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BACKGROUND: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease. AIM: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour. METHODS: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics. RESULTS: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes. CONCLUSIONS: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.

OBJECTIVES: Genetic variants within DLG5 were recently reported to be associated with inflammatory bowel disease (IBD). The aim of our study was to test for allelic and haplotype associations of six DLG5 variants in 668 IBD patients from two European populations. Furthermore, we evaluated whether DLG5 variants alter gastrointestinal permeability in Crohn's disease (CD). METHODS: Six DLG5 variants (p.R30Q, P.P1371Q, P.G1066G, rs2289308, DLG-e26, p.D1507D) were genotyped in two study populations: (1) German IBD patients (CD n = 250; ulcerative colitis (UC) n = 150) and German healthy controls (n = 422); (2) Hungarian IBD patients (CD n = 144; UC n = 124) and Hungarian healthy controls (n = 205). Subtyping analysis was performed in respect of CARD15 mutations and clinical characteristics. We also tested for differences within DLG5 genotypes in German CD patients with respect to gastroduodenal and intestinal permeability measured by triple-sugar-test. RESULTS: Allele as well as genotype frequencies of DLG5 variants did not differ between IBD patients and controls in either study population. Indeed, the p.R30Q polymorphism was found more frequently in controls than in patients. The distribution of DLG5 genotypes in German and Hungarian CD patients with CARD15 mutations was not different from patients without mutated CARD15. We did also not observe any association between DLG5 variants and clinical parameters. Importantly, DLG5 variants were not associated with gastroduodenal or intestinal permeability. CONCLUSIONS: We could not replicate that DLG5 is a relevant disease susceptibility gene for IBD in German or Hungarian subjects. In addition, we have no evidence that DLG5 variants are involved in altered gastrointestinal permeability in CD.

Summary Background : Mutations within the NOD2/CARD15 gene have recently been shown to be associated with Crohn's disease. Aims : To investigate the clinical impact of the three common NOD2/CARD15 mutations in patients with Crohn's disease. Methods : We investigated the prevalence of the three common NOD2/CARD15 mutations (Arg702Trp, Gly908Arg, 3020insC) in 180 patients with Crohn's disease, 70 patients with ulcerative colitis and 97 controls. In patients with Crohn's disease, prevalence of NOD2/CARD15 mutations were correlated to clinical and demographical parameters. Results : In Crohn's disease patients, 35.6% carried at least one mutant allele of NOD2/CARD15 mutations compared with 14.3% of patients with ulcerative colitis (P = 0.006) and to 15.5% of controls (P = 0.0001). Genotype phenotype analyses revealed that NOD2/CARD15 mutations determined younger age at disease diagnosis (P = 0.03), ileal disease location (P = 0.01) and ileocecal resections (P = 0.0002). Interestingly, reoperation with resection of the anastomosis was significantly more frequent in patients with NOD2/CARD15 mutations (P = 0.01). Conclusions : Our investigations support the current hypothesis that NOD2/CARD15 mutations are associated with a phenotype of Crohn's disease with younger age at diagnosis, ileal involvement, ileocecal resections and a high risk of postoperative relapse and reoperation. NOD2/CARD15 mutations might therefore be used to identify high risk patients for relapse prevention strategies.

