Scandinavian Journal of Gastroenterology. 2015; Early Online, 1–8
REVIEW
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Upper gastrointestinal physiology and diseases
HELGE L WALDUM1,2, PER M KLEVELAND1,2 & REIDAR FOSSMARK1,2 1
Department of Medicine, Norwegian University of Science and Technology, and 2Department of Gastroenterology and Hepatology, St Olavs Hospital, Trondheim, Norway
Abstract Nordic research on physiology and pathophysiology of the upper gastrointestinal tract has flourished during the last 50 years. Swedish surgeons and physiologists were in the frontline of research on the regulation of gastric acid secretion. This research finally led to the development of omeprazole, the first proton pump inhibitor. When Swedish physiologists developed methods allowing the assessment of acid secretion in isolated oxyntic glands and isolated parietal cells, the understanding of mechanisms by which gastric acid secretion is regulated took a great step forward. Similarly, in Trondheim, Norway, the acid producing isolated rat stomach model combined with a sensitive and specific method for determination of histamine made it possible to evaluate this regulation qualitatively as well as quantitatively. In Lund, Sweden, the identification of the enterochromaffin-like cell as the cell taking part in the regulation of acid secretion by producing and releasing histamine was of fundamental importance both physiologically and clinically. Jorpes and Mutt established a center at Karolinska Institutet in Stockholm for the purification of gastrointestinal hormones in the 1960s, and Danes followed up this work by excelling in the field of determination and assessment of biological role of gastrointestinal hormones. A Finnish group was for a long period in the forefront of research on gastritis, and the authors’ own studies on the classification of gastric cancer and the role of gastrin in the development of gastric neoplasia are of importance. It can, accordingly, be concluded that Nordic researchers have been central in the research on area of the upper gastrointestinal physiology and diseases.
Key Words: Gastritis, gastroduodenal-clinical, Helicobacter pylori, hormones and receptors
Introduction Most people have sometimes experienced reflux of sour gastric juice. Gastric acid has therefore naturally been ascribed to play an important role in the pathogenesis of symptoms from the upper gastrointestinal tract. It is also true that gastric acid plays a central role in gastroesophageal reflux disease and peptic ulcer disease, which previously was previously very prevalent, but now has become rarer. Accordingly, the regulation of gastric acid secretion has been of great interest. Combined with the relative ease with which gastric juice is collected from humans as well as animals, it is understandable that the regulation of gastric acid secretion is among the physiological processes most studied. In many ways, experimental animal research started with dogs provied
with fistula by Pavlov demonstrating the role of vagal nerves (acetylcholine) in regulating gastric acid secretion [1]. The hormonal concept was formulated by Bayliss and Starling based upon the stimulation of bicarbonate and water secretion from a denervated pancreas subsequent to acidification of the duodenal mucosa [2]. Shortly afterwards, Edkins postulated the presence of an antral hormone, gastrin, stimulating the oxyntic mucosa to secrete acid [3]. In 1920, Popielski described that histamine was an efficient gastric acid secretagogue [4], and for decades afterwards the interactions between these three (acetylcholine, gastrin and histamine) substances in the regulation of acid secretion was disputed. In the later elucidation of both the regulation of gastric acid secretion as well as identifying the cells producing the histamine, which stimulates gastric
Correspondence: Helge L Waldum, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. E-mail: [email protected]
(Received 6 December 2014; revised 5 January 2015; accepted 8 January 2015) ISSN 0036-5521 print/ISSN 1502-7708 online Ó 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1009157
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acid secretion, Nordic researchers have made major contributions. In the Nordic countries, science has had a strong position for a long time in Sweden and Denmark, whereas in Finland, Norway and Iceland, all three countries that became independent during the last century, the scientific tradition has been weaker. Sweden stayed out of the Second World War and continued to do medical research during that period. In all respects, including research on the gastrointestinal tract, Sweden was a great power in the first years after the war. The first decade after the war was used in Norway and Finland to rebuild the countries, but around 1960, science began to make its way into clinical medicine, including gastroenterology, also in these young countries. Siurala put Finland into a leading position within the research on gastritis [5], while the founder of Scandinavian Journal of