The Department of Veterans Affairs Medical Center, and The University of New Mexico, Albuquerque, New Mexico, USA.
Amnon Sonnenberg, Department of Veterans Affairs Medical Center 111F, 1501 San Pedro Drive SE, Albuquerque, New Mexico 87108, USA. E-mail: sonnbrg{at}unm.edu
In the landmark paper written by Mervyn Susser and his wife Zena Stein, it was shown that the temporal trends of peptic ulcer were more closely related to the time of birth of individual ulcer patients than to the time when they contracted their ulcer and died from it.1 When the original paper was published in The Lancet in 1962, the overall frequency of gastric and duodenal ulcer were still rising in the British population. The British birth-cohorts born between 1870 and 1890 carried the highest risk of developing gastric and duodenal ulcer, respectively. As these cohorts grew older and their general age-related mortality increased, the overall number of deaths associated with bleeding and perforated peptic ulcers was still rising in the population. Susser and Stein speculated that eventually, as these high-risk cohorts grew older and their proportion in the population declined, the occurrence and mortality of peptic ulcer would start to fall again. From their birth-cohort analysis of peptic ulcer mortality in England and Wales between 1900 and 1959, Susser and Stein were able to correctly predict a future decline of peptic ulcer disease 10 to 20 years prior to its actual occurrence.
William O Kermack and his co-workers were among the first investigators to speculate about the influence of early-life exposures on disease appearance in adulthood.2 The analysis of epidemiological data by year of birth was subsequently applied by Wade Hampton Frost and others to study the time trends of tuberculosis and cancer in the US.35 Although it constitutes an established technique in the armamentarium of epidemiologists, birth-cohort analysis is not well explained by most textbooks, and it takes mental effort to be fully understood. In spite of these obstacles The Lancet paper has remained part of the common knowledge among investigators interested in peptic ulcer disease. One obvious reason relates to its publication in a widely distributed and prestigious medical journal. The second reason was that people liked the article for the wrong reasons, as it was assumed to provide evidence for the psychosomatic nature of peptic ulcer. Susser and Stein speculated that the stress associated with urbanization in England around the turn of the century led to strong and lasting mental or physical imprints in subjects born during this transitional time period of English history. These imprints rendered subjects susceptible to peptic ulcer disease for the remainder of their life. When stress and psychological factors were still much in vogue to explain peptic ulcer, the influence of urbanization' seemed one of the strongest arguments in favour of such an hypothesis.
The Ubiquity of the Birth-cohort Phenomenon
Subsequent epidemiological analyses tested the presence of birth-cohort patterns in statistical data from other countries in Western Europe, North America, and Asia.68 The data from most countries whose vital statistics covered sufficiently long time periods revealed similar trends. In all statistics alike, the time of birth exerted a stronger and more obvious influence on ulcer mortality than the time of ulcer occurrence. Peptic ulcer mortality was highest among birth-cohorts born before the turn of the 19th century, with similar patterns observed in men and women. It decreased in subsequent generations born during the 20th century. Instead of showing the individual cohort-age contours, as done in the original article by Susser and Stein, one can also calculate an average age-standardized cohort mortality ratio (SCMR), which makes it easier to follow the rise and fall of ulcer mortality associated with consecutive birth cohorts. Figure 1 shows the time course of gastric ulcer, duodenal ulcer and ulcerative colitis from England and Wales. (The relevance of ulcerative colitis in the present context will be discussed later.) The peak of gastric ulcer preceded that of duodenal ulcer by 1020 years in most countries, and in none of the many countries did duodenal ulcer precede gastric ulcer (Figure 1
). This phenomenon was also present in Susser and Stein's original data, but the authors did not take pains to explain it, possibly because the hypothesis of urbanization did not account for such differences in the behaviour of the two ulcer types. Although many of the European countries and the US had experienced an industrial revolution at the beginning of the 19th century and a resultant expansion of their urban population throughout the remainder of 19th century, the socioeconomic changes and their impact on public health and culture, population growth, and the political climate were less dramatic than in England. Urbanization was deemed even less a suitable explanation for the birth-cohort phenomenon.
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Since genetically determined mechanisms stay unchanged during historical time periods, the marked temporal trends of gastric and duodenal ulcer disease indicate that their occurrence are largely influenced by exogenous risk factors. The simpler and more consistent pattern obtained by considering the patients' period of birth rather than death implies that influences during or shortly after birth are more important than those during the time of death. A birth-cohort pattern suggests that exposure to the relevant risk factors of the disease occurs during early life between the prenatal period and adolescence. The risk factors must exert their effect within a limited time interval, and the amount or type of exposure must be changing with time. Otherwise successive generations could not exhibit rapidly varying rates of disease occurrence. As the exposure changes over time, consecutive generations, i.e. birth-cohorts, come to reflect its varying influence on the risk of developing the disease.
