Jannis Kountouras

Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of common hepatic disorders in western countries, with multiple consequences and its incidence is paralleling the increasing numbers of overweight and obese individuals worldwide. The pathogenesis of NAFLD is thought to be related mainly with insulin resistance (IR) syndrome and oxidative stress; the latter resulting from mitochondrial fatty acids (FFAs) oxidation, nuclear factor-kappaB (NFkappaB)-dependent inflammatory cytokine expression and adipocytokines may promote hepatocellular damage, inflammation, fibrosis and progressive liver disease. Adipocytokines and other recognized cytokines produced partially by inflammatory cells infiltrating adipose tissue, play an important role in the pathogenesis of IR and NAFLD, through complex and interactive paracrine and endocrine mechanisms. Some adipocytokines, including adiponectin and leptin decrease IR, while others, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and resistin enhance IR. The multi-hit hypothesis provides a model that summarizes the complex factors and interactions leading from adipocytokines, FFAs metabolism and IR to NAFLD. This review outlines the pathways involved in adipocytokines, IR and NAFLD sequence; the first part describes the impaired IR pathway leading to NAFLD and the second part the mechanisms by which adipocytokines influence IR and NAFLD development and progression. Understanding these complex mechanisms has evoked new therapeutic approaches, which may provide promising results to date.

Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis.

Hypoadiponectinemia might represent a risk factor for nonalcoholic fatty liver disease (NAFLD). We performed a systematic review and meta-analysis to evaluate the serum total adiponectin levels in patients with simple nonalcoholic fatty liver (NAFL), those with nonalcoholic steatohepatitis (NASH), and controls. Data were extracted from PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases (up to December 2009). The main outcome was the weighted mean differences (WMDs) in adiponectin between comparison groups. Twenty-eight studies were included in the systematic review. A meta-analysis of 27 studies that reported data on 2243 subjects (698 controls and 1545 patients with NAFLD) was performed. Controls had higher serum adiponectin compared with NAFL patients (12 studies, random-effects WMD [95% confidence interval {CI}] = 3.00 [1.57-4.43], I² = 80.4%) or NASH patients (19 studies, random-effects WMD [95% CI] = 4.75 [3.71-5.78], I² = 84.1%). The NASH patients demonstrated lower adiponectin compared with NAFL patients (19 studies, random-effects WMD [95% CI] = 1.81 [1.09-2.53], I² = 71.7%). By performing a meta-regression analysis, body mass index, age, sex, and type 2 diabetes mellitus failed to account for heterogeneity. However, the performance of liver biopsy on controls had significant effect on the outcome and accounted for 76.7%, 85.5%, and 22.8% of the between-study variance for comparisons between controls vs NAFLD, NAFL, and NASH patients, respectively. Based on liver histology, serum adiponectin levels are similar in NAFL patients and controls, but hypoadiponectinemia may play an important pathophysiological role in the progression from NAFL to NASH.

The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease.

Non‐alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD.

The association between Helicobacter pylori infection and insulin resistance: a systematic review.

Background:  Helicobacter pylori infection has been associated with diverse extradigestive morbidity, including insulin resistance (IR) syndrome. The aim of this systematic review was to summarize the epidemiologic evidence concerning the association between H. pylori infection and IR quantitative indexes.

