Risks of anti-Helicobacter therapy and long-term therapy with antisecretory drugs

Abstract

Helicobacter pylori (H. pylori) infection has a protective effect on gastroesophageal reflux disease (GERD). Both of these diseases have a very high incidence and prevalence. As a result, GERD often recurs after anti-Helicobacter therapy. The problem of effective treatment of H. pylori infection and GERD is that the main groups of drugs [proton pump inhibitors (PPIs) and potassium-competitive acid blockers] have the possibility of side effects with use. Such supposed side effects have no evidence in randomized controlled trials that comply with the principles of evidence-based medicine. Morphological changes in the gastric mucosa after long-term use of antisecretory drugs should be considered as compensatory mechanisms of sanogenesis. The greatest concern for doctors who treat patients with antisecretory drugs is the risk of gastric carcinogenesis. This article presents an analysis of morphological and pathophysiological changes that occur after long-term use of antisecretory drugs (PPIs). Hypertrophy (hyperplasia) of G cells, enterochromaffin-like cells and possible fundic gland polyps (hyperplasia) are compensatory mechanisms of sanogenesis during long-term treatment with PPIs. These mechanisms are of primary importance for rehabilitation and prevention of complications in patients with GERD, non-steroidal anti-inflammatory drugs-gastropathy and other diseases during long-term treatment with PPIs. Understanding the pathophysiological and morphological mechanisms of compensation and adaptation, the mechanisms of sanogenesis and carcinogenesis will increase the number of indications for long-term use of PPIs with a high level of efficiency and safety of treatment. In addition, understanding the pathophysiological and morphological mechanisms of compensation and adaptation, the mechanisms of sanogenesis will allow us to forecast the side effects of long-term use of potassium-competitive acid blockers.

Key Words: Epidemiology; Gastroesophageal reflux disease; Proton pump inhibitor; Potassium-competitive acid blocker; Risk-benefit; Gastroprotection; Compensatory mechanisms; Helicobacter pylori infection; Sanogenesis

Core Tip: Helicobacter pylori (H. pylori) infection has a protective effect on gastroesophageal reflux disease. Both of these diseases have a very high incidence and prevalence. The main obstacle to effective treatment H. pylori infection and gastroesophageal reflux disease is the possible side effects after use of proton pump inhibitors (PPIs). The article provides a precise analysis of scientific reviews and meta-analyses, as well as experimental scientific morphological studies on this topic. The author presented his original field of vision. He convincingly substantiated his opinion, proposed to interpret possible morphological and functional changes in the gastric mucosa after long-term use of PPIs as compensatory mechanisms of sanogenesis. This field of view will increase the number of indications for the use of PPIs and other antisecretory drugs.

INTRODUCTION

The global prevalence of Helicobacter pylori (H. pylori) infection is very high. It was 52.6% among adults before 1990 and 43.9% in 2022. This reduction was achieved through expanded indications for anti-Helicobacter treatment[1]. H. pylori infection, affecting about half the world’s population, is the strongest risk factor for stomach cancer[2]. The Maastricht VI/Florence consensus report recommends anti-Helicobacter therapy using proton pump inhibitors (PPIs) for all infected patients, with a double dose recommended for increased eradication effectiveness[3]. Many authors discuss the relationship between H. pylori infection and gastroesophageal reflux disease (GERD), and the side effects of PPIs used for these conditions. Study results are often contradictory, with differing views on H. pylori’s protective effect against GERD[4,5]. Doctors don’t always consider the role of cytochrome P450 2C19 (CYP2C19) genetic polymorphisms when using PPIs to treat H. pylori infection and GERD. This large drug group is metabolized by the CYP2C19 enzyme at different rates, requiring personalized use[6]. Patients are categorized as rapid extensive, extensive, or poor metabolizers of PPIs, and genotyping is necessary before administering PPIs at a given dose. Poor metabolizers often experience side effects[7]. Esomeprazole, the S-isomer of omeprazole, is less affected by CYP2C19 polymorphism[8]. The Caucasian population comprises 70% fast, 25%-30% moderate, and 2%-5% slow metabolizers. This should be considered when using esomeprazole and rabeprazole[9]. Genetic polymorphism may influence the effectiveness and side effects of potassium-competitive acid blockers, as these drugs are metabolized in the liver by CYP enzymes[10].

RESULTS OF GERD TREATMENT USING ANTISECRETORY THERAPY

GERD has a very high prevalence and incidence, affecting up to 20% of adults in Western countries. It is a persistent, often recurrent disease[11]. Data on GERD incidence (per 100000) in 2019 show it significantly exceeds the incidence of type 1 diabetes (Figure 1)[12]. GERD’s persistent, recurrent nature necessitates continuous maintenance therapy with PPIs after initial treatment cessation[13]. PPIs are the most effective drugs for GERD pharmacotherapy[14]. Some authors suggest long-term PPI use can promote small intestinal bacterial overgrowth, Clostridium difficile, and other intestinal infections, and affect gut microbiota composition[15]. PPIs are also associated with bone fractures and electrolyte deficiencies[16], and may contribute to diarrhea, pneumonia, and peritonitis potentially caused by various infections[17]. Some recommend short-duration, reduced-dose PPI treatment for GERD to minimize side effects[18]. The lack of evidence on long-term PPI use has led to unfounded concerns about iatrogenic consequences like intestinal infections, bone fractures, malabsorption, gastric polyps, and various cancers. The hypothesized increased risk of gastric and colorectal cancer has not been confirmed[19]. Arab authors note untreated GERD can progress to severe complications, including esophagitis, esophageal erosions, bleeding, ulcers, strictures, Barrett’s esophagus, and adenocarcinoma[20]. Treatment adherence is crucial for drug therapy effectiveness, including PPIs[21]. Negative information about PPIs can obviously affect patient adherence.