Gastroenterology, Johs. Myren, together with another Editor-in-Chief, E. Gjone, initiated research within gastroenterology in Norway. Johs. Myren went to the inventor of the flexible endoscope, Basil Hirschowitz, in Birmingham, Alabama, to learn scientific methods, mainly related to the regulation of gastric acid secretion. Hirschowitz helped in many ways to establish Norwegian gastrointestinal research by later admitting professor Per Burhol and Arnold Berstad to his unit, and also contributed to Swedish science by accepting Prof Herbert Helander into his laboratory. During the same time period, Jorpes and Mutt were the leading scientists within gastrointestinal hormones [6], and during that decade, there was a tradition that ambitious researchers went to “Karolinska Institutet”, Stockholm, to identify and characterize a new gastrointestinal hormone. Thus VIP [7], GIP [8] and motilin [9] were found besides CCK and secretin, which were purified by Jorpes and Mutt themselves [6,10]. Nordic research on gastrointestinal hormones will be covered in a separate chapter by Prof Jens F. Rehfeld in this issue. Studies on the regulation of gastric acid secretion in animals and man: status in 1965 when Scandinavian Journal of Gastroenterology was founded The interaction between the three principal gastric acid secretagogues was still heavily disputed. Komarov had shown shortly before the Second World War that gastrin was not a histamine [11], and in 1961, Gregory and Tracy purified, sequenced and synthesized gastrin [12]. Kahlson and co-workers in Lund showed that food intake as well as (penta)- gastrin depleted the oxyntic mucosa of histamine and simultaneously stimulated histamine synthesis [13]. Nevertheless,
Leonard Johnson wrote in “Gastroenterology”: No room for histamine? [14]. This was, of course, abruptly changed by the description by Black of the histamine-2 (H-2)-receptor and the effect of H-2 antagonists on acid secretion [15]. The histamine producing enterochromaffinlike cell and the role of histamine in the regulation of gastric acid secretion Kahlson together with Rosengren [13] made important contributions to the study of regulation of release and synthesis of histamine at a time when the physiological role of histamine in the regulation of acid secretion [14] was disputed. Histamine research was continued in Lund by Håkanson and co-workers. In 1968, Håkanson and co-workers described the presence of histamine in a neuroendocrine cell in the oxyntic mucosa of the rat [16]. They named this cell the enterochromaffin-like (ECL) cell. Even then, many thought that mast cells produced the histamine participating in the regulation of acid secretion [17]. When immunohistochemistry with increased sensitivity was first used nearly 20 years later, showing histamine in a similar cell in many species including man [18], the ECL cell was generally accepted as central in the regulation of acid secretion. It is curious that so many for so long believed that the mast cell, a cell without a fixed position to the acidproducing parietal cell, took part in the regulation of acid secretion. Håkanson and his group continued their work related to histamine and acid secretion and described the regulation of decarboxylation of histidine, the most important step in histamine synthesis [19].Further elucidation of the regulation of histamine release was hampered for some time due to the lack of a sensitive method to determine histamine concentration, as well as histamine not being a hormone, but working locally as a paracrine substance. This was overcome when we used a sensitive radioimmunoassay for histamine [20], which was applied on the venous effluent from the totally isolated, acidproducing rat stomach [21]. These experiments proved that gastrin was a very potent stimulator of histamine release [22], resulting in histamine concentrations sufficient to explain the acid stimulatory effect of gastrin [23]. Later on, we were able to show that a functional CCK2/gastrin receptor was localized solely to the ECL cell in the oxyntic mucosa [24]. In isolated oxyntic mucosal cell fractions enriched by elutriation, we were able to show that gastrin released histamine [25]. However, not all cell preparations responded to gastrin by histamine release [25]. This method was improved by Prinz and co-workers by markedly increasing the percentage of ECL cells in
