Need for infliximab dose intensification in Crohn's disease and ulcerative colitis.

AIM: To compare the need for infliximab dose intensification in two cohorts of patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: Single centre, uncontrolled, observational study. Consecutive patients with CD and UC who responded to infliximab induction doses were included. Data collected in a prospectively maintained database were retrospectively analysed. Differences in the rates of dose intensification per patient-month and the intensification-free survival time were compared. We also evaluated the interval between the first infliximab induction dose and the first infliximab escalated dose. The weight-adjusted infliximab administration costs were also calculated. RESULTS: Fifty nine patients with CD and 38 patients with UC were enrolled. The rate of intensification per patient-month was 3.9% for UC and 1.4% for CD (P = 0.005). The median time from baseline to intensification was significantly shorter in UC compared to CD [6.6 mo (IQR: 4.2-9.5 mo) vs 10.7 mo (IQR: 8.9-11.7 mo), P = 0.005]. In the survival analysis, the cumulative probability of avoiding infliximab dose intensification was significantly higher in CD (P = 0.002). In the multivariate analysis, disease (UC vs CD) was the only factor significantly associated with dose intensification. The infiximab administration costs during the first year were significantly higher for UC compared to CD (mean ± SD 234.9 ± 53.3 Euros/kg vs 212.3 ± 15.1 Euros/kg, P = 0.03). CONCLUSION: The rate of infliximab dose intensification per patient-month is significantly higher in UC patients. The infliximab administration costs are also significantly higher in patients with UC.

Advantages of early cholecystectomy in clinical practice of a terciary care center.

BACKGROUND: Despite a number of studies show the superiority of early over delayed cholecystectomy in the treatment of acute cholecystitis, there is still controversy over the time for intervention. This study aimed to assess the use of early versus delayed cholecystectomy for the treatment of acute cholecystitis in terms of complications, conversion to open surgery and mean hospital stay. METHOD: We collected patients with acute cholecystitis treated at a referral center for a year, and retrospectively analyzed the chosen therapeutic approach, the percentage of conversion of early cholecystectomy to open surgery, appearance of surgical complications, and mean hospital stay. RESULTS: The study included 117 patients, 44 women and 73 men, who had a mean age of 67.36+/-15.74 years. Early cholecystectomy was chosen in 31 (26.5%) and delayed cholecystectomy in 74 patients (63.2%). Of the 74 patients, 28 (37.8%) required emergency performance of delayed cholecystectomy, and 19 (25.7%) had not undergone surgery by the end of the study. While no differences were observed between early and delayed cholecystectomy in terms of surgical complications and conversion to open surgery, mean hospital stay was nevertheless significantly shorter in the early versus the delayed cholecystectomy group (8.32+/-4.98 vs 15.96+/-8.89 days). CONCLUSION: Under the routine working conditions of a hospital that is neither specially dedicated to the surgical treatment of acute cholecystitis nor provided with specific management guidelines, early cholecystectomy can reduce the hospital stay without increase of the conversion rate or complications.

Relation of IL28B gene polymorphism with biochemical and histological features in hepatitis C virus-induced liver disease.

