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PubMed2002

The genetics of inflammatory bowel disease.

The complex genetics of IBD is characterized by more than one susceptibility locus, genetic heterogeneity, incomplete penetrance, and probable gene-gene and gene-environment interactions. Functional candidate gene association studies during the past few decades have revealed only modest associations between IBD and genetic variants in the HLA genes and a limited number of other genes that are involved in immune regulation and the inflammatory response. Important advances in IBD genetics research have come about from systematic genome searches for IBD loci. The identification of Crohn's disease-associated NOD2 genetic variants that appear to alter the innate immune response to bacteria is a seminal finding that perhaps is the greatest advance toward understanding the pathogenesis of IBD in decades. The future discovery of other IBD genetic risk factors, facilitated by the completion of the human genome sequencing and annotation, may allow the development of better therapies, possibly including preventive therapies, for patients with Crohn's disease and ulcerative colitis.

Carrier Proteins↗
PubMed2002

Pregnancy and nursing in inflammatory bowel disease.

The peak age of onset for IBD coincides with the peak age for conception and pregnancy. Women with inactive IBD who become pregnant do not have increased complications compared with age-matched controls. Most medications for IBD are safe in pregnancy. The greatest danger to a normal conception and pregnancy is active disease, not the medicine used to treat it. This article outlines fertility in IBD, the effect of IBD on pregnancy, the effect of pregnancy on IBD, and the medical therapy available.

Breast Feeding↗
PubMed2002

Endoscopy in the pregnant patient with inflammatory bowel disease.

Although little data exist directly evaluating the utility and safety of endoscopy in the pregnant woman with IBD, it appears to be well tolerated by both mother and fetus, and provides useful clinical information. When performed to evaluate gastrointestinal bleeding, EGD has a high diagnostic yield, while EGD for nausea and vomiting is less informative. In the patient without IBD presenting with hematochezia, unexplained diarrhea, severe abdominal pain, or severe rectal pain, careful sigmoidoscopic examination is indicated, often leading to a diagnosis of new-onset or unsuspected IBD. Likewise, the pregnant IBD patient with worsening symptoms, despite appropriate medical therapy, may also benefit from sigmoidoscopy. Colonoscopy is less often indicated, but can be safely performed in the carefully selected pregnant patient. In all cases obstetrical consultation should be obtained prior to endoscopy, and the risks and benefits of endoscopy to both mother and child should be considered. Close attention should be paid to appropriate drug selection for conscious sedation, and sedation should be administered to provide patient comfort, while avoiding oversedation. Extrapolating from data obtained during endoscopic examination of the pregnant non-IBD patient, fetal monitoring is generally not indicated, although it should be considered for the high-risk or late third-trimester patient. Following these principles assures that endoscopy can be safely performed in the pregnant IBD patient with the best possible outcome for both mother and baby.

Procedural Sedation↗
PubMed2004

A genetic contribution to inflammatory bowel disease in Iceland: a genealogic approach.

BACKGROUND AND AIMS: Both genetic and environmental factors play a role in the development of Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD). The aim of this study was to estimate the genetic component in IBD in Iceland. METHODS: A population-based sample, representing everyone diagnosed with IBD in Iceland from 1950 to 1996, was studied using a computerized population-wide genealogic database. The relationships among the patients were analyzed by calculating the kinship coefficient and the relative risk. RESULTS: The kinship coefficients for the patients were significantly greater than the mean kinship coefficient for the controls ( P < 10 -6 ). The risk ratio for siblings of IBD, UC, and CD patients was 5.0 ( P < 0.001), 5.9 ( P < 0.001), and 4.1 ( P = 0.033), respectively. The cross-risk ratio for siblings of UC patients developing CD (or vice versa) was 2.6 ( P = 0.015). CONCLUSIONS: The results indicate that the IBD patients are more closely related than the controls, which strongly supports the involvement of a genetic component in the development of IBD in Icelandic patients. We find that the increase in risk for relatives of UC probands to develop UC, or relatives of CD probands to develop CD, is greater than the increase in risk for relatives of UC probands to develop CD, or relatives of CD probands to develop UC.

