Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases

Helicobacter pylori (H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases.     

Potential role of Helicobacter pylori infection in nonalcoholic fatty liver disease

Accumulating evidence has implicated Helicobacter pylori(H.pylori)infection in extragastrointestinal diseases,including obesity,type 2 diabetes mellitus,cardiovascular disease,and liver disease.Recently,there has been a special focus on H.pylori infection as a risk factor for the development of nonalcoholic fatty liver disease(NAFLD).NAFLD is currently considered to be the most common liver disorder in western countries,and is rapidly becoming a serious threat to public health.The mechanisms of pathogenesis underlying NAFLD remain unclear at present and therapeutic options are limited.The growing awareness of the role of H.pylori in NAFLD is thus important to aid the development of novel intervention and prevention strategies,because the eradication of H.pylori is easy and much less expensive than long-term treatment of the other risk factors.H.pylori infection is involved in the pathogenesis of insulin resistance(IR),which is closely linked with NAFLD.It provides a new insight into the pathogenesis of NAFLD.This review probes the possible relationship between H.pylori and NAFLD,from the perspective of the potential mechanism of how H.pylori infection brings about IR and other aspects concerning this correlation.     

From the stomach to other organs: Helicobacter pylori and the liver

Many recent studies have examined the importance of Helicobacter pylori (H. pylori) infection in the pathogenesis of the diseases outside the stomach and explored the significance of this bacterium in the pathogenesis of some metabolic and cardiovascular diseases. Recent studies have provided evidence that H. pylori is also involved in the pathogenesis of some liver diseases. Many observations have proved that H. pylori infection is important in the development of insulin resistance, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis and cirrhosis. The worsening of liver inflammation of different origins also occurs during H. pylori infection. Some studies have indicated that H. pylori infection induces autoimmunological diseases in the liver and biliary tract. The potential significance of this bacterium in carcinogenesis is unclear, but it is within the scope of interest of many studies. The proposed mechanisms through which H. pylori impacts the development of hepatobiliary diseases are complex and ambiguous. The importance of other Helicobacter species in the development of hepatobiliary diseases is also considered because they could lead to the development of inflammatory, fibrotic and necrotic injuries of the liver and, consequently, to hepatocellular carcinoma. However, many contrary viewpoints indicate that some evidence is not convincing, and further studies of the subject are needed. This review presents the current knowledge about the importance of H. pylori in the pathogenesis of liver and in biliary diseases.     

Role of Helicobacter pylori infection on nutrition and metabolism

Helicobacter pylori (H. pylori) is a gram-negative pathogen that is widespread all over the world, infecting more than 50% of the world’s population. It is etiologically associated with non-atrophic and atrophic gastritis, peptic ulcer and shows a deep association with primary gastric B-cell lymphoma and gastric adenocarcinoma. Recently, the medical research focused on the modification of the gastric environment induced by H. pylori infection, possibly affecting the absorption of nutrients and drugs as well as the production of hormones strongly implicated in the regulation of appetite and growth. Interestingly, the absorption of iron and vitamin B12 is impaired by H. pylori infection, while infected subjects have lower basal and fasting serum levels of ghrelin and higher concentration of leptin compared to controls. Since leptin is an anorexigenic hormone, and ghrelin stimulates powerfully the release of growth hormone in humans, H. pylori infection may finally induce growth retardation if acquired very early in the childhood and in malnourished children. This review is focused on the nutritional effects of H. pylori infection, such as the reduced bioavailability or the malabsorbption of essential nutrients, and of gastrointestinal hormones, as well as on the relationship between H. pylori and the metabolic syndrome.     

Extraintestinal manifestations of Helicobacter pylori: A concise review

Helicobacter pylori (H. pylori) infection has been clearly linked to peptic ulcer disease and some gastrointestinal malignancies. Increasing evidence demonstrates possible associations to disease states in other organ systems, known as the extraintestinal manifestations of H. pylori. Different conditions associated with H. pylori infection include those from hematologic, cardiopulmonary, metabolic, neurologic, and dermatologic systems. The aim of this article is to provide a concise review of the evidence that supports or refutes the associations of H. pylori and its proposed extraintestinal manifestations. Based on data from the literature, PUD, mucosal associated lymphoid tumors lymphoma, and gastric adenocarcinoma has well-established links. Current evidence most supports extraintestinal manifestations with H. pylori in immune thrombocytopenic purpura, iron deficiency anemia, urticaria, Parkinson’s, migraines and rosacea; however, there is still plausible link with other diseases that requires further research.     

