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1.  Microalbuminuria in inflammatory bowel disease. 
Gut  1994;35(11):1599-1604.
Microalbuminuria independently predicts the development of nephropathy and increased cardiovascular morbidity and mortality in diabetic patients, but it may be an indicator of the acute phase response. This study examined microalbuminuria as a marker of the acute phase response in patients with inflammatory bowel disease and correlated it with the disease activity in 95 patients with inflammatory bowel disease (ulcerative colitis (n = 52), Crohn's disease (n = 43)) determined by the simple index of Harvey and Bradshaw. Fifty patients were in complete clinical remission and 45 patients had active disease. Microalbuminuria was detected in all patients with inflammatory bowel disease (147 (17) v 18 (2) microgram/min, inflammatory bowel disease v controls mean (SEM), p < 0.007). Patients with active inflammatory bowel disease had higher concentrations of microalbuminuria compared with patients in remission (206 (19) v 65 (8) microgram/min, mean (SEM), p < 0.0001). Eight patients with active inflammatory bowel disease who were sequentially followed up with measurements of microalbuminuria had significantly lower values, when the disease was inactive (active inflammatory bowel disease 192 (44) v inactive inflammatory bowel disease 64 (14) microgram/min, p < 0.03). There was a significant correlation with the simple index of Harvey and Bradshaw (r = 0.818, p < 0.0001). Microalbuminuria values were significantly lower in inflammatory bowel disease patients in remission, maintained with olsalazine compared with those patients maintained with mesalazine and salazopyrine, but no significant difference was seen in values of microalbuminuria in active inflammatory bowel disease patients receiving different salicylates. This study also measured serum amyloid-A as an indicator of the acute phase response in the same patients. Serum amyloid-A was significantly increased in active disease compared with inactive disease (151 (43) v 33 (7) or controls 11 (2) micrograms/ml, p < 0.05). In conclusion microalbuminuria is present in abnormal amounts in all patients with active inflammatory bowel disease, and values fall when the disease is quiescent. Microalbuminuria is probably a consequence of an acute phase response and provides a simple, rapid, and inexpensive test, which has the potential to monitor inflammatory bowel disease activity and response to treatment.
PMCID: PMC1375619  PMID: 7828980
2.  Simple objective criteria for diagnosis of causes of acute diarrhoea on rectal biopsy. 
Journal of Clinical Pathology  1997;50(7):580-585.
AIM: To identify simple, objective, accurate histological criteria for distinguishing acute infective-type colitis, chronic idiopathic inflammatory bowel disease, and irritable bowel syndrome on rectal biopsy in patients with acute onset diarrhoea at first presentation, one to 10 weeks after onset. METHODS: Cell counts and measurements of mucosal architecture were made on initial rectal biopsies from 18 patients with acute infective-type colitis, 17 patients with first acute presentation of chronic idiopathic inflammatory bowel disease, and 23 patients with irritable bowel syndrome. The data were analysed by ANOVA and discriminant analysis. RESULTS: Lamina propria cells were mainly in the upper third in irritable bowel syndrome patients. Increased lamina propria cellularity, mainly in the middle third, and numbers of crypt intraepithelial neutrophils distinguished acute infective-type colitis from irritable bowel syndrome in 93% of cases. Chronic idiopathic inflammatory bowel disease differed from irritable bowel syndrome and acute infective-type colitis in a decreased number of crypts and altered crypt architecture. Chronic idiopathic inflammatory bowel disease showed higher lamina propria cellularity, especially in the basal third, with an increased number of lamina propria neutrophils. On discriminant analysis, crypt numbers distinguished 86% of the cases of chronic idiopathic inflammatory bowel disease from the other groups. CONCLUSION: At one week or more from onset, acute infective-type colitis is characterised by a superficial increase in lamina propria cellularity, with only a slight increase in the number of polymorphs. At this stage, chronic idiopathic inflammatory bowel disease is characterised by a transmucosal increase in cellularity together with crypt loss and architectural abnormality. Thus, measurement of mucosal architecture establishes simple, accurate, objective criteria for routine biopsy diagnosis of chronic idiopathic inflammatory bowel disease from acute infective-type colitis and irritable bowel syndrome at initial presentation, one to 10 weeks after onset.
PMCID: PMC500059  PMID: 9306939
3.  Risk of cancer, with special reference to extra-intestinal malignancies, in patients with inflammatory bowel disease 
AIM: To determine the incidence and characteristics of intestinal and extra-intestinal cancers among patients with inflammatory bowel disease in a Spanish hospital and to compare them with those of the local population.
METHODS: This was a prospective, observational, 7-year follow-up, cohort study. Cumulative incidence, incidence rates based on person-years of follow-up and relative risk were calculated for patients with inflammatory bowel disease and compared with the background population. The incidence of cancer was determined using a hospital-based data registry from Hospital Universitario de Fuenlabrada. Demographic data and details about time from diagnosis of inflammatory bowel disease to occurrence of cancer, disease extent, inflammatory bowel disease treatment, cancer therapy and cancer evolution were also collected in the inflammatory bowel disease cohort.
RESULTS: Eighteen of 590 patients with inflammatory bowel disease developed cancer [cumulative incidence = 3% (95%CI: 1.58-4.52) vs 2% (95%CI: 1.99-2.11) in the background population; RR = 1.5; 95%CI: 0.97-2.29]. The cancer incidence among inflammatory bowel disease patients was 0.53% (95%CI: 0.32-0.84) per patient-year of follow-up. Patients with inflammatory bowel disease had a significantly increased relative risk of urothelial carcinoma (RR = 5.23, 95%CI: 1.95-13.87), appendiceal mucinous cystadenoma (RR = 36.6, 95%CI: 7.92-138.4), neuroendocrine carcinoma (RR = 13.1, 95%CI: 1.82-29.7) and rectal carcinoid (RR = 8.94, 95%CI: 1.18-59.7). Colorectal cancer cases were not found.