Background/Aims: To search for changes in body composition and energy metabolism associated with the repeatedly observed weight gain of cirrhotic patients after portosystemic shunting. Methods: Twenty-one patients were studied prospectively before and 6 and 12 months after transjugular intrahepatic portosystemic shunt (TIPS) to assess body cell mass by two independent methods (total body potassium counting: body cell mass determined by TBP, BCMTBP, bioelectric impedance analysis: body cell mass determined by BIA, BCMBIA), muscle mass (anthropometry), resting energy expenditure (REECALO) by indirect calorimetry, and nutritional intake by dietary recall analysis. Results: Prior to TIPS patients were hypermetabolic in terms of measured vs. predicted REE (REECALO median 1423 (range 1164– 1838) vs. REEPRED 1279 (1067 –1687) kcal; P< 0.05) and their body cell mass was lower (19.1 (10.9 –33.4) vs. 31.7 (16.8 –47.1) kg; P 5 0.001). After TIPS body cell mass (BCMBIA) increased to 23.5 (12.7 –44.3) ( P< 0.025) and 25.7 (14.2 – 39.7) kg (P 5 0.05) at 6 and 12 months after TIPS and this was confirmed by total potassium counting (BCMTBP before TIPS: 18.8 (10.6 –26.7) vs. 22.4 (12.9 – 28.5) kg at 6 months; P< 0.01). Hypermetabolism persisted throughout the study period. Energy and protein intake increased significantly by 26 and 33%. Conclusions: An increase of prognostically relevant variables body cell and muscle mass contributes to the weight gain after TIPS in malnourished patients with cirrhosis and hypermetabolism. q 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background & Aims: In nonrandomized trials, photodynamic therapy (PDT) had a promising effect on nonresectable cholangiocarcinoma (NCC). This prospective, open-label, randomized, multicenter study with a group sequential design compared PDT in addition to stenting (group A) with stenting alone (group B) in patients with NCC. Methods: In patients with histologically confirmed cholangiocarcinoma, endoscopic or percutaneous double stenting was performed. Patients fulfilling inclusion criteria were randomized to group A (stenting and subsequent PDT) and group B (stenting alone). For PDT, Photofrin 2 mg/kg body wt was injected intravenously 2 days before intraluminal photoactivation (wavelength, 630 nm; light dose, 180 J/cm 2 ). Further treatments were performed in cases of residual tumor in the bile duct. The primary outcome parameter was survival time. Secondary outcome parameters were cholestasis and quality of life. Results: PDT resulted in prolongation of survival (group A: n=20, median 493 days; group B: n=19, median 98 days; P Conclusions: PDT, given in addition to best supportive care, improves survival in patients with NCC. The study was terminated prematurely because PDT proved to be so superior to simple stenting treatment that further randomization was deemed unethical.

Background & Aims: Microorganisms that directly interact with the intestinal mucosa are obscured by fecal flora and poorly characterized. Methods: We investigated the mucosal flora of washed colonoscopic biopsies of 305 patients with bowel inflammation and 40 controls. The microbial cultures were validated by quantitative polymerase chain reaction with subsequent cloning and sequencing, fluorescence in-situ hybridization, and electron microscopy. Results: We found high concentrations of mucosal bacteria in patients with bowel inflammation, but not in controls. The concentrations of mucosal bacteria increased progressively with the severity of disease, both in inflamed and non-inflamed colon. In patients with >10,000 cfu/μL, a thick bacterial band was attached to the intact mucosa without signs of translocation. Patients with inflammatory bowel disease (IBD) and concentrations of mucosal bacteria >50,000 cfu/μL had characteristic inclusions of multiple polymorphic bacteria within solitary enterocytes located next to the lamina propria, without or having no contact with the fecal stream. The identified bacteria were of fecal origin. Conclusions: Our findings suggest that the changes in the mucosal flora in IBD are not secondary to inflammation, but a result of a specific host response. We hypothesize that the healthy mucosa is capable of holding back fecal bacteria and that this function is profoundly disturbed in patients with IBD. GASTROENTEROLOGY 2002;122:44-54

ISIS-2302, an antisense oligonucleotide directed against intercellular adhesion molecule 1, was effective in steroid refractory Crohn's disease in a pilot trial. The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn's disease (CACD).A dose-interval, multicenter, placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD (Crohn's Disease Activity Index [CDAI], 200-400). The primary endpoint was steroid-free remission (CDAI150) at week 14.Only 2 of 60 (3.3%) ISIS-2302-treated and no placebo patients reached the primary endpoint. Steroid-free remission at week 26 (secondary endpoint) was reached in 8 of 60 (13.3%) active treatment and 1 of 15 (6.7%) placebo patients. A greater proportion of ISIS-2302-treated than placebo patients achieved a steroid dose10 mg/day at weeks 14 and 26 (48.3% vs. 33.3% and 55.0% vs. 40.0%, respectively, and a glucocorticoid dose of 0 mg [prednisone equivalent] at week 26 [23.3% vs. 6.7%, respectively]). Treatment with ISIS-2302 was safe. The most common side effects were injection site reactions in the active treatment group (23% in ISIS-2302-treated patients vs. none in placebo patients). No statistically significant differences in the frequency of side effects were detected between dose groups.The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint. Positive trends were observed in some of the secondary endpoints.

