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The role of the host versus the environment in duodenal ulcer disease
J. Physiol. (Paris) 93 (1999) 413−417 © 1999 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved S0928425799001278/FLA
The role of the host versus the environment in duodenal ulcer disease Markéta Jablonská*, Vlasta Stupková IVth Medical Clinic, Charles University, Prague, Czech Republic
Abstract — Gastric functions can be understood only in the context of a network including the brain gut axis, neuro-endocrine and paracrine mechanisms and growth factors. These host factors including parietal cell sensitivity (PCS) may well interact with an important environmental factor, Helicobacter pylori (Hp), and help to explain its actions. The aim of this study was to investigate PCS related to Hp status and duodenal ulcer (DU). PCS was assessed by constructing dose-response curves after pentagastrin and calculating the D50. Five groups of patients were studied: I) active DU, Hp pos. (8); II) history of DU, Hp pos. (8); III) asymptomatic Hp pos. (8); IV) asymptomatic Hp neg. (10); V) DU on maintenance H2 blocker therapy, Hp pos. (20). PCS was repeated after Hp eradication. PCS was lowest in group IV, and in Hp pos. groups, was significantly higher, with insignificant differences among them, irrespective of DU. PCS declined significantly after Hp eradication. Group V showed an insignificant decline in PCS during treatment, not preventing recurrence. A higher PCS in Hp infection irrespective of DU, declining after eradication, suggests that this may be a reversible epiphenomena related to Hp infection. This may offer an explanation as to why DU develops only in some subjects with Hp, suggesting the importance of the host in the pathogenesis of DU. © 1999 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS Helicobacter pylori / duodenal ulcer / parietal cell sensitivity (PCS) / host factor
1. Introduction Digestive functions are regulated by a network of mechanisms and their interactions involved in the maintenance of normal activities [13, 26, 27, 29]. An important role is played by the interactions between environmental and host factors. This aspect has become particularly interesting in the era of Helicobacter pylori (Hp) which profoundly changed many previous concepts of gastric functions. Hp causes chronic gastritis developing through an inflammatory reaction triggered by products of the bacteria. This inflammation is usually asymptomatic, but underlying peptic ulcer disease, particularly duodenal ulcer, also gastric ulcer; moreover, gastric adenocarcinoma and mucosa associated lymphatic tissue (MALT lymphoma). The possibility to develop various conditions might be due to differences in the host, the bacterial strain infection of the host, environmental factors interacting with the bacteria of the host or in combination [7, 8, 11]. In spite of the strong clinical association of Hp and duodenal ulcer disease specificity has not been shown to date by any currently identified virulence factors. Thus, it appears that these factors may play rather a modulating role in the degree of inflammation than in the disease itself and that the determining factor may well relate to the host and not to the strain of Hp [11]. Many imbalances of gastric acid secretion in duodenal ulcer have been associated with the disease for more than half a century and higher rates of gastric acid secretion have been shown in duodenal ulcer patients than in healthy controls. Recently, it has been shown that the meal stimulated gastrin release in * Correspondence and reprints
duodenal ulcer disease does not seem to be related to duodenal ulcer directly but to Hp as a reversible phenomenon after Hp eradication [10]. This conclusion based on gastric acid secretion stimulated by GRP (gastrin releasing peptide – mammalian bombesin) suggested that the ability of the secretory system of the stomach to produce exaggerated amounts of acid in duodenal ulcer may be one of the genetic factors underlying the disease [21, 22]. The present study aims to review briefly these relationships and to evaluate parietal cell sensitivity (PCS) which might be a host factor in Hp infections associated with duodenal ulcer [14, 18, 19, 25].
2. Groups of patients and methods Five groups of patients were studied: – Patients with active duodenal ulcer confirmed by endoscopy with Hp positivity, 8 subjects, mean age 36 ± 7; – Patients with a history of duodenal ulcer and Hp positivity, without ulcer at the time of investigation, 8 subjects, mean age 44 ± 7; – Asymptomatic or slightly dyspeptic patients with Hp positivity, without duodenal ulcer at the time of investigation nor previously, 8 subjects, mean age 39 ± 9; – Asymptomatic subjects without ulcer at the time of investigation or previously, Hp negative, 8 subjects, mean age 46 ± 8; – Duodenal ulcer patients on maintenance therapy with H2 blockers, duodenal ulcer healed during this therapy, Hp positivity, 16 subjects, mean age 34 ± 7.
