Extra Digestive Disease and Helicobacter pylori Infection

Abstract

Helicobacter pylori infection has been associated with gastric pathology and gastric oncogenesis for many years, but its extra-digestive implications are less known. This chapter aims to provide up-to-date information on its potential role in neurological disease (Alzheimer’s disease, stroke, multiple sclerosis, Parkinson’s disease), dermatological disease (urticaria, rosacea, psoriasis), ophthalmological disease (glaucoma, chorioretinitis, blepharitis), hematologic disease (anemia, thrombocytopenia, neutropenia), as well as cardio-vascular disease (myocardial infarction, coronary atherosclerosis, hypertension), COVID-19, and metabolic pathology (diabetes mellitus, metabolic syndrome). For each group of diseases, a short description will be presented as well as information from published research. It will provide the reader with a global insight into the role of Helicobacter pylori in different pathologies.

1. Introduction

Helicobacter pylori (HP) is a gram-negative spiral bacillus discovered by Barry Marshall and Robin Warren in 1982. They isolated it in patients with chronic gastritis or gastro-duodenal ulcers, proving its importance as an etiologic factor for these conditions. The two pathologists received a Nobel Prize award for this discovery. In 1994, the World Health Organization recognized HP to be a group 1 gastric cancer carcinogen.

After discovering the multiple implications of HP in gastric pathology, the medical scientific community started to see associations between HP pylori and several extra-gastric diseases. As early as 1994 a relationship between HP infection and coronary heart disease was found in a pilot study on 111 male patients [1]. These results were the starting point of intense scientific efforts to elucidate the mechanisms through which HP contributes to atherosclerosis.

Many other diseases and syndromes and their possible association with HP started to be studied. Pathogenic mechanisms through which HP contributed to certain diseases were discovered. The next step was, naturally, to see if HP eradication improved the outcome of certain diseases or if it lowered the risk of developing certain medical conditions.

The current chapter offers an overview of HP’s association with several types of extra digestive diseases. It offers information on its pathogenic role and possible pathogenic mechanisms as well as the potential influence of eradication treatment upon the overall outcome. It covers various diseases (neurological, dermatological, ophthalmic, metabolic, cardiologic, and hematologic) and also discusses the influence of HP infection in COVID-19 patients.

There is a growing number of extra-digestive diseases that are studied in association with HP, and new mechanisms are discovered. This chapter includes only the seven most studied disease categories in relation to HP infection, with the intention of emphasizing the relationship between HP and different extra digestive disorders in this paper, which will enhance the comprehension of HP pathogenic mechanisms, improve clinical prognosis, and guide treatment.

2. Neurological diseases

As HP does not penetrate the central nervous system (CNS), it has been suggested that systemic immunological alterations caused by HP infection may play roles in neurological diseases.

Infection with HP has been demonstrated to induce regulatory T cells (Tregs), which can block adaptive immune responses, resulting in extra-gastric disease regulation [2, 3]. Multiple sclerosis, an inflammatory demyelinating disease of the CNS, has been linked to autoimmune T and B cell responses against CNS antigens; hence, the reduced prevalence of MS in HP-infected patients may be attributable to an increase in Tregs [3, 4].

By stimulating innate immunity, HP infection may contribute to the etiology of CNS disorders. Pro-inflammatory cytokines such as interleukin IL-1, IL-6, and tumor necrosis factor, as well as C-reactive protein, have been found to be elevated in patients with HP [5, 6]. Furthermore, individuals with Parkinson’s and Alzheimer’s disease had a greater incidence of HP infection compared to controls [7, 8]. Activation of brain resident innate cells, particularly microglia, is a common feature of CNS pathology in both Parkinson’s disease and Alzheimer’s disease [7].

Alzheimer’s disease is one of the most frequent forms of dementia. It causes a progressive decline in cognitive functions. It has a great impact on patients, their families as well as the whole society, as these patients soon require continuous care for long periods of time. Its cause is not well established and no curative treatment is found up to date [9]. HP infection in these patients proved to increase inflammation and negatively impact the cognitive status, patients with HP scored lower mini-mental state examination score [10]. Another study showed a poorer outcome in verbal memory tests in patients HP positive, compared with HP-negative Alzheimer patients [11]. Eradicating HP in these patients has not been proven to be a treatment for Alzheimer’s, but there is data indicating that HP treatment improved survival [12].

Ischemic stroke is the result of intracranial atherosclerosis. There are recognized risk factors for this condition: age, type 2 diabetes, arterial hypertension, and metabolic syndrome, but these cannot explain all the cases of stroke, so other causes have to be investigated [13]. As chronic inflammation is present in the process of plaque formation, chronic infections need to be investigated as potential risk factors. Several studies showed a correlation between HP and stroke. Positive anti-HP IgG, C-urea breath test, and antiCag-A were significantly associated with a higher risk of stroke [14]. The association is even more evident in women less than 60 years old [15].

