Commentary: Peptic ulcer and its discontents

Susan Levenstein

Via del Tempio 1A, 00186 Rome, Italy. E-mail: slevenstein{at}compuserve.com

‘While stress and diet can irritate an ulcer, they do not cause it. Ulcers are caused by the bacterium H. pylori.' Centers for Disease Control and Prevention1

‘Thus the dialectics of Hegel was placed upon its head; or rather, turned off its head, on which it was standing, and placed upon its feet.' Friedrich Engels2

Secular Trends in Peptic Ulcer: Whodunit?

Pushing forward to the end of an Agatha Christie novel after you've guessed the murderer is a peculiar reading experience. There is something similar in reading Susser and Stein's ‘Civilisation and Peptic Ulcer'3 with our present awareness that an infectious agent plays a role in this disease. The reader is constantly looking out for whether and how Helicobacter pylori (HP) may be the key to the temporal trends in ulcer mortality that seemed mysterious when they were laid out 40 years ago—the appearance of gastric and then duodenal ulcers on the scene beginning in the late 19th century, their swell into an epidemic over 50 years, and their progressive decline thereafter.

Since these classic analyses were published, the dominant model of peptic ulcer aetiology has been flipped topsy-turvy. Like Hegel's dialectics, it has been lifted off its head, upended, and landed solidly with its feet on the ground. The present commentary on Susser and Stein will aim chiefly at a contemporary perspective on the relation between civilization and peptic ulcer, but its subtheme will be to ask whether it was necessary for those who flipped ulcer aetiology from top to toes to finish off the job by abolishing psychosomatic explanations—by, so to speak, lopping off the head altogether.

Helicobacter Pylori Breaks In

In this Lancet article Susser and Stein stopped short of using their cohort observations as the basis for a grand conceptual leap when they limited themselves to psychosomatic reasoning, and thus failed to conclude that an important aetiological factor encountered in childhood appeared during a limited historical period in the late 19th century (see ref. 4). But their intuition that ulcer is ‘a disease of an early phase of urbanisation' still holds; current knowledge suggests the peptic ulcer syndrome could become widespread only when HP was able to settle into a particular niche due to society's arrival at a certain stage in its economic and social evolution.

Medical history offers examples of the rise and decline of micro-organisms, such as the scarlet fever strains of streptococcus, which caused time-limited disease outbreaks as they followed their own evolutionary paths. Helicobacter pylori is not one of these. According to prominent theorists HP has always inhabited the human stomach, but the pathology it caused was chiefly, until the late 19th century, not ulcer but gastritis and gastric cancer.5,6 Public health advances, which improved diet and diminished the overall disease burden in early childhood, then brought relative sparing of the gastric corpus which in turn resulted in some individuals having unimpaired acid secretion. The decreased prevalence of atrophic gastritis and the elevated load of acid being delivered to the duodenum caused a shift to peptic ulcer as the primary HP-related pathology.5,7,8 Forward displacement of the usual age at acquisition of HP from infancy into childhood9 may also be relevant, paralleling the emergence of paralytic poliomyelitis as a result of delay in the usual age of exposure to the polio virus. Thus to the extent that the 20th century epidemic of peptic ulcer is due to HP its root cause is the progress in public health that accompanies the process we may call civilization.

The falling tail of the ulcer epidemic, on the other hand, corresponds to HP losing access to its host altogether. By now general hygienic conditions have improved to the point that few young Americans acquire HP, and the current >=1%/year age gradient of active infection10 mainly reflects cohort effects.

Helicobacter pylori thus finds a historical window of opportunity along a society's way toward modernization—public health conditions that are better but not too much better—through which it can induce an epidemic of peptic ulcer.

Such reasoning can contribute to explaining not only the overall shape of the peptic ulcer epidemic but also its relations with socioeconomic status (SES). At the turn of the 21st century, ulcer is inversely associated with SES,11 largely because children who grow up in crowded households, sleep in shared beds, etc. are more likely to acquire HP;12 the HP status of adults is affected much more by childhood than by current SES.13

The SES trends of ulcer prevalence over time are complex. Susser and Stein's results demonstrate that the wave of ulcers began to recede earlier in the upper classes, but they also suggest that it peaked earlier in the upper classes, so that the socioeconomic gradient around 1900 was the reverse of the present one. This too can be understood in terms of the evolution of HP-host relations if we suppose that the high-SES cohort born in about 1850–1865 experienced the moderate improvement in childhood hygienic conditions required for the ulcer window of opportunity, while the HP which infected their lower class agemates was still causing gastritis and cancer.

It is evident from these observations that much of the responsibility for the sweeping trends in ulcer over the last century has to do with HP. Does ‘much' mean ‘all'?