Glucocorticoids are widely used in the treatment of inflammatory bowel disease (IBD). Up- and down-regulated expression of glucocorticoid receptors (GR) has been reported for different chronic inflammatory diseases. The aim of this study was to investigate the expression of GR and their apparent dissociation constant (Kd) in patients with IBD.Thirty-nine patients with IBD (22 with ulcerative colitis, 17 with Crohn's disease) and 35 normal controls were studied. Twenty-five patients did not receive steroids, 14 patients were treated with steroids. Peripheral blood mononuclear cells from patients and controls were isolated using the Ficoll-Hypaque gradient and a whole cell [3H]-dexamethasone binding assay and Scatchard plot analysis were performed to assess GR number and the apparent dissociation constant. Results were expressed as mean +/- standard deviation.Normal controls showed an expression of 3,969 +/- 1,555 GR per cell with an apparent dissociation constant of 6.16 +/- 3.8 nmol/L. IBD patients without steroids had a significant increase both in the expression of GR per cell (6,401 +/- 2,344; p0.0001; Wilcoxon-Mann-Whitney test) and in the apparent dissociation constant (11.02 +/- 7.57 nmol/L; p = 0.006). Expression of GR in IBD patients was suppressed to normal levels under steroid treatment (4,594 +/- 2,237; p = 0.024), but Kd remained elevated (13.56 +/- 9.05 nmol/L). Plasma cortisol levels were not different between IBD patients and the control group.Our data show a systemic increase in GR expression and a decrease in the affinity to the GR in IBD, in contrast to other inflammatory diseases such as rheumatoid arthritis and asthma. These changes point towards a systemic character of IBD, which might be considered in a decision between topical and systemic treatment.

Objectives Treatment results of advanced hepatocellular carcinoma have remained unsatisfactory; the response rates to intravenous doxorubicin are no better than 20%. Oral tamoxifen has been proposed on the basis of beneficial results in some trials. The aim of this study was to evaluate whether the addition of doxorubicin to oral tamoxifen improves survival compared to oral tamoxifen alone. Methods Thirty-two consecutive patients with a priori defined contra-indications against surgery (transplantation, resection) or chemo-embolization were evaluated to receive chemotherapy. All patients received oral tamoxifen 30 mg bid; 16 also received intravenous doxorubicin 50 mg/m 2 every 4 weeks. The control group consisted of the remaining 16 patients who either were considered unfit for doxorubicin because of a Karnofsky index < 50% (n = 5), cardiac disease (n = 6) or who refused to have cytotoxic drug therapy (n = 5). Results Median survival time was 148 days (95% Cl 89.2-206.8) in the doxorubicin group and 96 days (95% Cl 49.0-143.0) in the control group, and this was not significantly different (P= 0.408), regardless of the presence or absence of cirrhosis. Conclusions In conclusion, the results of our study indicate that combination therapy using doxorubicin and tamoxifen is unlikely to considerably improve survival compared to tamoxifen alone in patients with advanced hepatocellular carcinoma.

To investigate the clinical relevance of interleukin-6 (IL-6) serum levels in patients with Crohn's disease (CD), single point IL-6 measurements in sera from consecutive CD patients and healthy donors (HD), as well as longitudinal measurements during the course of steroid therapy for active CD were performed. Patients with steroid-induced remission were followed until clinical relapse.One hundred thirty-six CD patients without steroid or other immunosuppressive treatment within 2 months and surgical procedures within 3 months before study entry were investigated; 63 patients with active CD were enrolled into the follow-up program. Clinical activity was evaluated by the Crohn's disease activity index (CDAI) and serum IL-6 levels measured by enzyme-linked immunosorbent assay.IL-6 serum levels were significantly elevated in CD patients compared to HD (p0.001). In individual patients serum IL-6 levels correlated with corresponding CDAI scores in a subgroup referred to as primarily inflammatory patients presenting without bowel stenosis, previous intestinal resection, or concomitant inflammatory disorders (r = 0.72, p0.001). Primarily inflammatory patients displayed higher serum IL-6 levels (median: 6.0 pg/ml; range: 1.3-25) than CD patients with bowel stenosis (median: 2.0; range: 1.3-4.9; p0.01) or extensive intestinal resection (median: 1.5; range: 1.3-13.7; p0.001). Longitudinally measured serum IL-6 levels reflected the clinical response during steroid therapy and predicted clinical relapse after steroid-induced remission at week 9 of the treatment protocol.Serum IL-6 is a clinically relevant parameter for CD that correlates with inflammatory activity and implies a prognostic value after steroid-induced remission.