Colitis, Ulcerative↗
PubMed2000

Optimization of technetium-99m-HMPAO leukocyte scintigraphy in evaluation of active inflammatory bowel disease.

Although [99mTc]HMPAO-labeled leukocyte scintigraphy is widely used in the assessment of IBD, the time point chosen for imaging is still controversial. The aim of the present study was to determine the optimal scanning sequence to assess IBD extension and activity. Sixty-two consecutive patients with active and 18 with inactive IBD were prospectively studied. Clinical evaluation, colonoscopy, radiology, and scintigraphy were performed within three days, without changes in the patient's treatment. Compared to early scan (45 min), late scan (3 hr) had a higher sensitivity (85% vs 100%) and accuracy (85% vs 95%) in identifying patients with active IBD and in defining IBD extension. Combinations of values from both scans did not improve accuracy of scintigraphy, which is lower in Crohn's disease than in ulcerative colitis and also in patients receiving steroid treatment. In conclusion, a single late scintigraphy scan provides the best means to identify patients with active IBD and to assess disease extension.

Adolescent↗
PubMed2001

Reduced free protein S levels in patients with inflammatory bowel disease: prevalence, clinical relevance, and role of anti-protein S antibodies.

We evaluated free plasma levels of protein S, a natural anticoagulant factor, the prevalence of anti-protein S antibodies, a possible cause of protein S deficiency, and their correlation with anti-phospholipid antibodies in 53 patients with inflammatory bowel disease (IBD) and 53 age- and sex-matched controls. Mean free plasma protein S levels (+/- SD) were significantly lower in IBD patients (0.98+/-0.32 IU/ml) than in controls (1.06+/-0.28 IU/ml) (P < 0.05); only one patient showed protein S deficiency. Specific antibodies to protein S were found in four IBD patients (7.5%) and in one control (1.9%) (P = NS). Five IBD patients (9.4%) and none of the controls showed anti-phospholipid antibodies (P < 0.06). No correlation was found between free protein S levels and anti-protein S antibodies or between anti-protein S and anti-phospholipid antibodies. In conclusion, free plasma protein S levels are slightly but significantly decreased in IBD patients. The prevalence of anti-protein S and antiphospholipid antibodies is increased in IBD patients. Anti-protein S antibodies do not appear to determine low protein S levels or to overlap with or belong to anti-phospholipid antibodies.

Adult↗
PubMed2001

Genetic determinants of IL-6 expression levels do not influence bone loss in inflammatory bowel disease.

Bone loss in inflammatory bowel disease (IBD) is presumed to be mediated by inflammation. Increased levels of the multifunctional cytokine IL-6 in inflammatory diseases have been proposed to be the link in such "inflammation-mediated osteopenia." A recently described G/C polymorphism with an effect on transcription rate and plasma levels of IL-6 suggests a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals. This study aimed to assess the frequency of genotypes and haplotypes of the G/C polymorphism of IL-6 in IBD patients. A further aim was to assess whether carriage of the potentially protective CC genotype is favorable with respect to the development of bone disease in IBD. The IL-6 polymorphism was typed in 105 IBD patients and 113 healthy controls. Bone mineral density was evaluated at baseline and after a prospective 2-year-follow-up. The favorable CC genotype with decreased IL-6 release was not underrepresented in IBD patients compared to healthy controls. Carriage of this genotype was not protective with respect to the development of bone disease, either for the bone mineral density at baseline or for the prospectively observed bone loss. Within the subgroup of patients who did not receive steroids during follow-up, the prospectively observed bone loss was even slightly higher in CC carriers, but differences did not reach significance. Genetically determined differences in the degree of the IL-6 response to stressful stimuli are no major predictors for the degree of bone disease in IBD patients.

