Christos Zeglinas

Prevalence and Characteristics of Extra-intestinal Manifestations in a Large Cohort of Greek Patients with Inflammatory Bowel Disease

BACKGROUND AND AIMS Extraintestinal manifestations [EIMs] are common in inflammatory bowel disease [IBD]. Data on epidemiology and risk factors of EIMs in IBD patients are limited. The aim of this study was to investigate the prevalence of EIMs in a large cohort of Greek IBD patients and identify risk factors for their development. METHODS The study population consisted of IBD patients, who were followed in eight tertiary Greek hospitals. Demographic and clinical characteristics of patients were analysed. The diagnosis of EIMs was based on standard criteria and on specialist consultation. RESULTS In total, 1860 IBD patients (1001 with Crohns disease [CD], 859 with ulcerative colitis [UC]) were registered. Among them 615 [33.1%] exhibited at least one EIM; 238 patients [38.6%] developed an EIM before IBD diagnosis. An association between active IBD and presence of an EIM was established in 61.1% of the patients. Arthritic [peripheral arthritis], mucocutaneous [erythema nodosum], and ocular [episcleritis] were the most common manifestations. EIMs were more prevalent in females, patients with CD, smokers [for all p <0.0001], patients with extensive UC [p = 0.007], and patients with a previous appendectomy [p < 0.0001] or a major IBD-related surgery [p = 0.012]. CONCLUSIONS About one-third of Greek IBD patients developed at least one EIM. Of those, more than one-third had their EIM diagnosed before IBD, and in about two-thirds it was related to disease activity. EIMs were more frequently present in females and patients with extensive UC in multivariate analysis.

The Impact of Peri-operative Anti-TNF Treatment on Anastomosis-Related Complications in Crohn’s Disease Patients. A Critical Review

IntroductionTumor necrosis factor (TNF)α is a cytokine exerting pleiotropic effects on critical cell functions and, most importantly, is the main regulator of pro-inflammatory cytokine production and a key player in the pathophysiology of numerous autoimmune diseases, including Crohn’s disease.MethodsTNFα became a therapeutic target and TNFα blocking agents are currently used in the treatment of inflammatory diseases. Beyond the therapeutic benefits deriving from TNFα neutralization, amendments in the cellular functions of the immune system may as well induce potent immunosuppressive effects. An attenuated immune response may compromise the intestinal healing ability, thus leading to weaker anastomosis and increased risk of anastomotic leak and septic complications.ResultsThis hypothesis raises great concerns about the safety of perioperative administration of anti-TNF and has been the endpoint of numerous studies.ConclusionThe aim of this review is to critically evaluate the evidence regarding the role of TNFα in anastomosis related complications after abdominal surgery in Crohn’s disease patients.

Impact of reactive oxygen species generation on Helicobacter pylori-related extragastric diseases: a hypothesis.

Abstract Helicobacter pylori (H. pylori) induces reactive oxygen species (ROS) production that contribute to pathogenesis of a variety of H. pylori-related gastric diseases, as shown in animal and human studies. Helicobacter pylori infection is also associated with variety of systemic extragastric diseases in which H. pylori-related ROS production might also be involved in the pathogenesis of these systemic conditions. We proposed that Hp-related ROS may play a crucial role in the pathophysiology of Hp-related systemic diseases including Alzheimer’s disease, multiple sclerosis, glaucoma and other relative neurodegenerative diseases, thereby suggesting introduction of relative ROS scavengers as therapeutic strategies against these diseases which are among the leading causes of disability and are associated with a large public health global burden. Moreover, we postulated that H. pylori-related ROS might also be involved in the pathogenesis of extragastric common malignancies, thereby suggesting that H. pylori eradication might inhibit the development or delay the progression of aforementioned diseases. However, large-scale future studies are warranted to elucidate the proposed pathophysiological mechanisms, including H. pylori-related ROS, involved in H. pylori-associated systemic and malignant conditions.

