Meir Mizrahi

Adalimumab-induced autoimmune hepatitis.

Antitumor necrosis factor antibodies are widely used in the treatment of autoimmune diseases. We describe the occurrence of autoimmune hepatitis in a patient treated with adalimumab, a fully human IgG antibody against tumor necrosis factor, for psoriatic arthritis. The patient made a full recovery after discontinuation of adalimumab and treatment with steroids. This is the first reported case of adalimumab-induced autoimmune hepatitis.

Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells

Insulin resistance and metabolic syndrome are chronic inflammatory conditions that lead to hepatic injury and non‐alcoholic steatohepatitis (NASH). Bovine colostrum has therapeutic effects in a variety of chronic infections. However its effectiveness in NASH was never studied. Natural killer T (NKT) cells have been shown to be associated with some of the pathological and metabolic abnormalities accompanying NASH in leptin‐deficient (ob/ob) mice. In the present study, we used hyperimmune bovine colostrum to treat hepatic injury and insulin resistance and we also assessed the effects on NKT cells. We used ob/ob mice that were fed for 6 weeks with either 0·1 mg bovine colostrum prepared from non‐immunized cows, 0·1 mg hyperimmune colostrum raised against a bacterial lipopolysaccharide (LPS) extract or 0·001, 0·1 or 1 mg of immunoglobulin (Ig)G purified from hyperimmune colostrum (IgG–LPS). NKT cells were phenotyped by flow cytometry, and hepatic injury and insulin resistance were assessed by measuring fasting glucose levels, glucose tolerance tests and liver enzymes. Fat accumulation was measured in the liver and plasma. Oral administration of hyperimmune colostrums decreased alanine aminotransferase (ALT) serum levels and serum triglycerides compared to controls. Glucose intolerance was also improved by the hyperimmune colostrum preparations. These results were accompanied by a decrease in serum tumour necrosis factor (TNF)‐α levels following oral treatment with 0·1 or 1 mg of IgG–LPS. The beneficial effects of hyperimmune colostrums were associated with an increase in the number of splenic NKT cells. These data suggest that oral administration of hyperimmune colostrum preparations can alleviate chronic inflammation, liver injury and insulin resistance associated with NASH.

The Gut Mucosa as a Site for Induction of Regulatory T-Cells

Regulatory T lymphocytes (Tregs) are specialized for immune suppression and are important regulators of the immune response in various settings. Tregs actively suppress enteroantigen-reactive cells and contribute to the maintenance of intestinal immune homeostasis. Distinct Treg subsets coexist in the intestinal mucosa and mesenteric lymph nodes. Disturbances in Treg number and function are associated with immune-mediated disorders. Therefore, Tregs are potential targets for immunotherapies. The gut mucosal immune system is the largest lymphoid organ in the body. This site has continuous antigenic challenges from food antigens, antigens of the abundant normal bacterial flora, and pathogens. Despite this constant antigenic stimulation, controlled inflammatory responses and suppression of inflammation appear to be the rule. The gut immune system differentiates the antigenic signals from the high background noise of food and bacterial antigens. This tight regulation required to maintain homeostasis is achieved through multiple non-immune and immune factors. Oral tolerance is a mechanism in which the gastrointestinal immune system inhibits or promotes its reaction toward an orally administered antigen. Mucosal tolerance is attractive as an approach to the treatment of autoimmune and inflammatory diseases; the benefits of using an oral tolerance approach are: lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. Multiple mechanisms of tolerance are induced by oral antigen administration. Recent data suggest that oral antigen administration of antigens may promote activation of different types of regulatory T lymphocytes, enabling treatment of immune mediated disorders. This review summarizes the recent data on induction of regulatory T-cells by oral antigen administration as a possible mechanism of oral tolerance.

Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH

Background Nonalcoholic steatohepatitis (NASH) is considered to be part of the nonalcoholic fatty liver disorders and its incidence is increasing. Imm124-E (Immuron Ltd, Melbourne, Australia), containing hyperimmune bovine colostrum, has been shown to exert an immunomodulatory effect and to alleviate target organ damage in animal models of NASH. The aim of our study was to determine the safety and efficacy of oral administration of Imm124-E to patients with insulin resistance and NASH. Methods In an open-label trial, ten patients with biopsy-proven NASH and insulin resistance were orally treated with Imm124-E for 30 days. Results Oral administration of Imm124-E was safe, and no side effects were noted. Alleviation of insulin resistance was reflected by significantly improved hemoglobin A1c (HbA1c) values in all ten treated patients. For between five and eight responders, the following effects were noted: a decrease in fasting glucose levels; improved oral glucose tolerance test (OGGT) and homeostatic model assessment insulin resistance (HOMA) scores; and alleviation in lipid profile. These effects were accompanied by increased serum levels of glucagon-like peptide 1 (GLP-1), adiponectin and T regulatory cells. Conclusion Hyperimmune colostrum alleviates NASH.

