Helicobacter pylori: Friend or foe?

Abstract

Helicobacter pylori (H. pylori) is a Gram-negative spiral bacterium that is present in nearly half the world’s population. It is the major cause of peptic ulcer disease and a recognized cause of gastric carcinoma. In addition, it is linked to non-ulcer dyspepsia, vitamin B12 deficiency, iron-deficient anemia and immune thrombocytopenic purpura. These conditions are indications for testing and treatment according to current guidelines. An additional indication according to the guidelines is “anyone with a fear of gastric cancer” which results in nearly every infected person being eligible for eradication treatment. There may be beneficial effects of H. pylori in humans, including protection from gastroesophageal reflux disease and esophageal adenocarcinoma. In addition, universal treatment will be extremely expensive (more than $32 billion in the United States), may expose the patients to adverse effects such as anaphylaxis and Clostridium difficile infection, as well as contributing to antibiotic resistance. There may also be an as yet uncertain effect on the fecal microbiome. There is a need for robust clinical data to assist in decision-making regarding treatment of H. pylori infection.

Key Words: Helicobacter pylori, Treatment, Cost, Benefit, Cancer

Core tip:Helicobacter pylori (H. pylori) is found in more than half the world’s population. It is a major cause of peptic ulcer disease and gastric carcinoma. The overwhelming majority of those infected will not suffer any consequences during their lifetime. Furthermore, there may be a beneficial effect of H. pylori infection on allergy and asthma in young children and a protection against gastroesophageal reflux disease and its feared complication of esophageal carcinoma. Universal eradication will be prohibitively expensive, have adverse effects and needs to be evaluated on the basis of robust clinical data that is not yet available.

INTRODUCTION

Helicobacter pylori (H. pylori) is a Gram-negative bacterium found on the luminal surface of the gastric epithelium[1]. It induces chronic inflammation of the underlying mucosa. The infection is usually contracted in the first years of life and persists indefinitely unless treated[2]. The prevalence varies with age and socioeconomic status in childhood and therefore varies between countries[3].

Approximately 50% of the world’s population is infected with H. pylori[2]. H. pylori infection has been linked to gastric and duodenal ulcers (in 1%-10% of infected patients), gastric carcinoma (0.1%-3%) and gastric mucosa-associated lymphoid tissue lymphoma (less than 0.01%)[4]. However, the vast majority of the infected population will never develop symptoms related to H. pylori infection.

Consensus guidelines have been developed and updated[5] (Table 1). The recommendations for treatment include peptic ulcer, mucosa-associated lymphoid tissue (MALT)-lymphoma, gastric cancer, first-degree relatives of patents with gastric cancer, unexplained iron-deficiency anemia and immune thrombocytopenia. In addition, the Maastricht Guidelines state that “H. pylori-positive patients with fear of gastric cancer should receive eradication treatment”[5]. This last recommendation makes it likely that anyone found to be H. pylori-positive will receive eradication treatment.

Table 1 Recommendations for testing and treating Helicobacter pylori infection[5].

Recommendations
Do not test if not prepared to treat
Peptic ulcers
Unexplained iron deficiency anemia
Idiopathic thrombocytopenic purpura
Vitamin B12 deficiency
Long-term proton pump inhibitor therapy
Functional dyspepsia?
Family history of gastric cancer

EPIDEMIOLOGY

The prevalence of H. pylori infection varies from 20% to 50% in industrialized countries to over 80% in developing countries[4,6]. In developing countries, the majority of children are infected before the age of 10 and the prevalence peaks at more than 80% before the age of 50. In developed countries, infection in children is unusual but becomes more common in adulthood. Serology is negative in the vast majority under the age of 10, increases to 10% in those between 18 and 30 years and to 50% in those older than 60[7].

The route for infection by H. pylori is unclear[8]. It seems most likely to be by the oral-fecal or oral-oral route[9].