CONCLUSION: The overall risk of cancer did not significantly increase in our inflammatory bowel disease patients. However, there was an increased risk of urinary bladder cancer and, with less statistical power, an increased risk of appendiceal mucinous cystadenoma and of neuroendocrine tumors. Colorectal cancer risk was low in our series.
PMCID: PMC3882409  PMID: 24409063
Extra-intestinal cancer; Inflammatory bowel disease; Cancer risk; Background population; Urothelial carcinoma; Appendiceal mucinous cystadenoma; Neuroendocrine carcinoma; Rectal carcinoid
4.  Small bowel ulcerative lesions are common in elderly NSAIDs users with peptic ulcer bleeding 
AIM: To determine the frequency of small bowel ulcerative lesions in patients with peptic ulcer and define the significance of those lesions.
METHODS: In our prospective study, 60 consecutive elderly patients with upper gastrointestinal bleeding from a peptic ulceration (cases) and 60 matched patients with a non-bleeding peptic ulcer (controls) underwent small bowel capsule endoscopy, after a negative colonoscopy (compulsory in our institution). Controls were evaluated for non-bleeding indications. Known or suspected chronic inflammatory conditions and medication that could harm the gut were excluded. During capsule endoscopy, small bowel ulcerative lesions were counted thoroughly and classified according to Graham classification. Other small bowel lesions were also recorded. Peptic ulcer bleeding was controlled endoscopically, when adequate, proton pump inhibitors were started in both cases and controls, and Helicobacter pylori eradicated whenever present. Both cases and controls were followed up for a year. In case of bleeding recurrence upper gastrointestinal endoscopy was repeated and whenever it remained unexplained it was followed by repeat colonoscopy and capsule endoscopy.
RESULTS: Forty (67%) cases and 18 (30%) controls presented small bowel erosions (P = 0.0001), while 22 (37%) cases and 4 (8%) controls presented small bowel ulcers (P < 0.0001). Among non-steroidal anti-inflammatory drug (NSAID) consumers, 39 (95%) cases and 17 (33%) controls presented small bowel erosions (P < 0.0001), while 22 (55%) cases and 4 (10%) controls presented small bowel ulcers (P < 0.0001). Small bowel ulcerative lesions were infrequent among patients not consuming NSAIDs. Mean entry hemoglobin was 9.3 (SD = 1.4) g/dL in cases with small bowel ulcerative lesions and 10.5 (SD = 1.3) g/dL in those without (P = 0.002). Cases with small bowel ulcers necessitate more units of packed red blood cells. During their hospitalization, 6 (27%) cases with small bowel ulcers presented bleeding recurrence most possibly attributed to small bowel ulcers, nevertheless 30-d mortality was zero. Presence of chronic obstructive lung disease and diabetes was related with unexplained recurrence of hemorrhage in logistic regression analysis, while absence of small bowel ulcers was protective (relative risk 0.13, P = 0.05).
CONCLUSION: Among NSAID consumers, more bleeders than non-bleeders with peptic ulcers present small bowel ulcers; lesions related to more severe bleeding and unexplained episodes of bleeding recurrence.
PMCID: PMC4265959  PMID: 25512771
Non-steroidal anti-inflammatory drugs; Aspirin; Wireless capsule endoscopy; Small bowel ulcerative lesions; Peptic ulcer bleeding
5.  111Indium autologous granulocytes in the detection of inflammatory bowel disease. 
Gut  1985;26(9):955-960.
Indium leucocyte scanning and measurement of faecal Indium leucocyte excretion are techniques which have recently been introduced for assessing patients with inflammatory bowel disease. The methodology has recently been made more specific for acute inflammation by labelling pure granulocytes rather than the mixed leucocyte preparation. To determine the accuracy of this modified technique in detecting inflammatory bowel disease, we have prospectively compared Indium granulocyte scanning and faecal In granulocyte excretion with rectal histology and contrast bowel radiology as screening procedures in 100 patients with suspected inflammatory bowel disease. Thirty three patients were shown to have inflammatory bowel disease - 24 with Crohn's disease and nine with ulcerative colitis or indeterminate colitis. Overall the respective sensitivities for detecting inflammatory bowel disease were 97% for faecal Indium granulocyte excretion, 94% for Indium granulocyte scanning, 79% for radiology and 70% for rectal histology. The superiority of In granulocytes over radiology and rectal histology in detecting inflammatory bowel disease was, in the main, due to the difficulty in diagnosing Crohn's with conventional techniques. Although three of the patients with ulcerative colitis and indeterminate colitis had normal sigmoidoscopic appearances - all had abnormal rectal histology. No patient with a non-inflammatory bowel disorder had a positive In granulocyte scan or a raised faecal excretion. These results show that investigations using In granulocytes are accurate in identifying inflammatory bowel disease and offer important advantages over conventional procedures for detecting Crohn's disease.
PMCID: PMC1432869  PMID: 4029721
6.  Gastrointestinal symptoms in the irritable bowel compared with peptic ulcer and inflammatory bowel disease. 
Gut  1984;25(10):1089-1092.
