Editorial
 
Paradigm shift : Duodenal ulcer to reflux esophagitis and its relation to the longitudinal prevalence of H.pylori
 
Dr. HG Desai
Department of Gastroenterology
Jaslok Hospital & Research Centre,
Dr. G. Deshmukh Marg,
Mumbai - 400026, India.


Corresponding Author
: Dr. HG Desai
Email: desaihg@hotmail.com


Abstract

In the Caucasian adult population of western countries, the decreasing prevalence of ulcer disease in the duodenum (first part) and its increasing prevalence in the esophagus (lower one-third), has been observed during the last four decades. [1,2,3,4]The relationship of Helicobacter pylori (H. pylori) prevalence in the  population (in relation to time), to this paradigm shift, has been discussed here.
 
Duodenal ulcer (DU): origin, peak and decline
Till 1823, DU did not have a formal place in medical text books.[5] In the latter half of the 19th century, sporadic cases of DU on autopsy or the operating table (presenting with hematemesis or perforation), were reported.[6,7] In the beginning of the 20th century, a single study reported 1000 cases of peptic ulcer (529 DU)[8] and a book for the surgical treatment of DU was published.[9] The advent of barium meal x-rays (1914)[10] and fibre-optic endoscopy (1958),[11] for the precise diagnosis of DU, enabled proper documentation of the “epidemic” of DU in the 20th century.[12] In the adult Caucasian population of North America and Europe, the decreasing prevalence of DU has been noted during the last four decades (1961 – 2000).[1,2,3,13]
 
Aetiology of duodenal ulcer
In the beginning of the 20th century, DU was considered multifactorial - stress (hurry-worry), spices (curry), and smoking were convicted as major causes.[12,14,15] “No acid, no ulcer” (Schwarz 1910)[16] was recognised early in the development of this entity.[16] With the development of the augmented histamine test (1953),[17] for the accurate measurement of maximal acid output (MAO), the size of the parietal cell mass (PCM) was estimated.[18] A greater PCM, with higher MAO was blamed in about 50% of DU patients.[19,20] Accelerated healing of DU within a few weeks, with H2-receptor antagonists (1972)[21] or proton pump inhibitors (PPI) (1983)[22] compared to placebo, further emphasised the importance of acidpepsin in the aetiology of DU. In male DU patients from a developing country (like India), the values of MAO are significantly lower than those of patients from developed countries,[17,20] as H. pylori is present in the gastric body mucosa for several decades (prior to DU) in the former, compared to only a few years in the latter.[23]
 
A major breakthrough in our understanding of the etiology of DU, was the Nobel-prize winning discovery of H. pylori in the antral mucosal biopsy of humans, on upper gastroduodenal endoscopy (1983).[24] Antral gastritis (predominant) due to H.pylori, is the most important aetiological factor for DU: (i) as about 90% of DU patients had H. pylori in the antral mucosal biopsy,[25,26] (ii) following the eradication of H. pylori from the gastric mucosa, annual DU recurrence reduced to about 10% compared to 90% following healing with acid suppression treatment,[27,28] (iii) failure to eradicate H. pylori resulted in a higher recurrence rate of DU[28] (iv) treatment with antibiotics for eradication of H. pylori accelerates DU healing, compared to H2-receptor antagonists or proton pump inhibitors alone.[29] Antral mucosal damage decreases somatostatin secretion from the delta cells, which is an inhibitor of G cell secreting gastrin, resulting in hypergastrinaemia and an increased PCM, as gastrin is a trophic hormone.[30]
 
The major mode of H. pylori transmission is the faeco-oral route.[23] In developing countries, exposure to H. pylori occurs frequently and early in life (with poor sanitation) whilst it occurs occasionally and later in life in developed countries (with good sanitation).[23,24,25,26,27,28,29,30,31] Birth-cohort (individuals born during the same period) risks emphasised that babies born between 1870 and1900 had the highest risk of DU and that the cohort phenomenon began at an age below 5 years.[32] In the latter half of the 20th century (1961-2000), with continuous improvement in sanitation, the exposure to H.pylori is infrequent.[13,33,34,35,36] The annual exposure to H. pylori in adult individuals is estimated to be 0.5% in developed countries compared to 10% indeveloping countries.[37] The rate of acquisition was four fold greater in African Americans than in Caucasians.[31] H. pylori
 
infection causes of DU in only about 62% of patients at present,[13,36] in contrast to the 95% of patients in developed countries noted earlier (1985-1990).[27,28]
 