The risk of acquiring H. pylori is related to socioeconomic status and early life living conditions[10]. In some countries there is a link between a decline in H. pylori prevalence and economic development. In Japan, 70%-80% of adults born before 1950, 45% of those born between 1950 and 1960 and 25% of those born between 1960 and 1970 are infected[11].

Reinfection with H. pylori following successful bacterial eradication is unusual. In adults the rate is less than 2% per year[12] which is similar to the primary adult rate of infection[13].

DISEASES ASSOCIATED WITH H. PYLORI

H. pylori is present in the majority of the patients with uncomplicated duodenal ulcers, especially in those with no history of recent non-steroidal anti-inflammatory drug consumption[14]. H. pylori is not found in up to 27% of patients with endoscopically proven duodenal ulcers[15] and thus needs to be tested for. In addition H. pylori is found in the majority of uncomplicated gastric ulcers[16]. H. pylori infection has also been linked with unexplained iron deficiency anemia[17], vitamin B12 deficiency[18] and immune thrombocytopenic purpura[19]. It is clear that H. pylori should be tested and treated to eradication in the above cases.

H. pylori is also linked to gastric cancer. There is a 6-fold increase in the risk of gastric cancer in H. pylori-positive populations compared with uninfected populations[20]. In a nested case control study of Japanese Americans living in Hawaii, H. pylori seropositvity was present in 94% of those with gastric cancer compared with 76% of matched controls (OR = 6.0)[21].

There is also an association between H. pylori infection and MALT lymphoma[22]. In addition MALT lymphoma regresses following successful treatment for H. pylori.

In summary, H. pylori infection is clearly linked to peptic ulcer disease, gastric cancer and MALT lymphoma, immune thrombocytopenia and some cases of vitamin B12 and iron deficiency. In such situations, it is reasonable to proceed to eradication.

DIAGNOSIS OF H. PYLORI INFECTION

There are several methods for diagnosing H. pylori infection, both noninvasive and invasive. The invasive tests are performed on specimens obtained at endoscopy These include biopsy urease testing, histology and less commonly bacterial culture and sensitivity. The sensitivity of a biopsy urease test is between 90%-95% and the specificity is 95%-100%[15].

In addition, there are non-invasive tests, including urea breath testing, stool antigen testing, and serology. The urea breath test is based on the hydrolysis of urea by H. pylori to produce carbon dioxide and ammonia[23]. A labeled carbon isotope is given by mouth and H. pylori liberates tagged carbon dioxide that can be detected in the exhaled air.

Laboratory-based enzyme-linked immunosorbent assay testing to detect immunoglobulin G is inexpensive and non-invasive. There is a high sensitivity (90%-100%), but variable specificity (76%-96%). In low prevalence areas, a positive serology result has a low predictive value for active infection. In such areas, stool antigen or breath testing is recommended. Conversion of positive serology to negative 1 year after treatment suggests bacterial eradication[24].

The presence of H. pylori in the stool of infected patients has enabled the development of fecal assays[15] which have high sensitivity, specificity and diagnostic accuracy[25].

In summary, there are a range of tests, both invasive and non-invasive, that are available for the diagnosis of H. pylori infection.

INDICATIONS FOR H. PYLORI ERADICATION

Peptic ulcer disease

H. pylori is found in the majority of duodenal ulcers[14], especially if there is no history of consumption of nonsteroidal antiinflammatory drugs (NSAIDS). In those patients with a duodenal ulcer who do not have H. pylori infection, there seems to be a worse prognosis with a higher incidence of ulcer relapse, non-healed ulcer, and relapse of severe dyspeptic symptoms[26].

H. pylori seems to be associated with the majority of gastric ulcers[16] but again there is an increasing proportion of patients with gastric ulcers in whom H. pylori is not detected. Some of these cases may be related to surreptitious use of NSAIDS.

Thus, in cases of peptic ulcer disease, routine testing and treating of H. pylori is recommended and justified. The recommendations for testing and treatment of H. pylori are shown in Table 1.