Irisin in patients with nonalcoholic fatty liver disease

OBJECTIVE Irisin is a recently discovered myokine proposed to increase thermogenesis-related energy expenditure and improve metabolism. We aimed to comparatively evaluate serum irisin levels in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) vs. controls and study their association with disease severity. METHODS Fifteen and 16 consecutively enrolled patients with biopsy-proven nonalcoholic simple steatosis (NAFL) and steatohepatitis (NASH), respectively, and 24 lean and 28 obese controls without NAFLD were recruited. Irisin, established adipokines and biochemical tests were measured. RESULTS Serum irisin levels were statistically different in obese controls (33.7±2.7 ng/mL; p<0.001) and patients with NAFL (30.5±1.5 ng/mL; p<0.001) and NASH (35.8±1.9 ng/mL; p=0.001) compared with lean controls (47.7±2.0 ng/mL), but were similar among patients with NAFL, NASH and obese controls. This difference remained significant after adjustment for body mass index (or waist circumference), gender, age, insulin resistance (assessed by HOMA-IR or QUICKI), exercise and time since blood collection. Serum leptin and adiponectin, but not irisin, levels were independently from BMI correlated with insulin resistance and cardiometabolic factors. Serum irisin tended to be higher in patients with (36.7±2.4 ng/mL) than without (30.8±1.2 ng/mL; p=0.02) portal inflammation and independently associated with the latter; these data need to be confirmed by future studies. CONCLUSIONS Serum irisin levels differ between lean controls and obese controls or NAFLD patients. Despite similar circulating irisin levels between NAFL and NASH groups, irisin may be independently and positively associated with the presence of portal inflammation. Future clinical and mechanistic studies are needed to confirm and extend these data.

Apoptosis in hepatitis C

Summary. The apoptotic process appears to be a host defence mechanism against viral infections and tumourigenesis. However, many viral genomes encode proteins, which repress apoptosis so as to escape from immune attack by the host. Therefore, virus–host interactions may determine viral persistence, extent and severity of liver inflammation and possibly viral hepatocarcinogenesis. Apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. Pathomorphologic features of increased apoptosis include shrinkage and fragmentation of nuclei/cytoplasm in piecemeal necrosis areas, acidophilic bodies, and focal cell dropout in the liver lobule. The hepatitis C virus (HCV) core protein exhibits both proapoptotic or antiapoptotic actions. Modulation of apoptosis may involve binding of HCV core protein to the intracellular signal transducing portion of death receptors and displacement of signalling molecules. Apoptosis may occur in the absence of significant transaminase elevation, thereby explaining the lack of correlation between biochemical activity and liver cell histological injury. Monitoring caspase activation might provide a reliable tool to estimate the efficacy of HCV therapy, and might open challenging therapeutic strategies in HCV infection. The antiviral effect of interferon may be mediated through induction of apoptosis. Lastly, administration of the antiapoptotic ursodeoxycholic acid in HCV infection is compatible with the notion that apoptosis may represent a mechanism for viral shedding rather than for viral elimination, thereby raising the concept that inhibition of apoptosis could ameliorate hepatitis C.

Relationship between Helicobacter pylori infection and glaucoma

OBJECTIVE To determine the frequency of Helicobacter pylori (H. pylori) infection in glaucoma patients and in anemic control participants. DESIGN Prospective, nonrandomized, comparative study. PARTICIPANTS The authors investigated 32 patients with chronic open-angle glaucoma (COAG), 9 patients with pseudoexfoliation glaucoma (PEG), and 30 age-matched anemic control participants. METHODS Upper gastrointestinal endoscopy was performed to evaluate macroscopic abnormalities, and gastric mucosal biopsy specimens were obtained for the presence of H. pylori infection tested by rapid urease slide test (CLO test) and by Cresyl fast violet staining, Giemsa staining, or both. The presence of gastritis was classified in accordance with the Sydney system by using hematoxylin and eosin stain. In addition, intestinal metaplasia was evaluated with Alcian blue stain. Saliva samples were also tested by CLO. Serum was analyzed for the presence of H. pylori-specific IgG antibodies by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURE Histologic examination for the presence of H. pylori. RESULTS In 87.5% of the COAG patients, 88.9% of the PEG patients, and 46.7% of the anemic control participants, H. pylori infection was histologically confirmed (odds ratio, 8.00; chi-square, 11.81; P = 0.0006 and 9.14; chi-square, 5.01; P = 0.02, respectively). H. pylori was detected by urease test: (1) in the gastric mucosa in 71.9% of the COAG patients, in 77.8% of the PEG patients, and in 46.7% of the anemic control participants (P = 0.03 and P > 0.05, respectively); and (2) in the saliva in 37.5% of the COAG patients, in 55.6% of the PEG patients, and in 30% of the anemic control participants (P > 0.05). Sixty-eight percent of glaucoma patients and 30% of anemic control participants were seropositive for H. pylori (P = 0.002). When compared with anemic control participants, glaucoma patients exhibited less often endoscopic normal appearance of gastric mucosa (P = 0.01), and more often antral gastritis (P = 0.0004) or peptic ulcer disease (P = 0.01). Histologic grade 3 gastritis was observed only in the glaucoma patients (P = 0.03). CONCLUSIONS H. pylori infection seems more frequent in glaucoma patients. If confirmed, this may indicate either a common factor that causes susceptibilities to both glaucoma and H. pylori infection or that H. pylori may be a causal factor for developing glaucoma.