Gastric stimulation for weight loss

The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatments outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity.

Assessment of insulin resistance by a 13C glucose breath test: a new tool for early diagnosis and follow-up of high-risk patients.

Background/AimsInsulin resistance (IR) plays an important role in the pathogenesis of diabetes and non-alcoholic fatty liver disease (NAFLD). Current methods for insulin resistance detection are cumbersome, or not sensitive enough for early detection and follow-up. The BreathID® system can continuously analyse breath samples in real-time at the point-of-care. Here we determined the efficacy of the BreathID® using the 13C-Glucose breath test (GBT) for evaluation of insulin resistance.MethodsTwenty healthy volunteers were orally administered 75 mg of 13C-glucose 1-13C. An oral glucose tolerance test (OGTT) was performed immediately; followed by serum glucose and insulin level determinations using GBT. GBT and OGTT were repeated following exercise, which alters insulin resistance levels.ResultsWithin-subject correlations of GBT parameters with serum glucose and serum insulin levels were high. Before and after exercise, between-subjects correlations were high between the relative insulin levels and the % dose recoveries at 90 min (PDR 90), and the cumulative PDRs at 60 min (CPDR 60). Pairwise correlations were identified between pre-exercise Homeostasis Model Assessment (HOMA) IR at 90 min and PDR 90; HOMA B (for beta cell function) 120 and CPDR 30; HOMA IR 60 and peak time post-exercise; and HOMA B 150 with PDR 150.ConclusionsThe non-invasive real-time BreathID® GBT reliably assesses changes in liver glucose metabolism, and the degree of insulin resistance. It may serve as a non-invasive tool for early diagnosis and follow up of patients in high-risk groups.

The Complex Role of Anticoagulation in Cirrhosis: An Updated Review of Where We Are and Where We Are Going

Venous thromboembolism (VTE) in cirrhotic patients is an increasingly encountered problem in the daily clinical practice; there is still a debate on the ideal measures to be followed for prophylaxis and treatment of VTE among this population. Although traditionally, liver cirrhosis has been considered a disease with hypocoagulability state and increasing bleeding tendency due to severe homeostatic disruption in liver disease, until recently there is increasing awareness and evidence that cirrhotic patients are not completely protected from thrombotic events although they have an elevated international normalized ratio and auto anticoagulation. Furthermore, hypercoagulability is now an increasingly recognized aspect of chronic liver disease (CLD), and the bleeding risk of VTE prophylaxis and treatment remains unclear. In this review, we provide an updated discussion on the mechanisms involved in hemostasis in CLD as well as on the benefits and complications of anticoagulant therapy in cirrhotic patients. Overall, sufficient evidence exists, promoting the use of anticoagulation in cirrhotic patients for both VTE prophylaxis and treatment in carefully selected patients after consideration of pharmacologic or endoscopic variceal bleeding prophylaxis.

β-Glycoglycosphingolipid-induced augmentation of the anti-HBV immune response is associated with altered CD8 and NKT lymphocyte distribution: A novel adjuvant for HBV vaccination

BACKGROUND Non-responsiveness towards the currently used hepatitis B virus (HBV) vaccine is a major problem in attempts to protect against HBV infection. Several methods have been tested to overcome the lack of an effective immune response towards HBV antigens. Adjuvants that augment the immunologic reaction are essential components of the vaccines. Beta-glycosphingolipids exert a natural killer T cell (NKT)-mediated immunomodulatory effect in various disorders. AIMS The aim of the present study was to test the ability of these compounds to augment the immune response towards HBV antigens, making them potential adjuvants for HBV vaccines. Six groups of mice were injected with different formulations of an HBV vaccine, along with various doses of beta-glucosylceramide (beta-GC), beta-lactosylceramide (beta-LC), or a combination of both (IGL) in different doses. The effect of beta-glycosphingolipids on the immune response towards HBV was tested by fluorescence-activated cell sorting analysis of hepatic and splenic NKT and CD8 lymphocytes, and serum cytokine levels. RESULTS Beta-sphingolipid treatment altered the hepatic NKT and CD8 lymphocyte distribution. beta-LC, beta-GC, and the combination of both augmented anti-HBV immunity, increasing both the anti-HBs titers and the percentage of mice exhibiting high titers. This effect was associated with altered hepatic NKT and CD8+ lymphocyte distribution. CONCLUSIONS In summary, beta-glycosphingolipids increased the anti-HBV immune response in association with an altered NKT and CD8 lymphocyte distribution, making beta-glycosphingolipids potential potent adjuvants for overcoming non-responsiveness to HBV vaccination and augmenting the anti-viral immune response.