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Upper gastrointestinal physiology and diseases their cell fractions [26]. However, they were not able to correlate the stimulation of histamine release with the effect on acid secretion as we could [25]. Besides the isolated rat stomach and isolated oxyntic mucosal cells, Håkanson and co-workers introduced microdialysis to assess the regulation of histamine release [27]. There is a high degree of correlation between these three methods, and it may be concluded that gastrin is a potent stimulator of histamine release, which subsequently increases acid secretion through interaction with the CCK-2/gastrin receptor localized to the ECL cells. From the above achievements, it may be stated that Nordic researchers have been central in research on the role of histamine in regulation of acid secretion during the last 50 years. Studies on acid secretion in isolated organs, glands and cells Due to the relative ease with which gastric juice may be collected from animals and humans, gastric acid secretion has been extensively examined. However, the complexity of intact organisms has necessitated the development of methods to assess gastric acid secretion in less complex models. It was a major breakthrough when Öbrink and Berglindh with their co-workers in Uppsala developed methods allowing assessment of acid secretion in isolated oxyntic glands or parietal cells by measuring oxygen consumption and the accumulation of a radioactive weak base, aminopyrine [28,29]. They could not find any stimulation of acid secretion by gastrin in such preparations from rabbits [29]. On the other hand, Soll claimed that acid secretion was stimulated in isolated canine parietal cells by gastrin [30], a species very sensitive towards histamine with respect to stimulation of gastric acid secretion [31]. When we started with isolated rat stomachs, the belief was that they did not produce acid. However, previous studies on isolated stomachs had applied oxygenated buffers to perfuse the vascular bed. Considering that acid secretion produce an H+ gradient of more than 1 million, which is probably the most energy requiring process in the body, the oxygen supply by such an approach was obviously not sufficient. We therefore started to add erythrocytes to the perfusion buffer and used a membrane oxygenator developed at our university. At the same time, Short and co-workers [32] described success with ovine erythrocytes, which we adopted [33]. By this method, we could show that gastrin was very potent in stimulating histamine release [20], that gastrin in contrast to a cholinergic agent did not augment maximal gastrinstimulated acid secretion [21], and that from a functional point of view, stimulation of gastric acid secretion by gastrin could be solely due to stimulation
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of histamine [23]. Later studies in Lund on isolated ECL cells by the Håkanson group further elaborated the connection between the ECL cells and gastrin in the release and synthesis of histamine [34,35].Taken together, the long-term dispute about the interaction between the three secretagogues may be concluded by histamine and acetylcholine having a direct effect on the parietal cells, whereas gastrin has an indirect effect by stimulating the ECL cells to release histamine. Studies on the regulation of gastric secretion in animals and man Studying gastric acid secretion has been an old tradition in Sweden [36]. It was continued after the Second World War by studies in animals with pouches and vagal stimulation [37,38]. These studies were the background for the development of omeprazole [39], which binds covalently to the proton pump [40]. For more than a decade, the proton pump inhibitors (PPIs) were the top selling drugs. The development of omeprazole will be covered in a separate chapter in this issue by Lundell. In Norway, studies on the regulation of gastric acid secretion in man [41] started in the 1960s, followed by experimental studies on animals [42–44]. Berstad developed his own method to assess pepsin concentration in the gastric juice [45] and used it to study the regulation of pepsin secretion. Waldum studied pepsinogen in blood for use as a marker of gastric acid secretion [46] and Vatn studied the secretion of the intrinsic factor [47]. Since the time of experiments by Pavlov [1], the central role of the vagal nerves in the regulation of acid secretion has been known. Moreover, it was shown that patients with duodenal ulcer have increased acid secretion [48]. Accordingly, the reduction of gastric acid secretion by vagotomy was a possible treatment. However, due to inhibition of gastric emptying by truncal vagotomy, pyloroplasty as a drainage procedure had to be added. When proximal gastric vagotomy was introduced, the neural supply to the antrum was preserved and gastric emptying was less affected [49–51], so pyloroplasty could be avoided [52]. (Motility is covered in a separate chapter in this issue). Proximal gastric vagotomy markedly reduces gastric acid secretion [53]. It should also be added that we in Trondheim improved the insulin-test for testing the completeness of vagotomy by the glucose clamp technique [54]. Studies on gastrointestinal hormones Stockholm was, as previously stated, for a long period the center for detecting new gastrointestinal hormones
