Bacteriology

A spiral-shaped, Gram-negative, motile bacillus with multiple flagella, H. pylori is able to survive and thrive in the harsh acidic environment of the stomach (Fig. 30.1). H. pylori produces a protective urease enzyme that is able to convert urea to ammonia. The ammonia produced then serves as a buffering base to protect the organism from high gastric acidity. The organism is difficult to culture, but it can be demonstrated by histologic staining or by detection of its urease activity. Once the organism establishes itself in an individual’s gastric mucosa, it typically persists and becomes a long-term colonization or chronic infection. H. pylori elicits an inflammatory and immune response, with antibody production, but the organism is generally not eliminated from the host by this response. Chronic infection then ensues, typically with chronic gastritis. Initial gastric mucosal infection and persistence of infection are enabled by the bacteria’s motility, its production of urease, and its production of a variety of virulence proteins such as VacA and CagA (reviewed in reference 2).

Fig. 30.1 H. pylori image.

(Courtesy of www.hpylori.com.au)

Epidemiology

More than half of the world’s population is colonized with H. pylori! (This may beg the question; ‘What is “normal:” to be colonized or to be free of the organism?’) As shown in Table 30.1, the prevalence of ‘infection’ is 70–90% in less developed areas such as Asia, Africa, South and Central America, and Eastern Europe. Prevalence is much lower (though still in the range of 20%) in developed countries of Western Europe, North America, and Australia. It appears that the incidence in developed countries has decreased substantially since World War II, probably as a result of better sanitation and safe water supplies.

Table 30.1 Worldwide H. pylori prevalence and gastric cancer deaths

Country/region	H. pylori prevalence (%)	Gastric cancer mortality (deaths/100 000/yr)
Americas
USA/Canada	20–40	<10
Mexico	70	10–20
Andean So. Am.	80–90	>30
So. Am. (other)	80–90	10–20
Europe
Western	10–50	10–20
Eastern	70	20–30
Russia	70–80	>30
China/East Asia	60–80	20–30
India/SE Asia	70	10–20
Japan	50	>30
Africa	80–90	<10*
Australia	20–30	10

* Data not reliable.

Data derived from reference 27 and the Helicobacter Foundation website at www.helico.com

In developing countries, infection typically occurs at an early age (by age 5–10 years), and then persists throughout life. In developed countries such as the US, Finland, and Japan, H. pylori prevalence is high in older individuals (presumably a cohort infected early in their life), but is much lower in younger persons (presumably benefiting from improvements in sanitation). The organism can be found in feces, dental tartar, and gastric juice. From polymerase chain reaction (PCR) studies, it can apparently survive for several days in contaminated water. Thus, transmission of H. pylori may be by fecal–oral, oral–oral, or gastro–oral routes, or via contaminated water. Person-to-person spread is considered most likely. Presence of the bacteria in the mucus layer of gastric mucosa correlates with lower socioeconomic status, overcrowding, greater number of siblings, sharing a bed, and a lack of running water. Infection is shown to cluster within close household/family members, consistent with person-to-person transmission. Genetic predisposition to infection has also been suggested.

Pathogenesis and Symptoms

It is important to recognize that, while a majority of the world’s population is infected (or colonized) with H. pylori, the vast majority of these infected persons will have no significant symptoms or medical consequences of the infection! Nevertheless, H. pylori infection is associated with several serious potential diseases. Why some individuals develop disease, while most do not, is unclear. However, proteins produced by various H. pylori subspecies, and not by others (such as VacA and CagA) may be important virulence factors that may favor the development of mucosal ulceration or cancer. Additional environmental or genetic cofactors, as yet unrecognized, may also be involved. The following conditions have been associated with gastric H. pylori infection.

Peptic ulcer disease (duodenal ulcer/gastric ulcer)

It has been said that most duodenal and gastric ulcers are a result of H. pylori infection. In the US, and other developed countries where the prevalence of H. pylori has fallen, overall prevalence of ulcer disease has also fallen. Meanwhile, in the US, there has been a great increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which are themselves an independent risk factor for ulcers. Consequently, NSAID use has become an important ulcer risk factor in the US, particularly for gastric ulcers.

In the US, it has been estimated that peptic ulcers may occur in 10–20% of H. pylori-infected individuals, or a risk of 1% per year.³ Other estimates suggest a lifetime risk for ulcers of 3% for infected persons in the US, up to 25% for infected persons in Japan.² Barry Marshall, in his Helicobacter pylori Foundation website, gives a figure of 30% lifetime risk for ulcer in infected persons. Thus, risk estimates for duodenal and gastric ulcer range from 3–30%. However, in some other countries where H. pylori prevalence is very high (such as Africa), reported ulcer incidence appears to be lower than would be expected from H. pylori infection prevalence data. This seeming contradiction may be explained by differing production of bacterial virulence proteins (including VacA and CagA) in regional H. pylori subspecies, by under-recognition/under-reporting of ulcers, or by additional environmental and ethnic factors involved in ulcer genesis.

Classic ulcer symptoms include epigastric pain, food-related abdominal symptoms (discomfort relieved by eating or elicited by meals), ‘dyspepsia,’ nausea, and vomiting, as well as symptoms caused by ulcer complications. Complications include gastrointestinal (GI) bleeding (melena, hematemesis, or even occult blood loss with anemia), obstruction (emesis), and perforation (acute abdomen). However, many ulcers are asymptomatic, particularly in older individuals. All current medical guidelines call for H. pylori testing of patients with active ulcer disease, or history of ulcer disease, and treatment of individuals who test positive. Eradication of H. pylori is proven to facilitate ulcer healing and to substantially reduce the very high rate of ulcer recurrence (90%) that is seen in the absence of eradication.

The possibility of interactions between H. pylori and NSAIDs with respect to ulcer risk and complications is somewhat controversial. However, it is clear that both NSAIDs and H. pylori are independent risk factors for gastric and duodenal ulcers. Up to 20–30% of chronic NSAID users develop ulcer disease, and 1–1.5% of chronic NSAID users have bleeding per year. NSAID use is associated with 10 000–20 000 deaths from ulcer bleeding per year in the US.⁴ Risk for NSAID ulcer complications is increased for individuals older than 60 years, individuals with prior history of ulcer or ulcer complications, persons taking high-dose or multiple types of NSAIDs (such as NSAID plus cardioprotective aspirin), and persons concurrently taking prednisone or anticoagulants.⁴ Because of these added risks, it has been suggested that testing and treating H. pylori may reduce the chance for bleeding ulcer in such higher-risk persons who receive high-dose or long-term NSAIDs.^5,⁶

Gastritis

Initial infection with H. pylori appears to produce an acute neutrophilic gastritis with hypochlorhydria. Patients may have no symptoms, or they may experience acute dyspepsia – as described by Barry Marshall when he induced infection in himself.⁷ Typically, chronic infection or colonization of the gastric antrum (and to a lesser extent the gastric body and ectopic gastric mucosa in the duodenal bulb) ensues. Chronic infection is associated with the histologic appearance of chronic gastritis (Fig. 30.2). Mucosal gastritis may be appreciated visually during upper GI endoscopy, or the gastric mucosa may appear visually normal. Some subjects will develop more severe chronic gastritis that can progress to histologic atrophic gastritis and intestinal metaplasia. Intestinal metaplasia appears to be the histologic risk factor for development of distal gastric adenocarcinoma. Treatment of H. pylori may be able to cause regression⁸ or, at least, a reduced rate of progression of the histologic sequence.⁹ Patients with chronic gastritis from H. pylori also have subnormal acid production, and gastric acid production may actually increase after H. pylori infection has been eradicated.