Symptoms of 50 patients with the irritable bowel syndrome were compared with those of 49 with endoscopically proven peptic ulcer disease and 49 with radiologically or endoscopically proven inflammatory bowel disease using a questionnaire which was administered after the diagnosis was made. Symptoms of bowel dysfunction including pain related to bowel movements were more likely to occur in the irritable bowel syndrome than peptic ulcer disease. Only abdominal distension, straining at stool and scybala, however, were significantly more likely in the irritable bowel syndrome than inflammatory bowel disease. Four symptoms previously shown to be more common in irritable bowel syndrome than in organic abdominal disease were combined. The more of these symptoms that were present, the more likely were the patients to have the irritable bowel syndrome than peptic ulcer disease. Symptoms of gut dysfunction are highly discriminating between irritable bowel syndrome and peptic ulcer disease but less so between irritable bowel syndrome and inflammatory bowel disease.
PMCID: PMC1432538  PMID: 6479683
7.  Urinary crystalloid excretion in patients with inflammatory bowel disease 
Gut  1970;11(4):314-318.
Because of the potential relationship of increased urinary crystalloid excretion and concentration to stone formation, urinary calcium and uric acid excretion patterns were studied prospectively in 65 patients with inflammatory bowel disease and compared with excretion patterns in patients with functional bowel disease (controls) receiving similar dietary prescriptions.
Mean 24-hr urinary calcium excretion was higher in both ulcerative colitis (212 mg, p <0·02) and granulomatous bowel disease (168 mg, p = n.s.) than in controls (118 mg). Urinary calcium excretion exceeded 250 mg/24 hr in 11 of 34 patients with inflammatory bowel disease but in none of the controls. Eight of these 34 patients compared with one of 10 controls excreted urine with calcium concentrations greater than 20 mg/100 ml.
Mean 24-hr uric acid excretion was slightly higher in granulomatous bowel disease (520 mg) than in ulcerative colitis (450 mg) or functional bowel disease (451 mg). Eight patients with inflammatory bowel disease but no control subject excreted > 700 mg. The mean urinary uric acid concentration was significantly higher in ulcerative colitis (538 μg/ml, p <0·05) and granulomatous bowel disease (558 μg/ml, p <0·02) than in controls (338 μg/ml). The mean morning urine pH was lower (5·5, p <0·01) in ulcerative colitis than in the other groups.
These results indicate increased excretion and higher concentration of calcium and uric acid in some patients with inflammatory bowel disease on the usual treatment programmes. Only very long-term prospective studies of such patients can help to document the true contribution of increased crystalloid concentration and excretion to kidney stone formation in inflammatory bowel disease patients.
PMCID: PMC1411404  PMID: 5428854
8.  Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. 
Gut  1993;34(4):517-524.
The Jewish population has an increased frequency of inflammatory bowel disease compared with their non-Jewish neighbours. Genetic factors have been implicated in the aetiology of this disorder and may contribute to ethnic differences. This study determined the familial empirical risks for inflammatory bowel disease in the first degree relatives of inflammatory bowel disease probands (for both Jews and non-Jews) for the purpose of accurate genetic counselling and genetic analysis. A total of 527 inflammatory bowel disease patients from Southern California (291 Jews and 236 non-Jews) were questioned about inflammatory bowel disease in their first degree relatives (a total of 2493 individuals). Since inflammatory bowel disease has a variable and late age of onset, age specific incidence data were used to estimate the life time risks and to make valid comparisons between the different groups. In the first degree relatives of non-Jewish probands, the life time risks for inflammatory bowel disease were 5.2% and 1.6% when probands had Crohn's disease and ulcerative colitis respectively. These values were consistently lower than the corresponding risks for relatives of Jewish patients -7.8% and 4.5% for Crohn's disease and ulcerative colitis probands respectively (p value for comparison between Jews and non-Jews: 0.028; between ulcerative colitis and Crohn's disease: 0.005). These data provide the requisite basis for genetic counselling for these disorders in the white American population. In addition, these different empirical risks for relatives of Jewish and non-Jewish probands allow rejection of single Mendelian gene models for inflammatory bowel disease, but are consistent with several alternative genetic models.
PMCID: PMC1374314  PMID: 8491401
9.  An Antibiotic-Responsive Mouse Model of Fulminant Ulcerative Colitis  
PLoS Medicine  2008;5(3):e41.
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.
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
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
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
PMCID: PMC2270287  PMID: 18318596
10.  Analysis of Germline GLI1 Variation Implicates Hedgehog Signalling in the Regulation of Intestinal Inflammatory Pathways 
PLoS Medicine  2008;5(12):e239.
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.
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
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
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)
PMCID: PMC2596854  PMID: 19071955
11.  Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease 
Gut  2001;49(5):665-670.
BACKGROUND—Measurement of 6-thioguanine nucleotide concentrations may be useful for optimising treatment with azathioprine and 6-mercaptopurine.
METHODS—We conducted a study of 170 patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine to determine the relationship between 6-thioguanine nucleotide concentrations and both disease activity, as measured by the inflammatory bowel disease questionnaire (active disease <170, remission ⩾170) and leucopenia. Blood was submitted for whole blood 6-thioguanine nucleotide concentration and leucocyte count.
RESULTS—Mean (SD) inflammatory bowel disease questionnaire score was 176 (32). There was no correlation between inflammatory bowel disease questionnaire scores and 6-thioguanine nucleotide concentrations (rs=−0.09, p=0.24). Median 6-thioguanine nucleotide concentrations in 56 patients with active disease and 114 patients in remission were similar (139 v 131 pmol/8×108 red blood cells; p=0.26). There was no correlation between 6-thioguanine nucleotide concentrations and leucocyte counts.