BACKGROUND/AIMS: Polymorphism at the IL28B gene may modify the course of hepatitis C virus (HCV) chronic infection. Our aim was to study the influence of IL28B rs12979860 gene polymorphism on the biochemistry and pathology of HCV-induced disease in the clinical course from mild chronic hepatitis C to hepatocellular carcinoma. METHODS: We have determined the rs12979860 single nucleotide polymorphism (SNP) upstream IL28B gene in two groups of patients with HCV-induced chronic liver disease: 1) 268 patients (159 men) with biopsy-proven chronic hepatitis C, to analyse its relation with biochemical, virological and histological features; and 2) 134 patients (97 men) with HCV-related hepatocellular carcinoma. The distribution of the analysed SNP in hepatocellular carcinoma patients was compared with that found in untreated chronic hepatitis C patients. All patients were white and most were Spaniards. RESULTS: In multivariate analysis ALT values were higher (P = 0.001) and GGT values were lower (P<0.001) in chronic hepatitis C patients homozygotes for the major rs12979860C allele as compared with carriers of the mutated rs12979860T allele. Steatosis was more frequent (Odds ratio = 1.764, 95% C.I. 1.053-2.955) and severe (P = 0.026) in carriers of the rs12979860T allele. No relation was found between the analysed SNP and METAVIR scores for necroinflammation and fibrosis, and there were no differences in the distribution of the analysed SNP between hepatocellular carcinoma and untreated chronic hepatitis C patients. CONCLUSION: The IL28B rs12979860 polymorphism correlates with the biochemical activity and the presence and severity of liver steatosis in chronic hepatitis C.

Adalimumab reversed a severe lymphopenia in a patient with Crohn's disease.

Patients with Crohn's disease are frequently found to have low peripheral lymphocyte counts. Lymphopenia has been linked to disease activity, the effects of therapy and the presence of an abnormal T regulatory (T(reg)) function. We present a patient with Crohn's disease and a severe total and CD4 lymphopenia that did not resolve after discontinuation of immunosuppressive treatment and resective surgery. Complete clinical remission and persistent normal levels of total and CD4 lymphocytes were observed after starting therapy with the anti-tumor necrosis factor monoclonal antibody adalimumab.

Polymorphism of the TLR4 gene reduces the risk of hepatitis C virus-induced hepatocellular carcinoma.

OBJECTIVE: Toll-like receptor 4 (TLR4) signalling participates in the innate immune response against hepatitis C virus (HCV) infection. TLR4 gene polymorphisms may influence the risk of HCV-induced hepatocellular carcinoma (HCC). This is a single-centre-based study designed to analyse the distribution of several TLR4 gene single nucleotide polymorphisms in healthy controls and in patients chronically infected with HCV, with and without HCC. METHODS: We have determined three single nucleotide polymorphisms (rs2149356, rs4986791 and rs5030719) at the TLR4 gene in 155 patients with HCV-related HCC, 153 patients with chronic hepatitis C and 390 healthy controls. All were white and most were Spaniards. RESULTS: (1) rs5030719 was monomorphic and was not further analysed; (2) the rs2149356 T allele carrier state was significantly less frequent in patients with HCC than in healthy controls (OR 0.421, 95% CI 0.285-0.625) and in patients with chronic hepatitis C (OR 0.426, 95% CI 0.236-0.767); (3) the proportion of rs2149356 T allele carriers progressively diminished with increasing clinical stage of HCC; (4) no significant differences were observed for the rs4986791 T allele. CONCLUSION: The TLR4 rs2148356 T allele is associated with a reduced risk of HCC and could slow down its clinical progression in HCV-induced chronic liver disease.

Mucosal healing for predicting clinical outcome in patients with ulcerative colitis using thiopurines in monotherapy.

BACKGROUND: Mucosal healing (MH) has emerged as a desirable treatment goal for patients with ulcerative colitis (UC). Currently little is known about the efficacy of using thiopurine immunosuppressants in monotherapy to achieve and maintain long-term MH in UC. This study analyzes the efficacy and the clinical impact of MH in patients with UC responded to thiopurine immunosuppressants in the long term. METHODS: An open, observational, cohort study in 20 patients with UC had been in clinical remission in monotherapy with thiopurine immunosuppressants for at least 1 year. MH was assessed by endoscopy. The patients according to the Mayo Endoscopic Score (0 vs 1 and 2), were followed until the end of the study or patient relapse. (according to Truelove and Witts criteria). RESULTS: Mean treatment time was 5.4 years. Twelve (60%) patients presented a Mayo Endoscopic Score of 0. A total of 18 patients were followed up for a median of 27.1 months. After endoscopy, 4 patients (22.2%) presented relapse, with a mean time of 27.5 months for a score ≥1 (95% CI; 18.2-36.8) versus 54.3 months for a score=0 (95% CI 47.2-61.3) (p=0.032). CONCLUSIONS: This study shows the efficacy of thiopurine immunosuppressants in achieving mucosal healing in patients who respond to thiopurine immunosuppressants in the long term. We also observe the presence of endoscopy activity is not a rare event in this group of patients and is a predictor of early relapse.