Effect of infliximab on the healing of intestinal anastomosis. An experimental study in rats

BACKGROUND AND AIM Infliximab is effective in the induction and maintenance of remission in Crohns disease. Whether, the perioperative administration of anti-TNF-a compromises intestinal healing leading to anastomotic failure and increased risk of postoperative complications, remains controversial. The aim of the study was to evaluate the effect of Infliximab on intestinal anastomosis healing. METHODS Fifty six wistar rats were divided into 4 groups: (a) 20 rats were subjected to excision of part of the terminal ileum followed by anastomosis which was evaluated on the 3rd or 7th postoperative day; (b) 20 rats received Infliximab and thereafter, the same surgical protocol as group (a) was followed; (c) 8 rats received Infliximab and served as relative control group; and (d) 8 served as absolute control group. Bursting pressure was used for testing intestinal healing. Additionally, the anastomoses were examined macroscopically, histologically and immunohistochemically for TGFb1, MMP1, MMP2 and Collagen V. The results were confirmed by Western blot analysis. RESULTS There were no significant differences in bursting pressures and septic intra-abdominal events among non-Infliximab (a) and Infliximab-treated (b) groups. Infliximab-treated (b) group showed mild to moderate inflammation, whereas the non-Infliximab (a) group exhibited severe inflammation. Expression of TGFb1, MMP2 and collagen V was significantly higher in the Infliximab-treated (b) group. CONCLUSION Infliximab seems to influence intestinal healing in terms of less inflammatory activity and higher tissue remodeling activity.

Potential impact of Helicobacter pylori-related metabolic syndrome on upper and lower gastrointestinal tract oncogenesis

Both Helicobacter pylori infection and metabolic syndrome present significant global public health burdens. Metabolic syndrome is closely related to insulin resistance, the major underlying mechanism responsible for metabolic abnormalities, and Helicobacter pylori infection has been proposed to be a contributing factor. There is growing evidence for a potential association between Helicobacter pylori infection and insulin resistance, metabolic syndrome and related morbidity, including abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, all of which increase mortality related to cardio-cerebrovascular disease, neurodegenerative disorders, nonalcoholic fatty liver disease and malignancies. More specifically, insulin resistance, metabolic syndrome and hyperinsulinemia have been associated with upper and lower gastrointestinal tract oncogenesis. Apart from cardio-cerebrovascular, degenerative diseases and nonalcoholic fatty liver disease, a number of studies claim that Helicobacter pylori infection is implicated in metabolic syndrome-related Barretts esophagus and esophageal adenocarcinoma development, gastric and duodenal ulcers and gastric oncogenesis as well as lower gastrointestinal tract oncogenesis. This review summarizes evidence on the potential impact of Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease-Barretts esophagus-esophageal adenocarcinoma, gastric atrophy-intestinal metaplasia-dysplasia-gastric cancer and colorectal adenoma-dysplasia-colorectal cancer sequences. Helicobacter pylori eradication might inhibit these oncogenic processes, and thus further studies are warranted.

Isotretinoin and ulcerative colitis: A case report and review of the literature.

This case report describes a case of ulcerative colitis the onset of which occurred after the use of isotretinoin for acne treatment. Our patient, a healthy male young adult, after several months of isotretinoin use, developed gastrointestinal disorders and after thorough medical workup was diagnosed with ulcerative colitis. The literature regarding a possible correlation between isotretinoin use and ulcerative colitis is scarce. Nevertheless, recent epidemiological studies have shed more light on this possible association.

Letter: Helicobacter pylori-related non-alcoholic fatty liver disease with concomitant metabolic syndrome as risk factor for colorectal neoplasia.

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Helicobacter pylori-Related Impact on Glaucoma Pathophysiology.

