Characteristics of Helicobacter pylorinegative and -positive peptic ulcer disease

Age and Ageing 1998; 27: 427-43 I 1998, British Geriatrics Society Characteristics of Helicobacter pylorinegative and -positive peptic ulcer disease HELENA KEMPPAINEN, ISMO MIHA, HARRY KUJARI 1, LEIF SOURANDER Department of Geriatrics, University of Turku, Kunnallissawaalantle 20, FIN-20700 Turku, Finland I Department of Pathology, University of Turku, Finland Address for correspondence: H. Kemppainen. Fax: (+ 358) 2 2692 107 Abstract Objective: to examine histological and other features of patients with Helicobacter pylori-positive (HP+) and -negative (HP-) peptic ulcers and characterize typical features of peptic ulcer in elderly patients. Methods: 137 consecutive patients with peptic ulcer and 70 patients with dyspepsia were studied over 24 months. Endoscopy and a structured personal interview were carried out in all patients. Three histological specimens were obtained from the antral mucosa. Results: the mean age of ulcer patients was 62.4 (SD 15.7) years and that of dyspepsia patients was 56.9 (SD 18.1) years (p= 0.026). Of patients with HP- ulcers, 80.6% were aged 65 years or over; the corresponding proportion of patients with HP+ ulcer was 33.7% (P= 0.0001). The use of non-steroidal anti-inflammatory analgesics was more common among those whose ulcer was HP- (69.4% vs 33%, P = 0.0002). The occurrence of antral inflammation, atrophy and intestinal metaplasia did not differ between those with HP- and HP+ ulcers, but activity of gastritis was more common in HP+ than in HP- patients (94.9% vs 47.1%, P= 0.0001). In the logistic regression analysis, HP- peptic ulcer disease was independently associated with older age, bile reflux, the use of non-steroidal antiinflammatory analgesics and intestinal metaplasia, while HP+ ulcer disease was associated with active inflammation of the antral mucosa and tendency to ulcer recurrence. Conclusion: HP+ and HP- peptic ulcers have well-defined characteristics which probably reflect their different pathogenesis. Peptic ulcer disease of elderly people is mostly HP-. Keywords: dyspepsia, elderly people, gastritis, Helicobacter pylori, histology, intestinal metaplasia, peptic ulcer Introduction The prevalence of chronic gastritis increases with age and becomes so common that it has even been considered as a normal ageing phenomenon [1]. Chronic gastritis is predominantly caused by Helicobacter pylori, which is also a major cause of peptic ulcer disease [2-3]. Recent studies have suggested an association between dyspeptic symptoms and H. pylori-positive gastritis [4-5]. The prevalence of H. pylori increases with age, reaching 70% in patients over 70 years of age [6]. The increase in the prevalence of H. pylori occurs consistently with that of chronic antral gastritis [7-8]. The risk of childhood infection of H. pylori was high (over 50%) among those who were born at the beginning of this century; it is much lower (approximately 10%) in those born during the last two decades [9-10]. In addition to the growing use of non-steroidal anti-inflammatory drugs (NSAIDs), childhood infection is likely to explain the increase in the incidence rate of peptic ulcer disease in elderly subjects [11]. In particular, the proportion of complicated peptic ulcer disease rises sharply after the age of 75 [12, 13]. The typical signs of acute mucosal inflammation disappear after eradication of H. pylori [14]. Chronic antral gastritis may lead to mucosal atrophy and, with the development of intestinal metaplasia, predisposes to gastric dysplasia and malignancy [15]. While H. pylori infection is associated with chronic active antral gastritis [5, 16, 17], a lower prevalence of H. pylori has been found in patients with atrophic gastritis and intestinal metaplasia [5, 18]. Our aim was to examine histological and other features of patients with dyspepsia or peptic ulcer and determine predictors of H. pylori-positive and -negative 427