Improvement of health-related quality of life(HRQOL) is a major determinant in decisionmaking forsurgery in patients with Crohn's disease (CD). Thisstudy was designed to investigate the short- andlong-term effect of surgical resection for CD on HRQOL.Sixteen patients were investigated within one weekbefore surgery and 3, 6, and 24 months postoperatively.Besides the Crohn's disease activity index (CDAI), four instruments: the time trade-off technique(TTO), the direct questioning of objectives (DQO), therating form of inflammatory bowel disease patientsconcerns (RFIPC), and the Beck depression inventory-were used for assessment of HRQOL. CDAI decreasedsignificantly after operation and 10 patients remainedin remission for 24 months. Two patients hadpostoperative relapses and went into remission afterprednisolone treatment. Four patients developed chronicactive disease. HRQOL was significantly improved in allpatients three and six months postoperatively. Exceptfor the four patients with chronic active disease, all other patients (N = 12) had alsosignificantly improved HRQOL after 24 months. Inconclusion, surgical resections in CD lead to along-term improvement of HRQOL with the exception ofpatients with chronic active disease. This finding might be taken inconsideration for the indication of surgery inCD.

Background & Aims: Successful treatment in nonresectable Bismuth type III and IV cholangiocarcinoma is seldom achieved. The aim of this study was to evaluate the effect of photodynamic therapy on cholestasis, quality of life, and survival in these patients. Methods: Nine patients with advanced nonresectable cholangiocarcinomas Bismuth type III and IV, who showed no sufficient drainage (bilirubin decrease Results: After photodynamic therapy, bilirubin serum levels declined from 318 ± 72 to 103 ± 35 μmol/L ( P = 0.0039) with no significant increase during the two monthly follow-ups. Quality of life indices improved dramatically and remained stable (e.g., Karnofsky index from 32.2% ± 8.13% to 68.9% ± 6.1%; P = 0.0078). Thirty-day mortality was 0%, and median survival time was 439 days. Conclusions: This study provides clear evidence that photodynamic therapy is effective in restoring biliary drainage and improving quality of life in patients with nonresectable disseminated cholangiocarcinomas Bismuth type III and IV. Compared with published data, survival time seems to be prolonged. GASTROENTEROLOGY 1998;114:536-542

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P.01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P.01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P.001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P.03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.

Objective: To assess the prevalence of and risk factors for clinical and subclinical vitamin D deficiency in Crohn's disease. Patients: Vitamin D status was determined, in winter, in 50 consecutive outpatients with Crohn's disease and in 50 healthy controls. Methods: Vitamin D status was determined by measurement of 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25-(OH) 2 -D), vitamin-D-binding protein and of the C-terminal fragment of parathormone in serum, and by calculation of the free 1,25-(OH) 2 -D index [as a ratio of the molar concentrations of free 1,25-(OH) 2 -D and vitamin-D-binding protein]. Precise and evaluable dietary records were obtained from 18 patients only

Background Steroids, the mainstay of Crohn's disease treatment, have been associated with systemic side effects. Aim To evaluate the efficacy and tolerability of beclomethasone dipropionate for maintaining remission induced by a short course of systemic steroids in patients with Crohn's ileitis with or without right colonic involvement. Methods Patients (n = 84) with active Crohn's disease who achieved remission during a 2-week prednisone run-in period were randomised to receive beclomethasone dipropionate for 24 weeks or continue prednisone for a further 2 weeks followed by placebo for 22 weeks. The primary outcome was relapse rate (Crohn's Disease Activity Index score > 150 and an increase of ≥60 points from baseline) or withdrawal due to disease deterioration. Results The relapse rate was 23.3% and 53.8% in beclomethasone dipropionate and placebo groups, respectively (p = 0.027). According to Kaplan–Meier analysis, the cumulative relapse rate was 38.0% in the beclomethasone dipropionate group and 56.0% in the placebo group (p = 0.025). Six percent and 1.7% of all adverse events in the beclomethasone dipropionate and placebo groups, respectively, were endocrine-related. Conclusion These results demonstrate that beclomethasone dipropionate significantly reduces the relapse rate in post-active Crohn's ileitis patients compared with placebo after induction of remission with a short course of systemic steroids, and is well tolerated.

