A collection of the etiological theories, characteristics, and observations/phenomena of peptic ulcers in existing data

In this article, we compiled 13 etiological theories, 15 characteristics, and 81 observations/phenomena of peptic ulcers, reported in reproducible, peer-reviewed studies from the literature, to reflect the historical evolution of studies on peptic ulcers and to provide a multidisciplinary view of this disease. This data was collected during the systematic review of topics on peptic ulcers including genetics, etiology, epidemiology, psychology, anatomy, neurology, bacteriology, pathology, and clinical statistics. The data curated herein was extracted via application of recently published basic theories and methodologies.


a b s t r a c t
In this article, we compiled 13 etiological theories, 15 characteristics, and 81 observations/phenomena of peptic ulcers, reported in reproducible, peer-reviewed studies from the literature, to reflect the historical evolution of studies on peptic ulcers and to provide a multidisciplinary view of this disease. This data was collected during the systematic review of topics on peptic ulcers including genetics, etiology, epidemiology, psychology, anatomy, neurology, bacteriology, pathology, and clinical statistics. The data curated herein was extracted via application of recently published basic theories and methodologies.
& 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Similar literature review can be repeated for any disease. Accordingly, the data obtained can be used to challenge etiological theories and provide new insights for any disease.

Data
Over the past 300 years, many etiological theories have been proposed to explain the pathogenesis of peptic ulcers (including gastric ulcer and duodenal ulcer), but none of these theories have ever been able to explain all the characteristics and observations/phenomena of this disease [1]. Currently, it is widely believed that there is a causal relationship between Helicobacter pylori (H. pylori) and peptic ulcers due to the revolutionary discovery of H. pylori in 1982 [2]. However, the role of H. pylori in peptic ulcers is controversial, and how the bacterial infection can lead to ulceration is presently unknown [3][4][5][6]. To address these challenges, we systematically reviewed all the topics on peptic ulcers over the past 300 years and applied novel basic theories and methodologies to analyze the existing data. We summarized our results into 6 manuscripts (prepared, unpublished) to explain the pathogenesis of peptic ulcers. This article is a byproduct of our systematic review project and provides essential background information for all 6 manuscripts. Our extensive and in-depth literature review indicated that there were 13 etiological theories in history attempting to explain the pathogenesis of peptic ulcers (Table 1). We also found that the pathogenesis of peptic ulcers included 15 characteristics (Table 2) and 81 observations/phenomena, which were grouped into four tables based on diseases and H. pylori (Tables 3-6).

Materials and methods
We developed a four-step strategy to collect the data presented herein. First, we reviewed all the topics on peptic ulcers, such as genetics, etiology, epidemiology, psychology, anatomy, neurology, bacteriology, pathology, and clinical statistics. To achieve this goal, we searched Medline, Embase, Web of Science, and Google Scholar for articles published over the past 300 years. Books published on peptic ulcers and on the pathogenesis of human disease were also included. Our search was completed without language restrictions. Second, we extracted data on study year, etiological theories, characteristics, observations, and phenomena of peptic ulcers. If an etiological theory in history had yet to be officially named, we named it based on its central idea. For instance, we designate the etiological theory based on H. pylori infection as "Theory of H. pylori". Third, selected studies were summarized and unreproducible studies were excluded. If several studies had similar findings, we randomly selected one or two to avoid repetitive results. However, if a paper was identified to be the earliest study on a characteristic or phenomenon, this paper was selected because we determined the earliest paper provided the basis for the other similar studies that followed. Fourth, selected data was classified and curated into 6 tables. Table 1 Etiological theories in history.

Etiological theory
Founder & year Key points 1 Circulation Theory [7] John Hunter, 1772 Gastric acid is neutralized by the continuing circulation of alkaline blood through the tissue. 2 a Ischemia Theory [8] Rudolf Virchow, 1853 The presence or absence in the gastric mucosa of end arteries whose spasm or thrombosis might account for localized ulceration. 3 Digestion Theory [9] Heinrich Irenaeus Quincke, 1882 Peptic ulcer is caused by the proteolytic effects of pepsin and the corrosive effects of gastric acid. 4 No Acid, No Ulcer [10] Dragutin (Carl) Schwartz, 1910 Hypersecretion of gastric acid is the cause of peptic ulcer.