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All the patients were males. Hp was assessed with a rapid urease test and histologically from endoscopic biopsies, taken at least in three samples from the antral and two from the corporal mucosa. Patients from groups I, II and III and additionally from group V were treated with eradication therapy (amoxycilin and omeprazole, 2 weeks), or in the course of the later part of the study – amoxycilin, claritromycin and omeprazole, 1 week. When double therapy was not efficient (in six cases) treatment was repeated with triple therapy which was successful in all the cases treated. The patients from group V also had an eradication therapy after stopping maintenance therapy (after a 2-month interval, in three of them, treatment was repeated with triple therapy). Parietal cell sensitivity was assessed according to the classical studies of Grossman, Isenberg and others [14, 18, 19] with increasing doses of pentagastrin and calculating the half maximum response (D50) and constructing dose-response curves. This was performed in groups I, II and III before starting eradication therapy and in group I also 6 months or more after successful eradication. This interval seems to be important in view of recent studies showing that normalization of gastric acid disturbances may take 6 or more months after eradication [10]. In group V (from a previous study), PCS was assessed in all the subjects (16) before starting maintenance therapy with H2 blockers and in 8 after 4 and 8 months of treatment. In this group, eradication was performed usually in the first half of the second year of maintenance therapy (2 months after stopping therapy with H2 blockers).
3. Results Evaluation of results included: comparison of values of PCS between the results before and after eradication in group I; comparison of PCS (first test) among the five groups; evaluation of the histological picture of the gastric mucosa in all the patients. In all the patients under study routine investigation of gastric secretion (basal – BAO – and maximum acid output – MAO after pentagastrin stimulation) was also performed, results are discussed in a separate study).
Figure 1. Comparison between PCS in group I (active DU, Hp+) before and after Hp cure. Effects of increasing doses of pentagastrin.
Figure 2 shows the significant decline in PCS in group I after eradication of Hp, these values are only slightly (insignificantly) different from normal. Significant differences were found also between group II (history of DU, Hp pos.) and group IV (no ulcer, Hp neg.); between group V (healed ulcer, maintenance therapy, Hp pos.) and group IV. No significant differences were found between groups I and II (active ulcer and history of ulcer, both Hp pos.) and between II and III (history of ulcer – no ulcer, both Hp pos.), also between groups III and V (without ulcer, Hp pos. – healed ulcer, Hp pos.). Differences at the limit of significance were found between groups I and III (active DU – without DU not even previously, both Hp pos.), between III and IV (no ulcer, Hp pos. – no ulcer, Hp neg.). A summary of these differences among the groups is shown in table I. PCS during maintenance therapy with H2 blockers showed an insignificant decline after 4 and 8 months which did not prevent ulcer recurrence in the further clinical course before eradication of Hp.
3.1. PCS results The highest PCS (lowest D50) was found in group I (active DU, Hp pos.), which was significantly higher than in group IV (no ulcer, Hp neg.). Figure 1 shows the course of values for calculation of D50 with increasing doses of pentagastrin and statistical differences between the effect of individual doses.
Figure 2. Comparison between PCS in group I (active DU, Hp+) and IV (without DU, Hp–). Effects of increasing doses of pentagastrin.
The role of host vs. environment in duodenal ulcer disease
Table I. Significance of parietal cell sensitivity (PCS) between groups I to V among each other. DU, duodenal ulcer; Up, Helicobacter pylorii; HP positivity, Hp+; Hp negativity, Hp–; act., active; hist., history. Significant Group I II V
Group DU act. Hp+ DU hist.9 Hp+ DU healed Hp+
IV
DU
0
Hp–
III
DU
0
Hp+
Limit I IV
DU DU
act. 0 Hp+ 0 Hp–
Not significant Between all other groups Hp+ incl. groups III (DU 0) versus II (DU hist.)