Adult↗
PubMed1998

Activated protein C resistance, thrombophilia, and inflammatory bowel disease.

Thromboembolic events frequently complicate the clinical course of patients with inflammatory bowel disease (IBD). Hereditary thrombophilia may contribute to this tendency. Resistance to activated protein C is the most recently described thrombophilic state and may account for up to 40% of patients with thrombophilia. Thirty-seven patients with IBD were studied (mean age 44 years, range 18-82 years). Three patients had a history of thrombotic episodes. The 37 controls included 23 men and 17 women (mean age 48 years, range 16-89 years). Disease activity was assessed using the Harvey Bradshaw index for patients with Crohn's disease and the Truelove and Witts grading system for patients with ulcerative colitis. Levels of fibrinogen, antithrombin III (ATIII), protein C, protein S, activated protein C resistance (APCR), and the presence of a lupus anticoagulant (LA) were determined. Median ATIII levels in patients with IBD were significantly lower than controls (98% vs 106%, P = 0.007), while fibrinogen was elevated (4.2 vs 3.3 g/liter, P = 0.026) despite quiescent disease activity. LA was detected in 7/37 patients in the IBD group compared to 0/37 controls. (chi2 = 5.68, P = 0.017). No significant difference was observed in levels of inherited thrombophilic factors and in particular APCR between IBD patients and controls. In conclusion, the presence of inherited thrombophilic defects, in particular APCR, is uncommon in patients with IBD and does not merit routine screening.

Adolescent↗
PubMed2003

Elimination of local macrophages in intestine prevents chronic colitis in interleukin-10-deficient mice.

Uncontrolled activation of T cells and macrophages is involved in the development of inflammatory bowel disease (IBD). However, the precise role of intestinal macrophages for development of IBD is till unclear. To investigate the role of local macrophages for development of IBD, we developed poly-D, L-lactic acid microspheres containing dichloromethylene diphosphonate, which was specifically taken up by macrophages and depleted them, and then the animal model for human IBD was treated with this reagent. We have shown that rectal administration of the microspheres reduced the numbers of resident macrophages in the intestinal lymphoid follicles of interleukin-10-deficient mice. Importantly, depletion of intestinal macrophages was associated with suppression of development of chronic colitis. These results suggest that local macrophages in the intestine play a critical role in the development of chronic colitis in an animal model for IBD. Our study implies that elimination of resident macrophages in the intestine may become a therapeutic approach to IBD.

Animals↗
PubMed2006

Inflammatory bowel disease requires the interplay between innate and adaptive immune signals.

Inflammatory bowl disease (IBD) is a type 1 T helper cell (Th1)-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide (NO) released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Th1 cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-gamma (IFN-gamma)-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-gamma produced by Th1 cells.

Animals↗
PubMed2001

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21.

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

Alleles↗
PubMed2006

Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19.

Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this approximately 28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.

Alleles↗
PubMed2001

Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease.

The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non-specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases.

