An Israeli national survey on ischemic colitis induced by pre-colonoscopy bowel preparation (R1).

Background and study aims: Ischemic colitis (IC) may occur as a complication of colonoscopy. The aim of this study was to characterize patients with IC that occurred after exposure to bowel preparation laxatives, prior to an elective colonoscopy. Patients and methods: A survey among Israeli gastroenterologists. Information was collected regarding individual cases. Results: Eight patients, who developed IC after bisacodyl ingestion that was taken as part of pre-colonoscopy bowel preparation protocol, were reported. In all patients, severe abdominal pain and/or hematochezia started shortly after the ingestion of the first dose of bisacodyl. IC was found in 7 patients during the planned colonoscopy and in 1 patient using computerized tomography. All patients received supportive treatment and recovered. Conclusions: IC induced by bisacodyl is a rare phenomenon. Regardless of being rare, we would advise withholding bisacodyl bowel preparation in elderly subjects with risk factors for IC that are scheduled for a colonoscopy.

Severe hepatocytotoxicity linked to denosumab.

OBJECTIVE: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab. CASE REPORT: A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis. CONCLUSIONS: We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.

Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial.

Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

Metabolic syndrome is associated with increased prevalence of advanced colorectal polyps.

OBJECTIVES: To examine the association between metabolic syndrome (MetS) and/or its components and colorectal neoplasms in adult population undergoing screening colonoscopy. DESIGN: Cross-sectional study. SETTING: Institute of Gastroenterology, Kaplan Medical Center, Rehovot, Israel. PARTICIPANTS: Two hundred ninety nine consecutive outpatients undergoing screening colonoscopy. MEASUREMENTS: MetS was determined according to the Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) criteria. Blood test results and other clinical data were retrieved from the electronic medical records. RESULTS: In 94 patients (31.8%) polyps were detected. Thirty two (34%) of the polyps were advanced. Eighty one percent of patients with an advanced polyp met the criteria for MetS. About the same MetS prevalence (84%) was found in men, but not in women. An advanced polyp was detected in 14% of patients with MetS, compared to 5% of patients without MetS. Odds ratio for having an advanced polyp in a patient with MetS compared to a patient without MetS was 10.64. CONCLUSION: MetS was found to be a risk factor for advanced polyps. This association is suggestive of the need that patients with MetS should be urged to have a screening colonoscopy.

Combining physostigmine with meperidine for sedation and analgesia during colonoscopy.

BACKGROUND AND STUDY AIM: Opiate or benzodiazepine drugs are often used during colonoscopy, but they are associated with respiratory depression and prolonged recovery. Physostigmine, a tertiary anticholinesterase agent, is known to enhance analgesia and to reverse the central nervous system depressant effects of these drugs. This study compared the effect of giving meperidine alone with the effect of giving meperidine in combination with physostigmine in patients who were undergoing complete colonoscopy. PATIENTS AND METHODS: A total of 44 outpatients undergoing elective colonoscopy were randomly assigned to receive analgesia with either meperidine 0.5 mg/kg intravenously (group 1, n=24) or physostigmine 10 micrograms/kg intravenously, followed 5 minutes later by meperidine 0.5 mg/kg intravenously (group 2; n=20). The patients were assessed with regard to oxygen saturation, hemodynamic changes, pain perception and sedation scores, readiness to go home, and adverse effects. RESULTS: The group 1 patients' oxygen saturations consistently fell, both during the procedure and in the recovery period; in group 2, oxygen saturations remained stable throughout the procedure and recovery period (95.88%+/-0.99 vs. 98.15+/-0.99, P<0.001). Patients in group 2 reported lower pain perception scores during the procedure (measured using a visual analog scale) than patients in group 1 (1.46+/-0.31 vs. 1.75+/-0.41; F1,42=6.484, P<0.015) and were less sedated during recovery (F1,41=6.56, P<0.015). No significant differences were found between the two groups with regard to heart rate or arterial blood pressure. All patients in group 2 were ready to go home after 25 minutes in the recovery area; three patients in group 1 were not ready to leave at 25 minutes and left the facility after 60 minutes. Four patients suffered from minor side effects of physostigmine (sweating and nausea). CONCLUSIONS: Combining physostigmine with meperidine as preparatory treatment for patients undergoing colonoscopy prevents respiratory depression, improves analgesia, and shortens recovery time, with only mild side effects.

Early colonoscopy in patients with acute diverticulitis: results of a prospective pilot study.