The histological picture of the gastric mucosa showed antral gastritis, mostly with signs of activity, in all Hp positive cases. The highest degree of activity was in group I (active ulcer, Hp pos., in group IV; no ulcer, Hp neg.), the histological picture did not show any characteristic alterations. There was no case of chronic gastritis expanding to the corporal mucosa (pangastritis). Thus, on the whole, PCS was significantly higher in patients with duodenal ulcer disease (active or previous ulcer, Hp pos.) than in subjects without active or previous ulcer and Hp negativity. There were no statistically significant differences in PCS among the groups with active DU (I), a history of DU (II), healed DU on maintenance therapy (V), all of the mHp positive, nor was there any significant difference between groups III (no ulcer, but Hp pos.) versus the groups with a history of ulcer and/or healed ulcer and Hp positivity. Thus, differences tended to be less pronounced in Hp positivity, even when duodenal ulcer disease showed a different picture at the time of investigation (active, history, healed) or the ulcer was not present at all. A difference at the limit of significance was found between two Hp positive groups – I (active DU) and III (without DU, no previous DU). A limit of significance was found between group III (no DU, Hp pos.) and group IV (no DU, Hp neg.) 4. Discussion A markedly higher sensitivity to gastrin related to hypersecretion of acid in duodenal ulcer has been clearly shown by GRP stimulating both gastrin and somatostatin [4, 12]. Cure of Hp infection resulted in normalization. Reinterpretation of these results using
415
dose response curves and distinguishing Hp positive ulcer patients and Hp positive healthy subjects showed that H. pylori increased acid output irrespective of the presence of duodenal ulcer [6]. Increasing doses of gastrin resulted in slight increase of MAO in duodenal ulcer compared to healthy Hp positive subjects and healthy Hp negative subjects. However, sensitivity to gastrin showed much more marked effects in duodenal ulcer patients with Hp positivity than in Hp positive healthy subjects. Thus, Hp induces elevation of gastrin in subjects with and without duodenal ulcer, but the increase of acid is more marked in duodenal ulcer [6]. This points to a higher sensitivity to gastrin and also parietal cells, most probably a host factor, in part in combination with an increased parietal cell mass [6]. The high sensitivity of gastrin and parietal cells seems to be an important determinant of further development of duodenal ulcer disease. Recently, a strong correlation was found between acid hypersecretion induced by Hp and the extent of gastric metaplasia in the duodenum, contributing to further mucosal damage together with the increased load of acid. This damage will be even more pronounced due to the combined effect with Hp cag A positive strains due to the associated cytotoxin production [16, 23]. In our studies, the resulting relationship seems to be similar to those mentioned above. Besides the significant differences between active DU with Hp positivity and subjects without ulcer and Hp negativity, there was a significant decline in PCS after eradication; moreover, there were significant differences also between groups Hp positive and negative although in the Hp positive groups, the ulcer was not present at the time of investigation and in some cases had not been present for a very long time. This points to a relationship of higher sensitivity of the secretory mechanisms of the stomach to Hp infection based on differences in the host. The interesting question about a difference of PCS between Hp positive duodenal ulcer and healthy Hp positive subjects shows in this study only a difference at the limit of significance suggesting that this relatively high PCS in the Hp positive subjects without ulcer represents a host factor. The role of the host versus the environment in the pathogenesis of diseases can be explored by genetic studies. Studies of this type showed already before the Hp era that duodenal ulcer disease had a genetic component [9, 24]. Recent studies have confirmed this concept [21, 22]. Thus, from different points of view, it appears that in duodenal ulcer with Hp infection, genetics of the host and other host factors might be the most important factor in the pathogenesis of duodenal ulcer. A remaining question is the mechanism of increased release of gastrin in duodenal ulcer with Hp positivity.
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Possible mechanisms include particularly a decrease in the mucosal expression of somatostatin [5, 15]. This may relate to inflammatory mediators released by Hp gastritis [3], especially TNF alpha (tumor necrosis factor alpha), producing also a selective inhibition in the somatostatin response to CCK and gastrin [2]. The specific H3 agonist Ra methylhistamine decreases the release of somatostatin and increases the release of gastrin and histamine. The less specific agonist Na methylhistamine produced by Hp might cause suppression of D-cells [28]. Gastrin release may be elevated by products of the Hp enzyme urease by generating alkali or producing ammonia ions [17, 20]. Recent studies showed that Na methylhistamine produced by Hp acts on the parietal cell purely as an agonist to stimulate acid secretion. In the context of the functions of the gastric secretory mechanisms, parietal cell stimulation is linked to the regulation of gastrin. Histamine, locally stimulating parietal cells through H2 receptors is released from ECL cells (and also mast cells) by factors including gastrin; thus, an increased gastrin release will stimulate histamine release affecting both gastrin and histamine associated responses of the parietal cell [1].