Stress and Company: the Usual Suspects

The brief section in which Susser and Stein attempt to make sense of their findings in terms of the demands of industrial society or the upheavals of war is hamstrung by the assumption that psychological factors are the chief determinants of peptic ulcer, which has as its corollary that the task of epidemiologists in explaining observed historical trends is limited to discovering which stressors might be operative, where, and on whom. Since the HP bombshell landed many experts have gone to the opposite extreme, denying that stress or other psychological factors have anything to do with the aetiology of peptic ulcer.14 One reductionism has been replaced by its mirror image.

Though it was an error to take ulcer psychosomatics as an article of faith, care must be taken not to throw the baby out with the bath water by assuming that with the discovery of HP the case is closed. Only 20% of HP-infected individuals ever develop an ulcer,15 usually after several decades of infection, and many ulcers develop in the absence of HP.16 Helicobacter pylori must therefore be conceptualized not as the cause of peptic ulcer but as one risk factor among, potentially, many. Helicobacter pylori infection has been estimated to carry a risk ratio of approximately 4 for ulcer17 and to be responsible for 48% of the population attributable risk.18

Several previously known risk factors have been shown to act as co-factors in HP-related ulcer. A family history of ulcer, for example, far from being merely a marker of exposure to HP,19 elevates by 8-fold the risk that an HP-infected person will develop an ulcer.17 Gastric acid hypersecretion similarly retains its association with ulcer after HP is taken into consideration20 —patterns of bacterial colonization are affected by parietal cell function,21 and laboratory studies support the concept that duodenal acid load is likely to be a major determinant of HP-related duodenal ulcer.22 Smoking is still another ulcer risk factor whose association holds up in the HP era.23 Hard on-the-job physical exertion also seems to facilitate ulcer formation over and beyond the effect of low SES,24 perhaps by stimulating gastric acid secretion,25 though a degree of confounding of these findings by HP cannot be excluded.

What of psychological stress, the dethroned king of ulcerland? Its position had weakened even before a usurper arrived to claim its seat, since the period just before HP came into the picture saw both the advent of effective medical therapy for ulcer and several case-control studies finding no association of ulcer with stress.26–28

Some of the best case-control studies do support an association of ulcer with life stress;29,30 a cross-sectional association of ulcers with shift work31 is particularly convincing because of a bias in the opposite direction (sick workers are commonly assigned to the day shift) and is complemented by reports linking ulcer with poor sleep.32 But it is prospective studies, most of them published since 1990, that have provided the most compelling evidence of a causal role for psychological stress in peptic ulcer. A variety of natural and man-made catastrophes in various populations have been followed by surges in the number of diagnosed ulcers.33–36 Among defined cohorts initially free of ulcer, psychological stress and distress at baseline have generally been found to predict excess ulcer development over the following years,32,37–41 though there have also been contrary reports.42,43 Follow-up studies of patients with endoscopically diagnosed peptic ulcer have uniformly found stress and distress to worsen clinical course over months to years.44–48 On the basis of the published evidence I have estimated that psychological factors contribute to 30–65% of cases of peptic ulcer.49

The interactions among stress, HP, and ulcer have been little studied thus far. From the limited evidence that is available it would seem that emotional stress can precipitate ulcer in HP-positive individuals,50 and that it may enable ulcer development at low intensities of infection51 or in HP-negative individuals.52

It should be pointed out that bleeding or perforated ulcers, the implied topic of any examinations of trends in ulcer mortality, on the one hand are more often HP-negative than are uncomplicated ulcers53 and on the other hand have a particularly well documented association with stress.33–36

The imperfect coincidence between peptic ulcer and HP leaves room not only for co-factors but also for alternative pathogenetic pathways. Depending on the setting, between 4%54 and 44%55 of ulcers have been reported to develop in HP-negative individuals. Non-steroidal anti-inflammatory drugs are the best-recognized factor involved in ulcers which develop in the absence of HP,56 but it is not true (as once thought) that all HP-negative cases have taken these drugs.54,55 Bile reflux, intestinal metaplasia,57 elevated pepsinogen I,58 and stress54 have been implicated as other risk factors. On the other hand, smoking56 and type O blood59 probably increase the risk of peptic ulcer only in the presence of HP.

Though Susser and Stein may have had the chief culprit wrong, the confirmed importance of a whole cluster of secondary risk factors in the HP era means it was nonetheless correct for them to emphasize the multifactorial nature of peptic ulcer.

Murder on the Orient Express

Though the temporal parabola of peptic ulcer in the 20th century chiefly reflects the ecology of HP, authoritative observers have maintained that others among the factors listed above must also be invoked.60,61 For example, the two health risk behaviours most relevant to ulcer, cigarette smoking and aspirin taking, both became widespread early in the 20th century and could therefore have contributed to the rise of the peptic ulcer epidemic. Shifts in the workforce toward sedentary jobs in the last 50 years could on the other hand have contributed to its fall.62 As for whether psychological stress has increased or decreased over the last century, that is still anyone's guess.

