Helicobacter pylori (Hp) infection is closely associated with four diseases of the upper gastrointestinal tract: (1) chronic gastritis; (2) peptic ulcer; (3) MALT lymphoma; and (4) gastric cancer. Hp infection may play a role in the development of coronary heart disease, hypertension, cerebrovascular disease, immune disorders, nutritional and metabolic diseases and skin diseases.
Infection can induce a systemic immune response and a chronic inflammatory response, inducing the release of large amounts of inflammatory mediators, cytokines and acute reactants, which may underlie its pathophysiological basis in causing extragastric diseases, and this association may be characterized by the activation of inflammatory mediators or the induction of an autoimmune response.
The pathogenicity of Hp infection, which only colonizes the gastric mucosa, for other systemic diseases is based on the following characteristics: Hp infection is a chronic and persistent infection; local infection may cause a systemic response; and persistent infection may induce chronic inflammatory and immune responses, leading to in situ and distant damage. Hp infection, especially virulent strains, can be involved in pathogenesis by causing local inflammation of the stomach, releasing endotoxin into the blood, inducing increased inflammatory factors, increasing oxygen radical production and forming cross-immune reactions with the body.
Cardiovascular diseases
Coronary atherosclerotic heart disease (CHD) Long before Hp was discovered to be isolated, it was thought that CHD might have some connection with peptic ulcer disease. 1974 Sternby performed autopsies on 50,000 deceased persons between the ages of 40-59 in five European cities and found that more than 80% of patients with blockage of the left main trunk of the cardiac coronary artery had a history of gastric or In 1994, Mendall first reported that Hp infection might be associated with the development of coronary heart disease, suggesting that Hp infection could lead to a slow increase in serum C-reactive protein and fibrinogen levels and induce atherosclerotic plaque formation, and therefore Hp infection in childhood could lead to the development of coronary heart disease in adulthood. Concerning if this hypothesis is valid, the settlement of Hp in the gastric mucosa could serve as an independent risk factor for coronary heart disease; and since the bacterium can be eradicated, making this finding significant.
Following Mendall’s report, there have been at least 40 additional controlled clinical studies on the relationship between Hp infection and coronary artery disease, with very inconsistent results. Some studies support Mendall’s findings while suggesting that Hp infection may be associated with restenosis after PTCA for coronary artery disease. Accordingly, the hypothesis has been proposed that Hp infection, as a chronic persistent infection, may promote atherosclerotic plaque formation or contribute to atherosclerotic plaque instability through prolonged low-level inflammatory stimulation. Negative results have also been numerous in numerous studies. It has been suggested that the relationship between Hp and coronary artery disease may need to be discussed separately between stable coronary artery disease and acute coronary syndromes, but current studies have shown no more consistent results in either condition.
Although there is much controversy, most studies currently consider Hp infection as an independent risk factor for ischemic heart disease. Its mediated systemic inflammation may be achieved through C-reactive protein, cellular kinase, heat shock protein 60, cross-immune response to bacterial antigens and higher fibrinogen levels. hp infection leads to decreased serum HDL and apoA1 levels and increased apoB levels, promoting atheromatous plaque formation. increased oxygen free radical production, decreased antioxidants and increased inflammatory substances in hp infection, secondary to Hyperhomocysteinemia caused by impaired vitamin B12 absorption in Hp-associated chronic gastritis may also be involved in the development of coronary artery disease. Heat shock protein (hsp) has been observed to be expressed in atherosclerotic plaques secondary to infection, suggesting that 60 kDa-hsp from Hp organisms may cross-immune with hsp from human endothelial cells, leading to vascular wall damage through in situ immune complex formation. Although the current findings are very inconsistent, coronary artery disease is a major cause of death and disability worldwide, and if Hp infection is identified as an independent risk factor for it, it could provide meaningful help in the treatment of coronary artery disease due to the curable nature of the infection. This may need to be further confirmed by large scale, uniform diagnostic criteria, controlled multicenter prospective studies.
Other cardiovascular diseases Hp infection has recently been reported to be associated with the development of atrial fibrillation, but only a few reports have been seen.
Cerebrovascular disease Similar to coronary artery disease, the occurrence of stroke is associated with atherosclerosis and luminal narrowing of the cerebral and conus basalis arteries. 1995 Markus found an association between the occurrence of stroke and Hp infection. By ultrasonography, carotid artery stenosis was found to be more severe in Hp-infected individuals than in non-infected individuals. It is now thought that Hp may be involved in the development of cerebrovascular disease either alone or by influencing its risk factors.