the pathogenesis and further development of duodenal ulcer disease. References [1]
[2]
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[5]
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5. Conclusions Helicobacter pylori infection of the stomach is the cause of chronic gastritis and closely related to duodenal ulcer disease, also to gastric ulcer, to gastric adenocarcinoma and MALT lymphoma. In most cases, however, chronic Helicobacter gastritis is not associated with upper gastrointestinal disease. This association with different conditions may be the result of differences in the host, in bacterial strain infection or both. However, none of the currently identified putative virulence factors showed any disease specificity. The ability of the stomach with Hp infection in duodenal ulcer to produce abnormally large amounts of acid and to show an exaggerated response of gastrin and parietal cells to stimulation appears to be genetic, and other host factors and their effects a reversible phenomena related to Helicobacter infection rather than to disease specific abnormalities. This view is supported by recent genetic studies suggesting genetic components in the susceptibility to Hp infection in duodenal ulcer disease. The concept of the importance of the host is also supported by the results of our study showing significantly higher parietal cell sensitivity in duodenal ulcer with Hp positivity, normalization after cure of Hp infection and apparently -at least in part a more marked relation to the Hp infection than to the clinical features of the disease. Thus, on the whole, it appears that in Hp infection with duodenal ulcer disease, the host plays a most important role both in
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[11]
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[16]
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Beales I.L.P., Calam J., Effect of A-alpha methylhistamine on acid secretion on cultured rabbit parietal cells: implications for hypergastrinemia and acid secretion, Gut 38 (Suppl. 1) (1996) A37. Beales I.L.P., Post L., Srinivasan S. et al., Tumor necrosis factor alpha (TNF alpha) decreases somatostatin release and somatostatin content of cultured canine D-cells, Gut 37 (Suppl.) (1995) A84. Blaser M.J., Hypothesis on the pathogenesis and natural history of Helicobacter pylor-induced inflammation, Gastroenterology 102 (1992) 720–727. Calam J., Neales L.P., Gibbons M. et al., Effects of abnormalities of gastrin and somatostatin in Helicobacter pylori infection on acid secretion, in: Hunt H.H., Tytgat G.N.J. (Eds.), Helicobacter pylori. Basic Mechanisms to Clinical Cure, Kluwer, Dordrecht, 1996, pp. 108–122. Chiba T., Yamada T., Gut somatostatin, in: Walsh J.H., Dockray G.J. (Eds.), Gut Peptides, Biochemistry and Physiology, Raven Press, New York, 1994, pp. 123–145. Gillen D., El-Omar E., McColl K.E.L., Parietal cell sensitivity to gastrin distinguishes Helicobacter pylori duodenal ulcer patients from Helicobacter infected healthy volunteers, Gastroenterology 110A (1996) 116. Go M.F., Graham D.Y., Determinants of clinical outcome of H. pylori infection: duodenal ulcer, in: Hunt R.H., Tytgat G.N.J. (Eds.), H. pylori, Basic Mechanisms to Clinical Cure, Kluwer, Dordrecht, 1994, pp. 421–428. Go M.F., Graham D.Y., How does Helicobacter pylori cause duodenal ulcer disease: the bug, the host or both?, Gastroent. Hepatol. 9 (Suppl. 1, 3) (1994) 8–10. Gottlieb-Jensen K., Peptic ulcer: Genetic and epidemiological aspects based on twin studies, Munksgaard, Copenhagen, 1972. Graham D.F., Helicobacter pylori and perturbation in acid secretion: the end to the beginning, Gastroenterology 110 (1996) 1647–1650. Graham D.Y., Malaty H.M., Go M.F., Are there susceptible hosts to Helicobacter pylori infection, Scand. J. Gastroenterol. 205 (1994) 6–10. Hirschowitz B.I., Tim L.O. et al., Bombesin and G17 dose responses in duodenal ulcer and controls, Dig. Dis. Sci. 30 (1985) 1092–1103. Hojgaard I., Mertz Nielson A., Peptic ulcer physiology, acid, bicarbonate and mucosal fanctions, Scand. J. Gastroenterol. 31 (Suppl. 216) (1961) 10–15. Isenberg J.J., Grossman M.I. et al., Increased sensitivity to stimulation of acid secretion by pentagastrin in duodenal ulcer, J. Clin. Invest. 55 (1975) 330–337. Kaneko H., Nakada K., Mutsuma T. et al., Helicobacter pylori infection induces a decrease in immunoreactive somatostatin concentration of human stomach, Dig. Dis. Sci. 37 (1992) 409–416. Khulusi S., Patel P., Badve S. et al., Pathogenesis of gastric metaplasia in duodenal ulcer disease, Gut 36 (Suppl. 1) (1995) A51. Kopin A.S., Lee Y.M., McBride E.W. et al., Expression, cloning and characterization of the canine parietal cell gastrin receptor, Proc. Natl. Acad. Sci. USA 89 (1992) 3605–3609.