CONCLUSIONS—In patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine, 6-thioguanine nucleotide concentrations did not correlate with disease activity, as measured by the inflammatory bowel disease questionnaire, or leucocyte count. These findings are discrepant with most previous studies, possibly due to selection of responding patients who tolerated the medications. A prospective, randomised, dose optimisation trial using 6-thioguanine nucleotide concentrations is warranted.

Keywords: azathioprine; 6-mercaptopurine; thioguanine nucleotides; thiopurine methyltransferase; inflammatory bowel disease
PMCID: PMC1728511  PMID: 11600469
12.  Small Bowel Endoscopy in Inflammatory Bowel Disease 
Clinical Endoscopy  2013;46(4):321-326.
Crohn disease (CD) is a chronic inflammatory bowel disease that affects the entire gastrointestinal tract but is most frequently localized to the large and small bowel. Small bowel endoscopy helps with the differential diagnosis of CD in suspected CD patients. Early diagnosis of CD is preferable for suspected CD conditions to improve chronic inflammatory infiltrates, fibrosis. Small bowel endoscopy can help with the early detection of active disease, thus leading to early therapy before the onset of clinical symptoms of established CD. Some patients with CD have mucosal inflammatory changes not in the terminal ileum but in the proximal small bowel. Conventional ileocolonoscopy cannot detect ileal involvement proximal to the terminal ileum. Small bowel endoscopy, however, can be useful for evaluating these small bowel involvements in patients with CD. Small bowel endoscopy by endoscopic balloon dilation (EBD) enables the treatment of small bowel strictures in patients with CD. However, many practical issues still need to be addressed, such as endoscopic findings for early detection of CD, application compared with other imaging modalities, determination of the appropriate interval for endoscopic surveillance of small bowel lesions in patients with CD, and long-term prognosis after EBD.
PMCID: PMC3746136  PMID: 23964328
Crohn disease; Capsule endoscopy; Balloon assisted endoscopy; Endoscopic balloon dilation
13.  Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis 
Objective To evaluate whether including a test for faecal calprotectin, a sensitive marker of intestinal inflammation, in the investigation of suspected inflammatory bowel disease reduces the number of unnecessary endoscopic procedures.
Design Meta-analysis of diagnostic accuracy studies.
Data sources Studies published in Medline and Embase up to October 2009.
Interventions reviewed Measurement of faecal calprotectin level (index test) compared with endoscopy and histopathology of segmental biopsy samples (reference standard).
Inclusion criteria Studies that had collected data prospectively in patients with suspected inflammatory bowel disease and allowed for construction of a two by two table. For each study, sensitivity and specificity of faecal calprotectin were analysed as bivariate data to account for a possible negative correlation within studies.
Results 13 studies were included: six in adults (n=670), seven in children and teenagers (n=371). Inflammatory bowel disease was confirmed by endoscopy in 32% (n=215) of the adults and 61% (n=226) of the children and teenagers. In the studies of adults, the pooled sensitivity and pooled specificity of calprotectin was 0.93 (95% confidence interval 0.85 to 0.97) and 0.96 (0.79 to 0.99) and in the studies of children and teenagers was 0.92 (0.84 to 0.96) and 0.76 (0.62 to 0.86). The lower specificity in the studies of children and teenagers was significantly different from that in the studies of adults (P=0.048). Screening by measuring faecal calprotectin levels would result in a 67% reduction in the number of adults requiring endoscopy. Three of 33 adults who undergo endoscopy will not have inflammatory bowel disease but may have a different condition for which endoscopy is inevitable. The downside of this screening strategy is delayed diagnosis in 6% of adults because of a false negative test result. In the population of children and teenagers, 65 instead of 100 would undergo endoscopy. Nine of them will not have inflammatory bowel disease, and diagnosis will be delayed in 8% of the affected children.
Conclusion Testing for faecal calprotectin is a useful screening tool for identifying patients who are most likely to need endoscopy for suspected inflammatory bowel disease. The discriminative power to safely exclude inflammatory bowel disease was significantly better in studies of adults than in studies of children.
PMCID: PMC2904879  PMID: 20634346
14.  Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis 
PLoS Medicine  2008;5(3):e54.
MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis.
Methods and Findings
By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1β, TNF-α, and IFN-γ was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-γ, TNF-α, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis.
Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
Michael McGuckin and colleagues identify two mutations that cause aberrant mucin oligomerization in mice. The resulting phenotype, including endoplasmic reticulum stress, resembles clinical and pathologic features of human ulcerative colitis.
Editors' Summary
Inflammatory bowel diseases (IBD) are common disorders in which parts of the digestive tract become inflamed. The two main types of IBD are Crohn's disease, which mainly affects the small bowel, and ulcerative colitis (UC), which mainly affects the large bowel (colon). Both types tend to run in families and usually develop between 15 and 35 years old. Their symptoms include diarrhea, abdominal cramps, and unintentional weight loss. These symptoms can vary in severity, can be chronic (persistent) or intermittent, and may start gradually or suddenly. There is no cure for IBD (except removal of the affected part of the digestive tract), but drugs that modulate the immune system (for example, corticosteroids) or that inhibit “proinflammatory cytokines” (proteins made by the immune system that stimulate inflammation) can sometimes help.
Why Was This Study Done?
