Hepatic expression of CCL2 in alcoholic liver disease is associated with disease severity and neutrophil infiltrates.

Serum levels and liver expression of CCL2 are increased in patients with alcoholic hepatitis (AH). In an experimental model of alcoholic liver disease (ALD), CCL2 was implicated in proinflammatory cytokines activation and hepatic lipid metabolism, but its role in human disease is currently unknown. In a large cohort of ALD patients, we analysed plasma levels and liver expression of CCL2 and their association with liver disease severity and histological lesions. We also studied the relationship between -2518 A > G CCL2 and CCR2 190 A/G polymorphisms and severity of ALD. We show that CCL2 plasma levels are increased in ALD patients compared with healthy subjects. AH patients had significantly higher plasma levels and hepatic expression of CCL2 than patients without AH. Plasma levels and hepatic expression of CCL2 were associated with disease severity. CCL2 liver expression was correlated with neutrophil infiltrate and interleukin (IL)-8 expression, but not with steatosis. Moreover, there were more G-allele carriers of -2518 A > G CCL2 polymorphism in severe AH patients than in other ALD patients. Our results demonstrate that CCL2 is increased in ALD, particularly in severe forms, and suggest a role for CCL2 in the pathogenesis of ALD via neutrophil recruitment.

Percutaneous endoscopic jejunostomy in patients with gastroparesis following lung transplantation: feasibility and clinical outcome.

The aim of the present study was to describe success rates, complications, and outcome in patients who underwent percutaneous endoscopic jejunostomy (PEJ) because of gastroparesis due to previous lung transplantation. Between October 2008 and May 2011, 14 attempts at PEJ placement were made in 12 patients in our center. Of the 14 attempts, 11 were successful, giving a technical success rate of 78.6 %. Median duration of followup was8.5 months (2­15 months). No immediate complications were reported. Two severe complications occurred during follow up (one volvulus and one jejunocolic fistula). Jejunal nutrition was well tolerated in most of patients (9 /10). PEJ insertion is a feasible technique, which could help to provide nutritional support for patients with gastroparesis and previous lung transplantation.

Creation of a therapeutic digestive endoscopy suite in Senegal: renovation, training and university certification. Results of a Belgian-Senegalese inter-university project.

Therapeutic digestive endoscopy did not exist in sub-Saharan Africa before 2005. However, the prevalence of digestive diseases that could potentially benefit from basic endoscopic treatment is very high in this region. Portal hypertension with variceal bleeding and severe dysphagia associated with benign or malignant upper gastrointestinal tract diseases are prominent in these countries. The aim of the Project described in this report was to create a digestive endoscopy facility in Dakar (Senegal, West Africa), that would also provide local training in therapeutic endoscopy to doctors and nurses and facilitate regional autonomy with the opening of a University Certification in Gastroenterology. It took about 10 years to achieve these targets - 5 years to prepare realistic aims that took into account local needs, available local resources, and funding, and 4 years for the Project itself (2005-2009). At the present time, Senegalese colleagues and nurses are autonomous for basic therapeutic procedures in the upper and lower gastrointestinal tract. Two years after the end of funding, the rate of therapeutic activity has increased from 0% in 2005 to 12 % of digestive endoscopic activity in 2011. Key points of success were preparation, confidence of medical personnel, university involvement, shared funding, local multidisciplinary training, and facilitation of autonomy. Belgian healthcare workers were present on-site in Dakar for a total of about 6 months over the 4-year Project period, with an annual budget of less than € 80000. The Project has enabled an efficient North-South collaboration with a minimal budget, which has changed the healthcare provision of digestive endoscopy in Senegal, and has also provided autonomy, and facilitated the development of South-South cooperation.

A new partially covered nitinol stent for palliative treatment of malignant bile duct obstruction: a multicenter single-arm prospective study.