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[6–10]. The Nordic tradition of research on gastrointestinal hormones was maintained by JF Rehfeld in Copenhagen who was in the forefront of developing and characterizing radioimmunoassay for their determination, and particularly of the hormones belonging to the gastrin/CCK family [55–57]. Many other Danes studied other gastrointestinal hormones (see specific chapter by Rehfeld). Schrumpf in Oslo also developed a gastrin radioimmunoassay at an early stage [58]. Studies on gastric, duodenal and pancreatic bicarbonate secretion It had for long been presumed that the surface epithelium in the stomach and upper duodenum produced bicarbonate that diffused into the mucus layer to protect surface cells from destruction by acid and the proteolytic enzyme pepsin. Gastric bicarbonate secretion has been estimated by studying antral pouches, antral mucosa in Ussing chambers or in intact stomachs where acid secretion is heavily inhibited. Particularly, in the field of duodenal bicarbonate secretion, Flemström has been a pioneer [59]. Pancreatic bicarbonate secretion was studied by Petersen in Oslo [60]. By observing increased pancreatic bicarbonate secretion in a patient with gastrinoma, he got the idea of a positive trophic effect parallel to the functional effect, which resulted in a stay in Los Angeles and cooperation with Grossman [61]. Studies on gene-modified mice Duan Chen and his wife Chun Mei Zhao came from China to Lund to work with professor Håkanson. There, both wrote excellent theses in the field of gastric physiology [62,63]. Chen was called for professorship in Trondheim and they both have continued their work in the same area. In cooperation with different American groups, they have studied mice where gastrin and/or the CCK2 receptor have been knocked-out [64–66]. Of particular interest is their study of the role of the vagal nerves in gastric carcinogenesis [67]. Trophic effects of gastrointestinal hormones The positive trophic effect of gastrin on the oxyntic mucosa was indirectly shown by the succulent mucosa in patients with Zollinger–Ellison syndrome [68] and the atrophy of the oxyntic mucosa after removal of the antrum [69]. The development of ECL cell carcinoids after long-term hypergastrinemia either due to gastrinoma [70] or induced by hypoacidity secondary to atrophic gastritis [71] suggested a specific trophic effect on this cell. However, this was not focused on before
long-term, profound inhibition of acid secretion either by the insurmountable H-2 blocker loxtidine [72] or the PPI omeprazole [72] was reported to induce ECL cell neoplasia in rodents. It was soon realized that hypergastrinemia was the pathogenic factor for these tumors. Gastrin stimulates the proliferation of the ECL cells, a cell type that had been claimed not to divide [73]. We could show a close correlation between the stimulation of function (histamine release) and growth of the ECL cells and that maximal effects of gastrin were reached at much lower concentrations than anticipated [74]. Based upon our previous finding that the functional effect (stimulation of acid secretion) was indirect via simulation of histamine release [23] and that we could not find any binding of gastrin in the stem cell area [24], we postulated that the trophic effect on the oxyntic mucosa also was secondary to effects on the ECL cells. By differential counting of the oxyntic mucosal cells from hypergastrinemic rats, we found a disproportional increase in the ECL cells, whereas the number of parietal cells and the other mucosal cells only reflected the total number of mucosal cells [75]. This study thus shows that there is no specific trophic effect on other cell types than the ECL cells in the oxyntic mucosa, but does not exclude a direct effect on the stem cells. Anyhow, the trophic effect on the ECL cells by gastrin results in rebound hypersecretion of acid after a period with profound inhibition of acid secretion [76]. Maximal gastrin-stimulated acid secretion is inferior to maximal histamine-stimulated [21], and thus meal-stimulated acid secretion is restricted by the magnitude of histamine release, which depends of the ECL cell mass [77]. The clinical importance of rebound acid hypersecretion after a period of PPI dosing was shown by research groups from both Denmark [78] and Sweden [79]. Gastrin and neoplasia In studies on rats it was shown that ECL cells proliferate [80,81] and that long-term hypergastrinemia in that species induces ECL cell neoplasia whatever the cause of hypergastrinemia [72,82,83]. For the pharmaceutical company Astra that produced omeprazole, it was important to show that ranitidine could also induce ECL cell tumors in rats when given sufficient doses [84]. It could thus be concluded that the ECL cell tumors in rats after omeprazole was a consequence of its biological effect and not due to a specific carcinogenic effect. However, was the neoplastic effect of hypergastrinemia mainly confined to rats and without relevance for humans? We started to study gastric carcinomas from humans for ECL cell markers, and could find evidence for such origin in an important proportion of the tumors [85–89],
Upper gastrointestinal physiology and diseases particularly those described as being of diffuse type according to the Finnish pathologist Laurén [90]. In signet ring cell carcinomas, a subgroup of diffuse carcinomas, we found a high degree of neuroendocrine differentiation [91]and no sign of mucin expression when examined by in situ hybridization [92].
