the most common cause, vitamin B12 and folic acid deficiencies, along with the effects of pro-inflammatory cytokines, hemolysis, drug therapies, and myelosuppression, have also been identified as the underlying etiology in a number of patients. Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD. Because the diagnosis of anemia in IBD often presents a challenge, combinations of several hematimetric and biochemical parameters should be used. Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia, anemia due to chronic disease, or mixed anemia in IBD patients. With regard to treatment, the newly introduced intravenous iron formulations have several advantages over orally-administered iron compounds in treating iron deficiency in IBD. In special situations, erythropoietin supplementation and biological therapies should be considered. In conclusion, the management of anemia is a complex aspect of treating IBD patients, one that significantly influences the prognosis of the disease. As a consequence, its correction should be considered a specific, first-line therapeutic goal in the management of these patients.
doi:10.3748/wjg.v20.i13.3542
PMCID: PMC3974521  PMID: 24707137
Anemia; Inflammatory bowel disease; Iron deficiency; Anemia of chronic disease; Erythropoietin
25.  IBDsite: a Galaxy-interacting, integrative database for supporting inflammatory bowel disease high throughput data analysis 
BMC Bioinformatics  2012;13(Suppl 14):S5.
Background
Inflammatory bowel diseases (IBD) refer to a group of inflammatory conditions concerning colon and small intestine, which cause socially uncomfortable symptoms and often are associated with an increased risk of colon cancer. IBD are complex disorders, which rely on genetic susceptibility, environmental factors, deregulation of the immune system, and host relationship with commensal microbiota. The complexity of these pathologies makes difficult to clearly understand the mechanisms of their onset. Therefore, the study of IBD must be faced exploiting an integrated and multilevel approach, ranging from genes, transcripts and proteins to pathways altered in affected tissues, and carefully considering their regulatory mechanisms, which may intervene in the pathology onset. It is also crucial to have a knowledge base about the symbiotic bacteria that are hosted in the human gut. To date, much data exist regarding IBD and human commensal bacteria, but this information is sparse in literature and no free resource provides a homogeneously and rationally integrated view of biomolecular data related to these pathologies.
Methods
Human genes altered in IBD have been collected from literature, paying particular interest for the immune system alterations prompted by the interaction with the gut microbiome. This process has been performed manually to assure the reliability of collected data. Heterogeneous metadata from different sources have been automatically formatted and integrated in order to enrich information about these altered genes. A user-friendly web interface has been created for easy access to structured data. Tools such as gene clustering coefficients, all-pairs shortest paths and pathway lengths calculation have been developed to provide data analysis support. Moreover, the implemented resource is compliant to the Galaxy framework, allowing the collected data to be exploited in the context of high throughput bioinformatics analysis.
Results
To fill the lack of a reference resource for 'omics' science analysis in the context of IBD, we developed the IBDsite (available at http://www.itb.cnr.it/ibd), a disease-oriented platform, which collects data related to biomolecular mechanisms involved in the IBD onset. The resource provides a section devoted to human genes identified as altered in IBD, which can be queried at different biomolecular levels and visualised in gene-centred report pages. Furthermore, the system presents information related to the gut microbiota involved in IBD affected patients. The IBDsite is compliant with all Galaxy installations (in particular, it can be accessed from our custom version of Galaxy, http://www.itb.cnr.it/galaxy), in order to facilitate high-throughput data integration and to enable evaluations of the genomic basis of these diseases, complementing the tools embedded in the IBDsite.
Conclusions
Lots of sparse data exist concerning IBD studies, but no on-line resource homogeneously and rationally integrate and collect them. The IBDsite is an attempt to group available information regarding human genes and microbial aspects related to IBD, by means of a multilevel mining tool. Moreover, it constitutes a knowledge base to filter, annotate and understand new experimental data in order to formulate new scientific hypotheses, thanks to the possibility of integrating genomics aspects by employing the Galaxy framework. Discussed use-cases demonstrate that the developed system is useful to infer not trivial knowledge from the existing widespread data or from novel experiments.
doi:10.1186/1471-2105-13-S14-S5
PMCID: PMC3439730  PMID: 23095257

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