Although the clinical and pathological (disease-associated) features of Crohn's disease and UC are somewhat different, both disorders are probably caused by an immune system imbalance. Normally, the immune system protects the body from potentially harmful microbes in the gut but does not react to the many harmless bacteria that live there or to the food that passes along the digestive tract. In IBD, the immune system becomes overactive for unknown reasons, and lymphocytes (immune system cells) accumulate in the lining of the bowel and cause inflammation. In this study, the researchers use a technique called random mutagenesis (the random introduction of small changes, called mutations, into the genes of an organism using a chemical that damages DNA) to develop two mouse models that resemble human UC and that throw new light on to how this disorder develops.
What Did the Researchers Do and Find?
The researchers establish two mutant mouse strains—Winnie and Eeyore mice—that develop mild spontaneous inflammation of the colon and chronic diarrhea and that have more proinflammatory cytokines and more lymphocytes in their colons than normal mice. 25% and 40% of the Winnie and Eeyore mice, respectively, have severe clinical signs of colitis by 1 year of age. Both strains have a mutation in the Muc2 gene, which codes for MUC2 mucin, the main protein in mucus. This viscous substance (which coats the inside of the intestine) is produced by and stored in intestinal “goblet” cells. Mucus helps to maintain the intestine's immunological balance but is depleted in UC. The researchers show that the manufacture and assembly of Muc2 molecules is abnormal in Winnie and Eeyore mice, that less mucin is stored in their goblet cells than in normal mice, and that their intestinal mucus barrier is reduced. In addition, an incompletely assembled version of the molecule, called Muc2 precursor, accumulates in the endoplasmic reticulum (ER; the cellular apparatus that prepares newly manufactured proteins for release) of goblet cells, leading to overload with abnormal protein and causing a state of cellular distress known as the “ER stress response.” Finally, the researchers report that MUC2 precursor also accumulates in the goblet cells of people with UC and that even the noninflamed intestinal tissue of these patients shows signs of ER stress.
What Do These Findings Mean?
These findings indicate that mucin abnormalities and ER stress can initiate colitis in mice. Results from animal studies do not always reflect what happens in people, but these findings, together with those from the small study in humans, suggest that ER stress-related mucin depletion could be a component in the development of human colitis. The results do not identify the genetic changes and/or environmental factors that might trigger ER stress in human colitis, but suggest that once initiated, ER stress might interfere with MUC2 production, which would lead to a diminished mucus barrier, expose the lining of the intestine to more toxins and foreign substances, and trigger local mucosal inflammation. The release of inflammatory cytokines would then damage the intestine's lining and exacerbate ER stress, thus setting up a cycle of intestinal damage and inflammation. Clinical studies to look for genetic changes and environmental factors capable of triggering ER stress and for ER-stress related changes in human UC should now be undertaken to test this hypothesis.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on Crohn's disease and on 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
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
Wikipedia has pages on mucins and on mucus (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2270292  PMID: 18318598
15.  Using gene expression data to identify certain gastro-intestinal diseases 
Inflammatory bowel diseases, ulcerative colitis and Crohn’s disease are considered to be of autoimmune origin, but the etiology of irritable bowel syndrome remains elusive. Furthermore, classifying patients into irritable bowel syndrome and inflammatory bowel diseases can be difficult without invasive testing and holds important treatment implications. Our aim was to assess the ability of gene expression profiling in blood to differentiate among these subject groups.
Transcript levels of a total of 45 genes in blood were determined by quantitative real-time polymerase chain reaction (RT-PCR). We applied three separate analytic approaches; one utilized a scoring system derived from combinations of ratios of expression levels of two genes and two different support vector machines.
All methods discriminated different subject cohorts, irritable bowel syndrome from control, inflammatory bowel disease from control, irritable bowel syndrome from inflammatory bowel disease, and ulcerative colitis from Crohn’s disease, with high degrees of sensitivity and specificity.
These results suggest these approaches may provide clinically useful prediction of the presence of these gastro-intestinal diseases and syndromes.
PMCID: PMC3599448  PMID: 23171526
16.  Immunoregulatory function of human intestinal mucosa lymphoid cells: evidence for enhanced suppressor cell activity in inflammatory bowel disease. 
Gut  1983;24(8):692-701.
Abnormalities in immune regulation at the gut level may be relevant to the pathogenesis of inflammatory bowel disease, but little is known about the immunoregulatory properties of intestinal mononuclear cells. Therefore, we wished to see if lymphoid cells derived from the lamina propria of surgically resected bowel specimens have any modulatory effect upon the immune response of peripheral blood mononuclear cells from patients with ulcerative colitis or Crohn's disease. When autologous peripheral blood and intestinal lamina propria lymphoid cells were mixed at different ratios and cultured in the presence of phytohaemagglutinin, we were able to show that intestinal mononuclear cells had the capacity to modify the mitogenic response of the cultured cells. These intestinal immunoregulatory cells, when obtained from mucosa affected by inflammatory bowel disease, express a significantly enhanced suppressor cell activity as compared with those from non-inflamed control mucosa. Such suppressor cell activity varies with cell concentration and requires cell proliferation, but it is independent of anatomical origin (small vs large bowel), type of inflammatory bowel disease (ulcerative colitis vs Crohn's disease) or immunosuppressive therapy. These findings point to an important functional difference between inflammatory bowel disease and control intestinal mucosa mononuclear cells. The enhanced suppressor activity of lamina propria mononuclear cells may be associated with impairment of cell-mediated immunity at the gut level. This may be related to the pathogenesis of inflammatory bowel disease by leading to defective intestinal immune regulatory events, which may not be detectable at the peripheral level.