Multiple sclerosis is a chronic demyelinating disease of the central nervous system. Its cause is not discovered, but environmental factors are studied in the hope of finding its pathogenesis. Studies have surprisingly shown that HP is less common in patients with multiple sclerosis compared to patients with other neurological pathologies, as well as compared to controls [16, 17]. Experimental studies on mice showed that HP plays a beneficial role in reducing the severity of multiple sclerosis symptoms, possibly providing protection against demyelination [18]. These findings constitute a new direction in the study of the disease.

Parkinson’s disease is a degenerative disease affecting the cells in the substantia nigra, which lead to the progressive loss of dopaminergic neurons. Early studies already showed a correlation between HP and this disease, patients with Parkinson’s disease having a three times higher risk of testing positive for HP compared to controls [19].

HP infection seems to interfere with the treatment of Parkinson’s disease, possibly due to the damage caused by the infection on the mucosa of the duodenum., This leads to an impaired absorption of L-dopa medicine in these patients with the need to increase treatment doses. HP treatment improves patients’ response to L-dopa [20]. Eradicating HP proved to improve motor fluctuations and increase the daily ‘on’ time in advanced Parkinson patients, but no significant improvement in the quality of life was noted [21]. Based on numerous studies, in these patients, HP testing and evaluating the possibility of its eradication when present, seem to play a considerable role in improving treatment outcomes.

3. Dermatological diseases

Urticaria is a common skin disease characterized by edematous, erythematous, itching skin lesions that regress spontaneously within 24 hours. Chronic urticaria lasts more than 6 consecutive weeks and negatively influences the patient’s quality of life. Its etiology is not well determined, drugs, foods, malignancies, and autoimmune disease are incriminated, but in many patients, no etiological factors are detected. A study on urticaria patients found HP antigens in 69% of the study group [22]. Other studies did not find any difference between the occurrence rate of HP in chronic urticaria but found a statistically significant clinical improvement in the urticaria symptoms in those patients treated for HP. A slow urticaria symptoms rebound phenomenon was observed after 6 weeks post HP eradication therapy, possibly due to reinfection [23].

Rosacea is an inflammatory skin disease affecting the central part of the face. It presents as a mixture of papules, pustules, erythema, and telangiectasias. Its etiology is unknown. Epidemiological studies found an association between HP infection and the development of rosacea. Two mechanisms through which HP produces the rosacea skin lesions were identified: the increase of nitrous oxide at the skin level (responsible for inflammation, vasodilatation, and immune stimulation) and specific cytotoxic reaction [24]. Associating HP eradication treatment with routine treatment in these patients showed a better effect than routine therapy alone [25].

Psoriasis is a chronic skin disease presenting as erythema, papules, and scales. The lesions appear usually on the elbows and knees but can involve other skin areas too. It greatly influences the patient’s quality of life and up to date, no cure has been found. Symptomatic treatment can help in controlling the clinical manifestations. HP infections are statistically associated with psoriasis while psoriasis patients with HP infection seem to have a higher Psoriasis Severity Score Index [26] showing a contribution of HP in the development of psoriasis, while no data is available concerning the possibility of psoriasis making patients more prone to HP infections. A recent nationwide population-based cohort study on 41,500 patients with HP infection showed no association between HP and psoriasis, therefore further studies are needed to reach a conclusion [27].

In psoriasis patients with HP infection, eradicating the infection ameliorates psoriasis severity and the patients treated for both psoriasis and HP present rapid improvement compared to patients only treated for psoriasis [28, 29].

HP does not seem to be a causative factor in dermatological diseases, but HP eradication improves symptoms and positively impacts treatment results in these diseases, raising the theory of HP being a trigger for several chronic skin diseases.

4. Ophthalmic diseases

Central serous chorioretinopathy is usually unilateral and it is characterized by the presence of liquid accumulation under the macula. The visual acuity is reduced and the vision is blurred and distorted. In most cases, it is self-limited, but chronic, non-resolving, and recurrent forms are possible in 15% of patients [30]. The prevalence of HP infection in these patients was determined to be 2.5-fold higher compared to the control groups [31].

Treating the HP infection (if present) in patients with central serous chorioretinopathy proved to decrease both the duration of the disease and the rate of recurrence while improving distant prognosis [32].