BACKGROUND AND STUDY AIMS: Outcomes following early colonoscopy in patients with acute diverticulitis have not previously been studied. The present study describes the effects of early colonoscopy in patients with acute diverticulitis. PATIENTS AND METHODS: Consecutive patients hospitalized for acute diverticulitis were included in the study. In the first phase, patients with adjacent peridiverticular air or fluid on computed tomography (CT) were excluded. In the second phase of the study, only patients with free intraperitoneal air were excluded. RESULTS: The study population consisted of 107 patients. During the first phase of the study, 49 patients were included; 10 were excluded because of peridiverticular air or fluid. The remaining 39 patients underwent uneventful colonoscopy. During the second phase of the study, 58 patients were included; four were excluded because of free air in the peritoneum. The remaining 54 patients underwent colonoscopy, and perforation of the sigmoid colon occurred in one patient with peridiverticular air. Complete colonoscopy to the cecum or to the obstructing tumor was achieved in 76 patients (81.7 %). A second colonoscopy performed 6 weeks later in 16 of the remaining 17 patients was successfully completed. Findings during the first colonoscopy were polyps in nine cases, polyp with infiltrating adenocarcinoma in one, obstructing adenocarcinoma in one, and a bone trapped in a diverticulum in another one. The latter two patients had a more protracted course and were clearly the ones who benefited most from the colonoscopy. CONCLUSIONS: Early colonoscopy in patients with acute diverticulitis may alter the working diagnosis and be of therapeutic value. The rate of cecal intubation is lower and the perforation rate appears to be higher. A clear-cut indication therefore has to be evident clinically.

Role of circulating soluble CD40 as an apoptotic marker in liver disease.

OBJECTIVES: To measure levels of soluble CD40, a laboratory marker of apoptosis in patients with liver disease, determine its origin, and correlate the findings with disease activity and histology. DESIGN: Laboratory research study with comparison group. SETTING: Liver Institute, Laboratory of HLA Typing and Histopathology Department, Rabin Medical Center, Israel. SUBJECTS: One hundred ten patients with liver disease and 20 healthy controls. METHODS: Serum samples were collected from all patients; in addition, paired hepatic and portal vein samples were collected from 23 patients, and bile samples from 5 patients. Soluble CD40 was measured with an enzyme-linked immunosorbent assay. Apoptotic cells in liver tissue were identified by morphological criteria and quantified with the TUNEL assay. RESULTS: Soluble CD40 concentration was significantly higher in patients with liver disease than controls (mean 112.9 +/- 197.2 pg/ml vs. 24.2 +/- 9.1 pg/ml, p = 0.0001), with highest levels in the chronic viral hepatitis group (mean 131.7 +/- 137.5 pg/ml, p = 0.0001). Levels of sCD40 were correlated with serum creatinine, alkaline phosphatase, alpha-feto protein, and the apoptotic index. In the 23 paired samples, CD40 level was higher in the hepatic vein (mean 74.9 +/- 114.5 pg/ml) than the portal vein (mean 51.6 +/- 67.9 pg/ml); it was highly detectable in bile (mean 115.6 +/- 119.6 pg/ml, p = 0.0123). Untreated patients with chronic viral hepatitis (B and C) had higher levels (mean 106.2 +/- 76.5 pg/ml) than treated patients (mean 59.3 +/- 68.6 pg/ml, p = 0.049). CONCLUSIONS: Levels of soluble CD40 increase in different types of liver disease. It probably derives from the liver and is secreted into the bile. Levels correlate with the apoptotic index and are affected by antiviral treatment. Soluble CD40 may serve as a serum marker of apoptosis in liver disease.

Oral signs and symptoms in relation to disease activity and site of involvement in patients with inflammatory bowel disease.

OBJECTIVE: An assessment of oral symptoms and signs in patients with inflammatory bowel disease (IBD). METHODS: Fifty-four patients with IBD, 34 with Crohn's disease (CD) and 20 with ulcerative colitis (UC) participated in the study. Forty-two patients without gastrointestinal disease or complaints attending the orthopedic clinic served as controls. Each patient completed a written questionnaire and was subjected to an oral examination. RESULTS: The main findings of this study were the higher prevalence of halitosis (50% vs 10% P < 0.0008), nausea (30% vs 7%, P < 0.017) and reflux (regurgitation) (45% vs 17%, P < 0.017) in patients with UC, and nausea (50% vs 7%, P < 0.026), dry mouth and halitosis (29% vs 10%, P < 0.026) and vomiting (41% vs 5%, P = 0.01) in patients with CD, compared with controls. Patients with active CD had a higher prevalence of dry mouth, nausea and vomiting compared with controls (46, 69 and 54% vs 10, 7 and 5%, respectively, P < 0.001) and of reflux compared with non-active CD (46% vs 5%, P < 0.001). Patients with active UC had a higher prevalence of halitosis and regurgitation (50 and 60% vs 10 and 17%, P < 0.001) compared with controls. CONCLUSIONS: The present study demonstrates increased frequency of oral signs and symptoms in patients with IBD. Patients with active CD had more oral signs compared with non-active CD patients. Manifestations such as nausea, vomiting, regurgitation and dry mouth may have detrimental effects on teeth and soft tissues of the oral cavity. Communication between gastroenterologists and dentists is imperative for success of the overall treatment of their patients.