Migraine and primary Raynaud’s phenomenon The inflammatory response due to chronic persistent infection with Hp may affect the release of vasoactive substances such as cytokinase, prostaglandins, leukocyte chemokines, oxygen radicals, platelet-activating factor, and fibrinogen, which play a regulatory role in vasodilation. The occurrence of migraine and Raynaud’s phenomenon may be related to the dysregulation of vascular tone. Several studies have reported a high rate of Hp infection, especially in highly virulent strains, in patients with migraine and primary Raynaud’s phenomenon, and some patients obtained improvement in symptoms after successful eradication. However, there is a lack of support from large-scale clinical trials.
Hematologic disorders
Iron deficiency anemia The most definite association with Hp infection is currently thought to be iron deficiency anemia. Some authors have treated pediatric patients with severe iron deficiency anemia poorly with iron supplementation alone. The hemoglobin of patients with Hp infection was improved to varying degrees after Hp eradication, and the anemia symptoms improved. Annibale’s statistics show that about 18% of refractory anemia is associated with Hp infection.
The exact mechanism of iron deficiency anemia due to infection-associated gastritis has not been fully elucidated, but may be related to changes in gastric pH due to bacterial settlement in the stomach that affect iron absorption, use of serum iron for bacterial growth, and consumption of plasma transferrin, which is essential for Hp growth and reproduction. Hp may also affect iron absorption in the intestine by affecting the VitC pathway in gastric juice. At the same time, Hp infection persists and produces inflammatory mediators, resulting in chronic gastritis and ulcers, leading to digestive and malabsorption problems or chronic blood loss, and ultimately iron deficiency anemia. However, not all patients infected with Hp have iron deficiency anemia, so it should also be analyzed on a patient-by-patient basis.
Idiopathic thrombocytopenic purpura (ITP) and allergic purpura Most patients with idiopathic thrombocytopenic purpura have detectable specific platelet antibodies in the serum, suggesting that the disease is associated with autoimmune factors. It has been suggested that Hp infection may lead to the development of autoimmune disease through antigenic inverse action. It has been reported that platelet levels increased to normal after eradication treatment in patients with ITP infected with Hp, and some patients had disappearance of serum platelet antibodies; while the above two indicators did not change significantly during the follow-up period in patients without Hp infection and unsuccessful eradication. The pathogenesis of allergic purpura is unknown, but it may be due to the formation of immune complexes caused by bacterial or viral infections, other diseases, etc., which activate complement and cause necrotizing vasculitis. There is a case report of a patient with allergic purpura combined with Hp infection whose symptoms disappeared after Hp eradication and then relapsed after 10 months of follow-up, tested positive for Hp again and the symptoms disappeared again after successful eradication. Of course, the relationship between the two is not yet clear, and the mechanism of Hp’s role in pathogenesis is not yet elucidated, but eradication therapy for patients with the above-mentioned diseases in combination with Hp infection may be effective for some patients.
Leukemia The cause of leukemia is not known. Early viral infection has been repeatedly mentioned as a possible etiology. Among the causes that are not yet known with certainty, it has been reported that exposure to Hp during infancy may lead to the development of leukemia in childhood or adult stages. However, no evidence is available.
Respiratory diseases
Chronic bronchitis Long before Hp was discovered, epidemiological surveys showed that the incidence of chronic bronchitis was two to three times higher in patients with peptic ulcers than in those without ulcers. starting in 1999, some investigators found through surveys that the incidence of chronic bronchitis was significantly higher in those infected with Hp compared to controls without Hp infection. However, the association between Hp infection and chronic bronchitis is unknown, possibly because they are susceptible to a common factor or there is a causal relationship between the two. It is also possible that Hp infection acts as a pro-inflammatory mediator in conjunction with other specific environmental, genetic and unknown factors to stimulate the development of chronic bronchitis. However, the evidence for an association between Hp infection and chronic bronchitis is based on serologically controlled experiments and needs to be confirmed or excluded by further studies.
Bronchiectasis Some studies have found a higher rate of Hp infection in patients with bronchiectasis, but there is a lack of clinical data to confirm whether there is a causal relationship between the two.
Others The relationship between Hp infection and pulmonary tuberculosis, bronchial asthma and lung cancer has been reported, but there is no consensus and no definite conclusion.