Open-angle glaucoma is a disease of the optic nerve head associated with increased intraocular pressure. It is one of the most frequent causes of blindness worldwide. In 2000 a study confirmed the association of HP gastric infection with glaucoma in 88% of glaucoma patients. Later studies found the same association [33]. A meta-analysis including 2664 participants showed a positive association between HP and open-angle glaucoma [34].

Giving treatment for HP infection has not yet been proven to improve or cure open-angle glaucoma, but studies seem promising. Reduction in intraocular pressure was found after 2 months in glaucoma patients who received HP eradication therapy [35].

Blepharitis is a chronic inflammation of the eyelid margin that causes ocular irritation. It is one of the most common ophthalmic diseases [36]. Its connection with HP infection is not clearly determined. A study conducted on 186 patients with blepharitis showed an increased incidence of HP infection compared to the control group; the symptoms were more severe in HP-positive patients, and a clinical improvement in 50% of the patients treated for HP was observed. As both conditions are highly prevalent in the population, their relationship needs large studies in order to be exactly determined [37].

5. Hematological diseases

The association of HP infection with iron deficiency anemia is well documented. The guidelines for the treatment of HP state the necessity of eradicating HP infection in patients with iron deficiency anemia [38]. Hepcidin (a protein produced in the liver) has been studied as the key mechanism. This protein is responsible for the iron balance in the organism, regulating its intestinal absorption and its release from the macrophages [39, 40]. HP infection upregulates the levels of hepcidin, in this case, treatment with iron is less efficient [41]. Also, the higher gastric acidity in HP infection decreases dietary iron absorption. HP gastric lesions bleeding can also be a cause of anemia [42, 43].

Primary immune thrombocytopenia (autoimmune thrombocytopenic purpura) is an autoimmune disease characterized by an isolated low blood platelet count whose cause cannot be determined. Many studies have reported the association of this type of thrombocytopenia with HP infection. The pathogenic mechanism is complex. Eradication of HP in these patients proved to increase platelet count by 26–100% [43, 44, 45, 46].

Chronic vitamin B12 deficiency leading to pernicious anemia, peripheral neuropathy, and spinal cord lesions can be associated with HP infection [47]. The absorption of B12 at the gastric level is reduced in HP-related gastritis of the corpus. HP eradication treatment increases serum levels of B12 and decreases serum homocysteine (a component of the metabolic pathway of B12) [43].

Chronic idiopathic neutropenia’s association with HP infection was confirmed in several studies. These findings suggest that testing for HP in these patients and eradicating the infection can be beneficial [48, 49].

6. Cardio-vascular diseases

Coronary atherosclerosis and myocardial infarction are the most frequent causes of mortality in many countries. There are well-known risk factors: hypertension, diabetes, obesity, dyslipidemia, smoking, and family history, but they are not present in all patients [50, 51]. Other causes need to be investigated in order to improve treatment and prevention.

Extensive metanalysis on 20,900 participants showed a correlation between HP and coronary atherosclerosis, even when various HP-detecting methods were used (anti-HP IgG, positive anti-CagA, positive HP stool antigen, positive HP histological staining) [52]. The correlation is even stronger in patients with myocardial infarction [53].

The mechanism by which HP can cause coronary heart disease is complex. HP in the atherosclerotic plaque stimulates inflammatory cells, which produce cytokines. They determine endothelial and vascular dysfunction. HP also increases the production of interleukin 1 and 6, C-reactive protein, and TNF-α. These substances cause instability in the atherosclerotic plaque. HP secretes vacuolating cytotoxin A, which reduces nitric oxide concentration and further damages the endothelial function. HP infection also increases platelet aggregation [54, 55, 56, 57, 58].

Eradication treatment in these patients seems to be beneficial. Early HP treatment introduction, especially in younger patients (<65 years) patients improved survival and decreased the appearance of coronary heart disease. The benefit was modest when HP treatment was given to older patients [59].

Chronic arterial hypertension is one of the most common diseases worldwide. It is considered a global public health problem, leading to a multitude of serious complications [60]. A positive association with HP has been found, although no correlation was evident between the grades of hypertension and HP infection status [61, 62, 63].

HP eradication treatment in infected hypertensive patients proved to reduce the blood pressure values, even to normal values in some cases [64, 65].

7. Metabolic diseases

Diabetes is the most frequent disease worldwide. Studies have found that HP infection increases an individual’s risk of having type 1 or type 2 diabetes. There seems to be a correlation between HP infection and the levels of glycated hemoglobin in diabetic patients [66]. HP infection in patients with type 1 diabetes was associated with poorer glycemic control compared to patients without HP. Eradication of HP in these patients did not improve glycemic values in a short time follow-up [67].

Studies have shown an improvement in glucose homeostasis in patients with type 2 diabetes after HP eradication [68, 69].

