Ulcerative Colitis: Phelip JM

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, Germain E, Phelip JM, Ducros V, Pofelski J, Heluwaert F, Oltean P, Faucheron JL, Bonaz B. · Département d'hépatogastroentérologie, département de biologie appliquée, CHU de Grenoble, France. · Rev Med Interne. · Pubmed #16376461 No free full text.

Abstract: BACKGROUND: A high prevalence (52%) of hyperhomocysteinemia is observed in Crohn disease (CD), however it is not well documented in ulcerative colitis (UC). Furthermore, in the different works studying hyperhomocysteinemia the associated factors are different. AIM: Prospective evaluation of hyperhomocysteinemia in inflammatory bowel disease (IBD) patients, of the risk factors and the determination of a potential risk of colorectal carcinoma in case of hyperhomocysteinemia. PATIENTS AND METHODS: IBD patients followed in our department were prospectively recruited between November 2003-September 2004. To be included patients should have passed a coloscopy in the two years. Patients with kidney failure or drugs supposed, to interfere with homocystéine metabolism (folates, vitamin B12, methotrexate) were excluded from the study. The following parameters were analysed: age, sex, clinical activity indexes (CDAI for Crohn disease and CAI for ulcerative colitis), length-extent and type of the disease (CD or UC), smoking, plasma homocystein concentration, folates and vitamin B12. RESULTS: Eighty-one patients (60 CD, 21 UC, mean age 43.8 +/- 17.3) were included, 30 had an active disease at inclusion and 16 were smokers. The prevalence of high homocystein concentration was 55.6%. In univariate analysis a low rate of folates was the only risk factor for a high homocystein concentration (74 vs. 52.8%; P = 0.018). Smoking was almost an associated factor. In multivariate analysis, a low rate of folate was the only risk factor of hyperhomocysteinemia, OR = 3.59 [1.27-10.17]. Five endoscopic lesions considered as precancerous were described; these patients had all a hyperhomocysteinemia. CONCLUSION: The prevalence of hyperhomocysteinemia is high in UC and in CD. A low folate rate is the only risk factor observed in our study. There is a possible link between colorectal cancer and hyperhomocysteinemia. A high Plasma homocystein concentration must be search in inflammatory bowel disease patients and a substitutive treatment of folates and vitamin B12 is necessary in case of hyperhomocysteinemia.

Roblin X, Serre-Debeauvais F, Phelip JM, Faucheron JL, Hardy G, Chartier A, Helluwaert F, Bessard G, Bonaz B. · Département d'Hépato-Gastroentérologie, CHU de Grenoble, 38043 Grenoble Cedex, France. · Aliment Pharmacol Ther. · Pubmed #15801918 links to  free full text

Abstract: BACKGROUND: 6-Thioguanine (6-tioguanine) nucleotides are the active metabolites of azathioprine. AIM: The aim of the study was to evaluate the rate of clinical remission without steroids in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine, the medium- and long-term efficacy and the predictive factors of clinical response when monitoring 6-tioguanine. METHODS: Steroid-dependent Crohn's disease and ulcerative colitis patients receiving either azathioprine or not (treated later with a daily dose of 2.5 mg/kg) were prospectively included. 6-tioguanine was monitored at 1 and 2 months and every 3 months thereafter for 1 year. The azathioprine dose was adapted to reach a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells. Thiopurine methyltransferase genotype/phenotype was evaluated in some patients. RESULTS: A total of 106 patients were prospectively included (70 Crohn's disease, 36 ulcerative colitis). The clinical remission rate without steroids in patients receiving azathioprine, in intention-to-treat analysis, was 72% and 59% at 6 and 12 months, respectively. The remission rate was significantly higher in patients with 6-tioguanine >250 pmol/8 x 10(8) RBC (86% and 69% at 6 and 12 months, respectively; P < 0.01). No significant difference was observed between Crohn's disease and ulcerative colitis patients whether treated by azathioprine or not on inclusion. In the univariate analysis, the absence of Crohn's disease stenosis, a 6-tioguanine level >250 pmol/8 x 10(8) RBC, and an increase of erythrocyte mean corpuscular volume were the factors predictive of a favourable clinical response. In the multivariate analysis, only a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells was a predictive factor of favourable clinical remission. CONCLUSIONS: Clinical remission without steroids is significantly more likely when monitoring 6-tioguanine so as to reach a level of >250 pmol/8 x 10(8) red blood cells in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine (86% and 69% at 6 and 12 months, respectively).

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.