5
Nerve Theory [11] Von Bergmann G., 1913 The abnormality of neurotransmitters in the central nervous system is the cause of peptic ulcer. 6 Funktionell-mechanische Theorie [12] Ludwig Aschoff, 1918 Rubbing of food as it passes through the narrow pyloric portion of the stomach results in peptic ulcer. 7 Inflammation Theory [13] Georg Ernst Konjetzny, 1923 Chronic gastritis and duodenitis cause gastric and duodenal ulcers. 8 Psychosomatics Theory [14] Franz Gabriel Alexander, 1943 Social, psychological, and behavioral factors are the cause of peptic ulcer. 9 Stress Theory [15] Hans Selye, 1950 Stress induced by personality traits, and social and natural events is the cause of peptic ulcer. 10 Balance Theory [16] Shay

Table 2
Characteristics of peptic ulcers.

2007
10. Gastric ulcers can be induced in only 8-30% of mouse models [37]. 1991 11. Gastric ulceration begins in the mucosa and extends into the wall of the stomach [31]. 1952 12. Bleeding and perforation of gastric ulcers [33,38]. 1983 1991 13. Self-healing and effects of clinical therapy [39,40]. 1998 2004 14. Stress-related gastric lesions are 'brain-driven' events that may be more effectively managed through central manipulations than by altering local, gastric factors. For example, stimulation or lesions of the central nucleus of the amygdala produced or reduced gastric ulcers, respectively [37,41,42].
1980 1991 1998 15. Development of gastric ulcers elicited by cold stress was significantly decreased by i.p. pre-treatment with EDTA or a-methyl tyrosine, which depleted neurotransmitters. Gastric ulcers were significantly increased by pre-treatment with CaCl 2 [43]. 1998 16. The predilection sites of gastric ulcers are the gastric antrum and lesser curvature [23].
2 0 0 9 17. Vulnerability to gastric ulceration is modulated by psychologically meaningful experiences. Repeated stress of the same type generally, but not exclusively, provides some degree of protection against ulcer during the second or later exposures [37,44]. 3. Doll and Jones' survey suggested a positive correlation between stressful occupations and duodenal ulcer, and a decreased incidence of ulcer among agricultural workers [31,32]. 1951 1952 4. Studies suggest that severe anxiety caused acid hypersecretion which, in turn, contributed to ulceration and symptoms. The fact that acid hypersecretion and symptoms abated with alleviation of stress supports this hypothesis [33].

1983
5. Rates of recurrence in patients whose initial ulcers healed during conventional antisecretory therapy range from 60 to 100 percent per year [29]. 1995 6. Duodenal ulcer had higher incidence in large cities compared to rural areas in Africa since the 1950s [34]. Table 5 Both gastric and duodenal ulcer-related observations/phenomena.

Observations/phenomena Year
18. Birth-cohort Phenomenon: the mortality rate of gastric ulcers in England and Wales increased at the beginning of the 20th century, reached a peak and then began to fall in the early 1950s. Similar trends were found for duodenal ulcers, but followed approximately five years behind [45,46].

2006
19. Once an ulcer, always an ulcer [47]. 1994 20. Seasonal occurrence of peptic ulcer diseases [48,49]. 1984 1994 21. Patients free of ulcer distress for long periods of time were subjected to emotional trauma and feelings of insecurity during the symptom-free intervals [31].  23. There is no definitive study proving a causal relationship between psychological stress and the development of ulcer disease [51]. 2006 24. Feldman's multidimensional case-controlled study found that ulcer patients exhibited significantly more emotional distress in the form of depression and anxiety. Hypochondriasis, a negative perception of their life events, dependency, and lowered self-confidence were the four variables that best discriminated ulcer patients from controls [52]. 1986 25. Peptic ulcer is a rare disease in childhood [53,54]. 1961 2010 26. Although gastric ulcer and duodenal ulcer share something in common, they are believed to be different diseases [20,55].

2002
27. The final stage of ulceration is a corrosive rather than an infectious process [31,56]. 1945 1952 28. The gastric acid secretion of duodenal ulcer patients is much higher than normal controls, but only 7-8.5% of the duodenal ulcer patients suffer from gastric ulcer simultaneously [57,58]. 1999 2004 29. Severe emotional stress may contribute to ulcer perforation and bleeding in some patients [33]. 1983 30. Many uncomplicated lesions heal in spite of the presence of acid gastric content, as shown by the "spontaneous" remissions of the disease and by the healed scars found at x-ray and at autopsy; however, the healing of peptic ulcer is much more rapid when the lesion is protected from the action of acid gastric juice [31]. 1952 31. Autopsy reports showed: 20%-29% of males and 11%-18% of females were found to have suffered from ulcers in the past or present [59,60]. 1960 1978 32. It is believed that, not only should the prognosis and assessment of ulcer have mental assessment, but the treatment without mind adjustment is also incomplete [21]. 1986 33. Peptic ulcer patients may have "ulcer personality", such as immaturity, impulsivity, feelings of social isolation, and alienation [52]. 1986 34. In a 2-year study of Pima Indians, Hesse did not find any peptic ulcer disease [61]. 1959 35. In contrast to Pima Indians, 10% of Caucasians develop peptic ulcers [62,63]. 1955 1962 36. To date, no consistent pattern of factors, in either host or organism, has been identified that successfully predicts which infected persons will subsequently have ulcer disease [64]. 1990 37. The relationship between life event stresses, psychological factors and peptic ulcer diseases is not clearly established at the present time and warrants further study [52]. 1986 38. Richard emphasized the different aetiology of gastric and duodenal ulcers; persons with gastric and duodenal ulcers differ epidemiologically, behaviourally, and genetically [20,55]. 1967 2002 39. Gastric ulcer was more frequent than duodenal ulcer, 4 gastric:1 duodenal in 1900 versus 1 gastric:10 duodenal currently. More women than men had the disease (3F:1M), but now it has become reversed; as the ratio for gastric ulcer is now 1F:4M and 1F:10M for duodenal ulcer [20,65].