Endoscopic techniques and management of foreign body ingestion and food bolus impaction in the upper gastrointestinal tract : A retrospective analysis of 139 cases

Background Ingested foreign bodies and food bolus impaction are frequently seen in endoscopic practice. Successful foreign body and food bolus removal may depend on the method used, the choice of device, and the experience level of the endoscopist, although few papers report experience and outcome of tertiary centers. Aim To investigate the effectiveness of our protocol designed for removal of ingested foreign bodies and food boluses. Methods We retrospectively reviewed all patients with a diagnosis of foreign body ingestion and food bolus impaction from 1994 to 2005 identified by computer search. Patients were excluded if medical record was incomplete. Results The analysis included 171 patients. Foreign bodies and impacted food boluses were found in 77 and 62 patients, respectively. In 32 cases (23%), the foreign bodies passed spontaneously through the gastrointestinal tract. The overall success rate for endoscopic management was obtained in 137 patients (98.6%). Surgical removal of a foreign body was required in only 2 cases (1.4%). According to the type and location of the foreign object and food bolus we used Dormia baskets, retrieval forceps, polypectomy snares, and all sizes of Roth net. No complications relating to the endoscopic procedure were observed; 50 patients (35.2%) had an underlying esophageal disease. Conclusions Endoscopic removal of upper gastrointestinal tract foreign bodies and food bolus impaction is efficacious and safe. Especially the Roth net is the best device for safe retrieval of food boluses and button disc batteries.

Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis

Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Delivery of BMSCs in the cerebrospinal fluid via intracerebroventricular (ICV) transplantation is a useful tool to identify mechanisms underlying the migration and function of these cells. In the current study, BMSCs were ICV administered in severe and mild EAE, as well as naive animals; neural precursor cells (NPCs) served as cellular controls. Our data indicated that ICV-transplanted BMSCs significantly ameliorated mild though not severe EAE. Moreover, BMSCs exerted significant anti-inflammatory effect on spinal cord with concomitant reduced axonopathy only in the mild EAE model. BMSCs migrated into the brain parenchyma and, depending on their cellular density, within brain parenchyma formed cellular masses characterized by focal inflammation, demyelination, axonal loss and increased collagen-fibronectin deposition. These masses were present in 64% of ICV BMASC-transplanted severe EAE animals whereas neither BMSCs transplanted in mild EAE cases nor the NPCs exhibited similar behavior. BMSCs possibly exerted their fibrogenic effect via both paracrine and autocrine manner, at least partly due to up-regulation of connective tissue growth factor (CTGF) under the trigger of TGFb1. Our findings are of substantial relevance for clinical trials in MS, particularly regarding the possibility that ICV transplanted BMSCs entering the inflamed central nervous system may exhibit - under conditions - a local pathology of yet unknown consequences.

Extragastric Diseases and Helicobacter pylori.

The extragastric manifestations of Helicobacter pylori infection still remain a very strong topic throughout the H. pylori world. Indeed, H. pylori may interfere with many biological processes, both inside and outside of the stomach, possibly influencing or determining the occurrence of many diseases outside of the stomach. While its role in idiopathic thrombocytopenic purpura and sideropenic anemia has already been recognized, emerging evidence suggests that H. pylori may increase the risk of acute coronary syndrome, contribute to insulin resistance and be associated with neurodegenerative, respiratory, and other miscellaneous disorders previously associated with other conditions. Different pathogenic mechanisms have been hypothesized, including the induction of a low‐grade inflammatory state and the occurrence of molecular mimicry mechanisms. This review summarizes the results of the most relevant studies published on this topic in the last year.