Other digestive system diseases
Liver diseases Primary biliary cirrhosis is characterized by chronic damage to the exocrine glands, and patients are often associated with dry syndrome. PCR, in situ hybridization and DNA sequencing of liver biopsy specimens have shown a higher rate of Hp infection in patients with primary sclerosing cholangitis and biliary cirrhosis compared to non-biliary cirrhosis and healthy controls. It has been hypothesized that in addition to the factor of cross-immunity, infection with virulent strains of Hp can release toxins into the bloodstream and enter the hepatic blood sinusoids through the portal system, leading to progressive destruction of hepatocytes and small bile ducts.
Settling in the gastric mucosa and decomposing urea to produce ammonia, could this affect the blood ammonia levels in cirrhotic patients and lead to the development or exacerbation of hepatic encephalopathy? Animal experiments have found that live Hp bacteria in the stomach of cirrhotic rats can affect blood ammonia concentrations, with increased blood ammonia levels and reduced survival in Hp-infected cirrhotic rats compared to controls. However, in studies on humans, Hp infection or not appeared to have no effect on blood ammonia and the development of hepatic encephalopathy. It is not clear whether Hp infection is associated with hepatocarcinogenesis.
Pancreatic and biliary disorders Hp infection may affect pancreatic physiology through subsequent hypergastrinemia. Recent studies have confirmed the presence of Hp in the bile and gallbladder tissues of patients with chronic pancreatitis, and it is speculated that Hp may be one of the causes of 10-30% of what is currently classified as idiopathic pancreatitis, but it is not associated with pancreatic exocrine function. A higher rate of Hp infection has been found in patients with pancreatic cancer, but it is unclear whether there is a link between the two. Regarding the relationship between Hp infection and cholelithiasis, there are several reports from home and abroad in which antigen or bacteriophage protein components of Hp have been detected in the bile of patients, suggesting that Hp may be involved in the formation of gallstones.
Gastrointestinal MALT lymphoma The relationship between Hp and gastric MALT lymphoma has been recognized, and regression of gastric MALT lymphoma after Hp eradication has been reported. Recently, it has been found that Hp infection in the stomach is also associated with certain extragastric MALT lymphomas such as those of the salivary glands, small intestine and rectum, and that tumors at these sites dissipate after Hp eradication.
Autoimmune diseases
Dry syndrome (Sj?gren’s syndrome) As a common clinical disease related to immune dysfunction, dry syndrome manifests as a progressive destruction of exocrine glands, and patients develop spontaneous dry eyes, dry mouth and other symptoms of reduced glandular secretion. It has been found that patients with dry syndrome have a higher rate of Hp infection compared to other connective tissue diseases. figura studied four patients with primary dry syndrome and found that three of them were infected with Hp and had varying degrees of symptom relief after successful eradication therapy. One report found that patients with dry syndrome had a higher rate of both Hp infection and heat shock protein 60 antibody positivity than the remaining two groups. The authors speculated that Hp infection triggers a systemic inflammatory response in which the bacteriophage heat shock protein 60 may cross-immune with human autoantigens, leading to destruction by infiltration of plasma cells and lymphocytes in the exocrine glands. However, whether eradication therapy improves symptoms has not been reported in studies.
Autoimmune thyroiditis and diabetes mellitus has also been clinically observed in patients with autoimmune thyroiditis with a higher rate of Hp serology positivity than controls and a predominance of virulent strains, with a positive correlation between anti-microsomal antibody levels and anti-HpIgG levels in the patient’s serum. The serum Hp infection rate was higher in patients with insulin-dependent diabetes mellitus (IDDM), and the serum levels of mural cell antibodies and islet cell antibodies were also higher in patients with IDDM infected with Hp; the serum levels of anti-Hp antibodies and islet cell antibodies decreased correspondingly with the prolongation of the disease course. It has also been reported that Hp infection is associated with membranous nephropathy and postprandial hypoglycemia.
The associated pathogenic mechanisms of immune diseases are not clear, and Hp infection may be involved as a causative or aggravating factor in individuals with a predisposition to immune diseases. The hypothesis of cross-immune response suggests that bacterial infection induces autoantibody production and leads to cellular damage due to the bacterium itself having the same antigenic determinant cluster as multiple human epithelia. However, the incidence of autoimmune disease does not increase concomitantly in areas with high rates of Hp infection; and the explanation for the involvement of infections acquired at an early age, which took decades to cause the disease, is subject to more research.