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Helicobacter pylori The identification of Helicobacter pylori (HP) as the main cause of gastritis and peptic ulcer [93] and the subsequent recognition of the major role of HP in gastric carcinogenesis [94] were major breakthroughs in the last two decades of the 20th century. Swedish research groups contributed within this new field of research from the early 1990s [95,96]. In spite of tremendous efforts, no definitive mechanism of the carcinogenic effect of HP infection has been reached. However, the protective effect of duodenal ulcer against gastric cancer was described by Hansson [97] and the carcinogenic effect of HP infection seems to be related to its induction of atrophic corpus gastritis [98] resulting in hypergastrinemia [99]. Quite recently we showed that the hypergastrinemic effect of HP infection could explain the carcinogenic effects of HP [100]. In Norway, Arnold Berstad was the first to grasp the clinical importance of HP infection [101]. Lerang in Fredrikstad, Norway, conducted important studies related to the diagnosis of HP infection [102]. In Denmark, Schaffalitzky de Muckadell investigated the effectiveness of a HP test-and-treat strategy in dyspeptic patients after both short- and long-term follow-up [103,104].
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gastrointestinal tract during this period of 50 years. Gastrointestinal hormones were identified by Jorpes and Mutt in Stockholm in the 1960s; Rehfeld and coworkers in Copenhagen developed immunoassays of a more sophisticated level and studied the heterogeneity and the synthesis, particularly of peptides belonging to the CCK family; in Lund, Kahlson started research on the role of histamine in the regulation of acid secretion that was followed by Håkanson describing the ECL cells as the cells producing the histamine that participates in the regulation of acid secretion; Flemström in Uppsala has been a leader within research on protective factors of the mucosae exposed to gastric juice; and Öbrink and Berglindh and we in Trondheim have made important contributions related to the interaction between the gastric acid secretagogues as well as the localization of the gastrin receptor. The clinical consequence of gastrin as a trophic hormone has also been an important topic for us. Moreover, the discovery and development of the first PPI, omeprazole, was a natural consequence of the strength of Swedish research in gastric physiology. Finally, it has to be realized that Nordic research within gastroenterology, including all aspects, would have been much weaker had we not had our own journal, Scandinavian Journal of Gastroenterology. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper
References Epidemiology The Nordic countries are well organized and have had a homogenous and stable population, and thus these countries have been ideal for epidemiological studies. These characteristics are particularly true for Iceland – see separate chapter by Bjørnsson and Ekbom. Also in the other Nordic countries, important epidemiological studies on peptic ulcer disease [105–107] as well as dyspepsia [108] have been done. Of particular importance is the study in Northern Norway where a whole community was examined with upper gastrointestinal endoscopy [109] and the epidemiology of gastrointestinal reflux disease as a part of the so-called HUNT study where the population of a whole county was followed longitudinally [110]. Conclusion It may be concluded that Nordic research has been in the forefront in all aspects related to the upper
[1] Pavlov IP. The centrifugal (efferent) nerves to the gastric glands and the pancreas. In The work of the digestive glands. Philadelphia: Griffin and Co., Ltd; 1910. p 48–59. [2] Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902;28:325–53. [3] Edkins JS. On the chemical mechanism of gastric acid secretion. Proc R Soc Med 1905;76:376. [4] Popielski L. Beta-imidazolyläthylamin und die Organextrakte. beta-imidazolyläthylamin als Mächtiger ereger der Magendrüsen. Pflugers Arch 1920;178:214–36. [5] Siurala M, Isokoski M, Varis K, Kekki M. Prevalence of gastritis in a rural population. Bioptic study of subjects selected at random. Scand J Gastroenterol 1968;3:211–23. [6] Mutt V, Jorpes JE. Structure of porcine cholecystokininpancreozymin. 1. Cleavage with thrombin and with trypsin. Eur J Biochem 1968;6:156–62. [7] Mutt V, Said SI. Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination. Eur J Biochem 1974;42:581–9. [8] Brown JC, Mutt V, Pederson RA. Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol 1970;209:57–64. [9] Brown JC, Mutt V, Dryburgh JR. The further purification of motilin, a gastric motor activity stimulating polypeptide from
6
[10]
[11] [12]
Scand J Gastroenterol Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 04/15/15 For personal use only.