Carcinoma of the stomach

H. pylori is linked to the development of chronic active gastritis and atrophic gastritis which are early stages in the carcinogenesis sequence. There is a clear association between H. pylori infection and gastric adenocarcinoma. H. pylori has been recognized as a grade 1 carcinogen by the International Agency for Research on Cancer[27]. It is thought that long-term chronic inflammation caused by H. pylori is the main mechanism for the development of gastric carcinoma[28].

In spite of the definite connection between gastric carcinoma and H. pylori infection, it has not been convincingly shown that H. pylori eradication decreases the incidence of gastric carcinoma. This is due to the fact in order to perform trials with cancer as the endpoint, more than 18000 patients will need to be recruited and will need to be followed up for 10-20 years[29]. In addition, it may be unethical to include an untreated arm since H. pylori has been classified as a type 1 carcinogen. There are only two randomized controlled interventional trials with gastric cancer development as the primary outcome[30,31] (Table 2). Both of these studies were performed in high risk areas of the Far East. In the study of Wong et al[30], 1630 H. pylori-positive patients were followed up for 7 years. In the eradication group 7/817 (0.9%) of the patients developed gastric carcinoma compared with 11/813 (1.3%) in the placebo group (P = 0.33). It is of interest to note that none of the patients without precancerous lesions at baseline histology developed cancer. The authors suggest that the chemopreventive effect of H. pylori eradication is only effective before preneoplastic lesions have developed.

Table 2 Randomized controlled trials of Helicobacter pylori eradication and risk of gastric cancer.

Ref.	Province, country	Gastric cancer per 105	No. of patients treatment/control	Follow up (yr)	No. of patients with gastric cancer	P value
Wong et al[30]	Fujian, China	99/105	817/813	7.5	7 (0.9)/11 (1.4)	0.330
Fukase et al[31]	Japan	62/105	272/272	3	9 (3.3)/24 (8.8)	0.009

The majority of intestinal-type gastric carcinoma arises from atrophic gastric mucosa. Although eradication of H. pylori results in a decrease in inflammation, it is not clear that mucosal atrophy is improved by H. pylori eradication[32-35]. One study with follow-up of 13.7 years after H. pylori eradication found no significant inflammatory cell infiltration at the time of cancer diagnosis. This suggests that the decrease in mucosal inflammation resulting from H. pylori eradication is insufficient to prevent gastric carcinoma once severe mucosal atrophy has developed[25].

Fukase et al[31] enrolled 544 patients in a multicenter study with a 3 year follow-up. The odds ratio for developing gastric cancer was 0.353 in the eradication group (P = 0.009). A meta-analysis of published trials found gastric cancer in 33/3112 (1%) of eradication patients vs 50/3031 (1.6%) of untreated patients[36]. This had a relative risk of 0.65 (P = 0.05).

The influence of H. pylori eradication may decrease with time. In a study of 268 H. pylori-positive patients who had undergone endoscopic resection of early gastric cancer, there were 177 patients who had undergone successful H. pylori eradication and 91 who had persistent H. pylori infection[37]. Although the incidence of metachronous gastric carcinoma was lower in the eradicated group at 5 years of follow-up (P = 0.007), this difference was no longer significant in the follow-up period extending to 11.1 years (P = 0.262). Interestingly, in this study too, multivariate analysis showed severe mucosal atrophy, but not H. pylori status, as an independent risk factor for metachronous gastric cancer.

There may be a precancerous state, with moderate to severe gastric mucosal atrophy or intestinal metaplasia representing a point of no return in terms of developing gastric cancer, from which H. pylori eradication can no longer prevent gastric cancer. It thus may be preferable to try to identify those patients at risk of developing atrophic gastritis and then treat for H. pylori eradication. It has been suggested that H. pylori eradication will be most beneficial in terms of preventing cancer in patients who have chronic atrophic gastritis and negative serum pepsinogen[38].