PMCID: PMC1420224  PMID: 6223862
17.  Blastocystosis in patients with gastrointestinal symptoms: a case–control study 
BMC Gastroenterology  2012;12:122.
Blastocystosis is a frequent bowel disease. We planned to to evaluate the prevalence of Blastocystis spp. in patients who applied to the same internal medicine-gastroenterology clinic with or without gastrointestinal complaints to reveal the association of this parasite with diagnosed IBS and IBD.
A total of 2334 patients with gastrointestinal symptoms composed the study group, which included 335 patients with diagnosed inflammatory bowel disease and 877 with irritable bowel syndrome. Patients without any gastrointestinal symptoms or disease (n = 192) composed the control group. Parasite presence was investigated by applying native-Lugol and formol ethyl acetate concentration to stool specimens, and trichrome staining method in suspicious cases.
Blastocystis spp. was detected in 134 patients (5.74%) in the study group and 6 (3.12%) in the control group (p = 0.128). In the study group, Blastocystis spp. was detected at frequencies of 8.7% in ulcerative colitis (24/276), 6.78% in Crohn’s disease (4/59), 5.82% in irritable bowel syndrome (51/877), and 4.9% in the remaining patients with gastrointestinal symptoms (55/1122). Blastocystis spp. was detected at a statistically significant ratio in the inflammatory bowel disease (odds ratio [OR] = 2.824; 95% confidence interval [CI]: 1.149-6.944; p = 0.019) and ulcerative colitis (OR = 2.952; 95% CI: 1.183-7.367; p = 0.016) patients within this group compared to controls. There were no statistically significant differences between the control group and Crohn’s disease or irritable bowel syndrome patients in terms Blastocystis spp. frequency (p = 0.251, p = 0.133).
Blastocystosis was more frequent in patients with inflammatory bowel disease, especially those with ulcerative colitis. Although symptomatic irritable bowel syndrome and Crohn’s disease patients had higher rates of Blastocystis spp. infection, the differences were not significant when compared to controls.
PMCID: PMC3444885  PMID: 22963003
Ulcerative colitis; Crohn’s disease; Irritable bowel syndrome; Blastocystis spp
18.  Circulating von Willebrand factor in inflammatory bowel disease. 
Gut  1992;33(4):502-506.
Raised circulating von Willebrand factor is a recognised marker of vascular injury. To evaluate the role of vascular injury in the pathogenesis of inflammatory bowel disease, serum von Willebrand factor in Crohn's disease, ulcerative colitis, confirmed bacterial diarrhoea, and healthy subjects was measured. von Willebrand factor values were raised in 9/14 patients (p = 0.007) with active Crohn's disease, 15/28 (p = 0.0004) with inactive Crohn's disease, 16/23 (p = 0.0003) with active ulcerative colitis, 9/27 (p = 0.04) with inactive ulcerative colitis, and 15/17 (p = 0.0001) patients with bacterial diarrhoea. Serum von Willebrand factor was unrelated to disease activity in Crohn's disease but was significantly raised in active (p = 0.02) compared with inactive ulcerative colitis. In contrast to controls, the detection of von Willebrand factor from inflammatory bowel disease sera and that from fractured endothelial cells was significantly inhibited by the reducing agent, dithiothreitol, suggesting the presence of an additional dithiothreitol sensitive form of the molecule derived from injured endothelial cells in inflammatory bowel disease. That serum von Willebrand factor is raised in quiescent as well as active Crohn's disease is compatible with the proposal that vascular injury is a fundamental abnormality in this disorder. The raised von Willebrand factor values in active inflammatory bowel disease and bacterial diarrhoea could be caused by either vascular injury, occurring secondary to bowel inflammation, or to an acute phase response resulting from endothelial cell stimulation by mediators released during the inflammatory process. Raised circulating von Willebrand factor could contribute to the increased risk of thrombosis associated with active inflammatory bowel disease.
PMCID: PMC1374067  PMID: 1582595
19.  Monozygotic twins with Crohn's disease and ulcerative colitis: a unique case report 
Gut  1997;41(4):557-560.
Background—A large number of monozygotic and dizygotic twin pairs with inflammatory bowel disease have been reported. To date no twin pair has developed phenotypically discordant inflammatory bowel disease. This case report is the first documented occurrence of discordant inflammatory bowel disease occurring in monozygotic twins. 
Case report—Twenty two year old identical male twins presented within three months of each other with inflammatory bowel disease that proved to be discordant in overall disease type, disease distribution, clinical course, and histopathological findings. Twin 1 developed a severe pancolitis necessitating total colectomy while twin 2 developed a predominantly distal patchy colitis with frequent granulomas, controlled by aminosalicylates. Twin 1 was antineutrophil cytoplasmic antibody (ANCA) negative at the time of testing while twin 2 (Crohn's disease) was ANCA positive. Significantly, the twins possessed the HLA type DR3-DR52-DQ2 previously associated with extensive colitis. 
Conclusion—This case report confirms the important role played by genetic factors in the development of inflammatory bowel disease. It also highlights the crucial role of undetermined environmental agents in dictating disease expression and phenotype. 

Keywords: monozygotic twins; ulcerative colitis; Crohn's disease; inflammatory bowel disease
PMCID: PMC1891513  PMID: 9391259
20.  Bowel wall thickening at CT: simplifying the diagnosis 
Insights into Imaging  2014;5(2):195-208.
In this article we present a simplified algorithm-based approach to the thickening of the small and large bowel wall detected on routine computed tomography (CT) of the abdomen.
