The Crohn's disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn's disease (CDED-AD): an open-label, pilot, randomised trial.

BACKGROUND: The Crohn's disease exclusion diet (CDED) with partial enteral nutrition is effective for induction of remission in children with mild-to-moderate Crohn's disease. We aimed to assess the CDED in adults with Crohn's disease. METHODS: We did an open-label, pilot randomised trial at three medical centres in Israel. Eligible patients were biologic naive adults aged 18-55 years with mild-to-moderate Crohn's disease (defined by a Harvey-Bradshaw Index score of 5-14 points), a maximal disease duration of 5 years, with active disease on colonoscopy, or imaging with elevated inflammatory markers (C-reactive protein >5 mg/L or faecal calprotectin concentration >200 µ/g). Patients were randomly assigned (1:1) to CDED plus partial enteral nutrition or CDED alone for 24 weeks. Randomisation was via block randomisation (block sizes of six) using sealed, numbered, and opaque envelopes. Patients and investigators were aware of which group patients were assigned to due to the nature of the different interventions. The primary endpoint was clinical remission, defined as a Harvey-Bradshaw Index score of less than 5 at week 6. The primary endpoint was assessed in the intention-to-treat (ITT) population, which included all patients who used the dietary therapy for at least 48 h. We report results of the final analysis. This trial is registered with ClinicalTrials.gov, NCT02231814. FINDINGS: Between Jan 12, 2017, and May 11, 2020, 91 patients were screened, of whom 44 were randomly assigned to the CDED plus partial enteral nutrition group (n=20) or CDED alone group (n=24). 19 patients in the CDED plus partial enteral nutrition group and 21 patients in the CDED alone group received the allocated intervention for at least 48 h and thus were included in the ITT analysis. At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618). Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group). 14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group). No serious adverse events or treatment-related adverse events were reported in either group. INTERPRETATION: CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild-to-moderate biologic naive Crohn's disease and might lead to endoscopic remission. These data suggest that CDED could be used for mild-to-moderate active Crohn's disease and should be assessed in a powered randomised controlled trial. FUNDING: Azrieli Foundation and Nestle Health Science.

Moderate-to-severe Endoscopic Inflammation is Frequent After Clinical Remission in Pediatric Ulcerative Colitis.

OBJECTIVES: Pediatric ulcerative colitis (UC) is characterized by low sustained remission rates and frequent extension of disease even if clinical remission is obtained with therapy. Moderate-to-severe endoscopic activity is a risk factor for relapse while prospective evidence regarding early mucosal healing or persistence of inflammation after remission in children is not available. Our aim was to evaluate if significant inflammation is common after clinical remission and could explain the high relapse rate in pediatric UC. METHODS: Pediatric UC patients with clinical remission, defined as pediatric UC activity index (PUCAI) scores <10, were prospectively assessed for mucosal healing by endoscopy 3 to 5 months after remission was documented. Mayo score was assessed for each segment by a blinded adult gastroenterologist using central reading. Symptomatic patients before sigmoidoscopy were excluded. Sustained remission was assessed retrospectively at 18 months follow-up. RESULTS: Forty-two children were screened, 28 children in continuous clinical remission at time of sigmoidoscopy were included. Mayo 0 was present in 12/28 (42.86%), Mayo 1 in 2/28 (7.1%) and Mayo 2 to 3 in 14/28 (50.0%) endoscopies. Among 23 patients with follow-up through 18 months, remission was sustained in 6/12 (50.0%) with Mayo score 0 to 1 versus 2/11 (18.18%) of patients with Mayo 2 and 3. CONCLUSIONS: Over 50% of children assessed for mucosal healing 3 to 5 months after clinical remission is obtained, have endoscopic disease, primarily moderate-to-severe Mayo 2 to 3 inflammation, which was associated with lower sustained remission.

3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism.

BACKGROUND AND AIMS: Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage. METHODS: We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays. RESULTS: 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NFκB transcriptional activity and subsequent expression of TNFα and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNFα expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NFκB activity. PARP-1 knockout failed to affect NFκB and TNFα suppression by 3-AB in stimulated macrophages. CONCLUSIONS: Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.

Unusual cause of upper gastrointestinal bleeding.