H. Kemppainen et 0/. ulcer disease. In addition, we tried to characterize the typical ulcers of old age. Patients and methods One hundred and thirty-seven consecutive patients with peptic ulcer (68 men) and 70 with dyspepsia (23 men) were studied prospectively over 24 months. The mean age of the peptic ulcer patients was 62.4 years (SD 15.7, range 28-97)-56.8 years (SD 14.4, range 28-84) in men and 67.6 years (SD 15.1, range 37-97) in women. The mean age of patients with dyspepsia was 56.9 years (SD 18.1, range 17-93)-52.8 years (SD 19.5, range 23-87) in men and 59.1 years (SD 17.2, range 17-93) in women. A structured personal interview was carried out on all patients at the same session as the endoscopy took place. This included a survey of the daily use of NSAIDs: all patients were asked in detail about NSAID use giving them a list of commercial names. In addition, the use of NSAIDs was checked in patients' medical records and referrals. Previous ulcer history was determined. The use of acetylsalicylate was not taken into account, because it was mostly used for vascular prophylaxis and doses were small. Each patient was asked if any of his/her first-degree relatives had ever had a peptic ulcer. Endoscopy was performed in all patients in the Turku City Hospital by the same gastroenterologist. The instrument used was an Olympus GIFQ20 endoscope. The localization of the ulcer and the presence of duodenitis and bile reflux were recorded. Bile reflux was deemed to be present if the gastric juice was bilestained and bile was attached to the gastric wall. Three histological specimens were obtained from the antral mucosa and analysed by the same pathologist. The following features were recorded: inflammation (amount of mononuclear inflammatory cells), activity (amount of polymorphonuclear leukocytes), intestinal metaplasia and atrophy. The presence of H. pylori was recorded in Giemsa-stained histological slides. The pathologist was not aware whether the specimen was from a dyspeptic patient or from a patient with an ulcer. The histological findings were quantified according to the Sydney system [19]. In statistical analysis, comparisons between distributions of groups were performed using Pearson's x 2 test. To study various background factors of H. pylorinegative and -positive peptic ulcers, several explanatory variables were simultaneously analysed in the logistic regression analysis. P-values <0.05 were interpreted as being statistically significant. Results Table 1 shows the characteristics of H. pylori-negative and -positive patients with dyspepsia or peptic ulcer, compared by univariate analysis. H. pylori-negative peptic ulcers were predominantly found in patients aged over 65 years and in women. NSAID use and bile reflux at endoscopy were more common among H. pylori-negative peptic ulcer patients than in others. Fifty percent of H. pylori-positive ulcer patients smoked compared with 11-22% of patients in other groups. The mean (and SE) cigarette consumptions were 1.0 (1.2) in H. pylori-negative and 0.6 (1.7) in H. pylori-positive dyspepsia patients and 3.2 0.4) in H. pylori-negative and 8.2 (0.9) in H. pylori-positive ulcer patients (overall P < 0.001 in the analysis of variance). The results of histological investigations of the antral mucosa are shown in Table 2. Active inflammation and atrophy were more frequent in H. pylori-positive than in H. pylori-negative ulcer patients. Nevertheless, 47% Table I. Characteristics of patients with Helicobacter pylori-negative (HP-) and -positive (HP+) dyspepsia or peptic ulcer % of subjects with characteristic Dyspepsia Ulcer HP- HP+ HP- HP+ Characteristic (n=46) (n = 24) (n = 36) (n=101) P-value Age >65 years 39.1 41.7 80.6 33.7 <0.001 Female sex 76.1 50.0 66.7 44.6 0.0019 NSAID use 32.6 37.5 69.4 33.0 0.0011 Smoking 10.9 12.5 22.2 50.0 <0.001 Relative's ulcera 10.9 12.5 21.9 29.6 0.059 Bile reflux 2.2 4.2 16.7 4.1 0.023 Previous ulcer 0.0 0.0 44.4 49.0 <0.001 aulcer in a first-degree relative. NSAID, non-steroidal anti-inflammatory drug. 428