Functional dyspepsia

Dyspepsia is a common symptom with an extensive differential diagnosis. It is thought to be present in about 25% of the population in any year, although the majority of affected people do not seek medical care. About 25% of those suffering from dyspepsia have an underlying organic cause, but the remainder have nonulcer dyspepsia in which there is no clear organic cause after diagnostic evaluation. Functional dyspepsia (FD) is classified into postprandial distress syndrome and epigastric pain syndrome[39].

H. pylori eradication has been associated with significant benefits in a subset of patients suffering from FD[40]. Four hundred and four patients with FD who were infected with H. pylori were randomized to receive placebo or eradication treatment of H. pylori. At 12-mo follow-up, patients in whom H. pylori was eradicated were more likely to have symptomatic improvement compared with the control group (49% vs 36%, P = 0.01). In addition, a systematic review of 17 randomized controlled trials, including 3566 patients with FD, found that eradication of H. pylori was associated with a small but significant benefit; 14 patients needed to be treated in order to cure one case of FD[41].

However, it is possible that alterations in the upper gastrointestinal tract microbiome may result in the development of dyspepsia. Dyspepsia is more likely to occur after an episode of gastroenteritis[42,43]. It has been suggested that the effect of H. pylori therapy in improving the symptoms of FD is due to its impact on the gut microbiome rather than the eradication of H. pylori alone[44]. The clinical management of H. pylori infection has recently been reviewed[45].

BENEFICIAL EFFECTS OF H. PYLORI INFECTION

H. pylori has been colonizing the human stomach for more than 58000 years[46] and has been found in Egyptian mummies. This long-standing relationship suggests that there may be some adverse effects in altering the colonization of the human microbiome.

There does appear to be an inverse relationship between H. pylori infection and Barrett’s esophagus[47]. Sonnenberg et al[47] reported a study of more than 78000 patients in the United States who underwent upper gastrointestinal endoscopy and histopathological analysis of gastric biopsies. They found that there was a strong correlation between the presence of H. pylori, chronic gastritis and intestinal metaplasia. In addition, there was an inverse association with Barrett’s esophagus. Barrett’s esophagus is thought to be an intermediate lesion along the pathway between reflux esophagitis and esophageal adenocarcinoma. In recent years, there has been an increase in the incidence of esophageal adenocarcinoma in the developed world, together with an increase in the incidence of Barrett’s esophagus and esophageal reflux (Table 3)[48-53].

Table 3 Inverse association of Helicobacter pylori with asthma and allergy[55].

H. pylori status (H. pylori/cagA)	< 15 yr OR (95%CI)	> 15 yr OR (95%CI)
-	1	1
+/-	0.97 (0.65-1.45)	0.95 (0.68-1.33)
+/+	0.63 (0.43-0.93)	0.97 (0.72-1.32)

H. pylori:Helicobacter pylori.

H. pylori infection is usually acquired in childhood and generally persists for life[54]. Thus H. pylori has infected the majority of the world’s population for the majority of their lifetime[54] and in most cases causes no symptoms. In recent years, there has been a decrease in the prevalence of H. pylori infection in developed countries. In the United States less than 6% of children are infected by H. pylori[55]. A similar trend is becoming apparent in other parts of the developed world[56,57].

There have been reports of an inverse association between childhood-onset asthma and H. pylori infection[55,58,59] and protection from other infections[60,61] (Table 3). Recently, it has become clear that the gut microbiota has an important effect on many disease processes[62] and that disturbing the balance of the bacteria by antibiotics can produce a state of dysbiosis, with an effect on pathogen evolution[63]. Clostridium difficile infection linked to antibiotic use is one example of a deleterious effect related to antibiotic consumption and its effect on the microbiome.

Many organisms that are considered as commensals such as Kelbsiella, Strep viridans and Candida can become opportunistic pathogens, especially in the aged population. There is no coordinated attempt to eradicate these organisms from the human population and we suggest that there should not be a similar effort to eradicate H. pylori. There is a complex biological relationship between humans and commensal bacteria that is only now beginning to be understood. The “test and treat” approach to H. pylori does not address this issue at all.