In their meta-analysis, Zeng et al. showed a significant association between Helicobacter pylori infection (Hp-I) and open-angle glaucoma (OAG) but not pseudoexfoliation glaucoma (PXFG), for which we would like to add our interpretation based on the existing literature, including our own published data. Regarding the pathogenesis of PXFG, an infection appears to be one of the proposed pathogenetic mechanisms. In this respect, by using histology, representing the practical gold standard for Hp-I diagnosis, we documented for the first time to our knowledge a high prevalence of Hp-I in OAG and PXFG patients than in controls with mild iron deficiency anemia (IDA). It is important to note that, regarding the mild IDA controls used in our series, the link between Hp and IDA was well supported in the literature; the British Society of Gastroenterology and the recent Maastricht IV guidelines recommend Hp eradication in all patients with unexplained and/or recurrent IDA with a normal esophagogastroduodenoscopy and colonoscopy. Therefore, it was a ‘‘disadvantage’’ for us to use IDA controls, expected to exhibit a high Hp prevalence. However, we believed that it was not ethical to submit healthy subjects for endoscopic and histologic investigation. Nevertheless, the use of such IDA controls appears to reinforce our own results. In addition, apart from OAG, our results also showed significantly greater concentration of anti-Hp–specific IgG in the aqueous humor samples from patients with PXFG than in those from age-matched control cataract patients; a similar picture also was obtained from serum concentration of anti-Hp IgG antibodies.5 Therefore, it is conceivable that both forms of glaucoma may share a common infectious link. The possibility of an infectious pathogenetic mechanism in PXFG was further implied by an epidemiologic study in Norway, where the prevalence of this condition was significantly more common in spouses with the disease. One consequent study from Iran also showed significantly higher levels of anti-Hp IgG in the aqueous humor of PXFG patients compared to the cataract control group, though relative concerns were raised regarding mainly the methodology of this study. Moreover, one more subsequent study from India showed a trend of nonsignificant greater mean concentration of anti-Hp–specific IgG in the aqueous humor samples from patients with PXFG than in controls (8.87 6 30.25 vs. 2.65 6 2.87, P1⁄40.83).9 Thus, apart from OAG, the possibility of an association between infectious agents, such as Hp-I, and PXFG, might occur at least in some ethnic subpopulations, including Greek PXFG patients, but additional large-scale relative studies are required to elucidate the aforementioned possibility. Regarding the possible impact of Hp-I on glaucoma pathophysiology, the authors mentioned some possible mechanisms that can support the fact that Hp-I increases the risk of OAG. Adding some further insight on the pathophysiology proposed by the authors, Hp-I, by releasing several inflammatory mediators (e.g., cytokines and chemokines induced by Hp-I), could induce blood–brain barrier (BBB)/blood–ocular barrier (BOB) breakdown, thereby being involved in the pathogenesis of neuropathies, such as Alzheimer’s disease (AD) and glaucoma, also called ‘‘ocular AD.’’ Helicobacter pylori could indirectly affect the brain and other target organs, for example the heart, through the release of numerous cytokines, such as TNF-a acting at a distance; TNF-a is involved in BBB disruption through a mechanism involving matrix metalloproteinases upregulation. Tumor necrosis factor-a and IL-6 (TNF-a is the main trigger for the production of IL-6 by a variety of cells) have important roles in the regulation of the synthesis of other acute phase proteins that are established risk factors for atherosclerosis, such as fibrinogen and factor VIII. These cytokines also have profound effects on lipid metabolism directly at the site of the atherosclerotic lesion but could influence the atheroma process through blood circulating levels, distant production of cytokines, or through stimulating circulating white blood cells to produce them, thereby contributing to BBB/BOB disruption and pathogenesis of heart and brain neurodegenerative diseases including glaucoma. Furthermore, Hp antibodies circulating in the bloodstream can enter the aqueous circulation due to BOB disruption possibly contributing to glaucoma development and progression; when serum-specific antibodies access the brain, they are capable of killing retinal cells, thereby contributing to glaucoma pathologies. Likewise, an influx of Hp-infected monocytes, owing to defective autophagy resulting in Hp replication in autophagic vesicles, through the disrupted BBB/ BOB might lead to glaucoma neuropathy. In this regard, Hp VacA cytotoxin promotes intracellular survival of the bacterium and modulates host immune responses; Hp VacA also exhibits chemotactic activities to the bone marrow–derived mast cells (BMDMCs) and induces BMDMCs to produce proinflammatory cytokines, including the mentioned TNF-a; BMDMCs reside adjacent to blood and lymphatic channels, mainly under epithelial surfaces including the BBB and gastrointestinal tract. Helicobacter pylori stimulates mast cells directly or via gastrin induction, and mast cells are actively involved in the pathogenesis of Hp-associated pathologies. Apart from activated mast cells, VEGF, IL-8, chymase, or tryptase (a serine endoprotease released by mast cells) and mast cell growth factor linked to Hp-I, mast cells themselves can be stimulated by corticotropin-releasing hormone, secreted under stress, to release mediators, including histamine, IL-8, tryptase, and VEGF, which disrupt the BBB/BOB leading to brain pathologies. Moreover, human defensins can penetrate BBB and also might contribute to Hp-related brain pathophysiology by modulating innate and adaptive immune system responses; when Hp accesses the brain, it may trigger defensin-related dendritic cells maturation and activation leading to proinflammatory cytokine release by effector T cells, thereby promoting neuronal cell injury and death. Finally, since the oral cavity might act as Hp permanent reservoir, this bacterium may reach the eye through the nasal cavity, causing ophthalmic pathologies, possibly including glaucoma; Hp, through oral– nasal–olfactory pathway, might also access brain, thus leading to the development of degenerative diseases via abnormal regulation of innate and adaptive immune responses possibly mediated, at least partly, by defensins’ inappropriate stimulation. Therefore, Hp’s intranasal route appears to explain, at least partly, the demonstrated presence of Hp in tissue samples obtained during trabeculectomy in our series; quite recent data confirmed the hypothesis that neurodegenerative diseases, such as dementia and glaucoma are linked to each other and to Hp-I. Certainly, all the aforementioned speculations warrant clarification and confirmation by future relative studies.