H. pylori-negative and -positive peptic ulcer Table 2. Antral histology in patients with Helicobacter pylori-negative (HP-) and -positive (HP+) dyspepsia or peptic ulcer % of subjects showing histology Dyspepsia HP- HP+ HP- HP+ Histology (n = 46) (n = 24) (n= 36) (n = 101) P-value Inflammation (grade) 1 71.7 2 4.3 3 0.0 Total 76.1 Activity (grade) 1 6.5 2 2.2 3 0.0 Total 8.7 Atrophy (grade) 1 2.2 2 6.5 Total 8.7 Intestinal metaplasia (grade) 1 13.0 2 4.3 3 0.0 Total 17.4 Ulcer 20.8 50.0 7.9 58.3 32.4 51.5 20.8 11.8 40.6 100.0 94.1 100.0 <0.001 54.2 29.4 35.6 29.2 S.8 44.6 4.2 8.8 14.9 87.5 47.1 94.9 <0.001 16.7 22.9 32.7 4.2 0.0 1.0 20.8 22.9 33.7 0.013 16.7 11.1 21.8 12.5 27.8 11.9 0.0 2.8 2.0 29.2 41.7 36.7 0.069 of H. pylori-negative patients with ulcers had active antral gastritis. Active gastritis was rare in H. pylorinegative dyspepsia patients, but it was present in 88% of H. pylori-positive patients with dyspepsia. Atrophic changes were slight and they were most commonly observed in H. pylori-positive ulcer patients. Intestinal metaplasia was found in 37-42% of those with ulcer and in 18-29% ofthose with dyspepsia. In logistic regression analysis, advanced age, bile reflux, NSAID use and intestinal metaplasia were independently associated with H. pylori-negative ulcer (Table 3). Previous peptic ulcer and active inflammation of the antral mucosa were associated with H. pylori-positive ulcer (Table 4). Discussion In multivariate analysis, H. pylori-negative peptic ulcer disease was independently associated with advanced age, bile reflux, NSAID use and intestinal metaplasia, while H. pylori-positive peptic was predicted by previous ulcer and active inflammation of the antral mucosa. Thus, H. pylori-negative and H. pylori-positive ulcers seem to have typical features which probably reflect their different pathogenesis. H. pylori-positive peptic ulcer may be considered as 'classical' ulcer, characterized by the presence of chronic active antral gastritis and a tendency to recurrence. The most important and often only aetiological factor of ulcer is H. pylori. In contrast, the aetiology of H. pylorinegative peptic ulcer is multifactorial: advanced age and intestinal metaplasia may impair cytoprotection of the gastric mucosa making it more susceptible to injurious effects of NSAIDs and duo de no-gastric reflux. H. pylori declines when chronic superficial gastritis changes to atrophic gastritis, exposing the antral mucosa to intestinal metaplasia [5, IS). Bile acids may contribute to the pathogenesis of chronic gastritis and peptic ulcer [20). Bile reflux can also cause gradual elimination of H. pylori and, in addition, may increase the susceptibility to intestinal metaplasia [21). On the other hand, H. pylori may induce duodeno-gastric reflux and the two act synergistically to cause chronic gastritis [22). According to these findings, the key elements of peptic ulcer of elderly people would be earlier H. pylori infection, which has resulted in mucosal atrophy, and, in association with bile reflux, intestinal metaplasia with subsequent elimination of H. pylori. Under these circumstances, the risk of ulcer increases in the presence of an injurious exogenic factor such as NSAIDs. The ulcerogenic effect of NSAIDs increases when H. pylori is present [231. However, 429