COST OF ERADICATION OF H. PYLORI

The current recommendations for treating H. pylori make a strong case for universal eradication. The assertion that “H. pylori-positive patients with a fear of gastric cancer should receive eradication treatment”[5] makes it likely that the majority of the world’s infected population will receive treatment. The economic implications are enormous.

In the United States the population in 2012 was approximately 300 million. A urease breath test costs $15 and thus the cost of testing would be approximately $4.5 billion. Assuming a 30% positivity rate, then retesting to confirm eradication would need to be performed on 90 million people with an additional cost of $1.5 billion.

First-line therapy consisting of amoxycillin 1 g bid, omeprazole 20 mg bid, and clarithromycin 500 mg bid for 10 d costs $203 (based on http://www.goodrx.com). This would cost $18.27 billion for 90 million people who are H. pylori-positive. This treatment is about 80% effective and thus 18 million people would still be infected with H. pylori. Second-line therapy with omeprazole, bismuth subsalicylate, tetracycline and metronidazole costs $2.68 billion and is expected to be about 70% successful. Repeat testing of these 18 million people would cost $270 million and there would still be 5.4 million people infected with H. pylori.

Further treatment would require gastroscopy, biopsy, bacterial culture and sensitivity testing. The cost of gastroscopy to medicare in an ambulatory surgery clinic is $341 for the center and $351 for the physician and thus the total cost for 5.4 million people is $3.74 billion. The cost of a Helicobacter culture is $159 with a further $222 for susceptibility testing for 4 drugs (Ellie Goldstein, personal communication).This would result in a total cost of $2 billion for 5.4 million people. Thus the total cost for eliminating H. pylori from the population of the United States is in the region of $33 billion dollars!

IS ERADICATION OF H. PYLORI COST-EFFECTIVE ?

The question of whether eradication of H. pylori is cost-effective is complex. There is a difference between treating anyone found to be positive, or those with non-ulcer dyspepsia, or people with a high risk for gastric cancer. In addition there is still not a complete understanding of the beneficial effects of commensal H. pylori infection as well as the risks associated with universal treatment.

There have been studies estimating the financial implications of screening for H. pylori in a subpopulation of dyspeptic patients, or related to one H. pylori-associated disease such as peptic ulcer or gastric cancers[64,65]. In these studies, screening for and treating H. pylori was found to be cost-effective in patients with peptic ulcer or for preventing gastric cancer[65]. Furthermore it has been estimated that screening and treatment for H. pylori is likely to be cost-effective taking into account both gastric cancer and peptic ulcer disease[66,67]. A meta-analysis of trials of eradication therapy in H. pylori-positive peptic ulcer disease found a reduction in the recurrence of peptic ulcer disease and concluded that it was cost effective[68]. A comparison of a strategy of screening and treating everyone found to be positive vs testing and treatment only if symptoms arise found an incremental cost per case of $26 in the screened cohort[69].

A comprehensive cost-benefit analysis is difficult to perform since not all of the variables are known. The effect on the fecal microbiome of widespread eradication is not known. In addition, the decrease in prevalence of H. pylori will cause a corresponding decrease in the incidence of new infection in the next generation. To the best of our knowledge, a cost-benefit analysis incorporating these variables has not been performed.

In summary, H. pylori is a common infection of the human stomach. It is a major cause of peptic ulcer disease, a recognized carcinogen, and is linked to both iron and vitamin B12 deficiency. It may have some beneficial effects protecting from gastroesophageal reflux disease and associated esophageal carcinoma, as well as protecting young children from asthma and allergic diseases.

Near universal eradication, consistent with current guidelines, will be prohibitively expensive. Furthermore, it is likely there will be some fatalities from previously unknown allergic reactions to antibiotics employed, drug adverse effects, an increase in bacterial antibiotic resistance in treated populations, an increase in Clostridium difficile infection and unknown effects on the fecal microbiome.

There is an urgent need for robust clinical data to enable and support decisions regarding treatment of H. pylori infection before committing to a huge expenditure of limited health-care resources for which the overall impact is uncertain.