Triazolo- and tetrazolopyridazine derivatives and their hypotension and heart rate activity.

6-Chloro-, 6-morpholino- and 6-N-methylpiperazino-1,2,4-triazolo[4,3-b]- or 1,2,3,4-tetrazolo[1,5-b]pyridazines [II-VII] were synthesized from 3-chloro-6-hydrazinopyridazine [I]. Positive effect of a series of tetra- and triazolopyridazines for lowering blood-pressure without affecting the heart rate was found in tests on rats. Their lipophilicity and other properties are discussed.

Lung involvement and enzyme replacement therapy in Gaucher's disease.

Symptomatic lung involvement in Gaucher's disease is relatively rare, being restricted to patients with other severe manifestations. We describe our experience in eight of 411 patients in our referral clinic, who presented with prominent pulmonary signs or symptoms. There were four adults and four children; all have been successfully treated with enzyme replacement therapy. Routine means of monitoring pulmonary status including clinical assessment, chest X-ray, pulmonary function tests, and high-resolution CT (HRCT) were used. Enzyme treatment resulted in decreased hepatosplenomegaly, improved haematological parameters, and increased well-being; There was decreased clubbing and decreased dyspnoea in some of the patients, although on radiology, lung pathology had not normalized. All four children showed improved respiratory compliance, with significant improvement of the radiological findings in one and unchanged disease in the others. Two adults showed improvement in oxygen saturation but worsening of pulmonary hypertension. On chest X-ray, both had increased interstitial markings; one had gradual progression of pulmonary artery accentuation and fine interstitial stable pattern on HRCT. The other two adults had no change in lung function or on chest X-ray, but on HRCT there was apparent improvement in one patient. There is great heterogeneity in presentation and response to enzyme therapy in patients with Gaucher's disease and symptomatic lung involvement. Clinically, some benefited significantly from enzyme therapy, but in contrast to the dramatic reduction in organomegaly, there was no normalization in pulmonary function or lung architecture.

The effect of culture results for Helicobacter pylori on the choice of treatment following failure of initial eradication.

BACKGROUND: Current treatment for the eradication of Helicobacter pylori in patients with peptic disease is based on the combination of antibiotic and anti-acid regimens. Multiple combinations have been investigated, however no consensus has been reached regarding the optimal duration and medications. OBJECTIVES: To assess the efficacy of two treatment regimens in patients with peptic ulcer disease and non-ulcer dyspepsia, and to determine the need for gastric mucosal culture in patients failing previous treatment. METHODS: Ninety patients with established peptic ulcer and NUD (with previously proven ulcer) were randomly assigned to receive either bismuth-subcitrate, amoxycillin and metrnidazole (BAM) or lansoprasole, clarithromycine and metronidazole (LCM) for 7 days. Patients with active peptic disease were treated with ranitidine 300 mg/day for an additional month. RESULTS: Eradication failed in 8 of the 42 patients in the BAM group and in 2 of the 43 patients in the LCM group, as determined by the 13C urea breath test or rapid urease test (19% vs. 5%, respectively, P = 0.05). Five of these 10 patients were randomly assigned to treatment with lansoprazole, amoxycillin and clarithromycin (LAC) regardless of the culture obtained, and the other 5 patients were assigned to treatment with lansoprazole and two antibacterial agents chosen according to a susceptibility test. Eradication of H. pylori was confirmed by the 13C urea breath test. The same protocol (LAC) was used in all patients in the first group and in four of the five patients in the second group. The culture results did not influence the treatment protocol employed. CONCLUSIONS: Combination therapy based on proton pump inhibitor and two antibiotics is superior to bismuth-based therapy for one week. Gastric-mucosal culture testing for sensitivity of H. pylori to antibiotics is probably unnecessary before the initiation of therapy for patients with eradication failure.

The natural course of upper gastrointestinal submucosal tumors: an endoscopic ultrasound survey.

BACKGROUND: Differentiating between benign and malignant submucosal tumors is difficult. Moreover, the natural course of benign-appearing SMTs is not clearly elucidated. OBJECTIVES: To evaluate the natural course of upper gastrointestinal SMTs by endoscopic endosonography. METHODS: We followed 25 consecutive patients with small (< 40 mm) SMTs for a mean period of 19 months. Evaluation included maximal tumor diameter, internal echo pattern, and outer margin of lesions. RESULTS: Follow-up revealed no change in echo features in 24 of 25 patients (96%). In only one patient a homogenous hypoechoic smooth margin lesion converted to a non-homogenous tumor with an irregular outer margin. This lesion also increased in size from 30 to 38 mm. On surgical removal this tumor was found to be a stromal tumor with high malignant potential. CONCLUSIONS: Most small SMTs do not change during a period of 19 months and a conservative policy of surveillance is warranted.