BACKGROUND AND STUDY AIMS: Covered self-expanding metal stents (SEMSs) have proven effective for managing malignant bile duct strictures and may reduce risk of tumor ingrowth. A new nitinol partially covered biliary SEMS was prospectively evaluated. PATIENTS AND METHODS: 70 patients with inoperable extrahepatic biliary obstructions were enrolled in a prospective multicenter trial, and followed up to 6 months or death, whichever came first. Primary endpoint was adequate palliation defined as absence of recurrent biliary obstruction from partly covered SEMS placement to end of follow-up. RESULTS: Mean age of the patients was 69 years and 52 % were men. Pancreatic carcinoma was present in 68 %. One stent was placed in 67 patients, two patients received two, and in one patient a guide wire could not traverse the stricture. In 55 % of patients the SEMS was inserted de novo and in 45 % for exchange with a plastic stent. Technical success was 97 %. At 6 months, 62 % of patients were free of obstructive symptoms; compared with baseline the mean number of symptoms per patient was significantly reduced (3.1 at baseline, 0.6 at 6 months; P < 0.0001) and total bilirubin levels dropped by 73 %. There were four cases of recurrent biliary obstruction, due to stent migration (2), tumor overgrowth (1), and sludge formation (1). Device-related complications included cholecystitis (3), right upper quadrant pain (1), and moderate pancreatitis (1). No tumor ingrowth was reported. CONCLUSIONS: This new partially covered nitinol SEMS is easily inserted, and safe and effective in the palliation of biliary obstruction secondary to malignant bile duct strictures.

An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease.

In chronic liver disease, high circulating interleukin (IL)-6 contrasts with a poor acute phase response. We evaluated the impact of liver and circulating IL-6-receptor (IL-6R) forms on IL-6 bioactivity in chronic liver disease. IL-6, soluble IL-6-receptor and sgp130 levels were assayed in plasma from 45 patients with alcoholic liver disease, 84 with hepatitis C virus (HCV) infection undergoing transjugular liver biopsies and 15 healthy subjects. IL-6R mRNA was quantified on liver extracts from 54 patients with alcoholic liver disease with or without cirrhosis and 18 HCV-infected patients. The effect of gp130-Fc on fibrinogen secretion induced by IL-6 trans-signalling was evaluated on hepatocyte cultures. Levels of plasma IL-6 and sgp130, but not soluble IL-6R, increased with the stage of chronic liver disease, and correlated significantly with disease severity. Alcoholic liver disease patients had higher plasma IL-6 levels than hepatitis C, but lower liver IL-6R expression. In alcoholic and HCV-related liver diseases, liver IL-6R expression decreased with advanced fibrosis stage. In vitro, on hepatocytes, gp130-Fc blunted the acute phase response while soluble IL-6R enhanced IL-6 stimulation. In advanced chronic liver disease, high plasma IL-6 is associated with low liver IL-6R expression. This situation enables high plasma sgp130 to act as a major negative regulator of liver IL-6 trans-signalling, as demonstrated functionally here on hepatocytes. This might explain the poor acute phase response induced by IL-6 in chronic liver disease.

Endoscopic treatment of postoperative enterocutaneous fistulas after bariatric surgery with the use of a fistula plug: report of five cases.

Anastomotic leaks frequently occur after bariatric surgery and their management includes different options. The present study describes the management of enterocutaneous fistulas in patients in whom surgical or endoscopic treatments have failed, by insertion of a biomaterial (Surgisis fistula plug) to facilitate healing of the gastrocutaneous fistula. Five patients with leaks after bariatric surgery were treated. All patients had undergone previous failed surgical or endoscopic attempt(s) at closure. Our technique entailed insertion of the Surgisis fistula plug into the fistula tract by a "rendezvous" procedure, via both percutaneous and endoscopic routes. The data were collected retrospectively. Initially, two patients were treated by fistula plug alone and three received fistula plug plus a self-expanding stent. In two patients, cutaneous fistula outflow ceased within a few days. The other three patients required one additional endoscopic procedure. At the end we observed healed leaks in four of the five patients (80 %). The median follow-up duration was 18 months. In conclusion, the combined therapy consisting of fistula plug implantation with optional stenting helps closure in these difficult refractory cases of gastrocutaneous fistula.