Adolescent↗
PubMed1996

A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease: a pilot study.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a high prevalence of osteoporosis. A number of studies have found that corticosteroid use is associated with the development of osteoporosis in these patients. Calcium supplementation may be of benefit in corticosteroid-induced osteoporosis and calcium may be a nutrient that patients with IBD lack. AIM: To test the benefit of calcium supplementation on bone density in a pilot study over a 1-year period, in a group of corticosteroid-using patients with IBD, in a randomized, double-blind, placebo-controlled treatment study. METHODS: Corticosteroid-using patients with IBD including males over the age of 18 years and premenopausal females, were randomized to receive either calcium carbonate 1000 mg plus vitamin D 250 IU (Oscal) or an identically matched placebo. Dual energy X-ray absorptiometry measurements of bone density were obtained at entry and at 1 year. At entry, and every 3 months thereafter, serum was collected for the measurement of haemoglobin, biochemistry and bone hormones. Simultaneously a 24-h urine collection was analysed for calcium excretion and creatinine clearance, and a 4-day food record was collected to document dietary calcium and vitamin D ingestion. RESULTS: We found a high prevalence of moderately severe decreased bone density in corticosteroid-using patients with IBD. The dose of prednisone in the year prior to study entry was inversely correlated with bone density at the hip (R = -0.67, P = 0.004). At study entry serum osteocalcin was inversely correlated with corticosteroid dose in the year prior to the study (R = -0.64, P = 0.02) and at study end, directly correlated with the percentage change in spine bone density (R = 0.59, P = 0.01). The dietary calcium intake of these patients was close to the current RDA (recommended daily intake) for premenopausal, post-adolescent adults. Calcium supplementation with small extra doses of vitamin D conferred no obvious benefit to bone density at the end of 1 year. There was no correlation between oral calcium ingestion and bone mass measurements. Both the treatment and placebo groups' bone density remained relatively stable at 1 year, suggesting that bone loss in corticosteroid-using patients may peak early into the use of the corticosteroids. CONCLUSIONS: Calcium supplementation (1000 mg/day) conferred no significant benefit to bone density at 1 year in patients with corticosteroid-using IBD patients with osteoporosis. Future investigations should explore other therapeutic avenues that may have greater effects on increasing bone density in patients who already have considerable osteoporosis.

Absorptiometry, Photon↗
PubMed2000

Autoimmunity in ulcerative colitis (UC): a predominant colonic mucosal B cell response against human tropomyosin isoform 5.

We set out to examine if the IgG-producing cells in the colonic mucosa in UC are committed to tropomyosin isoform 5 (hTM5), a putative autoantigen in UC. Lamina propria mononuclear cells (LPMC) were isolated from colonoscopic biopsy specimens from recto-sigmoid and proximal colon. Twenty-three patients with UC, eight with Crohn's colitis (CC), and 10 non-inflammatory bowel disease (non-IBD) controls were included. The ELISPOT assays were used to quantify lamina propria B cells producing total immunoglobulin (IgA, IgG, IgM), IgG, IgA, as well as IgG against hTM5 isoform. The median value of percentage of total IgG-producing lymphocytes was similar in UC (12%) and CC (11%), but was significantly (P < 0.0002) higher than non-IBD controls (6%). However, in UC, but not in CC and non-IBD, a large number of lamina propria B cells produced IgG against hTM5 (median values: UC 42%, CC 2.5%, non-IBD 0%). This difference in UC when compared with CC and non-IBD was highly significant (P < 0.00001). Twenty-one of 23 (91%) patients with UC had percentage of anti-hTM5 IgG-producing immunocytes more than 2 s. d. above the mean for non-UC patients. In UC but not in CC and non-IBD controls, the increased number of IgG-producing cells are largely committed to produce IgG against hTM5-related epitope(s).

Adult↗
PubMed2000

Laboratory findings associated with thrombophilia are not more common in inflammatory bowel disease.

Thromboembolic disease (TED) has been recognized as a complication of inflammatory bowel disease (IBD) since the 1930s (Bargen & Barker 1936). The relative contributions of inherited or acquired thrombophilia and the inflammatory response to the mechanism of this tendency is unclear. Thrombotic events are more common in active disease although significant numbers also occur spontaneously, when the disease is in clinical remission (Talbot et al. 1986; Jackson et al. 1997). Studies looking at the prevalence of specific thrombophilic states such as Antithrombin III deficiency (Jackson et al. 1997; Lake, Stauffer & Stuart 1978; Cianco et al. 1996; Ghosh et al. 1983), Factor V Leiden mutation (APC Resistance) (Jackson et al. 1997; Probert et al. 1997; Ardizzone et al. 1998; Liebman et al. 1998), anticardiolipin antibodies (Ciancio et al. 1996), Protein C (Wyshock, Caldwell & Crowley 1988; Korsten & Reis 1992) and Protein S deficiencies (Jorens et al. 1990; Aadland et al. 1992) in IBD have been contradictory or equivocal. We had previously found that IBD patients with a history of TED are not more likely to have a laboratory thrombophilic abnormality than those with uncomplicated disease. We also demonstrated that the prevalence of heterogenous laboratory thrombophilic abnormalities (usually minor) in all IBD patients may be as high as 60%, much higher than the recognized prevalence of TED (Lim, Jones & Gould 1996). We wondered how this would compare with the healthy non-IBD population. We have therefore explored the prevalence of such thrombophilic abnormalities in a group of IBD patients who had no history of TED and compared them with healthy age and sex matched controls.