We report a case of recurrent severe upper gastrointestinal bleeding where the bleeding source was difficult to find during recurrent hospitalizations. Eventually videocapsule endoscopy was the modality that finally diagnosed an ulcerated lipoma within an area of intussuscepted jejunum. Segmental resection of small bowel was performed and no further bleeding episodes have occurred. Our case illustrates the value of capsule endoscopy and the rare potential of lipomas to cause serious gastrointestinal bleeding.

A rapid continuous-real-time 13C-urea breath test for the detection of Helicobacter pylori in patients after partial gastrectomy.

INTRODUCTION: Before the development of efficient medications for peptic ulcer disease many patients were treated surgically by partial gastrectomy. The pathogenetic role of Helicobacter pylori was also not known yet. Some of these patients may therefore still harbor H. pylori in their remnant stomach as a carcinogenic agent for gastric cancer. This could be even more relevant for patients who were operated for tumors in the stomach. The efficacy of the urea breath test (UBT) is not clear in this population. AIMS: To study the prevalence of H. pylori and to evaluate the sensitivity and specificity of the continuous UBT (BreathID) in postgastrectomized patients in Israel. In this system, the pH of the stomach is lowered by the addition of citric acid that may be beneficial in the smaller and more alkalic stomach. METHODS: We compared retrospectively the results of our continous UBT with a rapid urease test (RUT) and the histology in all our patients who underwent gastroscopy for any clinical indication, and had a history of partial gastrectomy during the years 2002 to 2010. Only patients in whom H. pylori was tested by all the 3 methods during the same day were included in the study. We identified 76 such patients older than 18 years and performed a statistical analysis of all possibly related clinical data. The 3 methods were compared with each other. RESULTS: H. pylori was positive in 14/76 (18.4%) patients when histology was considered as the gold standard method. The positive predictive value of the continuous UBT and the RUT was 0.64 and 0.35, respectively. The negative predictive value was high by both the methods, 0.92 and 0.95, respectively. Weight loss was correlated with positivity for H. pylori (P=0.032) and a longer gastric stump was marginally related to H. pylori (P=0.071). There was no difference for H. pylori positivity between patients with Billroth I or Billroth II operations. Prevalence of H. pylori was not lower in patients who had partial gastrectomy several years earlier. CONCLUSIONS: The prevalence of H. pylori is considerable even several years after partial gastrectomy. The BreathID is reliable to exclude H. pylori after partial gastrectomy. The positive predictive value of the UBT is not very high but better than the RUT. We suggest that all positive patients found by the breath test should be treated. Our results support the view that alternative noninvasive methods, such as the stool antigen test should be further studied and compared with the BreathID in larger populations.

Eradication of Helicobacter pylori can be accurately confirmed 14 days after termination of triple therapy using a high-dose citric acid-based 13C urea breath test.

BACKGROUND: Confirmation of Helicobacter pylori eradication by urea breath test (UBT) is currently performed 4-6 weeks after completion of therapy because of unacceptable false-negative results in UBTs performed earlier. Use of a high-dose citric acid test meal appears to enable accurate detection of H. pylori even during short term therapy with proton pump inhibitors. AIM: To evaluate if use of a high dose citric acid (4.0 g) test meal can decrease the interval required for confirmation of eradication after triple therapy. METHODS: 233 patients positive for H. pylori were randomized to undergo UBT at 7 days or 14 days after triple therapy, and again at 6 weeks. The latter test was considered the gold standard test. RESULTS: The UBT performed 6 weeks after the end of treatment found that 79.9% were cured. The same test 7 days after therapy found false-negative detection of H. pylori in 7.3% patients compared to 3.2% patients examined after 14 days. The sensitivity, specificity, positive and negative predictive values and accuracy for evaluation on day 14 were 80, 100, 100, 96.3 and 96.7%, respectively. CONCLUSIONS: High-dose citric acid-based UBT is a valid test for the assessment of H. pylori status 14 days after triple therapy. This may obviate the delay in instituting second-line eradication therapy, or further evaluation of the symptomatic patient unresponsive to therapy despite eradication.

A polymorphism in the TNF-alpha promoter gene is associated with pediatric onset and colonic location of Crohn's disease.

