Ulcerative Colitis: Flourie B

Phelip JM, Ducros V, Faucheron JL, Flourie B, Roblin X. · Department of Gastroenterology, University Hospital of Grenoble, France. · Inflamm Bowel Dis. · Pubmed #17941074 links to  free full text

Abstract: BACKGROUND: Folate deficiency associated with hyperhomocysteinemia might increase the risk of developing colorectal cancer. The aim of this study was to evaluate factors associated with colonic carcinogenesis, in particular, folate and homocysteinemia levels, in a cross-sectional study of patients with inflammatory bowel disease (IBD). METHODS: IBD patients with carcinogenic lesions discovered during colonoscopy [dysplasia-associated lesion or masses (DALM), colorectal cancer] were included and compared with the whole population of IBD patients with a normal colonoscopy performed during the same period. The following parameters were collected at the time of colonoscopy: age, sex, type, duration, activity, and extent of the disease, treatment, smoking status, and vitamin B12, folate, and homocysteinemia levels. Univariate and multivariate analyses were performed after adjusting for the main parameters. RESULTS: One hundred and fourteen patients [41 with ulcerative colitis (UC), 73 with Crohn's disease (CD)] were included. Twenty-six carcinogenic lesions were isolated: 18 DALM (7 high-grade and 11 low-grade dysplasia) and 8 colorectal cancers. In univariate analysis, the factors associated with carcinogenesis were: active smoking (P = 0.03), folate level < 145 pmol/L (P = 0.02), hyperhomocysteinemia > 15 micromol/L (P = 0.003), duration of disease > 10 years (P = 0.006), and UC (P = 0.02). In multivariate analysis, patients with hyperhomocysteinemia associated with folate deficiency had 17 times as many carcinogenic lesions as patients with normal homocysteinemia whatever the folate status and duration of the disease (P = 0.01). Patients with hyperhomocysteinemia without folate deficiency had 2.5 times as many carcinogenic lesions as patients with normal homocysteinemia (P = 0.08). CONCLUSIONS: Our data suggest that in IBD patients with normal homocysteinemia, the increase in carcinogenic risk is negligible. Conversely, in patients with hyperhomocysteinemia, folate deficiency may be associated with increased colorectal carcinogenesis in IBD patients.

Roblin X, Peyrin-Biroulet L, Biroulet LP, Phelip JM, Nancey S, Flourie B. · Department of Gastroenterology, CHU Grenoble, Grenoble, France. · Am J Gastroenterol. · Pubmed #19086961 No free full text.

Abstract: BACKGROUND AND AIMS: A therapeutic level of 6-thioguanine nucleotides (6-TGN) has been reported in inflammatory bowel disease (IBD) patients under azathioprine (AZA). We investigated the threshold value of 6-TGN that may be predictive of AZA refractoriness and its impact on safety profile. METHODS: Patients with normal thiopurine methyltransferase (TPMT) activity (7.5-14 U/mL erythrocytes), suffering from steroid-dependent or active IBD despite AZA use for at least 6 months, were prospectively included. Clinical efficacy, adverse events, and thiopurine metabolite levels were recorded at baseline, 1 month after each dose escalation, and thereafter every 3 months. RESULTS: Fifty-five patients were included (43 with Crohn's disease, 12 with ulcerative colitis). After a mean follow-up of 12 months, 31 patients (56.3%) did not reach clinical remission despite a gradual increase in AZA dose and 6-TGN level of >400 pmol/8 x 10(8) erythrocytes, and were considered refractory to AZA (sensitivity 45%, specificity 100%). Adverse events occurred more frequently in these patients than in responders (42%vs 25%, respectively, P= 0.02). Among 55 patients, 15 cases of myelotoxicity associated with elevated levels of total methylated metabolites (14,500 pmol/8 x 10(8) erythrocytes vs 5,230 pmol/8 x 10(8) erythrocytes in patients without myelotoxicity, P= 0.03) were observed. Patients with total methylated metabolites of >11,100 pmol/8 x 10(8) erythrocytes had an increased risk of developing myelotoxicity (odds ratio [OR] 11.0, 95% confidence interval [CI] 1.1-250, P= 0.05). CONCLUSION: A 6-TGN level of >400 pmol/8 x 10(8) erythrocytes in IBD patients with normal TPMT activity and steroid-dependent or active disease despite an optimal AZA regimen may predict refractoriness to this drug. Furthermore, high levels of methylated derivatives are associated with an increased risk of myelotoxicity.