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[18] Lam S.K., Pathogenesis and pathophysiology of duodenal ulcer, in: Clinics in Gastroenterology, W.B. Saunders Comp., 1984, pp. 447–472. [19] Lam S.K., Isenberg J.J. et al., Gastric acid secretion is abnormally sensitive to endogenous gastrin released after peptome test meal in duodenal ulcer patients, J. Clin. Invest. 65 (1980) 555–559. [20] Levi S., Beardshall K., Hackland G. et al., Campylobacter pylori and duodenal ulcers: the gastric link, Lancet 1 (1989) 1167–1168. [21] Malaty H.M., Engstrand L., Pedersen N.L. et al., H. pylori infection: genetic and environmental influences. A study of twins, Ann. Int. Med. 120 (1994) 992–996. [22] Malaty H.M., Pedersen N.L., Engstrand L. et al., Genetic and environmental influences of peptic ulcer disease, Gastroenterology 110A (1996) 184. [23] McColl K.E.L., Gillen D., El-Omar E. et al., Helicobacter pylori gastritis and gastric secretory function - an integrated approach, in: Hunt H.H., Tytgat G.N.J. (Eds.), Helicobacter pylori. Basic Mechanisms to Clinical Cure, Kluwer, Dordrecht, 1996, pp. 122–131.
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[24] McConnel R.B., Peptic ulcer-early genetic evidence - families, twins and markers, in: Rotter M., Samloff I.M., Rimoin D.L. (Eds.), The Genetics and Heterogenity of Common Gastrointestinal Disorders, Academic Press, New York, 1980, pp. 31–41. [25] Moss S.F., Calam J., Acid secretion and sensitivity to gastrin in patients with duodenal ulcer: effect of eradication of H. pylori, Gut 34 (1993) 888–892. [26] Qlan R., Danielsson A. et al., Vagal regulation of the gastrointestinal neuroendocrine system, Rev. Scand. J. Gastroenterol. (1996) 529–570. [27] Tache Y., Brown M.R., Central nervous control system of gastric secretion: role of neuropeptides, in: Bloom S.R., Polak J.M. (Eds.), Gut Hormones, Churchill Livingstone, 1981, pp. 471–476. [28] Vuyyru L., Schubert M.L., Harrington L. et al., Dual inhibitory pathways link antral somatostatin and histamin secretion in human, dog and rat stomach, Gastroenterology 109 (1995) 1566–1574. [29] Wood J.O., The brain gut axis, in: Yamada T. et al. (Eds.), Textbook of Gastroenterology, J.B. Lipincott, 1995, pp. 71–80.