Helicobacter pylori infection and diabetes: Is it a myth or fact?

Helicobacter pylori(H.pylori)is one of the most common human bacterial pathogens,and infection causes a wide array of gastric disorders,including simple gastritis,peptic ulcers and gastric malignancies.Gastrointestinal inflammation caused by H.pylori can influence the absorption of glucose and lipids,which are also abnormal in diabetes mellitus.Type 2 diabetes mellitus(T2DM),formerly known as non-insulin-dependent diabetes mellitus or adult-onset diabetes,is a metabolic disorder that is characterized by high levels of blood glucose resulting from insulin resistance and relative insulin deficiency.It is an emerging pandemic and is rapidly becoming a serious threat to public health.Emerging data now indicate a strong relationship between H.pylori infection and the incidence of T2DM.The mechanisms underlying the pathogenesis of diabetes are complex,involving insulin resistance,chronic inflammation,insulin secretion deficiency as a result of pancreasβ-cell dysfunction,glucotoxicity,and lipotoxicity.H.pylori infection is known to be involved in the pathogenesis of insulin resistance,and the growing awareness of its role in diabetes is important for the early detection of glucose dysregulation and prevention of T2DM in high-risk communities.This review probes the possible relationship between H.pylori and diabetes according to epidemiological surveys and discusses putative mechanisms underlying this correlation.     

High antibiotic resistance rate: A difficult issue for Helicobacter pylori eradication treatment

Helicobacter pylori (H. pylori) infection is associated with a variety of upper gastrointestinal diseases, including gastric cancer. With the wide application of antibiotics in H. pylori eradication treatment, drug-resistant strains of H. pylori are increasing. H. pylori eradication treatment failure affects the outcome of a variety of diseases of the upper gastrointestinal tract. Therefore, antibiotic resistance that affects H. pylori eradication treatment is a challenging situation for clinicians. The ideal H. pylori eradication therapy should be safe, effective, simple, and economical. The eradication rate of triple antibiotic therapy is currently less than 80% in most parts of the world. Antibiotic resistance is the main reason for treatment failure, therefore the standard triple regimen is no longer suitable as a first-line treatment in most regions. H. pylori eradication treatment may fail for a number of reasons, including H. pylori strain factors, host factors, environmental factors, and inappropriate treatment.     

Cytokines,cytokine gene polymorphisms and Helicobacter pylori infection: Friend or foe?

Helicobacter pylori(H.pylori)is a flagellated,spiralshaped,microaerophilic Gram-negative bacillus that colonises the gastric mucosa of more than 50%of the human population.Infection is a risk factor for gastritis,ulcer disease and stomach cancer.Immunity against H.pylori is mainly related to Th1/Th17 skewing,and the activation of regulatory T cells is the main strategy used to limit inflammatory responses,which can result in the pathogen persistence and can lead to chronic gastrointestinal diseases,including cancer.Furthermore,host genetic factors that affect cytokines may determine differences in the susceptibility to many diseases.In this review,we present the cytokine profiles and the main cytokine gene polymorphisms associated with resistance/susceptibility to H.pylori and discuss how such polymorphisms may influence infection/disease outcomes.     

Helicobacter pylori seropositivity among the patients with acute dyspepsia

Acute dyspepsia is a common gastrointestinal problem in clinical practice. This disease is due to the poor dietary behavior and there is a scientific evidence that the gastric infection by Helicobacter pylori is the cause of this medical disorder. Here, the authors report on the prevalence of Helicobacter pylori seropositivity among the patients presenting with acute dyspepsia in a primary care center.     

Mechanisms of glucose intolerance in patients with chronic hepatitis C: Implications for treatment

Both diabetes and chronic hepatitis C virus (HCV) infection are common conditions that often coexist in the same subject. Studies seem to confirm the presence of an association between them. Mechanisms leading to HCV-induced insulin resistance and glucose intolerance are beginning to be elucidated. Insulin resistance in the setting of chronic HCV infection could be related etiologically to viral factors but is also often seen with concomitant nonalcoholic fatty liver disease, the hepatic manifestation of the metabolic syndrome. Insulin resistance decreases the likelihood of response to interferon-based therapies and may be an independent risk factor for the progression of HCV-related liver disease.     

A unifying working hypothesis for juvenile polyposis syndrome and Ménétrier's disease: Specific localization or concomitant occurrence of a separate entity?