Esophageal ulcer: Origin, increase and peak
An ulcer in the lower one-third of the esophageal mucosa, due to gastroesophageal reflux of acid-pepsin, was observed in the early 20th century.[38,39,40,41,42] During the last four decades of the 20th century, a gradual increase in gastroesophageal reflux disease (GERD) - erosions, ulcer, stricture and its complications (Barrett’s esophagus and esophageal adenocarcinoma) has been noted in the Caucasian adult population of developed countries.[43,44] Amongst Asians, the incidence of esophageal ulcer and its complications is low, as the values of MAO are low, due to H. pylori exposure early in life.[20,45,46,47,48]er, even in the few affluent Asian countries (Japan, Singapore, Malaysia), such an increase in esophageal ulcers with endoscopic esophagitis was reported, in the beginning of the 21st century.[45,46,49,50,51]
 
Aetiology of esophageal ulcer
Esophageal ulcer with esophagitis was earlier linked to hiatus hernia but it was soon realised that it occurs even in the absence of the same.[52,53] Esophageal damage in the presence of hiatus hernia is usually severe and refractory to medical treatment.
 
The relationship of H. pylori infection of gastric mucosa and esophageal ulceration is complex and controversial. .
 
Absence of H. pylori in the gastric mucosa and esophageal ulcer:
 
(i) Lack of Exposure
In serum, H. pylori antibody (HPA) prevalence was 50%, at age 5 years in developing countries and at age 50 years in developed countries.[54,55] With continuous improvement of sanitation in developed countries during the last four decades, the prevalence of H.pylori in the gastric mucosa is decreasing and the lifetime risk of exposure is only about 10%.[37] The decreasing prevalence of duodenal ulcer and gastric carcinoma and the increasing prevalence of endoscopic esophagitis and its complications, also indicate the decreasing exposure to H. pylori.[34,35,56,57,58]
 
In developed countries, the increased prevalence of esophageal ulcer is at present restricted to the Caucasian adult population,[59] as the prevalence of H. pylori antibody (IgG) in the serum is low in whites (26.2%) but high in non- Caucasians (non-Hispanic African Americans: 52.7%, Mexican Americans 61.6%).]59] Furthermore, during a 12-year follow up, the disappearance of H pylori was 50% in Caucasians and only 4% in African Americans .[31]
 
(ii) Following eradication therapy
Absence of H. pylori in the gastric mucosa may also result following successful eradication therapy.  Eradication of H. pylori from the gastric mucosa resulted in a higher prevalenceof endoscopic esophagitis compared to control subjects.[60] During a 3-year follow-up, of the 286 patients who received H. pylori eradication therapy or no therapy, the prevalence of reflux esophagitis was 18% and 0.3% respectively.[60] Similar observations of endoscopic esophagitis have been made in patients of DU in whom H. pylori eradication was achieved.[61]
 
Absence of H. pylori in the gastric mucosa (either from lack of exposure or eradication therapy) results in increased acid in the stomach; H. pylori causes diminished acid output initially by secreting a protein inhibitor, and later through chronic corpus gastritis.[50,62,63,64,65]ce of corpus gastritis results in higher volume and concentration of gastric juice in the gastric lumen, causing greater esophageal damage resulting in esophageal ulcer.[32] The prevalence of H. pylori was lower in short segment Barrett’s esophagus (18.7%) and zero in long segment Barrett’s oesophagus.[50] These observations suggest that the absence of H. pylori corpus gastritis may increase the incidence of esophageal ulcer and its complications.[60,61]
 
Presence of H. pylori and/or corpus gastritis and esophageal ulcer
(i) Presence of H. pylori
In patients with esophagitis and control subjects, the presence of H.pylori infection in the gastric mucosa was not different, indicating H.pylori (alone) in the gastric mucosa does not affect the incidence of esophageal ulcer.[65] However a negative association between H.pylori prevalence and esophagitis was observed in subjects over 60 years.[66] In contrast, when H. pylori infection was reported on histology, rapid urease test, H. pylori antibody (IgG) in serum, the prevalence of H. pylori was significantly lower in GERD patients (30%) compared to control subjects (71.2%) indicating that the presence pf H.pylori chronic gastritis is important in reducing the incidence of esophageal ulcer.[50,65,67]
 