[13]
[14] [15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23]
[24]
[25]
[26]
[27]
[28]
[29]
H.L. Waldum et al. the mucosa of the small intestine of hogs. Can J Physiol Pharmacol 1971;49:399–405. Mutt V, Jorpes JE, Magnusson S. Structure of porcine secretin. The amino acid sequence. Eur J Biochem 1970; 15:513–19. Komarov SA. Gastrin. Soc Exp Biol Med 1938;38:514–16. Gregory RA, Tracy HJ. The preparation and properties of gastrin. J Physiol 1961;156:523–43. Kahlson G, Rosengren E, Svahn D, Thunberg R. Mobilization and formation of histamine in the gastric mucosa as related to acid secretion. J Physiol (Lond) 1964;174: 400–16. Johnson LR. Control of gastric secretion: no room for histamine? Gastroenterology 1971;61:106–18. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2 -receptors. Nature 1972;236:385–90. Hakanson R, Lilja B, Owman C. Cellular localization of histamine and monoamines in the gastric mucosa of man. Histochemie 1969;18:74–86. Soll AH, Lewin K, Beaven MA. Isolation of histaminecontaining cells from canine fundic mucosa. Gastroenterology 1979;77:1283–90. Simonsson M, Eriksson S, Hakanson R, Lind T, Lonroth H, Lundell L, et al. Endocrine cells in the human oxyntic mucosa. A histochemical study. Scand J Gastroenterol 1988;23:1089–99. Hakanson R, Liedberg G. The role of endogenous gastrin in the activation of gastric histidine decarboxylase in the rat. Effect of antrectomy and vagal denervation. Eur J Pharmacol 1970;12:94–103. Sandvik AK, Waldum HL, Kleveland PM, Schulze Sognen B. Gastrin produces an immediate and dosedependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1987;22:803–8. Kleveland PM, Waldum HL, Larsson H. Gastric acid secretion in the totally isolated, vascularly perfused rat stomach. A selective muscarinic-1 agent does, whereas gastrin does not, augment maximal histamine-stimulated acid secretion. Scand J Gastroenterol 1987;22:705–13. Sandvik AK, Waldum HL. Rat gastric histamine release: a sensitive gastrin bioassay. Life Sci 1990;46:453–9. Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrinhistamine sequence in the regulation of gastric acid secretion. Gut 1991;32:698–701. Bakke I, Qvigstad G, Sandvik AK, Waldum HL. The CCK-2 receptor is located on the ECL cell, but not on the parietal cell. Scand J Gastroenterol 2001;36:1128–33. Brenna E, Waldum HL. Studies of isolated parietal and enterochromaffin-like cells from the rat. Scand J Gastroenterol 1991;26:1295–306. Prinz C, Kajimura M, Scott DR, Mercier F, Helander HF, Sachs G. Histamine secretion from rat enterochromaffinlike cells. Gastroenterology 1993;105:449–61. Kitano M, Norlen P, Hakanson R. Gastric submucosal microdialysis: a method to study gastrin- and food-evoked mobilization of ECL-cell histamine in conscious rats. Regul Pept 2000;86:113–23. Bergqvist E, Obrink KJ. Gastrin-histamine as a normal sequence in gastric acid stimulation in the rabbit. Ups J Med Sci 1979;84:145–54. Berglindh T, Bergqvist E. Regulation of histamine release induced by gastrin and acetylcholine in isolated rabbit gastric glands. Gastroenterology 1984;86:1024.
[30] Soll AH, Amirian DA, Thomas LP, Reedy TJ, Elashoff JD. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984;73:1434–47. [31] Waldum HL, Sandvik AK, Brenna E. Gastrin: HistamineReleasing Activity. In Walsh JH, editor. Gastrin. New York: Raven Press Ltd; 1993. [32] Short GM, Wolfe MM, McGuigan JE. Pentagastrin-stimulated gastric acid secretion by the isolated perfused rat stomach. Life Sci 1984;34:2515–23. [33] Kleveland PM, Haugen SE, Sandvik S, Waldum HL. The effect of pentagastrin on the gastric secretion by the totally isolated vascularly perfused rat stomach. Scand J Gastroenterol 1986;21:379–84. [34] Andersson K, Cabero JL, Mattsson H, Hakanson R. Gastric acid secretion after depletion of enterochromaffin-like cell histamine. A study with alpha-fluoromethylhistidine in rats. Scand J Gastroenterol 1996;31:24–30. [35] Lindstrom E, Bjørkqvist M, Boketoft A, Chen D, Zhao CM, Kimura K, et al. Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. Regul Pept 1997;71:73–86. [36] Uvnäs B. The part played by the pyloric region in the cephalic phase of gastric secretion. Acta Physiol Scand 1942;4:Suppl. XIII. [37] Linde S. Studies on the stimulation mechanism of gastric secretion.Acta Physiol (Oxf) 1950;21:Supplementum74:1–94. [38] Olbe L. Significance of vagal release of gastrin during the nervous phase of gastric secretion in dogs. Gastroenterology 1963;44:463–8. [39] Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Sjostrand SE, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase. Nature 1981; 290:159–61. [40] Sachs G, Chang HH, Rabon E, Schackman R, Lewin M, Saccomani G. A nonelectrogenic H+ pump in plasma membranes of hog stomach. J Biol Chem 1976;251:7690–8. [41] Myren J, Semb LS. The number of parietal cells and the rates of gastric secretion before and after subcutaneous injection of large doses of histamine. Gastroenterologia 1962;98:207–16. [42] Burhol PG. Gastric secretion in the chicken. Scand J Gastroenterol 1971;6:Supplement 11:1–65. [43] Grabner P, Donahue PE, Grabner ET, Kalahanis NG, Bombeck CT, Nyhus LM. Non-gastrin, intestinal-phase secretion. Experimental confirmation in the dog. Scand J Gastroenterol 1980;15:165–70. [44] Guldvog I. Vagally innervated and denervated gastric pouch in one and the same dog–a new model. Scand J Gastroenterol 1980;15:921–8. [45] Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 1970;5:343–8. [46] Waldum HL, Burhol PG, Straume BK. Serum group I pepsinogens during prolonged infusion of pentagastrin and secretin in man. Scand J Gastroenterol 1979;14:761–8. [47] Vatn MH. Haemoglobin-coated charcoal for estimation of gastric intrinsic factor. Scand J Gastroenterol 1973;8:755–60. [48] Wormsley KG, Grossman MI. Maximal histalog test in control subjects and patients with peptic ulcer. Gut 1965; 6:427–35. [49] Moberg S, Carlberger G. The effect on gastric emptying of test meals with various fat and osmolar concentrations. Scand J Gastroenterol 1974;9:29–32. [50] Amdrup BM, Griffith CA. Selective vagotomy of the parietal cell mass: Part II: With suprapyloric ucosal antrectomy and suprapyloric antral resection. Ann Surg 1969;170:215–20.
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Upper gastrointestinal physiology and diseases [51] Amdrup BM, Griffih CA. Selective vagotomy of the parietal cell mass: Part I: With preservation of the innervated antrum and pylorus. Ann Surg 1969;170:207–14. [52] Amdrup E, Jensen HE. Selective vagotomy of the parietal cell mass preserving innervation of the undrained antrum. A preliminary report of results in patients with duodenal ulcer. Gastroenterology 1970;59:522–7. [53] Roland M, Berstad A, Liavag I. Acid and pepsin secretion in duodenal ulcer patients in response to graded doses of pentagastrin or pentagastrin and carbacholine before and after proximal gastric vagotomy. Scand J Gastroenterol 1974;9:511–18. [54] Qvigstad G, Bjorgaas M, Eide I, Sandvik AK, Waldum HL. Vagal stimulation augments maximal (penta) gastrinstimulated acid secretion in humans. Acta Physiol Scand 1999;165:277–81. [55] Rehfeld JF, Stadil F, Rubin B. Production and evaluation of antibodies for the radioimmunoassay of gastrin. Scand J Clin Lab Invest 1972;30:221–32. [56] Stadil F, Rehfeld JF. Determination of gastrin in serum. An evaluation of the reliability of a radioimmunoassay. Scand J Gastroenterol 1973;8:101–12. [57] Rehfeld JF, Schwartz TW, Stadil F. Immunochemical studies on macromolecular gastrins: evidence that "big big gastrins" are artifacts in blood and mucosa, but truly present in some large gastrinomas. Gastroenterology 1977; 73:469–77. [58] Schrumpf E, Sand T. Radioimmunoassay of gastrin with activated charcoal. Scand J Gastroenterol 1972;7:683–7. [59] Flemström G. Gastric and duodenal mucosal secretion of bicarbonate. In Johnson LR, editor. Physiology of the Gastrointestinal Tract. New York: Raven Press; 1994. p 1285–309. [60] Petersen H. The relationship between the gastric and pancreatic secretion in man. Scand J Gastroenterol 1969;4: 345–51. [61] Petersen H, Grossman MI. Pancreatic exocrine secretion in anesthetized and conscious rats. Am J Physiol 1977;233: E530–6. [62] Chen D. The biology of the rat stomach ECL cells: Responses to gastrin and cholecystokinin. Sweden: University of Lund; 1994. [63] Zhao C-M. Exocytic and crinophagic pathwaysin ECL cells of the rat stomach. Sweden: University of Lund; 1999. [64] Chen D, Zhao CM, Al-Haider W, Håkanson R, Rehfeld JF, Kopin AS. Differentiation of gastric ECL cells is altered in CCK(2) receptor-deficient mice. Gastroenterology 2002;123: 577–85. [65] Chen D, Zhao CM, Håkanson R, Samuelson LC, Rehfeld JF, Friis-Hansen L. Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology 2004;126:476–87. [66] Zhao CM, Martinez V, Piqueras L, Wang L, Tache Y, Chen D. Control of gastric acid secretion in somatostatin receptor 2 deficient mice: shift from endocrine/paracrine to neurocrine pathways. Endocrinology 2008;149:498–505. [67] Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med 2014;6:250ra115. [68] Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955;142:709–23; discussion 24-8. [69] Lees F, Grandjean LC. The gastric and jejunal mucosae in healthy patients with partial gastrectomy. AMA Arch Intern Med 1958;101:943–51.