Adult↗
PubMed1996

Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease.

OBJECTIVES: To explore the relationships between vitamin D intake, serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (250HD) concentrations, and bone mineral density (BMD) in inflammatory bowel disease (IBD). SETTING: A university hospital clinic in Finland. SUBJECTS: One hundred and fifty randomly selected patients with IBD from the hospital register and 73 healthy controls. MEASUREMENTS: BMD of the lumbar spine and the proximal femur was measured with dual energy X-ray absorptiometry. Vitamin D intake and serum levels of 250HD and PTH were determined. RESULTS: The IBD patients had a lower serum 250HD concentration (28.4 [SD 12.0] nmol L-1) than the controls (36.1 [16.7] nmol L-1; P = 0.001), whereas no differences in the vitamin D intake or the serum PTH levels were found. The serum 250HD concentrations and the vitamin D intake of the patients with ulcerative colitis (n = 67) were similar to those of the Crohn's disease patients (n = 76). The patients with Crohn's disease of the small bowel had slightly, but not significantly, lower serum 250HD concentrations (25.6 [11.0] nmol L-1) than the other Crohn's disease patients (31.4 [14.3] nmol L-1; P = 0.061). In the IBD patients, the vitamin D intake and the serum 250HD and PTH concentrations were not associated with BMD. CONCLUSIONS: Patients with IBD have lower serum levels of 250HD than healthy controls, but similar serum PTH concentrations and vitamin D intake. Vitamin D intake, and the serum levels of 250HD and PTH are not associated with BMD, and malabsorption is unlikely to be a major factor in the aetiology of bone loss in unselected IBD patients.

Adult↗
PubMed1999

Increased mucosal production of granulocyte colony-stimulating factor is related to a delay in neutrophil apoptosis in Inflammatory Bowel disease.

Tissue accumulation of polymorphonuclear neutrophils (PMN) in Inflammatory Bowel disease (IBD) might be, in part, due to a delay in apoptotic processes associated with the effects of their specific growth factors and inflammatory cytokines. We addressed this hypothesis by examining the activity of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) in the organ culture supernatants of colonic mucosal specimens and their regulatory effects on PMN apoptosis in patients with IBD. The contents of G-CSF and GM-CSF in the supernatants were measured by the enzyme-linked immunosorbent assays and PMN apoptosis was evaluated by acridine orange/ethidium bromide staining, respectively. Mucosal specimens obtained from patients with active IBD exhibited higher levels of G-CSF and GM-CSF activity than controls. Notably, the levels of G-CSF activity were approximately 1000-fold higher than those of GM-CSF activity. Freshly isolated PMN showed a time-related increase in the proportion of cells with characteristic features of apoptosis when they were incubated with the culture medium alone and exposure of PMN to recombinant G-CSF and GM-CSF caused a concentration-dependent inhibition of apoptosis. Incubation of PMN with the supernatants from patients with active IBD induced an inhibitory effect on PMN apoptosis; this effect was abrogated to a significant degree by pre-incubation of the supernatants with anti-G-CSF serum. This study suggests that PMN apoptosis may be delayed under the influence of soluble mediators, especially G-CSF, in the microenvironment of IBD-affected mucosa, thus providing possible mechanisms for tissue accumulation of PMN in IBD.

Acridine Orange↗