Endotipsitis-persistent infection of transjugular intrahepatic portosystemic shunt: pathogenesis, clinical features and management.

Transjugular intrahepatic portosystemic shunt (TIPS) is in widespread use for the decompression of portal pressure. The entity of persistent TIPS infection, also known as ‘endotipsitis’ is a rare but serious complication of TIPS insertion. The exact definition of ‘endotipsitis’ is still debated, but involves persistent bacteremia and fever together with either shunt occlusion, or vegetation, or bacteremia in the presence of a patent shunt, when other sources of bacteremia have been ruled out. To date, approximately 40 cases of ‘endotipsitis’ have been described, with predominance for male and alcoholic hepatitis patients. The clinical course is variable, but fever and chills are a constant feature. Bacteremia, can either occur early (<120 days) or late (>120 days) after stent insertion, with some cases occurring many years after the procedure. Although no predominant bacterial species have been described in ‘endotipsitis’, staphylococci and other Gram‐positive bacteria are more commonly seen in early infection. The diagnosis of ‘endotipsitis’ is difficult and requires a high index of suspicion. A rigorous imaging work‐up to rule out other sources of endovascular infection is usually required including ultrasonography, computed tomography and echocardiography. Because removal of the infected stent is impractical, treatment is empirical and based on a prolonged course of antibiotics. If eligible, some patients may be referred for liver transplantation. The use of prophylactic antibiotics during the initial TIPS procedure is controversial, and despite the lack of evidence, prophylaxis is the common practice. The aim of this review was to describe the definition, clinical course, diagnosis, pathogenesis, microbiology, treatment and outcome of endotipsitis.

Randomized Comparison of 3 High-Level Disinfection and Sterilization Procedures for Duodenoscopes

BACKGROUND AND AIMS Duodenoscopes have been implicated in the transmission of multidrug-resistant organisms (MDRO). We compared the frequency of duodenoscope contamination with MDRO or any other bacteria after disinfection or sterilization by 3 different methods. METHODS We performed a single-center prospective randomized study in which duodenoscopes were randomly reprocessed by standard high-level disinfection (sHLD), double high-level disinfection (dHLD), or standard high-level disinfection followed by ethylene oxide gas sterilization (HLD/ETO). Samples were collected from the elevator mechanism and working channel of each duodenoscope and cultured before use. The primary outcome was the proportion of duodenoscopes with an elevator mechanism or working channel culture showing 1 or more MDRO; secondary outcomes included the frequency of duodenoscope contamination with more than 0 and 10 or more colony-forming units (CFU) of aerobic bacterial growth on either sampling location. RESULTS After 3 months of enrollment, the study was closed because of the futility; we did not observe sufficient events to evaluate the primary outcome. Among 541 duodenoscope culture events, 516 were included in the final analysis. No duodenoscope culture in any group was positive for MDRO. Bacterial growth of more than 0 CFU was noted in 16.1% duodenoscopes in the sHLD group, 16.0% in the dHLD group, and 22.5% in the HLD/ETO group (P = .21). Bacterial growth or 10 or more CFU was noted in 2.3% of duodenoscopes in the sHLD group, 4.1% in the dHLD group, and 4.2% in the HLD/ETO group (P = .36). MRDOs were cultured from 3.2% of pre-procedure rectal swabs and 2.5% of duodenal aspirates. CONCLUSIONS In a comparison of duodenoscopes reprocessed by sHLD, dHLD, or HLD/ETO, we found no significant differences between groups for MDRO or bacteria contamination. Enhanced disinfection methods (dHLD or HLD/ETO) did not provide additional protection against contamination. However, insufficient events occurred to assess our primary study end-point. ClinicalTrials.gov no: NCT02611648.