Helicobacter Pylori Infections: Casual and Causative Associations

Alberto Rodríguez Varón, MD. (1)

(1) Professor of Internal Medicine and Gastroenterology, Director of the Department of Internal Medicine at Pontificia Universidad Javeriana and San Ignacio University Hospital in Bogota, Colombia.

Received:     21-08-14   Accepted:     26-08-14

Helicobacter pylori (HP) is the most prevalent chronic bacterial infection in the whole world. There is evidence that suggests that HP infections might have been present in human beings for over a thousand years, and there are pathology specimens from the late 19th century in which these bacteria have been retrospectively identified. However, after the 1982 publications of Marshall and Warren described, typified and cultivated the bacteria, intense research began to establish the pathophysiological and therapeutic implications of this “new infection”. Its biological plausibility was quickly accepted, and the mechanisms through which HP could colonize the gastric mucosa in healthy individuals and trigger an inflammatory response were described. These are currently recognized as the most frequent etiology of chronic gastritis (CG).

Associations between HP infections and several gastrointestinal diseases were established almost simultaneously. First, it was not easy to establish causal relations with these associations since they did not meet the Koch postulates for establishing causality. The controversy generated within the medical community regarding the etiological implications of HP infections began to emerge when the first studies appeared showing the beneficial effects of eradicating the infection. Eradication modified the clinical courses of diseases reversed some of the inflammatory changes of chronic gastritis, led to remission and healing of an important percentage of MALT lymphoma patients and dramatically decreasing recurrences. This evidence resulted in one of the most important changes in the etiological, diagnostic and therapeutic approaches to these diseases. This is how the acid paradigm, once the etiological pillar of peptic ulcer disease, was replaced by HP infection as its main etiology.

Accepting that HP is the most frequent cause of GC and that the carcinogenesis sequence described by Pelayo Correa begins with GC made it inevitable that gastric cancer would be related to HP. Multiple studies have shown that the eradication of the infection can stabilize and decrease the risk of progression of some lesions which are precursors of malignancy and therefore can decrease the incidence of gastric cancer. This is why HP infections are currently classified as a type I carcinogen.

The accumulation of evidence, not only from studies showing the association but, fundamentally from those that show the benefit of interventions, affirms that HP infection is the most important etiology in chronic gastritis, peptic ulcer disease, MALT lymphoma and gastric adenocarcinoma and that its eradication modifies the natural history of these diseases.  

Since HP is the most prevalent chronic infection in humans, more associations have been sought with other extra-gastric diseases usually classified as multifactorial chronic infections which have the corresponding inflammatory responses associated with HP that could be part of its etiology.

Most of these associations are derived from studies that report associations using relative risk (RR) which is a very useful indicator. Nevertheless, it must be carefully interpreted in a way that takes into account both its meaning and its correct interpretation in terms of causality and clinical significance. When the relative risk is greater than 2.0, there is usually a clear association, but numbers below 2.0, especially those closer to 1.0, must be interpreted with caution both because they show weak associations and because they might be explained by random variability or sample errors.

Since HP infections are so prevalent, it is statistically possible that they are associated with many entities. However, associations do not always imply causality: they may be spurious associations or non-causal risk markers. In addition, not everything that is statistically significant is clinically significant which is why physicians must correctly interpret statistical results before making decisions that modify patient management.

There are several associations between HP infection and extra-gastric diseases that have been described which makes it important to review the evidence of eradication’s impact in the natural history of these entities.

When reviewing some of the extra-gastric associations that have been described, we find that in cases of patients with Iron Deficiency Anemia of unspecified causes after the most frequent cases of iron deficiency have been ruled out, the eradication of HP combined with the administration of iron supplement is more effective than monotherapy with iron substitute. This is why most consensuses and practical clinical guides currently recommend eradication therapy for patients with unspecified iron deficiency anemia.

Also, various studies have shown that eradicating HP from patients with Idiopathic Thrombocytopenic Purpura has a positive effect. A meta-analysis and two systematic reviews have shown significant increases in the number of platelets in patients who received HP eradication when compared to control groups.

HP infections have been associated with malabsorption of several micronutrients, especially with vitamin B12 deficiency. Although the relation between HP and vitamin B12 has not been completely elucidated, there is a systematic review that shows lower levels of vitamin B12 in infected patients and a statistically significant increase in cobalamin levels after HP eradication. These findings support the search for, and eradication of, HP in patients with vitamin B12 deficiency. Nevertheless, more evidence is needed to make a definitive recommendation.

Worth mentioning are the multiple associations have been proposed between HP and chronic inflammatory dermatitis including with rosacea and chronic urticaria.  Associations have even been proposed with coronary disease. The results of these studies suggest that possible associations are controversial and that clear benefits from eradication of the infection in these entities has yet to be proven. Hence, we can conclude that even though statistically significant, they are not clinically relevant and there is no evidence to support interventions like the eradication of HP.

Finally, it is worth insisting that when a “risk factor” is very prevalent, such as HP infection, it is possible to find multiple associations with diverse diseases. Even though these associations may be statistically significant, this does not mean that they are true in every case or that they are clinically significant. In these cases the effect of eradication could be clinically irrelevant and inappropriate.

Clinical physicians must carefully and critically analyze information in order to make decisions that are clinically relevant and pertinent for managing our patients.

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