The role of the host versus the environment in duodenal ulcer disease Markéta Jablonská*, Vlasta Stupková IVth Medical Clinic, Charles University, Prague, Czech Republic
Abstract — Gastric functions can be understood only in the context of a network including the brain gut axis, neuro-endocrine and paracrine mechanisms and growth factors. These host factors including parietal cell sensitivity (PCS) may well interact with an important environmental factor, Helicobacter pylori (Hp), and help to explain its actions. The aim of this study was to investigate PCS related to Hp status and duodenal ulcer (DU). PCS was assessed by constructing dose-response curves after pentagastrin and calculating the D50. Five groups of patients were studied: I) active DU, Hp pos. (8); II) history of DU, Hp pos. (8); III) asymptomatic Hp pos. (8); IV) asymptomatic Hp neg. (10); V) DU on maintenance H2 blocker therapy, Hp pos. (20). PCS was repeated after Hp eradication. PCS was lowest in group IV, and in Hp pos. groups, was significantly higher, with insignificant differences among them, irrespective of DU. PCS declined significantly after Hp eradication. Group V showed an insignificant decline in PCS during treatment, not preventing recurrence. A higher PCS in Hp infection irrespective of DU, declining after eradication, suggests that this may be a reversible epiphenomena related to Hp infection. This may offer an explanation as to why DU develops only in some subjects with Hp, suggesting the importance of the host in the pathogenesis of DU. © 1999 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS Helicobacter pylori / duodenal ulcer / parietal cell sensitivity (PCS) / host factor
1. Introduction Digestive functions are regulated by a network of mechanisms and their interactions involved in the maintenance of normal activities [13, 26, 27, 29]. An important role is played by the interactions between environmental and host factors. This aspect has become particularly interesting in the era of Helicobacter pylori (Hp) which profoundly changed many previous concepts of gastric functions. Hp causes chronic gastritis developing through an inflammatory reaction triggered by products of the bacteria. This inflammation is usually asymptomatic, but underlying peptic ulcer disease, particularly duodenal ulcer, also gastric ulcer; moreover, gastric adenocarcinoma and mucosa associated lymphatic tissue (MALT lymphoma). The possibility to develop various conditions might be due to differences in the host, the bacterial strain infection of the host, environmental factors interacting with the bacteria of the host or in combination [7, 8, 11]. In spite of the strong clinical association of Hp and duodenal ulcer disease specificity has not been shown to date by any currently identified virulence factors. Thus, it appears that these factors may play rather a modulating role in the degree of inflammation than in the disease itself and that the determining factor may well relate to the host and not to the strain of Hp [11]. Many imbalances of gastric acid secretion in duodenal ulcer have been associated with the disease for more than half a century and higher rates of gastric acid secretion have been shown in duodenal ulcer patients than in healthy controls. Recently, it has been shown that the meal stimulated gastrin release in * Correspondence and reprints
duodenal ulcer disease does not seem to be related to duodenal ulcer directly but to Hp as a reversible phenomenon after Hp eradication [10]. This conclusion based on gastric acid secretion stimulated by GRP (gastrin releasing peptide – mammalian bombesin) suggested that the ability of the secretory system of the stomach to produce exaggerated amounts of acid in duodenal ulcer may be one of the genetic factors underlying the disease [21, 22]. The present study aims to review briefly these relationships and to evaluate parietal cell sensitivity (PCS) which might be a host factor in Hp infections associated with duodenal ulcer [14, 18, 19, 25].
2. Groups of patients and methods Five groups of patients were studied: – Patients with active duodenal ulcer confirmed by endoscopy with Hp positivity, 8 subjects, mean age 36 ± 7; – Patients with a history of duodenal ulcer and Hp positivity, without ulcer at the time of investigation, 8 subjects, mean age 44 ± 7; – Asymptomatic or slightly dyspeptic patients with Hp positivity, without duodenal ulcer at the time of investigation nor previously, 8 subjects, mean age 39 ± 9; – Asymptomatic subjects without ulcer at the time of investigation or previously, Hp negative, 8 subjects, mean age 46 ± 8; – Duodenal ulcer patients on maintenance therapy with H2 blockers, duodenal ulcer healed during this therapy, Hp positivity, 16 subjects, mean age 34 ± 7.
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All the patients were males. Hp was assessed with a rapid urease test and histologically from endoscopic biopsies, taken at least in three samples from the antral and two from the corporal mucosa. Patients from groups I, II and III and additionally from group V were treated with eradication therapy (amoxycilin and omeprazole, 2 weeks), or in the course of the later part of the study – amoxycilin, claritromycin and omeprazole, 1 week. When double therapy was not efficient (in six cases) treatment was repeated with triple therapy which was successful in all the cases treated. The patients from group V also had an eradication therapy after stopping maintenance therapy (after a 2-month interval, in three of them, treatment was repeated with triple therapy). Parietal cell sensitivity was assessed according to the classical studies of Grossman, Isenberg and others [14, 18, 19] with increasing doses of pentagastrin and calculating the half maximum response (D50) and constructing dose-response curves. This was performed in groups I, II and III before starting eradication therapy and in group I also 6 months or more after successful eradication. This interval seems to be important in view of recent studies showing that normalization of gastric acid disturbances may take 6 or more months after eradication [10]. In group V (from a previous study), PCS was assessed in all the subjects (16) before starting maintenance therapy with H2 blockers and in 8 after 4 and 8 months of treatment. In this group, eradication was performed usually in the first half of the second year of maintenance therapy (2 months after stopping therapy with H2 blockers).