OBJECTIVES: Studies suggest that pediatric onset of Crohn's disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-alpha expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-alpha function may influence variability of disease location and AOO of CD. METHODS: We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-alpha promoter region. RESULTS: Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-kappaB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p= 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p= 0.008) and positively associated with isolated colitis (OR = 2.16, p= 0.008, OR = 2.12, p= 0.03 corrected) and familial disease (p= 0.004). CONCLUSIONS: Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-kappaB in TNF-alpha promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.

NOD2/CARD15 mutations and presence of granulomas in pediatric and adult Crohn's disease.

OBJECTIVES: The etiology and mechanism leading to granuloma formation in patients with Crohn's disease (CD) are presently unknown. The first susceptibility gene to be identified as a risk factor for CD is the NOD2/CARD15 gene on Chromosome 16. Mutations in NOD2 could affect the intracellular response to bacterial products and may eventually lead to granuloma formation. The association between NOD2 and granulomas has not been previously explored. We evaluated a possible association between NOD2 mutations and granuloma formation, and compared the prevalence of granulomas in both pediatric and adult cohorts. METHODS: Patients were consecutively recruited through pediatric gastroenterology and adult gastroenterology programs. Patients were eligible if CD was confirmed, and they had undergone full colonoscopy with biopsy and/or surgical resection. Patients underwent genotyping for NOD2 disease-associated mutations. RESULTS: A total of 230 patients were enrolled into the study, of whom 169 patients met all inclusion/exclusion criteria (Group 1, 77 patients [age range 1-16 years]; Group 2, 92 patients [age range 17-68 years]). Surgical resection was performed more often in adults (P < 0.005), and gastroscopy was performed more frequently in children (P < 0.001). Granulomas were found in 34% of the patients studied. The prevalence of granulomas did not differ by age, age group, or gender. A disease-associated NOD2 mutation was found in 37.8% of patients. Granulomas were found in 39% of patients with NOD2 mutations compared with 31% of those without NOD 2 mutations (difference was not significant). In addition, no difference was noted for the specific mutations. CONCLUSIONS: We did not find any correlation between NOD2 mutations and granuloma formation. The cause of granulomas in CD remains elusive.

Glycine modulates cytokine secretion, inhibits hepatic damage and improves survival in a model of endotoxemia in mice.

BACKGROUND AND AIM: There is substantial experimental evidence that the amino acid glycine may have a role in protecting tissues against insults such as ischemia, hypoxia and reperfusion. Our aim was to investigate the ability of the amino acid glycine to prevent hepatic damage induced by injection of lipopolysaccharide and d-galactosamine (d-Gal), to modulate pro- and anti-inflammatory cytokine levels, and to improve survival. METHODS: Mice were challenged with an intraperitoneal injection of d-Gal (16 mg/mouse) and lipopolysaccharide (LPS, 1 microg/mouse). The intervention group also received an intraperitoneal injection of glycine (150 mg/kg) in two doses: 24 h before and just after LPS challenge. Serum cytokine levels were measured 2 h after challenge, and liver enzymes and histology were determined 16 h after LPS. Separate groups of mice received the same treatment and the survival rate was determined 24 h and ten days after endotoxin administration. In in vitro experiments, cultured mononuclear cells were stimulated by LPS, and TNF-alpha and IL-10 secretion were measured, in the presence or absence of glycine. RESULTS: In the glycine-treated mice, the serum levels of liver enzymes and TNF-alpha, the histologic necroinflammation score and the mortality rate were significantly reduced compared to control mice (P<0.001). Serum IL-10 levels in the glycine-treated mice were increased (P<0.01). In vitro studies in cultured lymphocytes isolated from either normal or glycine pretreated mice, demonstrated a significant and dose-dependent inhibition of LPS-induced TNF-alpha secretion and increase in IL-10 response after treatment with glycine (P<0.01). In conclusion, glycine reduces hepatic damage and improves survival rate in this mouse model of endotoxemia. The protective effect of glycine is associated with modulation of TNF-alpha and IL-10 secretion.

Chronic cholestasis associated with Turner's syndrome: 12 years of clinical and histopathological follow-up.

Clinically significant liver disease is probably a rare condition in Turner's syndrome and only a few cases of severe liver disease have been described. The natural history of patients with Turner's syndrome and elevated cholestatic liver enzymes is unclear. We report a case with a long history of intrahepatic cholestasis and without clinical or histopathological progression in 12 years of follow-up. Like some other reports our case suggests, also histologically, that the liver disease in these patients runs a benign course.