Intraductal optical coherence tomography during endoscopic retrograde cholangiopancreatography for investigation of biliary strictures.

BACKGROUND AND STUDY AIMS: Optical coherence tomography (OCT) uses infrared light reflectance to produce high-resolution cross-sectional tissue images. The aim of this study was to demonstrate the feasibility of biliary intraductal OCT during endoscopic retrograde cholangiopancreatography (ERCP) and to assess the potential of the method to detect malignant biliary strictures. PATIENTS AND METHODS: Thirty-seven patients with biliary strictures were studied during therapeutic ERCP. Malignant strictures were defined as those that demonstrated malignant cells in brushing and/or biopsy specimens, and/or endoscopic ultrasound-guided fine-needle aspiration and/or surgery. Strictures that did not have malignant cells in resected specimens and were without clinical/radiological evidence of disease progression for at least a 12-month follow-up period were considered as benign. Two OCT criteria for malignancy were considered: unrecognizable layer architecture; and presence of large, nonreflective areas compatible with tumor vessels. Sensitivity and specificity for brushings/biopsies as well as OCT criteria were calculated. RESULTS: Nineteen patients had malignant and 16 had benign strictures. In two patients, OCT assessment could not be performed due to tight strictures. Malignancy was confirmed by biliary brushings/biopsies in 12/19 (63 %) patients. OCT revealed that two malignancy criteria were encountered in 10/19 (53 %) and at least one criterion in 15/19 (79 %) patients with malignant strictures. No patient with benign stricture met both criteria and 5/16 met one criterion (31 %). Combining brushings/biopsy with the observation of at least one OCT criterion resulted in the diagnosis of malignancy in 16/19 (84 %) patients. CONCLUSIONS: OCT may improve the sensitivity and diagnostic accuracy of biliary brushings/biopsies alone.

Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

Transoral gastroplasty is safe, feasible, and induces significant weight loss in morbidly obese patients: results of the second human pilot study.

BACKGROUND AND STUDY AIMS: Bariatric surgical treatments have been proven to induce long-term weight loss in morbidly obese patients, but complications are relatively frequent. We recently reported a first human multicenter trial assessing the safety, feasibility, and weight loss results of the Transoral Gastroplasty (TOGA) system (Satiety Inc., Palo Alto, CA) at 6 months. Here we report the 6-month results of the second phase of the pilot trial with the TOGA system, with technical improvements to the device. PATIENTS AND METHODS: Patients met established criteria for bariatric surgery. The TOGA system, a set of transoral endoscopically guided staplers, was used to create a stapled restrictive pouch along the lesser curvature of the stomach. Follow-up was at 1 week and at 1, 3, and 6 months. At 3 months, re-treatment consisting in additional distal restrictions was allowed if necessary. RESULTS: Data were available for 11 patients in our center (7 female, mean age 44.2 years, mean body mass index 41.6). The procedure was completed safely in all patients. There were no serious adverse events. Mean excess weight loss was 19.2 %, 33.7 %, and 46.0 % at 1, 3, and 6 months, respectively. Average body mass index decreased from 41.6 before treatment to 33.1 at 6 months. Absolute mean weight loss was 9.9 kg, 17.5 kg, and 24.0 kg at 1, 3, and 6 months, respectively. A dramatic improvement in quality-of-life measures was observed in all patients. CONCLUSIONS: This second pilot trial confirmed the feasibility and safety of transoral gastroplasty. The early results and technical improvements reported in the present study are encouraging in terms of safety, early weight loss, and quality of life, and clearly allowed multicenter trials, which are planned to start soon.