Background

Juvenile polyposis syndrome with gastric involvement may mimic Ménétrier's disease, which is correlated to transforming growth factor (TGF)α overproduction and PDX1 upregulation in the gastric fundus.

Aim

We report a family with juvenile polyposis syndrome where one member showed typical features of Ménétrier's disease and concomitant Helicobacter pylori infection.

Methods

We studied a 31-year-old woman belonging to a family with juvenile polyposis syndrome, who exhibited a particular form of hyperplastic gastropathy diagnosed as Ménétrier's disease with Helicobacter pylori infection.

Results

TGFα overexpression and undetectable PDX1 expression were demonstrated in the fundic gastric biopsy specimens. In all affected members of the family we identified a 4-bp deletion in exon 9 of SMAD4 gene, a mutation usually associated with a more virulent form of juvenile polyposis syndrome with a higher incidence of gastric and colonic polyposis.

Conclusion

To explain the association of juvenile polyposis syndrome with Ménétrier's disease we hypothesized a new mechanism that involves TGFβ-SMAD4 pathway inactivation and TGFα overexpression related to Helicobacter pylori infection.     

Management of Helicobacter pylori infection: Guidelines of the Italian Society of Gastroenterology (SIGE) and the Italian Society of Digestive Endoscopy (SIED)

Helicobacter pylori infection is very common and affects more than one-third of adults in Italy. Helicobacter pylori causes several gastro-duodenal diseases, such as gastritis, peptic ulcer and gastric malignancy, and extra-gastric diseases. The eradication of the bacteria is becoming complex to achieve due to increasing antimicrobial resistance. To address clinical questions related to the diagnosis and treatment of Helicobacter pylori infection, three working groups examined the following topics: (1) non-invasive and invasive diagnostic tests, (2) first-line treatment, and (3) rescue therapies for Helicobacter pylori infection. Recommendations are based on the best available evidence to help physicians manage Helicobacter pylori infection in Italy, and have been endorsed by the Italian Society of Gastroenterology and the Italian Society of Digestive Endoscopy.     

Metabolic consequences of Helicobacter pylori infection and eradication

Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications(peptic ulcer,gastric cancer,lymphoma)and remote manifestations.While H.pylori does not enter circulation,these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa.The epidemiologic link between the H.pylori infection and metabolic changes is inconstant and controversial.Growth delay was described mainly in low-income regions with high prevalence of the infection,where probably other nutritional and social factors contribute to it.The timely eradication of the infection will lead to a more healthy development of the young population,along with preventing peptic ulcers and gastric cancer An increase of total,low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications,myocardial infarction,stroke and peripheral vascular disease.Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions.In case of glucose metabolism,the most consistent association was found between H.pylori and insulin resistance:again,proof that eradication prevents this common metabolic disturbance is expected.The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients,thus,more active regimens must be found to obtain better results.Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations,while in others no such changes were encountered.Uncertainities of the metabolic consequences of H.pylori infection must be clarified in the future.     

Gastric cancer and Helicobacter Pylori infection in the Eastern Libya: A descriptive epidemiological study

Background and study aimsThe aim of this study was to determine the pattern of histologically-proven gastric cancer in Eastern Libya and explore its association with Helicobacter pylori infection.Patients and methodsThe registries of the Departments of Histopathology, Faculty of Medicine, Benghazi University and Oncology, Al-Jomhoria Hospital, Benghazi, were reviewed for cases with primary gastrointestinal cancer from January 2000 to December 2002 (sole Histopathology and Oncology Departments in Eastern Libya). Slides of hematoxylin and eosin stain of gastric cancer patients were re-stained to detect H. pylori. The American Joint Committee on Cancer Tumor, Node, Metastasis staging was used for clinical and pathologic staging. Gastric cancer biopsy materials were classified into intestinal or diffuse type according to Lauren criteria.ResultsOne hundred and fourteen cases of gastric cancer were diagnosed. Tumor stages were: 2 (14%), 3 (21%), 4 (57%) and unknown (8%). Most common site of involvement was the antrum (48%). Diffuse adenocarcinoma occurred in 56 patients (49.1%), intestinal adenocarcinoma in 46 (40.4%) and malignant gastric lymphoma in 12 (10.5%). The overall frequency of H. pylori infection was 63.2% (72/114), more frequent in intestinal adenocarcinoma (71.7%) and malignant lymphoma (66.6%) than diffuse adenocarcinoma (55.3%). The frequency of gastric cancer increased throughout the three years of study.ConclusionThe majority of the patients were diagnosed in locally advanced or metastatic stage. Clearly more efforts need to be given to early detection. We showed a stronger association of H. pylori infection with intestinal type gastric adenocarcinoma and malignant lymphoma than diffuse adenocarcinoma suggesting that H. pylori infection is the most probable causal factor of gastric cancer in this part of Libya.     