3. Results Evaluation of results included: comparison of values of PCS between the results before and after eradication in group I; comparison of PCS (first test) among the five groups; evaluation of the histological picture of the gastric mucosa in all the patients. In all the patients under study routine investigation of gastric secretion (basal – BAO – and maximum acid output – MAO after pentagastrin stimulation) was also performed, results are discussed in a separate study).
Figure 1. Comparison between PCS in group I (active DU, Hp+) before and after Hp cure. Effects of increasing doses of pentagastrin.
Figure 2 shows the significant decline in PCS in group I after eradication of Hp, these values are only slightly (insignificantly) different from normal. Significant differences were found also between group II (history of DU, Hp pos.) and group IV (no ulcer, Hp neg.); between group V (healed ulcer, maintenance therapy, Hp pos.) and group IV. No significant differences were found between groups I and II (active ulcer and history of ulcer, both Hp pos.) and between II and III (history of ulcer – no ulcer, both Hp pos.), also between groups III and V (without ulcer, Hp pos. – healed ulcer, Hp pos.). Differences at the limit of significance were found between groups I and III (active DU – without DU not even previously, both Hp pos.), between III and IV (no ulcer, Hp pos. – no ulcer, Hp neg.). A summary of these differences among the groups is shown in table I. PCS during maintenance therapy with H2 blockers showed an insignificant decline after 4 and 8 months which did not prevent ulcer recurrence in the further clinical course before eradication of Hp.
3.1. PCS results The highest PCS (lowest D50) was found in group I (active DU, Hp pos.), which was significantly higher than in group IV (no ulcer, Hp neg.). Figure 1 shows the course of values for calculation of D50 with increasing doses of pentagastrin and statistical differences between the effect of individual doses.
Figure 2. Comparison between PCS in group I (active DU, Hp+) and IV (without DU, Hp–). Effects of increasing doses of pentagastrin.
The role of host vs. environment in duodenal ulcer disease
Table I. Significance of parietal cell sensitivity (PCS) between groups I to V among each other. DU, duodenal ulcer; Up, Helicobacter pylorii; HP positivity, Hp+; Hp negativity, Hp–; act., active; hist., history. Significant Group I II V
Group DU act. Hp+ DU hist.9 Hp+ DU healed Hp+
IV
DU
0
Hp–
III
DU
0
Hp+
Limit I IV
DU DU
act. 0 Hp+ 0 Hp–
Not significant Between all other groups Hp+ incl. groups III (DU 0) versus II (DU hist.)
The histological picture of the gastric mucosa showed antral gastritis, mostly with signs of activity, in all Hp positive cases. The highest degree of activity was in group I (active ulcer, Hp pos., in group IV; no ulcer, Hp neg.), the histological picture did not show any characteristic alterations. There was no case of chronic gastritis expanding to the corporal mucosa (pangastritis). Thus, on the whole, PCS was significantly higher in patients with duodenal ulcer disease (active or previous ulcer, Hp pos.) than in subjects without active or previous ulcer and Hp negativity. There were no statistically significant differences in PCS among the groups with active DU (I), a history of DU (II), healed DU on maintenance therapy (V), all of the mHp positive, nor was there any significant difference between groups III (no ulcer, but Hp pos.) versus the groups with a history of ulcer and/or healed ulcer and Hp positivity. Thus, differences tended to be less pronounced in Hp positivity, even when duodenal ulcer disease showed a different picture at the time of investigation (active, history, healed) or the ulcer was not present at all. A difference at the limit of significance was found between two Hp positive groups – I (active DU) and III (without DU, no previous DU). A limit of significance was found between group III (no DU, Hp pos.) and group IV (no DU, Hp neg.) 4. Discussion A markedly higher sensitivity to gastrin related to hypersecretion of acid in duodenal ulcer has been clearly shown by GRP stimulating both gastrin and somatostatin [4, 12]. Cure of Hp infection resulted in normalization. Reinterpretation of these results using
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dose response curves and distinguishing Hp positive ulcer patients and Hp positive healthy subjects showed that H. pylori increased acid output irrespective of the presence of duodenal ulcer [6]. Increasing doses of gastrin resulted in slight increase of MAO in duodenal ulcer compared to healthy Hp positive subjects and healthy Hp negative subjects. However, sensitivity to gastrin showed much more marked effects in duodenal ulcer patients with Hp positivity than in Hp positive healthy subjects. Thus, Hp induces elevation of gastrin in subjects with and without duodenal ulcer, but the increase of acid is more marked in duodenal ulcer [6]. This points to a higher sensitivity to gastrin and also parietal cells, most