The relevance of the birth-cohort patterns has been questioned and various critiques have been raised. Some investigators assumed that recent changes in treatment (or diagnosis) had benefited young more than old patients and had, thus, contributed to the differential time trends of old versus young patients. If newer life-saving therapies benefited younger patients more than older patients, for instance, younger age groups would show a more pronounced time-dependent decline of ulcer mortality than older patients. Similarly, the utilization of endoscopic procedures to diagnose peptic ulcers may have been utilized more in young than old patients. A more refined procedure to diagnose abdominal symptoms seemingly reduced the number of true peptic ulcers among young patients, while old patients subjected to less diagnostic scrutiny were still being erroneously diagnosed with peptic ulcers based on symptoms alone that in reality stemmed from other diseases. Other more elaborate schemes were concocted to explain away the birth-cohort patterns. Such arguments failed to account for the fact, however, that in some countries with far reaching vital statistics, the rise and fall of peptic ulcer can be appreciated even in a single age group. Others argued that, considering a case-fatality rate of less than 5%, mortality was an unreliable parameter to assess the time trends of peptic ulcer. The vital statistics are particularly suited to analyse temporal trends of diseases, because they have been recorded for the longest time periods and because they are available from many different countries. Subsequent studies showed that a birth-cohort pattern shaped the time trends of various other parameters of ulcer morbidity besides mortality, such as hospitalization, disability pensions, and perforations.912
Lastly, people questioned the uniqueness of the birth-cohort phenomenon in peptic ulcer and wondered whether time trends of other diseases would show similar patterns. As a matter of fact, a few other diseases, such as coeliac sprue, tuberculosis, laryngeal cancer, and lung cancer, do reveal birth-cohort patterns, but their individual trends are rather dissimilar. In laryngeal and lung cancer, for instance, it can be related to the acquisition of smoking habits during adolescence. The ascent and decline occur slower and the peak is much broader than in peptic ulcer. Generations born around 1920 are the ones most affected, and the rise and fall of smoking-related cancers show primarily in men. Compared with men, the initial rise appears delayed in women, and the recent decline appears more blunted in women than men.1315 Ulcerative colitis is the only other gastrointestinal disease found to present with a clear-cut birth-cohort pattern (Figure 1).
A Strange Link with Inflammatory Bowel Disease
Similar to peptic ulcer disease, the epidemiology of ulcerative colitis and Crohn's disease is also characterized by marked socio-demographic, geographical and temporal variations. Such variations point to the existence of environmental influences that must be shaping the occurrence of both types of inflammatory bowel disease (IBD). In the age-specific mortality data of ulcerative colitis from England and Wales, the cohort-age contours are aligned to form a clear-cut hyperbola with its peak located around 1890.16,17 Subsequent analyses confirmed similar birth-cohort patterns in the time trends of ulcerative colitis from most western countries.18 The data further suggest that in many countries alike, ulcerative colitis and duodenal ulcer exhibit similar birth-cohort patterns that affect exactly the same generations with a peak occurring around 1890 (Figure 1). The close similarity between duodenal ulcer and ulcerative colitis is especially striking because it is confined to these very two diseases and does not involve gastric ulcer or gastric cancer, which are both characterized by distinctly different birth-cohort patterns. The similarity indicates that the aetiologies of ulcerative colitis and duodenal ulcer may share a common pathway and that this pathway relates to some environmental exposure before or during childhood.
The trends of Crohn's disease reveal yet another rather peculiar pattern. Ever since its inclusion into vital statistics in 1950 until about 1970, mortality from Crohn's disease was rising and then started to fall upon reaching the level of ulcerative colitis (Figure 2). It appeared as if mortality associated with Crohn's disease failed to continue its rise above the level of mortality associated with ulcerative colitis. This pattern was discernible in each age group, in each gender, and as subsequently shown, in different countries.16,19 As gastric ulcer is obviously linked to duodenal ulcer, and Crohn's disease is linked to ulcerative colitis, there appears to be some single mechanism that influences a large portion of gastroenterology's most important diseases.