(ii) Evidence of corpus gastritis
The prevalence of chronic corpus gastritis and its severity was lower in GERD patients than in control subjects.[65] The corpus gastritis was associated with a 54% reduced risk of endoscopic oesophagitis.[65] Furthermore, the prevalence of CagA positivity in the serum was 42.3% in control subjects, 38.9% in GERD patients, 13.3% in Barrett’s esophagus and 0% in esophageal adenocarcinoma indicating that the presence of the pathogenic H. pylori in the gastric mucosa causing corpus gastritis, protects against the development of GERD complications.[68,69]
 
Conclusions
Antral gastritis (predominant) due to H. pylori infection causes hypergastrinemia and greater parietal cell mass (with higher values of acid output) and is the cause of DU – a disease of the 20th century. In contrast, the absence of H. pylori in the gastric mucosa with improved sanitation, results in increased acid output in the stomach (in the absence of corpus gastritis), precipitating peptic esophageal ulcer - a disease of the 21st century. This paradigm shift of ulceration from the duodenum to the esophagus, observed recently in developed countries, results from the differences of H. pylori prevalence in the gastric mucosa of the population, in relation to time (with improvedsanitation). Such a shift is likely to extend to developing countries in the 21st century, with assumed improvement in sanitation and hygiene.
References
1.       Wylie CM. The complex wane of peptic ulcer. I. Recent national trends in deaths and hospital care in the United States. J Clin Gastroenterol. 1981;3:32732.
2.       Wylie CM. The complex wane of peptic ulcer. II. Trends in duodenal and gastric ulcer admissions to 790 hospitals, 1974-1979. J Clin Gastroenterol. 1981;3:3339.
3.       El-Serag HB, Sonnenberg A. Opposing time trends of peptic ulcer disease and reflux disease. Gut 1998;43:32733.
4.       Graham DY. The changing epidemiology of GERD, geography and Helicobacter pylori. Am J Gastroenterol. 2003;98:146270.
5.       Philip APW. A treatise on indigestion and its consequence. 3rd ed. London. Thos & Geo Underwood, 1823, p.409.
6.       Wilkie R. Observations on the pathology and etiology of duodenal ulcer. Edinburgh Med J. 1914;13:196.
7.       Mayo WJ. Duodenal ulcer, a clinical review of fifty-eight operated cases with some remarks on gastroenterology. Ann Surg. 1904;90:9008.
8.       Friedenwald J. A clinical study of a thousand cases of ulcer of the stomach and duodenum. Am J Med Sci. 1912;144:157.
9.       Moynihan BGA. Duodenal ulcer. 2nd ed. Philadelphia and London, WB Saunders, 1912.
10.    George AW, Gerber I. The direct method of diagnosis of duodenal ulcer by means of the roentgen ray. 1988;150:72130.
11.    Hirschowitz BI, Curtiss LE, Peters CW, Pollard HM. Demonstration of a new gastroscopy – the “fibroscope”. Gastroenterology. 1958;35:513.
12.    Jones FA. Annual Oration on peptic ulcer – in perspective. Trans Med Soc Lond. 19851986;102:10112.
13.    Aro P, Storskrubb T, Ronkainen J, Bolling-Sternevald E, Engstrand L, Vieth M, et al. Peptic ulcer disease in a general adult population: the Kalixanda study: a random population-based study. Am J Epidemiol. 2006;163:102534.
14.    Mayo WJ. Chronic duodenal ulcer. JAMA 1915;64;2036.
15.    Doll R, Jones FA, Pygoff F. Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet. 1958;1:65762.
16.    Schwarz K. Uber penetrierende magenund jejunalgeschwure. Beitr Klin Chirurgie. 1910;5:96.
17.    Kay AW. Effects of large doses of histamine on gastric secretion of HCL. An augmented histamine test. Brit Med J. 1953;2:7780.
18.    Card WI, Marks IN. The relationship between the acid output of the stomach following ‘maximal’ stimulation and the parietal cell mass. Clin Sci. 1960;19:14763.
19.    Baron JH. An assessment of the augmented histamine test in the diagnosis of peptic ulcer. Gut. 1963;4:24353.