Figure 1 Gastroesophageal reflux disease incidence in 2019 (per 100000). GRED: Gastroesophageal reflux disease.

ANTISECRETORY THERAPY AND GASTROPROTECTION

Worldwide, 240 million people use non-steroidal anti-inflammatory drugs (NSAIDs) for osteoarthritis[22], and 103 million suffer from lumbar spinal stenosis, also requiring long-term NSAID treatment[23]. Patients using NSAIDs and anticoagulants need long-term gastroprotection with PPIs[24]. Lack of gastroprotection with these ulcerogenic drugs inevitably leads to severe complications like gastrointestinal bleeding and ulcer perforation[25]. The annual incidence of hemorrhagic gastropathy is 84-100 per 100000, with a 3%-10% mortality rate[26]. Gastroprotective PPIs prevent dyspepsia, heartburn, and deaths from upper gastrointestinal hemorrhages[27]. Continuous PPI treatment is necessary for patients on antiplatelet and anticoagulant drugs to prevent hemorrhagic complications[28]. Elwood et al[29] concluded from systematic reviews and meta-analyses that aspirin reduces metastatic cancer and vascular complications in patients with 18 cancer types, suggesting its widespread use for cancer prevention, with benefits outweighing risks.

IS THERE A DANGER OF INCREASING THE RISK OF GASTRIC CARCINOGENESIS WITH LONG-TERM USE OF ANTISECRETORY THERAPY?

The potential for gastric polyps, carcinoids, and cancer is the most controversial consequence of long-term PPI use (Table 1)[30]. The hypothesis that PPI-induced hypergastrinemia plays a carcinogenic role has not been supported by randomized controlled trials. Bacterial overgrowth’s involvement in gastric carcinogenesis is also unproven. Lack of evidence only allows for assumptions about a relationship between long-term PPI use and gastric cancer[31]. Reviews of existing studies argue these studies lack the rigor of evidence-based medicine. No randomized trials convincingly confirm long-term PPI use’s negative effects[32,33]. The purported association between fundic gland polyps, enterochromaffin-like cell hyperplasia, and long-term PPI use lacks consistent morphological or functional interpretation[33,34]. Early experimental trials confirmed hypochlorhydria, hypergastrinemia, and hyperhistaminemia after long-term PPI use, correctly interpreting the morphological changes. Hypergastrinemia may enhance ulcer healing by increasing cell proliferation. Omeprazole’s suppression of gastric acid did not alter parietal cell turnover[35-37]. An analysis of these contradictions led to an original scheme on long-term PPI safety (Figure 2). The American Gastroenterological Association’s updated Best Clinical Practice Advice regulates PPI use safety in various GERD scenarios[38]. Some suggest potassium-competitive acid blockers are more effective than PPIs for suppressing gastric acid[39]. However, their use is limited by potential side effects, tolerability, and drug interactions. Potassium-competitive acid blockers (e.g., Vonoprazan) require further study[40]. Currently, their efficacy is established only in short-term anti-Helicobacter therapy and other acid-related conditions[41-44]. Observational studies on their long-term use are lacking, so side effects are unknown[45-47]. Some studies noted the risk of vonoprazan side effects in H. pylori infection treatment and experimental observations[48,49]. A meta-analysis of randomized controlled trials found no adverse effects after 8 weeks of treatment for erosive esophagitis and functional dyspepsia[50,51]. Intermittent and on-demand therapy are proposed as alternatives to continuous antisecretory drug administration[52]. Modern drug development utilizes artificial intelligence-driven modeling of pharmacokinetics, pharmacodynamics, and physiological processes, including predicting therapeutic and side effects[53,54]. Primary prevention of common diseases, including H. pylori infection, is the most effective method of control. It should also be taken into account that H. pylori infection is a family epidemiological disease[55]. The strategy of implementing preventive control of common diseases will help avoid frequent use of drugs and their side effects.

Figure 2 Compensatory mechanisms of sanogenesis during long-term treatment with proton pump inhibitors. ECL: Enterochromaffin-like; PPI: Proton pump inhibitor; ATP: Adenosine triphosphate.

Table 1 List of possible consequences of long-term use of proton pump inhibitors.

No.	Possible consequences of long-term use of proton pump inhibitors
1	Significant deficiency of vitamins (B12 and C) and minerals (iron, calcium and magnesium)
2	Potential risk of congenital malformations in pregnant women
3	Infections of the intestine including Clostridium difficile, respiratory and urinary tract
4	Hypergastrinemia, which ultimately mediates the development of gastric polyps, gastric carcinoids and gastric cancer
5	Concomitant use of proton pump inhibitors with antiplatelet drugs such as clopidogrel may cause serious adverse cardiac events in patients
6	Osteoporosis-related fractures
7	Dementia
8	Rebound effect, hypersecretion after proton pump inhibitor withdrawal
9	Atrophy of the gastric mucosa (glands)

CONCLUSION

G-cell and enterochromaffin-like cell hypertrophy (hyperplasia) and potential fundic gland polyps are compensatory sanogenetic mechanisms during long-term PPI treatment. These are crucial for rehabilitation and preventing complications in patients with GERD, NSAID-gastropathy, and other conditions requiring long-term PPIs. Understanding these compensatory, adaptive, sanogenetic, and carcinogenic mechanisms will expand indications for long-term PPI use safely and effectively. Furthermore, this understanding will allow for predicting the side effects of long-term potassium-competitive acid blocker use.