Impact of nitroglycerin and glucagon administration on selective common bile duct cannulation and prevention of post-ERCP pancreatitis.

Abstract Objective: Easy common bile duct (CBD) cannulation is associated with low complication rate. This study aimed to investigate the potential impact of nitroglycerin and glucagon administration on selective CBD cannulation and prevention of post-ERCP pancreatitis. Methods: A prospective single center, double–blind randomized study in which a total of 455 patients were randomly assigned to CBD cannulation by receiving 6 puffs (2.4 mg) sublingual nitroglycerin and glucagon 1 mg intravenously (n = 227, group A) or 6 puffs sterile water and 20 mg hyoscine-n-butyl bromide intravenously (n = 228, group B). After ERCP, patients were followed for the development of drugs’ side-effects and post-ERCP complications. Results: There were no statistically significant differences between the two groups regarding demographic data and ERCP findings. Success rate of selective CΒD cannulation was 95.15% in group A versus 82.29% in group B (p < .001). Time required for CBD cannulation was 2.82 ± 2.31 min in group A versus 4.27 ± 3.84 min in group B (p = .021). Needle-knife papillotomy was used in 11 (4.85%) patients of group A and 39 (17.11%) patients of group B (p = .001). The frequency of post-ERCP pancreatitis was significantly lower in group A than in group B (3.08% versus 7.46%, p = .037). No difference was observed between the two groups with regard to the occurrence of post-procedure hemorrhage. There was no procedure-related mortality; no adverse event related to the combination regimen was observed. Conclusions: Combined nitroglycerin and glucagon administration achieves a high selective CBC cannulation rates with concomitant reduction of post-ERCP pancreatitis incidence. However, further relative large-scale studies are needed to confirm our findings before definite conclusions can be drawn (Clinical trial registration number: NT: 4321).

Helicobacter pylori-related chronic hepatitis C infection and the risk for cardiovascular disease

To the Editor: In their review, Domont et al. (1) reported that chronic hepatitis C virus (HCV) infection was associated with cardiovascular disease (CVD) increased risk and interferonbased therapy (IBT) revealed a beneficial impact on this risk (1). Apart from other infectious agents associated with CVD, mentioned by the authors (1), the widespread Helicobacter pylori infection (HpI) is strongly associated with chronic HCV liver disease in Europe and other ethnic populations and Hp eradication holds promise for the improvement of the longterm health condition of patients with chronic HCV infection (2, 3). Moreover, a large body of evidence has linked HpI to CVD (2, 4). In this regard, our series demonstrated that increased fibrinogen levels (a serum inflammatory marker mentioned by the authors (1) and an independent risk factor for CVD), are associated with HpI and can be significantly reduced by Hp eradication. Other relative followup studies also reported that Hp eradication is associated with modification of certain CVD clinical and biochemical parameters (2, 4). In a systematic review (5), we also reported an association between HpI and insulin resistance (IR), the pathogenetic key of metabolic syndrome (MetS) and its related morbidity, including nonalcoholic fatty liver disease (NAFLD) and CVD the endpoint of MetS; there is a causal link between hepatic IR and NAFLD development/ progression and CVD. Moreover, MetS has a significant association with prior infections with Chlamydia pneumoniae and viruses, also mentioned by the authors (1), and Hp-I is one of the independent risk factors for the development of NAFLD, the hepatic manifestation of IR. Apart from its effect on fibrinogen levels, Hp could influence the development of CVD through many other mechanisms (2, 4, 5). For instance, Hp stimulates the expression of plasminogen activator inhibitor1, a major player in CVD pathogenesis; Von Willebrand factor antigen is strongly associated with HpI, providing solid evidence that Hppositive patients have CVD increased risk; HpI induces platelet activation/aggregation, thereby contributing to Hprelated CVD risk; HpI is associated with increased tumour necrosis factorα, a circulating cytokine able to exert its effects at distance, playing important roles in the regulation of other acute phase proteins’ synthesis, which are established risk factors for atherosclerosis; and circulating lipid peroxides, associated with cardiovascular risk, are raised in Hp (+) patients. Therefore, apart from IBT, Hp eradication therapy might display a positive impact on Hprelated chronic HCV infection associated with NAFLD and CVD development/progression. However, further largescale studies are needed to clarify these fields.