Contains fulltext : 81167.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (pCA) are associated with risk factors such as alcohol intake and tobacco smoking. Microsomal epoxide hydrolase (EPHX1) is a phase II detoxifying enzyme capable of tobacco-borne toxicant inactivation. We studied the role of the EPHX1 c.337T>C (p.Y113H) variant, whichleads to altered enzyme activity, in pancreatic diseases. METHODS: We genotyped 2391 patients by melting curve analysis. We enrolled 367 patients with pCA, 341 patients with alcoholic CP (aCP), 431 patients with idiopathic CP or hereditary pancreatitis, 192 patients with acute pancreatitis, and 679 controls of German descent. We replicated data in 77 patients with aCP and 304 controls from The Netherlands. RESULTS: In German patients with aCP, Y113 was more common than in controls (allele frequencies, 0.73 vs 0.68; risk ratio, 1.21 [95% confidence interval, 1.05-1.39]). However, we could not confirm this association in the Dutch population (allele frequencies, 0.62 vs 0.68, P=not significant). In total, Y113 frequency was 0.71 in aCP and 0.68 in controls (P = not significant). Allele frequencies did not differ in the other disease groups (acute pancreatitis, 0.69; idiopathic CP or hereditary pancreatitis, 0.68; pCA, 0.68; and control, 0.68). CONCLUSIONS: The EPHX1 Y113H variant is not associated with pancreatic diseases indicating that EPHX1 does not play a significant role in the initiation of pancreatic inflammation or cancer.

1. Aliment Pharmacol Ther. 2006 Apr 15;23(8):1117-25. Antibiotic treatment of Crohn's disease: results of a multicentre, double blind, randomized, placebo-controlled trial with rifaximin. Prantera C, Lochs H, Campieri M, Scribano ML, Sturniolo GC, Castiglione F, Cottone M. Operative Unit of Gastroenterology, St Camillo-Forlanini Hospital, Rome, Italy. prantera@tin.it BACKGROUND: Clinicians often employ antibiotics in Crohn's disease. Rifaximin is active against bacteria frequently found in the intestinal mucosa of Crohn's disease patients. AIM: To evaluate the difference in efficacy between once and twice/daily oral administration of rifaximin and placebo in the treatment of active Crohn's disease. METHODS: We enrolled 83 patients with mild-to-moderate Crohn's disease and randomized to three treatments for 12 weeks: Group A (rifaximin 800 mg o.d. + placebo), Group B (rifaximin 800 mg b.d.) and Group C (placebo b.d.). RESULTS: Clinical remission was achieved by 52% of Group B, 32% (A) and 33% (C). Clinical response was seen in 67% (B), 48% (A) and 41% (C), without reaching a statistically significant difference. Treatment failures were: 4% (B), 12% (A) and 33% (C), (P = 0.010). Remission and response rates of rifaximin 800 mg b.d. were significantly higher than those of placebo and rifaximin 800 mg o.d. in patients with elevated C reactive protein values (P < 0.05). CONCLUSIONS: Rifaximin 800 mg b.d. was superior to placebo in inducing clinical remission of active Crohn's disease. Although this difference was not statistically significant, the number of the failures in the placebo group was significantly higher than those who received rifaximin 800 mg b.d. PMID: 16611272 [PubMed - indexed for MEDLINE]

Background The proteolysis-inducing factor (PIF) was identified as a tumour product in various gastrointestinal cancers. A previous study in pancreatic cancer patients suggested PIF expression as a tumour marker, which is not related to tumour size. We hypothesized that PIF could be a useful marker to exclude benign pancreatic tumors, as chronic pancreatitis with a pancreatic mass. Methods Urine of patients with a pancreatic mass of uncertain malignancy was investigated for PIF expression by Western blot. Sufficient urine protein for analysis was available in 59 patients. The diagnosis was established by histology in 54 patients and by follow up in five patients with chronic pancreatitis. In addition, serum CA19-9 was measured. Results The sensitivity (specifity) for the detection of a malignant pancreatic tumour was 90% (75%) and 54% (71%) for CA19-9 and PIF, respectively. The sensitivity (specifity) for the distinction of pancreatic cancer from chronic pancreatitis was 89% (80%) and 57% (63%) for CA19-9 and PIF, respectively. Conclusion Evaluation of PIF in urine is of no diagnostic value in patients with a pancreatic mass of unknown malignancy.

In approximately 25% of patients with acute or chronic pancreatitis the cause remains unclear. Despite progress in understanding so-called idiopathic pancreatitis, more diagnostic criteria are needed. We report on a patient who presented with jaundice, but without pain or fever. Under the assumption of pancreatic cancer the patient underwent hemipancreatoduodenectomy. Histological examination showed chronic sclerosing inflammation of the pancreas and bile ducts without any signs of malignancy. Ten weeks later he developed bilateral parotid swelling and recurrent bouts of fever. Again liver enzymes were elevated and unsuccessfully treated with antibiotics for bacterial cholangitis. Further biopsies from submandibular gland, lymph nodes and liver again showed chronic sclerosing inflammation with lymphoplasmacytic infiltration. For sicca symptoms the diagnosis of a primary Sjogren's syndrome was proposed. However, with corticosteroid treatment the patient improved remarkably but after tapering he relapsed. On the basis of established criteria, we diagnosed autoimmune pancreatitis with (1) diffuse swelling of the pancreas, (2) irregularities of the pancreatic duct, (3) lymphoplasmacytic infiltration, (4) response to corticosteroids, (5) hypergammaglobulinaemia, and (6) disproportionately raised IgG4. In addition, the patient fulfilled the criteria for secondary Sjogren's syndrome. Autoimmune pancreatitis may present as an isolated or syndromic disease. It is an autoimmune disorder of unknown cause and should be included in the differential diagnosis of pancreatic disorders.