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The discovery of H. pylori has changed our concepts of peptic ulcer disease and gastric cancer. In developing countries with high prevalence rates of H. pylori, the infection is acquired during early childhood, and by the age of 20 years, over 80% of the population have become infected.20 Since the immune system is unable to rid the body of H. pylori, any infection acquired during early childhood remains a lifelong event. The rise and fall of peptic ulcer could, thus, represent the historic scars of rising and falling infection rates experienced during early childhood by large fractions of the population as in a birth-cohort phenomenon.21 The marked decline in the occurrence of peptic ulcer during the past two decades is matched by a steep decline in the infection rates with H. pylori in all western countries.22 Urbanization and the crowded living conditions of the expanding cities during the beginning of the industrial revolution at the onset of the 19th century probably meant a decline in hygiene for large fractions of the population with a concomitant rise in exposure to H. pylori. Subsequently, the increase in knowledge about the importance of hygiene in preventing the spread of diseases led to various governmental and municipal efforts to improve sanitation and supply clean water to urban residents. These efforts probably resulted in a decline of H. pylori infection rate.21
Unresolved Issues
Even if the decline in peptic ulcer during the second half of the 20th century can be explained by improvements in hygiene and a reduction in H. pylori transmission, it remains unresolved why peptic ulcer rose so suddenly 100 years earlier.23 Most epidemiological evidence suggests that H. pylori has been a human pathogen for thousands of years. The world-wide distribution of H. pylori even among remote populations on four continents mitigates against the contention that H. pylori infection spread only recently among populations of western or industrialized countries.24 Gastric cancer is actually the only disease whose trends vary in the time-dependent fashion one would expect from a well-behaved H. pylori-related disease.25 It remained stable in among consecutive generations until the turn of the 19th century and has declined ever since. The rise in the occurrence of gastric and duodenal ulcer during the 19th century is difficult to explain utilizing H. pylori as the sole explanation.
Some gastroenterologists have tried to explain the initial rise of peptic ulcer based on a set of complex interactions among varying modes of H. pylori acquisition, dietary factors, and other childhood infections in the 19th century.26,27 Malnutrition and weakening of the immune system by infectious diarrhoea or other intercurrent infections may render the host more susceptible to persistent gastric colonization with H. pylori. Healthy well-nourished children may be more capable of fending off an early invasion by H. pylori. Subjects who become infected with H. pylori at a young age are more likely to develop chronic or atrophic gastritis with a subsequent reduction of acid secretion that protects them from developing duodenal ulcer. Such gastritis is associated with development of gastric ulcer, as well as gastric cancer. In contradistinction to gastric ulcer, duodenal ulcer seems to develop primarily in subjects who contract H. pylori infection at the end of childhood or later. Some reservation towards these hypotheses stems from their complexity and the ever-increasing number of interrelated factors necessary to explain one characteristic feature of ulcer epidemiology. It is difficult to envisage how a multitude of individual risk factors, each one characterized by its own temporal, geographical and demographic variation, could align in many different countries at the same time to cause a unique, clear-cut and sharp rise and fall of ulcer risk among consecutive human generations. The contribution of several factors should have caused at least some blurs or spread of the cohort pattern, which we do not observe.
Conclusions
It would take probably another landmark paper to resolve the mystery of the interrelated time trends of several gastrointestinal diseases. One potential hypothesis holds that another Helicobacter species may be responsible for ulcerative colitis. The birth-cohort phenomenon could stem from an underlying general variation in the yet poorly understood infection mode of Helicobacter species. For instance, helminths could affect the acquisition of H. pylori, possibly, by functioning as direct carriers (vectors) of the bacterium into the human body or by facilitating its spread among populations through diarrhoea and other influences on the gastrointestinal tract. Infection with helminths rather than H. pylori would then be the primary driving force behind the birth-cohort pattern. Yet another hypothesis assumes that the four birth-cohort phenomena result from the superimposition of one major declining trend and multiple rising trends. This joint influence of declining and rising trends would cause a succession of peaks affecting consecutive generations with gastric ulcer, duodenal ulcer, ulcerative colitis, and lastly Crohn's disease. Rather than being influenced by a single agent, each one of the four diseases would be caused by the interaction of at least two distinct environmental influences. Improvements in hygiene and a general decline in enteric infections, including H. pylori, could be responsible for the declining trend, whereas a rise in exposure to different types of viruses or other environmental agents could be responsible for the rising trends. At the present time such concepts are purely speculative, and there is little or no evidence to support or refute them.
It is amazing that even current books and review articles about peptic ulcer fail to mention the birth-cohort phenomenon. It may reflect some general difficulty in understanding complex temporal patterns that defy a simple explanation. Rather than giving a conclusive answer, it keeps pointing at the persistence of a big gap in our understanding of peptic ulcer and inflammatory bowel disease. Once resolved, the mystery of the birth-cohort phenomena carries the potential for finding a profound link among these seemingly heterogeneous diseases.
Acknowledgments
Amnon Sonnenberg was supported by a grant from the Centers for Disease Control and Prevention, Atlanta, GA.
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