probably a host factor, in part in combination with an increased parietal cell mass [6]. The high sensitivity of gastrin and parietal cells seems to be an important determinant of further development of duodenal ulcer disease. Recently, a strong correlation was found between acid hypersecretion induced by Hp and the extent of gastric metaplasia in the duodenum, contributing to further mucosal damage together with the increased load of acid. This damage will be even more pronounced due to the combined effect with Hp cag A positive strains due to the associated cytotoxin production [16, 23]. In our studies, the resulting relationship seems to be similar to those mentioned above. Besides the significant differences between active DU with Hp positivity and subjects without ulcer and Hp negativity, there was a significant decline in PCS after eradication; moreover, there were significant differences also between groups Hp positive and negative although in the Hp positive groups, the ulcer was not present at the time of investigation and in some cases had not been present for a very long time. This points to a relationship of higher sensitivity of the secretory mechanisms of the stomach to Hp infection based on differences in the host. The interesting question about a difference of PCS between Hp positive duodenal ulcer and healthy Hp positive subjects shows in this study only a difference at the limit of significance suggesting that this relatively high PCS in the Hp positive subjects without ulcer represents a host factor. The role of the host versus the environment in the pathogenesis of diseases can be explored by genetic studies. Studies of this type showed already before the Hp era that duodenal ulcer disease had a genetic component [9, 24]. Recent studies have confirmed this concept [21, 22]. Thus, from different points of view, it appears that in duodenal ulcer with Hp infection, genetics of the host and other host factors might be the most important factor in the pathogenesis of duodenal ulcer. A remaining question is the mechanism of increased release of gastrin in duodenal ulcer with Hp positivity.
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Possible mechanisms include particularly a decrease in the mucosal expression of somatostatin [5, 15]. This may relate to inflammatory mediators released by Hp gastritis [3], especially TNF alpha (tumor necrosis factor alpha), producing also a selective inhibition in the somatostatin response to CCK and gastrin [2]. The specific H3 agonist Ra methylhistamine decreases the release of somatostatin and increases the release of gastrin and histamine. The less specific agonist Na methylhistamine produced by Hp might cause suppression of D-cells [28]. Gastrin release may be elevated by products of the Hp enzyme urease by generating alkali or producing ammonia ions [17, 20]. Recent studies showed that Na methylhistamine produced by Hp acts on the parietal cell purely as an agonist to stimulate acid secretion. In the context of the functions of the gastric secretory mechanisms, parietal cell stimulation is linked to the regulation of gastrin. Histamine, locally stimulating parietal cells through H2 receptors is released from ECL cells (and also mast cells) by factors including gastrin; thus, an increased gastrin release will stimulate histamine release affecting both gastrin and histamine associated responses of the parietal cell [1].
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5. Conclusions Helicobacter pylori infection of the stomach is the cause of chronic gastritis and closely related to duodenal ulcer disease, also to gastric ulcer, to gastric adenocarcinoma and MALT lymphoma. In most cases, however, chronic Helicobacter gastritis is not associated with upper gastrointestinal disease. This association with different conditions may be the result of differences in the host, in bacterial strain infection or both. However, none of the currently identified putative virulence factors showed any disease specificity. The ability of the stomach with Hp infection in duodenal ulcer to produce abnormally large amounts of acid and to show an exaggerated response of gastrin and parietal cells to stimulation appears to be genetic, and other host factors and their effects a reversible phenomena related to Helicobacter infection rather than to disease specific abnormalities. This view is supported by recent genetic studies suggesting genetic components in the susceptibility to Hp infection in duodenal ulcer disease. The concept of the importance of the host is also supported by the results of our study showing significantly higher parietal cell sensitivity in duodenal ulcer with Hp positivity, normalization after cure of Hp infection and apparently -at least in part a more marked relation to the Hp infection than to the clinical features of the disease. Thus, on the whole, it appears that in Hp infection with duodenal ulcer disease, the host plays a most important role both in
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