Background. Keratin 8 is a major component of intermediate filaments in single-layered epithelia of the gastrointestinal tract. Keratin 8 deficient mice display signs of colitis and diarrhoea characteristic for inflammatory bowel disease. Very recently, two keratin 8 mutations, Y54H and G62C, were identified. Aims. We investigated if these keratin 8 missense mutations were associated with inflammatory bowel disease. Patients. In total, 217 German patients with Crohn’s disease, 131 German patients with ulcerative colitis, and 560 German control subjects were enrolled in this study. Methods. Samples were analysed by PCR amplification and subsequent melting curve analysis using fluorescence resonance energy transfer probes. Results. The G62C mutation was detected in five (2.3%) patients presenting with Crohn’s disease and in three (2.3%) with ulcerative colitis. In comparison, 9 (1.6%) out of 560 controls were heterozygous for this mutation. No patient or control was homozygous for this mutation. Patients carrying one mutant allele did not show any noticeable characteristics in their corresponding phenotype. In contrast, the Y54H mutation was observed in neither any of the 348 patients with inflammatory bowel disease nor in any control subject. Conclusions. Our data indicate that both keratin 8 mutations, G62C and Y54H, do not play a relevant pathogenic role in inflammatory bowel disease.

Non-Alcohol Induced Steatohepatitis in Non-Obese Patients: Treatment With Ursodeoxycholic Acid

Background : Evidence-based guidelines for artificial nutrition in hyperacute (HLF), acute (ALF) and subacute liver failure (SLF) cannot be given at present due to scarcity of clinical studies. Methods : Current nutritional practice was surveyed using a questionnaire which was answered by 33 hepatology units (2–170 cases/year) in 11 European countries. Results : All units used specific nutrition support regimes in liver failure patients. Eight units (385 patients/year) preferentially used tube-feeding with standard diets, 25 units (377 patients/year) used parenteral nutrition (PN). For PN glucose was infused at 4.0 g/kg d (median; range 0.6–10.0). Intravenous fat was given only by some units: (18/33) in HLF at 0.9 g/kg d (0.3–2.0), (21/33) in ALF at 1.0 g/kg d (0.3–2.0), and (23/33) in SLF at 1.0 g/kg d (0.3–3.0). Amino acid solutions, predominantly enriched in branched-chain amino acids, were used in HLF (19/33 units) and in ALF (23/33) at 0.9 g/kg d (0.5–1.5) and in SLF (24/33) at 1.0 g/kg d (0.7–1.5). Conclusion : Hepatology units use a considerable variety of specific nutrition support strategies in liver failure. About 50% of patients receive enteral nutrition. Dosage and monitoring of PN is similar to other critical illness with a wide variety of infusion rates and accepted ranges of substrate plasma concentrations.

An increased prevalence of elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels in patients with Crohn's disease (CD) has been described. The aim of the present work was to investigate serum ASCA levels during the courses of prednisolone and mesalamine therapy in CD patients.Serum samples of 25 patients with active CD were studied for ASCA levels before as well as 2 and 9 wk after initiation of a prednisolone tapering regimen. The influence of mesalamine (4 g o.d.) on serum ASCA levels compared to that of placebo was tested over 1 yr in 38 patients (20 mesalamine and 18 placebo) participating in a postoperative prophylaxis study. Serum IgG and IgA ASCA levels were measured by ELISA. Sera of 91 CD and 40 ulcerative colitis (UC) patients as well as 334 healthy donors were tested for ASCA to recalculate new cut-off values.For IgG ASCA cut-off values were determined to be 17.0 U and 25.0 U, and for IgA ASCA 9.3 U and 14.0 U. At baseline visit, 73.0% (46/63) of patients displayed serum ASCA positivity. During prednisolone therapy, a decrease in serum IgG and IgA ASCA levels from baseline to wk 2 (p0.0001 and p0.001, respectively) as well as to wk 9 (p0.001 and p = 0.01, respectively) was observed. A trend toward an association of ASCA positivity and steroid responsiveness was calculated (p = 0.07). During mesalamine treatment, no differences in changes of ASCA levels were observed compared to placebo at any time point.ASCA are stable markers during steroid and mesalamine treatment, highlighting their reliability for use in diagnosis of CD.