1967
40. Stress ulcers in the rat are primarily gastric rather than duodenal, the latter typically requiring additional artificial chemical potentiation (e.g., histamine) [37]. 1991 41. Many ulcer patients and some physicians believe that symptomatic exacerbations of peptic ulcer disease occur during or shortly after stressful events [33,66,67].
2 0 0 9 2013 43. The spontaneous remissions and relapses of peptic ulcers have never been explained [31]. 1952 44. The pathophysiology of peptic ulcer has centred on an imbalance between aggressive and protective factors [70].  Only the presence of duodenal ulcers, and not gastric ulcers, was associated with increasing H. pylori density.
The association between gastric ulcers and H. pylori infection is less clear [71].

1992
48. Only 27% of symptomatic children with peptic ulcers were H. pylori positive [72]. 2 0 0 1 49. 48% of patients developed ulcers within six months of healing, but the re-infection rate after eradication was very low ( o2%) [5]. 1994 50. In developing countries with uniformly high prevalence of H. pylori infection, there are marked regional differences in the prevalence of duodenal ulcers, which could not be explained by the more toxic CagA and VacA H. pylori strains [6]. 1999 51. In the countries with low prevalence of H. pylori, 30-40% or more of duodenal ulcer patients are H. pylori negative, and the absence of H. pylori infection in early cases of duodenal ulcers was also reported [6,73].
2 0 0 2 55. No H. pylori, No Ulcer; peptic ulcer is an infectious disease [75]. 1989 56. In spite of a high prevalence of H. pylori infection worldwide, the incidence of duodenal ulcer disease in both adults and children is low in comparison [72,[76][77][78]. 1987 1988 1991 2001 57. Kato and colleagues' retrospective analysis found that H. pylori prevalence in gastric ulcer did not reach 50%; they concluded while H. pylori infection appears to be a risk factor in gastric ulcer, other causes are responsible for most cases. Only 56-96% of gastric ulcer patients are H. pylori positive, so other factors must be involved [34,79].

2004
60. There are basically three different types of peptic ulcer: H. pylori-related peptic ulcer; NSAID-related peptic ulcer; and Non-H. pylori, non-NSAID ulcer [70]. H. pylori infection in rats was successful and was accompanied by a mild to moderate mucosal inflammation. After H. pylori inoculation, an ulcer was induced in the oxyntic mucosa of both infected and uninfected rats by exposing the serosal side to acetic acid [85]. 1998 65. More than 95% of patients with duodenal ulcers and more than 80% of patients with gastric ulcers are infected with H. pylori [29,[86][87][88]. 1991 1994 1995 66. The corresponding ulcer areas in the H. pylori-infected rats were significantly larger in the infected than in the uninfected rats, and ulcer healing was delayed in the infected rats. Eliminating H. pylori accelerates the healing of ulcer [85,[89][90][91]. 1992 1997 1998 2003 67. Eradication of H. pylori in gastric ulcer patients has also been shown to be associated with a significant reduction in ulcer relapse rate, compared with those who remain infected [29,34]. 1995 68. Clinical data reported that the recurrence rate is as high as 74-80% in H. pylori positive group of duodenal ulcer patients who have healed, but the negative group is only 0-28%. The discrimination was remarkable [57]. 1999 69. A negative interaction between H. pylori and NSAIDs on duodenal ulcers suggests that H. pylori reduces the development of ulcers in NSAIDs users [34]. 1995 70.~20% of peptic ulcers in the Polish population are unrelated to H. pylori and NSAIDs use (idiopathic ulcers) [90]. 1997 71. The prevalence of H. pylori in patients with bleeding ulcers may be 15-20% lower than in patients with nonbleeding ulcers [38,89,90,92].