Thickening of the small or large bowel wall may be caused by neoplastic, inflammatory, infectious, or ischaemic conditions. First, distinction should be made between focal and segmental or diffuse wall thickening. In cases of focal thickening further analysis of the wall symmetry and perienteric anomalies allows distinguishing between neoplasms and inflammatory conditions. In cases of segmental or diffuse thickening, the pattern of attenuation in light of clinical findings helps narrowing the differential diagnosis.
Focal bowel wall thickening may be caused by tumours or inflammatory conditions. Bowel tumours may appear as either regular and symmetric or irregular or asymmetric thickening. When fat stranding is disproportionately more severe than the degree of wall thickening, inflammatory conditions are more likely. With the exception of lymphoma, segmental or diffuse wall thickening is usually caused by benign conditions, such as ischaemic, infectious and inflammatory diseases.
Key points
• Thickening of the bowel wall may be focal (<5 cm) and segmental or diffuse (6-40 cm or >40 cm) in extension.
• Focal, irregular and asymmetrical thickening of the bowel wall suggests a malignancy.
• Perienteric fat stranding disproportionally more severe than the degree of wall thickening suggests an inflammatory condition.
• Regular, symmetric and homogeneous wall thickening is more frequently due to benign conditions, but can also be caused by neoplasms such as well-differentiated adenocarcinoma and lymphoma.
• Segmental or diffuse bowel wall thickening is usually caused by ischaemic, inflammatory or infectious conditions and the attenuation pattern is helpful in narrowing the differential diagnosis.
PMCID: PMC3999365  PMID: 24407923
Computed tomography; Inflammatory bowel disease; Small bowel intestinal neoplasms
21.  Role of Alvimopan (Entereg) in Gastrointestinal Recovery And Hospital Length of Stay After Bowel Resection 
Pharmacy and Therapeutics  2012;37(9):518-525.
A retrospective chart review revealed that patients receiving alvimopan after bowel surgery had faster recovery times, better surgical care, and lower costs of care compared with patients who did not receive the drug.
Postoperative ileus (POI) can delay gastrointestinal (GI) recovery after bowel resection. Alvimopan (Entereg), a peripherally acting mu-opioid receptor antagonist, is thought to favorably reduce various outcome measures such as the length of stay (LOS) and time from surgery to hospital discharge following partial-bowel, large-bowel, or small-bowel resection surgery with primary anastomosis. We undertook a study to compare these outcome measures in alvimopan-treated patients undergoing laparoscopic or open-bowel resection against a control group. We also sought to determine whether any other factors—Diagnosis-Related Group (DRG) status, complications, inflammatory bowel disease, type of surgery, age, sex, intestinal cancer, diverticular disease, number of chronic conditions, and operative time—were predictive of a more favorable (shorter) time to GI recovery.
Patients’ charts were retrospectively reviewed at a large 591-bed teaching hospital in suburban New York City between June and August 2010. We applied descriptive statistics for five outcome variables to compare alvimopan-treated patients with non-users. The main outcome variable was the time from surgery to hospital discharge. Secondary outcome variables were the time to pass gas, time to a liquid diet, time to a solid diet, and total LOS. We compared the outcome variables for three groups of DRG codes (329, the most complicated cases; 330, intermediate; and 331, least complicated) to determine which variables influenced these outcome measures. Multivariate analysis with stepwise multiple linear regression analysis was performed to determine independent predictors of shorter times of outcome variables.
Of 80 patients, 43 received alvimopan (53.75%), and 37 (46.25%) did not. The female-to-male ratio was about 50:50 (56.25% vs. 43.75%). The mean age (standard deviation) was 66.0 (14.9) years (range, 30–92 years). In the multivariate analysis (adjusted for demographics, DRG status, type of surgery, complications, comorbidities, and operative time), for all of our outcome variables (except for time to a liquid diet), patients receiving alvimopan had shorter times to GI recovery (about 25% less) than controls did (p < 0.05). DRG status, complications, inflammatory bowel disease, type of surgery, and age were also significantly predictive of one or more outcome variables, whereas sex, intestinal cancer, diverticular disease, the number of chronic conditions, and operative time were not predictive of any outcomes.
GI recovery times were generally shorter for alvimopan-treated patients than for those who did not receive the study drug (P < 0.05). Alvimopan improved quality of life and reduced the cost of surgical care. This medication was considered to be a good choice for the perioperative management of patients requiring segmental bowel resection with primary anastomosis.
PMCID: PMC3462601  PMID: 23066346
22.  Diagnosis of small bowel Crohn’s disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis 
Gut  2005;54(12):1721-1727.
Background and aims: The diagnostic yield of capsule endoscopy (CE) compared with magnetic resonance imaging (MRI) in small bowel Crohn’s disease is not well established. We prospectively investigated CE, MRI, and double contrast fluoroscopy in patients with suspected small bowel Crohn’s disease.
Methods: Fifty two consecutive patients (39 females, 13 males) were investigated by MRI, fluoroscopy and—if bowel obstruction could be excluded—by CE. In 25, Crohn’s disease was newly suspected while the diagnosis of Crohn’s disease (non-small bowel) had been previously established in 27.
Results: Small bowel Crohn’s disease was diagnosed in 41 of 52 patients (79%). CE was not accomplished in 14 patients due to bowel strictures. Of the remaining 27 patients, CE, MRI, and fluoroscopy detected small bowel Crohn’s disease in 25 (93%), 21 (78%), and 7 (of 21; 33%) cases, respectively. CE was the only diagnostic tool in four patients. CE was slightly more sensitive than MRI (12 v 10 of 13 in suspected Crohn’s disease and 13 v 11 of 14 in established Crohn’s disease). MRI detected inflammatory conglomerates and enteric fistulae in three and two cases, respectively.