High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn's disease.

AIM: To examine the detection rate of viable Mycobacterium avium subspecies paratuberculosis (MAP) in patients with inflammatory bowel disease [Crohn's disease (CD) and ulcerative colitis (UC)]. METHODS: Thirty patients with CD (15 with at least one NOD2/CARD15 mutation), 29 with UC, and 10 with no inflammatory bowel disease (IBD). were tested for MAP by polymerase chain reaction (specific IS900 fragment) and blood culture. RESULTS: MAP DNA was detected in all original blood samples and 8-wk blood cultures (CD, UC and non-IBD). Positive MAP DNA status was confirmed by dot blot assays. All 69 cultures were negative by acid-fast Ziehl-Neelsen staining. Viable MAP, in spheroplast form, was isolated from the 18-mo blood cultures of all 30 CD patients, one UC patient, and none of the non-IBD controls. No association was found between positive MAP cultures and use of immunosuppressive drugs or CD-associated single nucleotide polymorphisms. CONCLUSION: MAP is widely present in our area and MAP DNA can be recovered from the blood of CD, UC and non-IBD patients. However, MAP spheroplasts were only found in CD patients.

CD40: novel association with Crohn's disease and replication in multiple sclerosis susceptibility.

BACKGROUND: A functional polymorphism located at -1 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves' disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves' disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn's disease (CD) lesions. METHODOLOGY: Genotyping of rs1883832C>T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. PRINCIPAL FINDINGS: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p = 0.025; OR (95% CI) = 1.12 (1.01-1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p = 0.002; OR (95% CI) = 1.19 (1.06-1.33)]. This increased predisposition was not detected in UC patients [p = 0.5; OR (95% CI) = 1.04 (0.93-1.17)]. CONCLUSION: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.

Study of chromosomal region 5p13.1 in Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

Chromosomal region 5p13 includes regulatory elements of the prostaglandin receptor EP4 (PTGER4) gene and is associated with inflammatory bowel disease (IBD) susceptibility. We aimed at corroborating the association of the PTGER4 risk variant in IBD. Given the proinflammatory activity of prostaglandin E(2) in rheumatoid arthritis (RA), the reduction in incidence and severity of collagen-induced arthritis observed in mice deficient in the prostaglandin receptor EP4, and a modest signal of association found in an RA genome-wide scan, we proposed to extend the investigation of this locus to RA patients. A total of 709 Crohn's disease (CD) patients, 662 ulcerative colitis (UC) patients, and 1369 control subjects were genotyped for rs17234657. This polymorphism was also analyzed in 605 RA patients, and rs6871834 was studied in the RA patient group. Replication of the previous finding in CD was achieved in our independent collections, although with a milder effect (odds ratios = 1.23) than that originally described. No further association of the previously mentioned polymorphisms was detected with either UC or RA patients. We validated this 5p13 signal as a genuine susceptibility factor for CD in Caucasian populations. Our data seem to rule out a major influence of these polymorphisms on UC or RA predisposition.

Non-invasive evaluation of the fibrosis stage in chronic hepatitis C: a comparative analysis of nine scoring methods.