Metabolic syndrome has five components: central obesity, high blood glucose (insulin resistance), high triglycerides, low HDL, and high blood pressure. In order to establish the diagnosis of metabolic syndrome, at least three of the components have to be present. The disorders are evaluated by measuring the following: fasting glucose levels, triglycerides levels, HDL levels, cholesterol levels, blood pressure, and waist circumference. The presence of this syndrome elevates the risk of an individual developing atherosclerotic cardiovascular disease, diabetes mellitus, and neurological and vascular complications [70, 71].

HP infection determines chronic inflammation and immune response. Inflammatory cytokines and adipokines are present. HP induces low leptin and high TNF-α in infected patients. This leads to insulin resistance, which is an important component of the metabolic syndrome [72, 73, 74].

Several studies have addressed this correlation. They showed that people with obesity had a 46% increase in the chance of being infected with HP compared to normal weight controls. The chance of diabetic patients to develop an HP infection is 27% higher than non-diabetic persons [75, 76]. Several studies have shown a correlation between HP infection and metabolic syndrome [77, 78, 79, 80]. Nevertheless, there are a small number of studies that found no statistical association between them [81, 82].

The question of the benefit of HP eradication treatment on metabolic syndrome components has been investigated. A study showed beneficial change after treatment, with a reduction in total cholesterol, and LDL, an increase of HDL, and a reduction in waist circumference. No influence was seen on body weight, blood pressure, and triglyceride values [83].

In a South Korean study, 2267 subjects were followed for 5 years after HP eradication. The follow-up focused on metabolic parameters. The results showed that HP treatment significantly increased HDL in female patients, especially at the 1st year follow-up. Body mass index increased in males over time. No statistically significant influence was found for other factors [84]. A study conducted in Taiwan showed significant improvement in metabolic parameters after eradication treatment [85].

8. COVID-19

Although not a causative factor for COVID-19, recent studies have targeted a possible interaction between SARS-CoV-2 infection and concomitant HP presence in patients. The association of these two pathogens seems to make patients more prone to severe forms with digestive manifestations of COVID-19 [86].

In patients with both infections, there was no statistically significant difference in the severity of common symptoms (fever, dry cough, dyspnea, loss of taste, loss of smell headache, nausea, vomiting) compared to COVID-19 patients without HP infection [86].

Patients with HP use a lot of anti-acid and acid-reducing medicine (proton pump inhibitors), which leads to a higher gastric pH. Gastric acidity is considered to offer digestive protection for COVID-19, so in these patients stopping the anti-acid and related medicine might be considered during the acute phase of COVID-19 [87].

The vascular endothelium is an important factor in vascular homeostasis, it regulates fibrinolysis, blood viscosity, monocyte/leucocyte adhesion, and angiogenesis. Endothelial vascular cells regulate inflammatory response at inflammation sites. Markers of vascular endothelial dysfunction (V-CAM, ICAM, TNF-α, IL-8, IL-1β) were present in severe forms of COVID-19 [88, 89]. Inflammatory activation is also caused by HP infection, so a strong inflammatory response can be seen in patients with both pathogens, leading to severe forms of COVID-19 [90].

In future studies, as more SARS-COV2 data will be available, more information concerning the results and consequences of the coexistence of these two infections will be discovered, leading to a better treatment choice.

9. Conclusions

Helicobacter pylori’s implication in human disease goes beyond gastric localization. Studies have shown its detrimental effect on various types of diseases, from neurological and hematological, to skin and metabolism.

The mechanisms through which HP contributes to the pathogenesis or influences the severity of extra gastric diseases are complex and partially understood, but they seem to have a common pathway-systemic inflammation. HP infection determines the release of proinflammatory factors (e.g., IL-1, IL-6, TNF, C-reactive protein) which lead to chronic inflammation. Chronic inflammation contributes to several chronic diseases affecting different organs and systems, such as dermatological, cardio-vascular hematological, metabolic, ophthalmic, and COVID-19. This mechanism seems to be similar in most chronic neurological diseases, except for multiple sclerosis, where the change of immune profile induced by HP infection, leading to an increase of Treg may have, according to some studies, a favorable effect on disease progression by reducing demyelination. Also, HP gastric infection can influence the response to treatment in certain diseases by decreasing drug absorption.

Future studies will give more information and will help in providing better treatment strategies for a lot of different diseases. Large-scale studies will provide even better information in this domain and molecular studies will give more information on etiopathogenic mechanisms.

Doctors of all specialties should take into consideration the possible presence of HP and consider its implications. They should evaluate the potential beneficial effect of eradication treatment upon the evolution of the disease they are treating or the health risk reduction it might provide.

Conflict of interest

The authors declare no conflict of interest.