H. Kemppainen et al. Table 3. Variables predicting Helicobacter pylori-negative ulcer in logistic regression analysis {3 estimate SE P-value Intercept -12.15 2.77 <0.001 Age >65 years 7.19 2.45 0.0034 Female sex 0.71 0.66 0.28 Bile reflux 1.64 0.76 0.031 Relative's ulcera 1.06 0.64 0.10 NSAID use 1.24 0.57 0.029 Previous ulcer 0.46 0.29 0.11 Atrophyb -0.41 0.57 0.47 Inflammation b -0.25 0.49 0.62 Activityb -0.41 0.38 0.28 Intestinal metaplasia b 0.68 0.32 0.036 aulcer in a first-degree relative. boichotomized into grade 0 versus grades 1-3. NSAIO, non-steroidal anti-inflammatory drug; SE, standard error. Wyatt et al. [24] found that, in patients over 70 years of age, peptic ulcer was associated with the use of NSAIDs but not with H. pylori. No association between the long-term use of NSAIDs and gastric atrophy has been found [25]. The occurrence of H. pylori-positive peptic ulcer was associated with active inflammation of the antral mucosa and a tendency to ulcer recurrence. The histological features of gastritis did not differ between patients with H. pylori-positive peptic ulcer and those with H. pylori-positive dyspepsia. Half of H. pylorinegative ulcer patients had active antral gastritis as well, whereas only a few patients with H. pylorinegative dyspepsia had inflammatory activity. While H. pylori infection is the most important factor in the development of chronic diffuse superficial gastritis [2, 26], the aetiology of gastritis in H. pylori-negative ulcer patients remains obscure. A false-negative result in the determination of H. pylori may be possible but this is unlikely in the present study because active gastritis was rare in H. pylori-negative patients with dyspepsia. It is more likely that exogenic irritative factors or earlier H. pylori infection might explain gastritis in H. pylori-negative ulcer patients. In conclusion, H. pylori-negative peptic ulcer disease was associated with advanced age, bile reflux, NSAID use and intestinal metaplasia, while H. pyloripositive ulcer was associated with active inflammation of the antral mucosa and the tendency to ulcer recurrence. Table 4. Variables predicting Helicobacter pylori-positive ulcer in logistic regression analysis {3 estimate Intercept -2.8 Age >65 years -5.34 Female sex -0.35 Bile reflux -0.67 Relatives' ulcera 0.29 NSAID use 0.14 Previous ulcer 0.88 Atroph~ -1.31 Inflammation b 0.92 Activityb 0.99 Intestinal metaplasia b -0.22 SE 11.79 1.55 0.49 0.92 0.55 0.48 0.34 0.44 0.38 0.34 0.28 P-value 0.12 0.73 0.48 0.47 0.59 0.77 0.0094 0.99 0.016 0.0033 0.43 "Ulcer in a first-degree relative. bdichotomized into grade 0 versus grades 1-3. NSAID, non-steroidal anti-inflammatory drug; SE, standard error. 430

H. pylori-negative and -positive peptic ulcer Acknowledgements We thank Pirjo Piekka for secretarial and Hans Helenius for statistical assistance. This study was supported by the Finnish Foundation for Gastroenterological Research and the Eemil Aaltonen Foundation. Key points Helicobacter pylori-positive and -negative peptic ulcers have well-defined characteristics which probably reflect their different pathogenesis. The occurrence of H. pylori-negative peptic ulcer is attributable to old age, use of non-steroidal antiinflammatory analgesics, duodeno-gastric reflux and intestinal metaplasia of the antral mucosa. H. pylori-positive ulcer is associated with active inflammation of the gastric mucosa and a tendency to ulcer recurrence. Peptic ulcer disease in old age is predominantly H. pylori-negative. References 1. Colin-Jones DG, Golding PL. What is a normal upper gastro-intestinal tract? Br MedJ 1991; 302: 742. 2. Rauws EA, Lengenberg W; Houthoff HJ, Zanen HC, Tytgat GN. 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Miss Davies peeling apples for church supper pies, Miller Place, Long Island, USA, 1958. Magnum/Eve Arnold.