Safety, feasibility and weight loss after transoral gastroplasty: First human multicenter study.

OBJECTIVE: To evaluate the safety and feasibility in human subjects of a new transoral restrictive procedure for the treatment of obesity. METHODS: The protocol was approved by the institutional review boards (IRBs) of both centers involved, and all patients gave informed consent. Patients met established inclusion criteria for bariatric surgery. The TOGa system (Satiety Inc., Palo Alto, CA), a set of transoral endoscopically guided staplers, was used to create a stapled restrictive pouch along the lesser curve of the stomach. Patients were hospitalized overnight for observation and underwent barium upper gastrointestinal (UGI) the next morning. Post procedure, all patients were placed on a liquid diet for 1 month and asked to begin an exercise program. Follow-up was carried out at 1 week and 1, 3, 4, 5, and 6 months. RESULTS: Twenty one patients were enrolled [17 female, age 43.7 (22-57) years, BMI 43.3 (35-53) kg/m(2)]. Device introduction was completed safely in all patients. There were no serious adverse events (AEs). The most commonly reported procedure or device related adverse events were vomiting, pain, nausea, and transient dysphagia. At 6 month endoscopy, all patients had persistent full or partial stapled sleeves. Gaps in the staple line were evident in 13 patients. Patients lost an average 17.6 pounds at 1 month, 24.5 pounds at three months, and 26.5 pounds at 6 months post-treatment [excess weight loss (EWL) of 16.2%, 22.6%, and 24.4%, respectively]. CONCLUSIONS: There is great interest in new procedures for morbid obesity that could offer lower morbidity than current options. Early experience with the TOGa procedure indicates that this transoral approach may be safe and feasible. Further experience with the device and technique should improve anatomic and functional outcomes in the future. Additional studies are underway.

Endotherapy including temporary stenting of fistulas of the upper gastrointestinal tract after laparoscopic bariatric surgery.

BACKGROUND: Reoperations for complications of bariatric surgery are associated with high morbidity and mortality. It is not known whether endoscopic treatment may reduce reoperation rates. METHODS: Twenty-one patients underwent endoscopic treatment for persisting large anastomotic leaks before considering redo surgery. Eight patients had a gastric bypass, eight had a sleeve gastrectomy combined with a duodenal switch (SDS), four had a sleeve gastrectomy alone, and one had a Scopinaro procedure (biliopancreatic diversion). Fistulas were gastrocutaneous in 15 patients, duodenocutaneous in 2, gastroperitoneal in 3, and gastrobronchial in 1. Partially covered self-expanding metal stents (SEMSs) were used, followed by additional endoscopic procedures if the SEMS failed. SEMSs were removed by traction alone or by insertion of a self-expanding plastic stent (SEPS) followed by extraction of both stents together. RESULTS: SEMS insertion led to 62 % (13/21) primary closures. Complementary endoscopic treatment led to 4 secondary closures. Total success rate was 81 % (17/21). Three patients in whom SEMSs failed underwent reoperation but died during postoperative follow-up; one patient died from pulmonary embolism before SEMS extraction. The success rates of endotherapy were 100 % (8/8) in the gastric bypass group, 62.5 % (5/8) in the SDS group, 75 % (3/4) in the sleeve gastrectomy group, and 100 % (1/1) for the Scopinaro procedure. Gastrocutaneous fistulas on sleeve sutures were successfully treated in 60 % of cases (6/10), while other anastomotic fistulas were successfully treated in 100 % of cases (11/11) ( P = 0.0351). CONCLUSIONS: Endoscopic treatment using SEMSs for complications of bariatric surgery is feasible. Healing of severe leaks was obtained in 81 % (17/21) of patients, avoiding high-risk reintervention. Gastrocutaneous fistulas on a sleeve suture are the most difficult condition to treat.

Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria.