OBJECTIVE: Liver biopsy is an invasive procedure and new surrogate markers to assess fibrosis are needed. We performed a comparative external evaluation of nine non-invasive scores of liver fibrosis and tried to identify other potential biochemical markers of low-stage liver fibrosis in chronic hepatitis C (CHC). MATERIAL AND METHODS: We included 429 previously untreated consecutive patients from a single centre who underwent a liver biopsy between January 1999 and April 2009. Biopsies were evaluated for the stage of fibrosis according to the METAVIR scoring method. RESULTS: None of the evaluated scores were adequate to disclose null-low fibrosis due to a lack of specificity at the proposed cut-offs and the poor sensitivity of lower cut-offs. Serum ferritin and cholesterol values were found to be independently related to the fibrosis stage and their inclusion in the best performing scores at lower cut-off values (the APRI and King's scores) improved the sensitivity for null-low fibrosis by 8% with a specificity >or= 93%. CONCLUSIONS: Approximately 30% of patients with null-low fibrosis may be accurately identified by supplementing current scores with new independent variables (serum ferritin and cholesterol), thus obviating the need for a liver biopsy.

Analysis of a non-synonymous single nucleotide polymorphism of the human diamine oxidase gene (ref. SNP ID: rs1049793) in patients with Crohn's disease.

OBJECTIVE: To analyse the possible influence of a non-synonymous single nucleotide polymorphism (SNP) of the histamine-degrading enzyme diamine oxidase (DAO) on genetic susceptibility to Crohn's disease (CD). MATERIAL AND METHODS: In this prospective, case-control study, 210 unrelated Caucasian consecutive CD patients were recruited at the Inflammatory Bowel Disease Unit of a single tertiary centre (Hospital Clínico San Carlos) in Madrid, Spain. A total of 261 healthy volunteers from the same geographic area were also recruited and matched with patients. Both cases and controls were analysed for the presence of a non-synonymous SNP (rs1049793) of DAO using amplification-restriction procedures of the genotype obtained in a blood sample. RESULTS: No significant differences were found in the distribution of carriers of the non-synonymous SNP of DAO between CD patients and controls (OR 1.2 (95% CI 0.9-1.6; p=0.3)). Nor were any differences found between carriers and non-carriers of the non-synonymous SNP in demographic characteristics, phenotypes, complications or treatment of CD. CONCLUSIONS: The study of a non-synonymous SNP (rs1049793) of DAO does not seem to be of use in assessing susceptibility to CD, either as a marker of disease activity or as a marker of clinical behaviour in patients with the disease.

Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease.

OBJECTIVES: Genome-wide association studies have reported the role of the interleukin (IL) 2-IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs). METHODS: Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohn's disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case-control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry. RESULTS: The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44-0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58-0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58-0.92)). CONCLUSIONS: Polymorphisms within the IL2-IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.

Specific association of a CLEC16A/KIAA0350 polymorphism with NOD2/CARD15(-) Crohn's disease patients.

Independent genome-wide association studies highlighted the function of CLEC16A/KIAA0350 polymorphisms modifying the risk to either multiple sclerosis (rs6498169) or type 1 diabetes (rs2903692). This C-type lectin gene maps to a linkage disequilibrium block at 16p13 and a functional role of this gene could be envisaged for other immune-related conditions, such as inflammatory bowel disease (IBD). The present study, aimed at investigating the association of those two polymorphisms with IBD, included 720 IBD patients and 550 ethnically matched healthy controls. The effect of rs2903692 previously described in diabetes was observed specifically for Crohn's disease (CD) patients lacking the main susceptibility factor described to date, that is, three polymorphisms within another pattern recognition gene, NOD2/CARD15 (NOD2(-) vs NOD2(+) CD patients, G vs A: P=0.008; OR (95% CI)=1.54 (1.10-2.15); NOD2(-) CD patients vs controls: P=0.008; OR (95% CI)=1.37 (1.08-1.73)). Replication of these findings was performed in independent Spanish cohorts of 544 IBD patients and 340 controls and the combined data yielded significant differences (405 NOD2(-) vs 204 NOD2(+) CD patients, G vs A: P=0.0012; OR(M-H) (95% CI)=1.49 (1.17-1.90); NOD2(-) CD patients vs controls: P=0.0007; OR(M-H) (95% CI)=1.35 (1.13-1.60)). The pooled analysis of the ulcerative colitis patients vs controls also yielded a significant risk (P=0.0005; OR (95% CI)=1.52 (1.19-1.93)). These data would suggest that microbial recognition through different pathways seems to converge in the development of these polygenic bowel diseases.