In a 70-year-old patient who had been treated for a renal cell carcinoma, a pancreatic mass was detected on CT scan. To differentiate a pancreatic metastasis of the renal cell carcinoma from a pancreatic carcinoma, an echo-enhanced power Doppler sonography was performed. The pancreatic mass demonstrated a strong echo enhancement, proving its hypervascularization. This behaviour favoured the diagnosis of a pancreatic metastasis of the renal cell carcinoma which was confirmed by histology. The principles and the role of echo-enhanced power Doppler sonography in the differential diagnosis between a primary pancreatic carcinoma and a metastasis of a renal carcinoma in the pancreas are discussed. We conclude that this technique can provide an important contribution to the diagnosis in this special instance. However, histology is the standard in the differential diagnosis of pancreatic tumours.

The vast majority of Caucasian patients presenting with hereditary hemochromatosis demonstrate a single homozygous missense mutation in the HFE gene (C282Y). The underlying genetic defects in hemochromatosis patients of non-Caucasian origin are largely unknown. A 48-year-old man of Vietnamese origin presented with insulin-dependent diabetes mellitus, tertiary adrenocortical insufficiency, and laboratory results highly indicative of hereditary hemochromatosis. Because the patient was negative for the known HFE gene mutations C282Y, H63D, and S65C HFE, the entire coding region and intron/exon boundaries of the HFE gene was investigated. Sequencing studies identified a homozygous G-to-A transition at position +1 of intron 5 (IVS5+1 G/A). This newly described mutation alters the invariant G at position +1 of the 5' splice site causing altered mRNA splicing and exon skipping with exon 4 being spliced to exon 6. Both heterozygously affected children (age 19 and 20 years) had moderately increased ferritin levels with normal serum iron concentration and transferrin saturation. The newly described mutation was not detected in a control group consisting of 220 Caucasian individuals as verified by allele-specific polymerase chain reaction. We describe for the first time a homozygous HFE splice site mutation (IVS5+1 G/A) in a non-Caucasian patient with hereditary hemochromatosis. Although the absence of this novel HFE gene mutation in Caucasian subjects suggests that the mutation is exclusive to this family, mutation screening in populations of different ethnic background is recommended to precisely define its contribution to hereditary hemochromatosis in non-Caucasian patients.

WILLIAM J. SANDBORN,*,‡ BRIAN G. FEAGAN,§ STEPHEN B. HANAUER,*,‡ HERBERT LOCHS,* ROBERT LOFBERG,* ROBERT MODIGLIANI,*,\ DANIEL H. PRESENT,*,‡ PAUL RUTGEERTS,* JURGEN SCHOLMERICH,* EDUARD F. STANGE,* and LLOYD R. SUTHERLAND* *The Clinical Trials Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD), ‡The Clinical Alliance of the Crohn’s and Colitis Foundation of America, the §Clinical Network of the Crohn’s and Colitis Foundation of Canada, and the \Groupe d’Etude Therapeutique des Affections Inflammatoires Digestives. See Appendix I for institutional affiliations for each author and for the complete membership of the IOIBD Clinical Trials Task Force

Background & Aims: This study investigated if long-term treatment with high-dose mesalamine reduces the risk of clinical relapse of Crohn's disease after surgical resection. Methods: In a prospective, randomized, double-blind, multicenter study, 4 g of mesalamine (Pentasa; Ferring A/S, Vanlose, Denmark) daily was compared with placebo in 318 patients. Treatment was started within 10 days after resective surgery and continued for 18 months. Primary outcome parameter was clinical relapse as defined by an increase in Crohn's Disease Activity Index, reoperation, septic complication, or newly developed fistula. Risk factors for recurrence were prospectively defined to be analyzed in a stepwise proportional hazards model. Results: Cumulative relapse rates (±SE) after 18 months were 24.5% ± 3.6% and 31.4% ± 3.7% in the mesalamine (n = 152) and placebo (n = 166) groups, respectively ( P = 0.10, log-rank test, 1-sided). Retrospective analysis showed a significantly reduced relapse rate with mesalamine only in a subgroup of patients with isolated small bowel disease (n = 124; 21.8% ± 5.6% vs. 39.7% ± 6.1%; P = 0.02, log-rank test). Probability of relapse was predominantly influenced by the duration of disease ( P = 0.0006) and steroid intake before surgery (additional risk, P = 0.0003). Conclusions: Eighteen months of mesalamine, 4 g daily, did not significantly affect the postoperative course of Crohn's disease. Some relapse-preventing effect was found in patients with isolated small bowel disease. GASTROENTEROLOGY 2000;118:264-273