Brain-gut axis in the pathogenesis of Helicobacter pylori infection

Helicobacter pylori(H.pylori)infection is the main pathogenic factor for upper digestive tract organic diseases.In addition to direct cytotoxic and proinflammatory effects,H.pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis,similar to other microorganisms present in the alimentary tract.The brain-gut axis integrates the central,peripheral,enteric and autonomic nervous systems,as well as the endocrine and immunological systems,with gastrointestinal functions and environmental stimuli,including gastric and intestinal microbiota.The bidirectional relationship between H.pylori infection and the brain-gut axis influences both the contagion process and the host’s neuroendocrine-immunological reaction to it,resulting in alterations in cognitive functions,food intake and appetite,immunological response,and modification of symptom sensitivity thresholds.Furthermore,disturbances in the upper and lower digestive tract permeability,motility and secretion can occur,mainly as a form of irritable bowel syndrome.Many of these abnormalities disappear following H.pylori eradication.H.pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes,or by microelement deficiency secondary to functional and morphological changes in the digestive tract.In digestive tissue,H.pylori can alter signaling in the brain-gut axis by mast cells,the main brain-gut axis effector,as H.pylori infection is associated with decreased mast cell infiltration in the digestive tract.Nevertheless,unequivocal data concerning the direct and immediate effect of H.pylori infection on the brain-gut axis are still lacking.Therefore,further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H.pylori infection pathophysiology and suggest new therapeutic approaches.     

Hepatitis C infection and nonalcoholic fatty liver disease

In hepatitis C virus (HCV) infection, significant hepatic steatosis or superimposed nonalcoholic steatohepatitis is associated with disease severity and poor response to antiviral therapy. Nonalcoholic fatty liver disease (NAFLD) and HCV are common causes of chronic liver disease in Western countries and are strongly linked to concurrent obesity, insulin resistance, and the metabolic syndrome. With the escalating prevalence of obesity in North America, insulin resistance and the metabolic syndrome are major public health problems that have a significant impact on morbidity and mortality associated with NAFLD and HCV. This article focuses on the current understanding of the interplay between host and viral factors that are involved in the interaction between NAFLD and HCV.     

Review: Myths and misconceptions in the management of Helicobacter pylori infection

The discovery of Helicobacter pylori infection in 1984 revolutionised the management of several common upper gastrointestinal diseases. However, some of the clinical practices that were adopted following discovery of this organism have become less appropriate over the intervening years. This article discusses five ‘myths and misconceptions’ that we believe have now emerged and which we argue need re-evaluation. Although the prevalence of H. pylori infection is decreasing in some developed countries, it remains a huge global problem and the most serious consequence of infection, gastric adenocarcinoma, is still a major cause of mortality. The epidemiology of H. pylori-related diseases is also changing and careful testing remains crucially important, especially in patients with peptic ulceration. Eradication of H. pylori infection has also become much more difficult over recent years as a result of the widespread acquisition of antibiotic resistance. Routine assessment of the success of eradication should therefore now be performed. Finally, there has been increased awareness about the role of H. pylori in the multistep pathway of gastric carcinogenesis, about the opportunities to prevent cancer development by eradicating this infection in some individuals and about detecting high-risk preneoplastic changes via endoscopic surveillance. The discovery of H. pylori was rightly honoured by the award of the Nobel prize for Physiology and Medicine in 2005. However, unless we re-evaluate and update the ways in which we manage H. pylori infection, much of the fantastic progress that has been made in this field of medicine may tragically be lost once again.     