FcRL3 gene promoter variant is associated with peripheral arthritis in Crohn's disease.

BACKGROUND: The mechanisms responsible for the pathogenesis of peripheral arthropathies (PA) in Crohn's disease (CD) are largely unknown, although many studies indicate that genetic and environmental factors are likely to contribute to risk. METHODS: Because variants in the Fc receptor-like 3 (FcRL3) gene have recently been associated with rheumatoid arthritis and several other autoimmune diseases, we tested 2 FcRL3 promoter variants (-169 C>T and -110 G>A) for association with PA in Spanish CD patients that were recruited from a single center and followed for at least 4 years (mean follow-up time, 11 years). RESULTS: Among the 342 CD patients evaluated, there were 88 cases of peripheral arthropathy; 31 were classified as arthritis and 57 were classified as arthralgia. We used contingency tables and logistic regression to test for association between PA or either subtype and FcRL3 and other factors that have previously been associated with extraintestinal manifestations in CD. CONCLUSIONS: We found that female sex, colonic involvement, and the AA genotype at -110 G>A were associated with increased risk of both subtypes of PA, although the association appears to be stronger for arthritis than for arthralgia.

Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn's disease.

The hypothesis postulating that Mycobacterium avium paratuberculosis (MAP) is the cause of Crohn's disease (CD) has been circulating for many years. Advances in molecular techniques, such as polymerase chain reaction and culture methods, have enabled researchers to demonstrate that there is an association between MAP and CD. Recently, genome-wide association studies have identified novel susceptibility genes for CD, which are critical for generation of an adaptive immune response that is protective against intracellular pathogens, including M. tuberculosis infection. However, the role of MAP as a cause of CD suffered a setback with the report that administration of antimycobacterial therapy failed to lead to a sustained response in CD patients. Accordingly, this review sought neither to confirm nor refute this, but instead to survey recent literature on the role of MAP in CD.

Prevalence of functional gastrointestinal disorders in patients with fibromyalgia and the role of psychologic distress.

BACKGROUND & AIMS: Fibromyalgia is a rheumatologic disorder associated with somatic and psychologic conditions. Although fibromyalgia is associated with irritable bowel syndrome, its relationship with other functional gastrointestinal disorders (FGID) is unclear. We evaluated the prevalence of FGID in patients with fibromyalgia and the role of psychologic factors in this relationship. METHODS: From a Spanish population, 100 patients with fibromyalgia and 100 matched controls completed the Rome II Integrative Questionnaire to assess the prevalence of FGID and the Symptom Checklist-90 Revised (SCL-90R) to evaluate psychologic distress. Patients completed the Fibromyalgia Impact Questionnaire to evaluate the overall impact of fibromyalgia and controls filled out the Chronic Widespread Pain Questionnaire to detect potential cases of fibromyalgia. RESULTS: Ninety-three percent of the total study population was female, with a mean age of 50 years. We identified 6 cases of widespread pain among controls. The average Fibromyalgia Impact Questionnaire score for patients was 67.28 +/- 14.25. All gastrointestinal symptoms except for vomiting were more frequent in patients. Ninety-eight percent of patients with fibromyalgia had at least one FGID, compared with only 39% of controls. Fibromyalgia was correlated most highly with irritable bowel syndrome. Patients presented with significantly higher scores of psychologic distress than controls, especially those with fecal incontinence. CONCLUSIONS: There is a prevalence of FGID in patients with fibromyalgia and a wider distribution of such symptoms along the gastrointestinal tract compared with controls. We propose that an increased degree of psychologic distress in these patients predisposes them to FGID, especially significant for anorectal syndromes.

Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases.

BACKGROUND: Selenoprotein S (SelS) protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. RESULTS: Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171) were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. CONCLUSION: Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

IL23R and IL12B polymorphisms in Spanish IBD patients: no evidence of interaction.

BACKGROUND: Recent genomic surveys have identified IL23R and IL12B as susceptibility loci for inflammatory bowel disease (IBD). Our aim in the present study was to ascertain whether the IL23R and IL12B associations with IBD are also observed in our population, and to analyze possible genetic interactions between polymorphisms at IL12B and IL23R, ligand and receptor, respectively. METHODS: In all, 707 IBD patients (344 with Crohn's disease and 363 with ulcerative colitis) and 547 healthy controls from the same ethnic origin (Caucasian Spaniards) were included in the present study. Two single nucleotide polymorphisms (SNPs) in IL23R (rs7517847 and rs11209026) and 2 in IL12B (rs3212227 and rs6887695) genes were analyzed by TaqMan technology. Genetic frequencies were compared with a chi-square test. Interaction between genes was analyzed by case-only comparisons. RESULTS: The data show an association of both IL23R SNPs with overall IBD (statistically stronger, rs7517847; odds ratio [OR] = 0.79, 95% confidence interval [CI]: 0.67-0.94, minor allele frequencies: 0.355 in IBD patients versus 0.410 in controls; P = 0.005), somewhat stronger in Crohn's disease (OR = 0.74, 95% CI: 0.61-0.91) than in ulcerative colitis (OR = 0.84, 95% CI: 0.69-1.03). IL12B rs6887695 showed a weak association with IBD (OR = 1.24, 95% CI: 1.04-1.47, minor allele frequencies: 0.375 in IBD patients versus 0.326 in controls, P = 0.012), stronger in UC (OR = 1.31, 95% CI: 1.07-1.60, P = 0.007). No statistically significant differences were apparent when patients were stratified according to clinical characteristics. No interaction was observed between any of the polymorphisms studied at IL12B and IL23R. CONCLUSIONS: Our study confirms the association of IL23R and IL12B with IBD in the Spanish population, but no interaction between either loci could be detected.

Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding.

OBJECTIVES: To analyze whether gene variants leading to impaired drug metabolism are related with acute gastrointestinal bleeding after nonsteroidal anti-inflammatory drugs (NSAID) use. METHODS: Common CYP2C8 and CYP2C9 polymorphisms were studied in a cross-sectional study, involving 134 NSAID-related bleeding patients and in 177 patients receiving NSAID with no adverse effects. RESULTS: Among patients receiving NSAID that are CYP2C8/9 substrates the frequencies for carriers of variant alleles versus control patients were CYP2C8*3: 0.50 vs. 0.23 [odds ratio (OR); 95% confidence interval (CI)=3.4; 1.5-7.5; P=0.002], CYP2C9*2: 0.48 vs. 0.26 (OR; 95% CI=2.7; 1.2-5.8; P=0.013) and CYP2C9*3: 0.24 vs. 0.20 (OR; 95% CI=1.3; 0.5-3.1; P=0.578). The frequencies for carriers of the CYP2C8*3+CYP2C9*2 genotype were 0.40 vs. 0.15 (OR; 95% CI=3.7; 1.6-8.9; P=0.003). These findings were not influenced by sex, age, smoking or drinking habits. Among bleeding patients receiving NSAID that are not extensively metabolized by CYP2C8/9, no differences in genotypes or allele frequencies were observed as compared with control patients. CONCLUSION: The combined presence of CYP2C8*3 and CYP2C9*2 (CYP2C8*3+CYP2C9*2 genotype), is a relevant determinant in the risk to develop gastrointestinal bleeding in patients receiving NSAID that are CYP2C8/9 substrates.