At the present moment, when the class differences in rates of HP acquisition are particularly striking, they overshadow all other factors in the SES gradient of peptic ulcer. There are, however, additional, non-infectious, reasons for a high rate of peptic ulcer in lower SES individuals, including their greater likelihood of exposure to hard on-the-job physical labour24 and to psychological stress.63 Non-HP factors may also have contributed to the reverse SES gradient of a century ago, if higher socioeconomic strata were the ones to pioneer the use of substances such as cigarettes and aspirin which are important behavioural risk factors for ulcer.

Susser and Stein wrote that no ulcer treatment was effective enough to condition the trends they observed. This is no longer the case: the drop in ulcer mortality has undoubtedly been accelerated by the introduction of effective medical treatments beginning in the late 1970s. Documented morbidity has fallen still more, since a large proportion of ulcers are cured without ever being diagnosed now that ulcer-like dyspepsia is commonly treated empirically with powerful antisecretory drugs and sometimes even with HP eradication therapy. Current ulcer incidence and prevalence figures are therefore suspect, making it unlikely there will be a Susser and Stein of the year 2012. But the lines of research indicated in 1962—such as explaining the high rate of gastric ulcer perforations in young women around the turn of the 20th century—remain to be fully mined out, though they are by now of more historical than clinical interest.

The detectibility of aetiological factors using epidemiological means can vary according to time and place. In the case of peptic ulcer, a few decades ago virtually all Western adults were infected with HP. Due to this very ubiquity, genetic predispositions and adult modes of life were major visible determinants of who among the infected actually developed an ulcer; this would have been the case even had the existence of HP been known. On a clinical level we may also recall what Osler said of tuberculosis at a time when infection was nearly universal: ‘So widely spread everywhere is the seed, that the soil, the conditions suitable for its growth, is practically of equal moment'.64 Now that HP is harboured by a minority of adults, but a minority substantial enough for it to be involved in most ulcers, the infectious contribution to determining who does and who does not develop gastroduodenal lesions stands out with particular prominence.

Host Factors in the Mix

If ulcer or at least one category of ulcer is in some sense an infectious disease, broader issues of the nature of microbiological aetiology are raised by the peptic ulcer story.

Early in the antibiotic era the medical profession understandably paid little attention to the role of host factors in infectious diseases, as it gloried in drugs that could eradicate ever-wider spectra of micro-organisms. But after several decades of serial triumphs came the first setbacks. The emergence of drug resistance showed that the antibiotic approach had limitations, and revived interest in factors that might impair or bolster host defences. With the advent of iatrogenic immunosuppression and then AIDS, conditions in which fatal infections could result from usually harmless organisms, the potential primacy of host factors became even more evident.

More recently support for the importance of host factors has arrived from a line of research suggesting that many chronic diseases previously considered of unknown origin might be related to infectious processes. Marshall's revelations of the bacterial component in peptic ulcer blazed the trail for similar investigations of diseases ranging from Hashimoto's thyroiditis65 to coronary artery disease66 and multiple sclerosis.67 Though these infectious links are still largely speculative, they have fuelled a new boom of interest in the role of host factors in infectious diseases; even if Chlamydia pneumoniae does indeed turn out to prime the formation of arteriosclerotic plaques in the coronary arteries, it will remain difficult to deny the role of smoking or of hypercholesterolaemia. The degree of our knowledge of risk factors for coronary artery disease, and the success of their modification in reducing incidence and case-fatality rates, should make it unlikely that microbiological reductionism will take over aetiological models of, say, coronary artery disease as it did for peptic ulcer.

Mycobacterium tuberculosis provides an instructive parallel to HP as an infection acquired in childhood but causing disease only in a minority of hosts and often after decades of latency. As with peptic ulcer, a vast literature on host factors was discarded once effective antibiotic therapy was developed. And as with peptic ulcer, some of the older observations of non-microbiological risk factors for tuberculosis—poor nutrition, emotional stress, etc—probably have a core of validity68 and are increasing in relevance as clinicians encounter new difficulties related to drug resistance and to immunosuppressed populations.

Advances in genetic research have added plausibility to the concept of host factors in infection, as hereditary influences are being detected in pathologies as unlikely as otitis media.69 Psychological stress similarly seems capable of worsening some infections, in part though immune mechanisms.70 Although this literature has concentrated on viral diseases, immunologically mediated effects of psychosocial factors on bacteria including HP cannot be excluded.71

All these developments are forcing a reconceptualization of the interactions between an infectious agent and its host. The emerging model of infectious disease is inherently multifactorial, since the foothold of germ on organism is now known to be influenced by host factors ranging from genetic to iatrogenic to nutritional to behavioural to psychological. A variant of Susser and Stein's multifactorial model of ulcer aetiology, updated to include HP infection as well as heredity, psychology, and lifestyle, is therefore not only plausible but in exciting concordance with the zeitgeist of the new millenium.

Acknowledgments

Thanks to Terri Ballard, Katherine Flegal, Francesco Forastiere, David Graham, Phyllis Levenstein, and John Spitzer for useful comments on drafts of this paper.

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