Diabetes and gastric cancer: The potential links

This article reviews the epidemiological evidence linking diabetes and gastric cancer and discusses some of the potential mechanisms,confounders and biases in the evaluation of such an association.Findings from four meta-analyses published from 2011 to 2013 suggest a positive link,which may be more remarkable in females and in the Asian populations.Putative mechanisms may involve shared risk factors,hyperglycemia,Helicobacter pylori(H.pylori)infection,high salt intake,medications and comorbidities.Diabetes may increase the risk of gastric cancer through shared risk factors including obesity,insulin resistance,hyperinsulinemia and smoking.Hyperglycemia,even before the clinical diagnosis of diabetes,may predict gastric cancer in some epidemiological studies,which is supported by in vitro,and in vivo studies.Patients with diabetes may also have a higher risk of gastric cancer through the higher infection rate,lower eradication rate and higher reinfection rate of H.pylori.High salt intake can act synergistically with H.pylori infection in the induction of gastric cancer.Whether a higher risk of gastric cancer in patients with diabetes may be ascribed to a higher intake of salt due to the loss of taste sensation awaits further investigation.The use of medications such as insulin,metformin,sulfonylureas,aspirin,statins and antibiotics may also influence the risk of gastric cancer,but most of them have not been extensively studied.Comorbidities may affect the development of gastric cancer through the use of medications and changes in lifestyle,dietary intake,and the metabolism of drugs.Finally,a potential detection bias related to gastrointestinal symptoms more commonly seen in patients with diabetes and with multiple comorbidities should be pointed out.Taking into account the inconsistent findings and the potential confounders and detection bias in previous epidemiological studies,it is expected that there are still more to be explored for the clarification of the association between diabetes and gastric cancer.     

High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity

Background &; aims. Some phytochemicals present in coffee have a potential antioxidant role which seems to protect the human body against cardiovascular diseases, liver disease and malignancies. Nonalcoholic fatty liver disease is a common disease with limited therapeutic options. This study investigated the antioxidant effect of coffee by measuring antioxidant enzymes and lipid peroxidation markers in patients with nonalcoholic fatty liver disease.Material and methods. We performed a case-control study at the University Hospital, Mexico City. Anthropometric, metabolic, dietary and biochemical variables of all patients were determined and compared. The presence of nonalcoholic fatty liver disease was established by ultrasonography. All patients completed a dietary questionnaire in order to determine their of coffee consumption. Catalase, superoxide dismutase and thiobarbituric acid reactive substances were measured in all of the patients.Results. Seventy-three subjects with and 57 without nonalcoholic fatty liver disease were included. Patients with nonalcoholic fatty liver disease had significantly higher body mass index, blood glucose, homeostasis model of assessment-insulin resistance and insulin values in comparison to patients without nonalcoholic fatty liver disease. On the one hand, there was a significant difference in coffee intake between the groups (p < 0.05, for all comparisons). There was no significant difference between groups in catalase (0.39 ± 0.74 vs. 0.28 ± 0.69 nM/min/mL), superoxide dismutase (5.4 ± 3.45 vs. 4.7 ± 2.1 U/mL) or thiobarbituric acid-reactive substances (4.05 ± 1.87 vs. 3.94 ± 1.59 μM/mL).Conclusions. A high intake of coffee has a protective effect against nonalcoholic fatty liver disease however there was no significant difference in the antioxidant variables analyzed.     

非酒精性脂肪性肝病与多囊卵巢综合征相关性研究

目的探讨非酒精性脂肪肝(NAFLD)与多囊卵巢综合征(PCOS)的相关性。方法选择PCOS患者47例和非PCOS患者47例,比较两组患者NAFLD、胰岛素抵抗(IR)、丙氨酸氨基转移酶(ALT)升高发生情况及一般临床参数。结果 PCOS组NAFLD、IR、ALT升高的发生率分别为42.6%、68.1%、34.0%,与对照组(分别为17.0%、10.6%、8.5%)比较显著增高,差异有统计学意义(P0.01);PCOS组伴NAFLD患者与不伴NALFD患者比较,ALT、睾酮(TESTO)显著增高,差异有统计学意义(P0.01)。体重指数(BMI)、促卵泡成熟激素(FSH),人促黄体生成激素(LH2)、睾酮(TESTO)两两相比较,差异有统计学意义(P0.05);PCOS伴NAFLD患者年龄小于不伴NAFLD的PCOS患者(P0.01);多因素Logisitc回归分析提示ALT的异常及胰岛素抵抗状态是PCOS伴发NAFLD的主要风险因素(ALTOR=1.12,P=0.01;HOMA-IROR=1.58,P=0.01)。结论 NAFLD在PCOS患者中患病率高,提示两种疾病有临床相关性,对年轻的PCOS患者有必要尽早进行肝脏疾病的相关检查。