20.    Desai HG, Zaveri MP, Mohalla DJ, Antia FP. Acid output in control subjects and patients with duodenal ulcer using fixed doses of histamine. Indian J Med Res. 1970;58:338.
21.    Feldman M, Burton ME. Histamine2-receptor antagonists. Standard therapy for acid-peptic diseases. 1. N Engl J Med. 1990;323:167280.
22.    Lind T, Cederberg C, Ekenved G, Haglund U, Olbe L. Effect of omeprazole – a gastric proton pulp inhibitor – on pentagastrin stimulated acid secretion in man. Gut. 1983;24:2706.
23.    Gill HH, Desai HG. Helicobacter pylori and gastroduodenal disorders in India. Lessons from epidemiology. 1993;16:69.
24.    Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1984;1:13115.
25.    Graham DY. Treatment of peptic ulcers caused by H. pylori. N Engl J Med. 1993;328:34950.
26.    Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:117586.
27.    Coghlan JG, Gilligan D, Humphries H, McKenna D, Dooley C, Sweeney E, et al. Campylobacter pylori and recurrence of duodenal ulcers: A 12 month follow-up study. Lancet 1987;2:110911.
28.    Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet. 1990;335:12335.
29.    Huang JQ, Sridhar S, Wilkinson J, Chen Y, Hunt RH. Antibiotics accelerate healing of duodenal ulcer (DU) when combined with proton pump inhibitors or H2-receptor antagonists. Gastroenterology 1996;110:A137.
30.    Olbe L, Hamlet A, Dalenback J, Fandriks L. A mechanism by which Helicobacter pylori infection of the antrum contributes to the development of duodenal ulcer. Gastroenterology. 1996;110:138694.
31.    Malaty HM, Graham DY, Wattigney WA, Srinivasan SR, Osato M, Berenson GS. Natural history of Helicobacter pylori infection in childhood: 12-year follow-up cohort study in a biracial community. Clin Infect Dis.  99;28:27982.
32.    Sonnenberg A. Geographic and temporal variations in the occurrence of peptic ulcer disease. Scand J Gastroenterol. 1985;110(Suppl):1124.
33.    Malaty HM, Graham DY. Effect of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection. Gut. 1994;35:7425.
34.    Haruma K, Okamoto S, Kawaguchi H, Gotoh T, Kamada T, Yoshihara M, et al. Reduced incidence of Helicobacter pylori infection in young Japanese persons between 1970s and the 1990s. J Clin Gastroenterol 1997;25:5836.
35.    Haruma K. Trend toward a reduced prevalence of Helicobacter pylori infection, chronic gastritis, and gastric cancer in Japan. Gastroenterol Clin North Am. 2000;29:62331
36.    Ciociola AA, McSorley DJ, Turner K, Sykes D, Palmer JB. Helicobacter pylori infection rates in duodenal ulcer patients in the United States may be lower than previously estimated. Am J Gastroenterol. 1999;94:183440.
37.    Parsonnet J. The incidence of Helicobacter pylori infection. Aliment Pharmacol Ther. 1995;9 Suppl 2:4551.
38.    Tileston W. Peptic ulcer of the oesophagus. Am J Med Sci 1906;132:24065.
39.    Jackson C. Peptic ulcer of the esophagus. JAMA 1929;92:36972.
40.    Winkelstein A. Peptic oesophagitis. A new clinical entity. JAMA 1935;104:906.
41.    Lyall A. Chronic peptic ulcer of the oesophagus: a report of eight cases. Br J Surg 19361937;24:53447.
42.    Allison IR. Peptic ulcer of the esophagus. J Thoracic Surg 1946;15:30817.
43.    Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, et al Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous cell carcinoma of oesophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst. 2004;96:38896.
44.    Solaymani-Dodaran M, Logan RF, West J, Card T, Coupland C. Risk of oesophageal cancer in Barrett’s oesophagus and gastroesophaeal reflux. Gut. 2004;53:10704.
45.    Rajendra S, Ackroyd R, Robertson IK, Ho JJ, Karim N, Kutty KM. Helicobacter pylori, ethnicity and the gastroesophageal reflux disease spectrum: a study from the East. Helicobacter. 2007;12:17783.