Skin diseases
Chronic urticaria Hp infection may be associated with a variety of dermatological conditions including chronic urticaria, pruritus epidermidis, and erythema multiforme, and treatment to eradicate Hp may improve dermatological symptoms. Higher rates of Hp infection have been reported in patients with chronic urticaria than in healthy individuals. The majority of patients with Hp infection obtained clinical remission or disappearance of symptoms after successful eradication of the bacteria, while patients without Hp infection or without eradication had no symptom relief. It has been suggested that chronic persistent infection with Hp can lead to increased permeability of skin vessels through the action of inflammatory mediators and the formation of an urticaria-like rash. More studies are needed to confirm whether Hp infection causes an increase in serum IgE levels.
Food allergy Some studies suggest that Hp colonization can impair the protective effect of the gastric mucosal barrier, increasing the chance of food allergy.
Rosacea One study diagnosed rosacea and tested 290 dermatologic patients for Hp and found that the rate of Hp infection was much higher in rosacea patients than in non-rosacea patients. Hp eradication was obtained in 51 of 53 infected patients after treatment, with 51 having disappearance of symptoms, 1 significant improvement and 1 no change after 2-4 weeks; and no spontaneous symptom reduction in uninfected patients. Plasma levels of IL-8 and TNFα showed a significant decrease after treatment. Eradication treatment led to dramatic improvement in rosacea symptoms, and many other studies have achieved similar results.
Other diseases associated with Hp infection
Oral colonization and periodontal disease The route of transmission of Hp is still not fully understood. Most studies suggest that in the natural environment, humans are the only source of infection and that human-to-human transmission is an important route, with most suggesting that transmission by the fecal-oral, oral-oral, and gastro-oral routes is more likely. Hp has been reported to be detected in saliva and dental plaque, and the same form of Hp was found to be present in gastric mucosa and dental plaque in the study, and the oral cavity may be the residence and reinfection source of Hp by the presence of multiple Hp strains at the same time. The presence of Hp in plaque is related to the depth of periodontal pockets and the inflammatory status of periodontitis patients, and the detection rate of Hp is higher in the presence of inflammation and moderate depth of periodontal pockets. However, due to the low sensitivity of existing methods to detect Hp in dental plaque, current studies have not yet reached a unified opinion on the relationship between Hp infection and periodontal disease.
Developmental growth retardation in children and fetuses Often, Hp infection is also associated with socioeconomic status and living environment, and crowded conditions, which can also affect child development. Yan et al. found that smoking (p=0.001), maternal height, and Hp seropositivity were all independent risk factors for IUGR in their investigation of Hp and intrauterine growth retardation (IUGR). independent risk factors for the development of IUGR, and Hp infection in pregnant women may affect fetal development in utero. There is no good explanation for this.
Prospects for research on infection and extragastric diseases
The prevalence of Hp infection suggests that even if Hp plays a clear and important role in the development of many different diseases, it is only a synergistic factor; it is possible that Hp infection triggers or exacerbates systemic inflammation or a predisposition to pre-existing disease, participating in pathogenesis.
The curable nature of Hp infection provides a new and effective means of treatment for certain diseases associated with it, such as coronary heart disease. However, the determination of this conclusion requires further argumentation. First, larger clinical epidemiological studies should be conducted to exclude the influence of associated risk factors, such as studying the relationship between Hp infection and coronary vascular lesions in younger patients with coronary artery disease than in older patients. Uniform diagnostic criteria or gold standards should be used in the studies as much as possible to make the conclusions more consistent. Second, research should be devoted to the study of its pathogenesis, clarifying the role of the direct action of bacteria, the toxin action of virulent strains, the systemic inflammation caused by infection and the autoimmune response caused by the similarity of antigens in the development of the disease. With so many diseases associated with Hp infection, the same pathogenic pathways may exist. The elucidation of the pathogenic mechanism can help to affirm the correlation between Hp and extragastric diseases and provide a basis for treatment. Third, the effectiveness of antimicrobial therapy must be clarified by large-scale controlled prospective studies, and objective criteria are needed to judge the efficacy and exclude the influence of other factors. Since antibiotics are not specific for Hp infection, diseases that may have infectious factors involved, such as rosacea, need to be controlled with common antimicrobial therapy. Patients in the treatment and control groups should be followed up over a longer period of time to exclude other factors and the effect of spontaneous healing.
Never before has a causative agent been found to be associated with so many diseases as Hp, and the effectiveness of eradication therapy is even more encouraging. Further research will certainly advance the understanding of the pathogenesis and treatment of Hp and extragastric diseases.