Conclusion: CE and MRI are complementary methods for diagnosing small bowel Crohn’s disease. CE is capable of detecting limited mucosal lesions that may be missed by MRI, but awareness of bowel obstruction is mandatory. In contrast, MRI is helpful in identifying transmural Crohn’s disease and extraluminal lesions, and may exclude strictures.
PMCID: PMC1774782  PMID: 16020490
capsule endoscopy; Crohn’s disease; small bowel endoscopy; inflammatory bowel disease; digestive system endoscopy
23.  The Role of Fecal Calprotectin in Investigating Inflammatory Bowel Diseases 
Clinics (Sao Paulo, Brazil)  2009;64(5):421-425.
Invasive and non-invasive tests can be used to evaluate the activity of inflammatory bowel diseases.
The aim of the present study was to investigate the role of fecal calprotectin in evaluating inflammatory bowel disease activity and the correlation of fecal calprotectin with the erythrocyte sedimentation rate and C reactive protein values in inflammatory bowel disease.
Sixty-five patients affected with inflammatory bowel disease were enrolled. Twenty outpatients diagnosed with inflammatory bowel disease comprised the control group.
In the present study, all patients in the control group had an fecal calprotectin value lower than the cut-off point (50 mg/kg).
In conclusion, fecal calprotectin was found to be strongly associated with colorectal inflammation indicating organic disease. Fecal calprotectin is a simple and non-invasive method for assessing excretion of macrophages into the gut lumen. Fecal calprotectin values can be used to evaluate the response to treatment, to screen asymptomatic patients, and to predict inflammatory bowel disease relapses.
PMCID: PMC2694246  PMID: 19488608
Inflammatory bowel diseases; Irritable bowel syndrome; Fecal calprotectin
24.  Activation and Perceived Expectancies: Correlations with Health Outcomes Among Veterans with Inflammatory Bowel Disease 
Inflammatory bowel disease imposes psychosocial stress on the patient. Patients′ adaptive capacities may predict quality of life. We examined two adaptive capacity measures and their association with quality of life.
Cross-sectional mail survey of patients with inflammatory bowel disease. The Patient Activation Measure (PAM) assesses knowledge, skill, and confidence in self-health management. The Perceived Expectancies Index (PEI) measures perceived competence and dispositional optimism.
Four hundred and seventy-seven veterans at VA-Tennessee Valley Healthcare System.
Main Outcome Measure
Primary outcome was health-related quality of life (measured by the Short Inflammatory Bowel Disease Questionnaire). Bivariate analysis assessed unadjusted correlations. Sequential multivariate linear regression tested theoretical model relationships by calculating the variation in each dependent variable accounted for by independent variables (R-squared statistic).
Two hundred and sixty surveys were returned with usable data (54.5%). Median age was 63 years (range 19–91); 90.8% were men and 86.9% self-identified as white. Fifty percent reported having ulcerative colitis, 36.5% Crohn’s disease, and 12.3% uncertain type. Unadjusted bivariate analysis revealed positive correlations between the PAM and PEI and the Short Inflammatory Bowel Disease Questionnaire (correlation coefficient = 0.35 and 0.60, respectively; p < 0.0001). Multivariate model including the PAM accounted for 26% of the variation in Short Inflammatory Bowel Disease Questionnaire scores, while the model including the PEI accounted for 50% (p < 0.0001).
There are positive, highly significant correlations between adaptive capacities and health-related quality of life in patients with inflammatory bowel disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-009-1002-0) contains supplementary material, which is available to authorized users.
PMCID: PMC2695514  PMID: 19444526
psychosocial stress; inflammatory bowel disease; Veterans; health outcomes
25.  Nutritional impact of inflammatory bowel diseases on children and adolescents☆  
Revista Paulista de Pediatria  2014;32(4):403-411.
To perform a sistematiy review of the literature about the nutritional impact of inflammatory bowel diseases in children and adolescents.
A systematic review was performed using PubMed/MEDLINE, LILACS and SciELO databases, with inclusion of articles in Portuguese and in English with original data, that analyzed nutritional aspects of inflammatory bowel diseases in children and adolescents. The initial search used the terms "inflammatory bowel diseases" and "children" or "adolescents" and "nutritional evaluation" or "nutrition deficiency". The selection of studies was initially performed by reading the titles and abstracts. Review studies and those withouth data for pediatric patients were excluded. Subsequently, the full reading of the articles considered relevant was performed.
237 studies were identified, and 12 of them were selected according to the inclusion criteria. None of them was performed in South America. During the analysis of the studies, it was observed that nutritional characteristics of patients with inflammatory bowel disease may be altered; the main reports were related to malnutrition, growth stunting, delayed puberty and vitamin D deficiency.
There are nutritional consequences of inflammatory bowel diseases in children and adolescents, mainly growth stunting, slower pubertal development, underweight and vitamin deficiencies. Nutritional impairments were more significant in patients with Crohn's disease; overweight and obesity were more common in patients with ulcerative rectocolitis. A detailed nutritional assessment should be performed periodically in children and adolescents with inflammatory bowel disease.
PMCID: PMC4311796  PMID: 25511006
Nutritional assessment; Nutritional status; Inflammatory bowel diseases; Child; Adolescent

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