Objective: Budesonide, although only topically active, is effective in the treatment of Crohn’s disease. This study was performed to compare the clinical efficacies of budesonide and prednisolone in relation to the activation status of circulating leukocytes. Methods: Twenty-four patients with active Crohn’s disease were randomized to treatment with either budesonide or 6-methylprednisolone. Clinical response was monitored by the Crohn’s disease activity index, C-reactive protein, and orosomucoid. Expression of CD25 and CD71 on T cells and CD64 on neutrophils was determined by flow cytometry. The release of TNF-α and IL-1β by peripheral blood mononuclear cells was measured by ELISA. Results: After 2 wk of treatment a clinical response was observed in both groups, but it was more accentuated in patients treated with prednisolone. At baseline an upregulation of CD71 and CD64, but not CD25, was found in active patients. Prednisolone significantly decreased the expression of CD64 and the release of TNF-α and IL-1β, but did not alter the expression of CD25 and CD71. Budesonide treatment failed to exert any effect on circulating leukocytes. Conclusions: The inability of budesonide to downregulate activated circulating leukocytes may contribute to the somewhat lower clinical efficacy of this topical steroid in the treatment of active Crohn’s disease.

Background & Aims: Although multiple studies have focused on Helicobacter pylori , little is known about the mucosa-associated flora of the colon. The aim of this study was to detect bacteria directly in colonic mucosa from patients screened for colorectal cancer. Methods: Bacteria were quantified with the polymerase chain reaction and identified by comparative sequence analysis in colonoscopic biopsy specimens from 31 asymptomatic and 34 symptomatic controls with normal colonoscopic findings, 29 patients with colonic adenoma, and 31 patients with colorectal carcinoma. In 41 patients, intra- and extracellular location of bacteria was confirmed with the gentamicin protection assay. Results: No bacteria were detected in biopsy specimens from 97% of asymptomatic and 69% of symptomatic controls. In contrast, bacterial concentrations of 10 3 –10 5 colony-forming units per microliter were detected in biopsy specimens from both malignant and macroscopically normal tissue in 90% and 93% of patients with adenoma and carcinoma, respectively. E. coli and coli -like bacteria were shown to colonize the colonic mucosa in 82% of these patients. The gentamicin protection assay indicated that E. coli was partially intracellular in 87% of patients with adenoma and carcinoma and in none of the controls. Conclusions: The colonic mucosa of patients with colorectal carcinoma but not normal colonic mucosa is colonized by intracellular E. coli . GASTROENTEROLOGY 1998;115:281-286

Introduction. Results from clinical trials often employ the odds ratio or relative risk to compare the proportion of subjects responding to experimental treatment to the proportion responding to control treatment. These measures have the advantage of using a single index to summarize the study results, but neither measure provides information that is intuitively meaningful to clinicians, and both can vary in different ways depending on the response to control treatment. Methods. We calculated the odds ratio and relative risk for responses to control treatment varying from 5% to 75% with a fixed difference of 20% between experimental and control responses. We then compared these values to those for two measures of effect size: number-needed-to-treat (NNT; N Engl J Med 1988; 318:1728-1733) and Probabilistic Index (Statist Med 2006; 25:591-602). Results. The Figure illustrates that with a fixed difference between responses to control and experimental treatment, as the response to control treatment increases, the odds ratio decreases to a plateau and then increases, whereas the relative risk decreases progressively. Since NNT and Probabilistic Index depend only on the difference between response to control and experimental treatment, values for these measures do not change with changing response to control treatment. That is, for a 20% difference between control and experimental responses, the NNT of 5 gives the number of experimental subjects needed to obtain one more success than treating the same number of control subjects. The Probabilistic Index for these same data is 0.6, and gives the probability that a randomly selected experimental subject has an outcome preferable to that from a randomly selected control subject. Conclusion. The NNT and Probabilistic Index depend only on the difference between responses to control and experimental treatment and can help clinicians assess the potential clinical significance of different values of the odds ratio and relative risk.

Liver cirrhosis in erythropoietic protoporphyria: improvement of liver function with ursodeoxycholic acid