46.    Rajendra S, Kutty K, Karim N. Ethnic differences in the prevalence of endoscopic esophagitis and Barrett’s esophagus: the long and short of it all. Dig Dis Sci. 2004;49:23742.
47.    Malkan G, Mohandas KM. Epidemiology of digestive cancers in India. I. General principles and oesophageal cancer. Indian J Gastroenterol. 1997;16:98102.
48.    Goh KL, Chang CS, Fock KM, Ke M, Park HJ, Lam SK. Gastrooesophageal reflux disease in Asia. J Gastroenterol Hepatol. 2000;15:2308.
49.    Suzuki H, Hibi T, Marshall BJ. Helicobacter pylori : present status and future prospects in Japan. J Gastroenterol. 2007;42:115.
50.    Abe Y, Ohara S, Koike T, Sekine H, Iijima K, Kawamura M, et al. The prevalence of Helicobacter pylori infection and the status of gastric acid secretion in patients with Barrett’s esophagus in Japan. Am J Gastroenterol. 2004;99:121321.
51.    Lim SL, Goh WT, Lee JM, Ng TP, Ho KY. Changing prevalence of gastroesophageal reflux with changing time: longitudinal study in an Asian population. J Gastroenterol Hepatol. 2005;20:9951001.
52.    Cohen S, Harris LD. Does hiatus hernia affect competence of the gastroesophageal sphincter? N Engl J Med. 1971;284:10536.
53.    Palmer ED. The hiatus-hernia-oesophagitis-oesophageal stricture complex: Twenty-year prospective study. Am J Med. 1968;44:56679.
54.    Graham DY, Adam E, Reddy GT, Agarwal JP, Agarwal R, Evans DJ Jr, et al. Helicobacter pylori infection in India. Comparison of developing and developed countries. Dig Dis Sci. 1991;36:10848.
55.    Gill HH, Majmudar P, Shankaran K, Desai HG. Age related prevalence of Helicobacter pylori antibodies in serum of Indian subjects. Indian J Gastroenterol. 1994;13:924.
56.    Sonnerberg A. Temporal trends and geographical variations of peptic ulcer disease. Aliment Pharmacol Ther.1995;9 Suppl 2:312.
57.    Ho KY, Chan YH, Kang JY. Increasing trend of reflux oesophagitis and decreasing trend of Helicobacter pylori infection in patients from a multicentric Asian country. Am J Gastroenterol. 2005;100:19238.
58.    El-Serag HB. Time trends of gastroesophageal reflux disease: A systematic review. Clin Gastroenterol Hepatol. 2007;5:1726.
59.    Everhart JE, Kruszon-Moran D, Perez-Perez GI, Tralka TS, McQuillan G. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:135963.
60.    Hamada H, Haruma K, Mihara M, Kamada T, Yoshihara M, Sumii K, et al. High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: impacts of hiatal hernia and corpus gastritis. Aliment Pharmacol Ther. 2000;14:72935.
61.    Labenz J, Blum AL, Bayerdörffer E, Meining A, Stolte M, Börsch G.. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux oesophagitis. Gastroenterology. 1997;112:14427.
62.    Cave DR, Vargas M. Effect of a Campylobacter pylori protein on acid secretion by the parietal cells. Lancet. 1989;2:1879.
63.    McGowan CC, Cover TL, Blaser MJ. Helicobacter pylori and gastric acid: biological and therapeutic implications. Gastroenterology. 1996;110:92638.
64.    El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology. 1997;113:1524.
65.    El-Serag HB, Sonnenberg A, Jamal MM, Inadomi JM, Crooks LA, Feddersen RM. Corpus gastritis is protective against reflux oesophagitis. Gut. 1999;45:1815.
66.    Haruma K, Hamada H, Mihara M, Kamada T, Yoshihara M, Sumii K, et al. Negative association between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter. 2000;5:249.
67.    Contractor QQ, ul Haque I, Saka H, Contractor TQ. Corpus gastritis and erosive oesophgagitis: a report from the Middle East. Indian J Gastroenterol. 2006;25:2957.
68.    Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology. 1998;115:507.
69.    Loffeld RJ, Werdmuller BF, Kuster JG, Pérez-Pérez GI, Blaser MJ, Kuipers EJ.Colonization with cagA-positive H. pylori stains is inversely associated with reflux oesophagitis and Barrett’s esophagitis. Digestion. 2000;62:959.