BACKGROUND: We report a case of domino liver transplantation using the liver harvested from a patient who underwent a combined liver and kidney transplantation for primary hyperoxaluria (PH). METHOD: A cadaveric liver transplantation was performed in a 19-year-old man with PH. In a second step, the PH liver harvested from the first patient was transplanted in a 69-year-old man with hepatitis C-related cirrhosis, not a candidate for a classic liver graft owing to multifocal hepatocellular carcinoma. RESULTS: At 8 months after transplantation, the domino recipient has normal hepatic function and no signs of tumoral recurrence, but he progressively developed hyperoxalemia, hyperoxaluria, and renal insufficiency. CONCLUSION: Regarding the favorable postoperative clinical evolution, domino liver transplantations using livers from PH patients may represent a new opportunity for marginal candidates for liver transplantation. However, the progressive renal insufficiency expected in such domino recipients should limit this procedure to selected cases.

Selenium deficiency and thyroid fibrosis. A key role for macrophages and transforming growth factor beta (TGF-beta).

Free radical damage and fibrosis caused by selenium deficiency are thought to be involved in the pathogenesis of myxoedematous cretinism. So far, no pathway explains the link between selenium deficiency and tissue fibrosis. Pharmacological doses of iodine induce necrosis in iodine-deficient thyroids. Necrosis is much increased if the glands are also selenium-deficient, which then evolve to fibrosis. This rat model was reproduced to explore the role of selenium deficiency in defective tissue repair. At first, proliferation indexes of epithelial cells and fibroblasts were comparable between selenium-deficient and control groups. Then, in selenium-deficient thyroids the inflammatory reaction was more marked being mainly composed of macrophages. The proliferation index of the epithelial cells decreased, while that of the fibroblasts increased. These thyroids evolved to fibrosis. TGF-beta immunostaining was prominent in the macrophages of selenium-deficient rats. Anti TGF-beta antibodies restored the proliferation indexes, and blocked the evolution to fibrosis. In selenium deficiency, an active fibrotic process occurs in the thyroid, in which the inflammatory reaction and an excess of TGF-beta play a key role.

Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response.

AIM: To evaluate the efficacy of early interferon alpha-2b in non-post-transfusion acute hepatitis C virus: a prospective study with historical comparison. PATIENTS: Group A: 28 patients prospectively treated for acute hepatitis C virus with daily regimen of interferon 5 million units for 2 months. Group B: historical series of 16 patients with untreated acute hepatitis C virus. RESULTS: There was no significant difference between the two groups with regard to gender, age, icterus, alanine aminotransferase, or genotypes. In group B, hepatitis spontaneously resolved in three of 16 (19%) patients (follow-up 1-7 years). In group A, 21 of 25 patients became sustained viral responders (75%; P = 0.0003 vs. group B). Factors include not predictive of sustained viral response: age, gender, sources of infection, presence of icterus, alanine aminotransferase peak, bilirubin peak, incubation period, presence of hepatitis C virus antibodies at presentation, or genotypes. The time from presentation to the start of therapy was, however, significantly shorter in sustained viral responders (43 +/- 31 days) than in relapsers or non-responders (88 +/- 52 days) (P = 0.016). CONCLUSIONS: Early treatment of acute hepatitis C virus with interferon prevents chronicity. A short waiting time from presentation to treatment appears as the most relevant predictive factor for sustained response.

N-acetylcysteine decreases severity of acute pancreatitis in mice.

Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.

Right hepatic artery pseudoaneurysm and cystic duct leak after laparoscopic cholecystectomy.

Laparoscopic cholecystectomy (LC) seems to be associated with an increased risk of biliary or vascular injuries. Hepatic artery pseudoaneurysms (HAP) are rare complications of LC. HAP can occur in the early or late postoperative period. Patients with HAP present with abdominal pain, hemobilia, and liver function test (LFT) alterations. We report the case of a patient who was affected with a cystic duct stump leak associated with a right HAP and was treated by endoscopic biliary drainage and angiographic coil embolization.