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[70] Solcia E, Capella C, Buffa R, Usellini L, Frigerio B, Fontana P. Endocrine cells of the gastrointestinal tract and related tumors. Pathobiol Annu 1979;9:163–204. [71] Wilander E, El-Salhy M, Pitkanen P. Histopathology of gastric carcinoids: a survey of 42 cases. Histopathology 1984;8:183–93. [72] Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 1986;35:42–55. [73] Barrett P, Hobbs RC, Coates PJ, Risdon RA, Wright NA, Hall PA. Endocrine cells of the human gastrointestinal tract have no proliferative capacity. Histochem J 1995;27:482–6. [74] Brenna E, Waldum HL. Trophic effect of gastrin on the enterochromaffin like cells of the rat stomach: establishment of a dose response relationship. Gut 1992;33:1303–6. [75] Bakke I, Qvigstad G, Brenna E, Sandvik AK, Waldum HL. Gastrin has a specific proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell: a study by elutriation centrifugation. Acta Physiol Scand 2000;169:29–37. [76] Waldum HL, Arnestad JS, Brenna E, Eide I, Syversen U, Sandvik AK. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996;39:649–53. [77] Waldum HL, Lehy T, Brenna E, Sandvik AK, Petersen H, Sognen BS, et al. Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa. Scand J Gastroenterol 1991;26:23–35. [78] Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009;137:80–7. [79] Niklasson A, Lindstrom L, Simren M, Lindberg G, Bjornsson E. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebocontrolled trial. Am J Gastroenterol 2010;105:1531–7. [80] Ryberg B, Tielemans Y, Axelson J, Carlsson E, Håkanson R, Mattson H, et al. Gastrin stimulates the self-replication rate of enterochromaffin-like cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats. Gastroenterology 1990;99:935–42. [81] Tielemans Y, Willems G, Sundler F, Håkanson R. Self-replication of enterochromaffin-like cells in the mouse stomach. Digestion 1990;45:138–46. [82] Mattsson H, Havu N, Brautigam J, Carlsson K, Lundell L, Carlsson E. Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffin-like cell carcinoids in the rat. Gastroenterology 1991;100:311–19. [83] Poynter D, Pick CR, Harcourt RA, Selway SA, Ainge G, Harman IW, et al. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut 1985;26:1284–95. [84] Havu N, Mattsson H, Ekman L, Carlsson E. Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion 1990;45:189–95. [85] Qvigstad G, Falkmer S, Westre B, Waldum HL. Clinical and histopathological tumour progression in ECL cell carcinoids. APMIS 1999;107:1085–92. [86] Qvigstad G, Sandvik AK, Brenna E, Aase S, Waldum HL. Detection of chromogranin A in human gastric adenocarcinomas using a sensitive immunohistochemical technique. Histochem J 2000;32:551–6. [87] Qvigstad G, Qvigstad T, Westre B, Sandvik AK, Brenna E, Waldum HL. Neuroendocrine differentiation in gastric
8
[88]
[89]
Scand J Gastroenterol Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 04/15/15 For personal use only.
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
H.L. Waldum et al. adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia. APMIS 2002;110:132–9. Waldum HL, Haugen OA, Isaksen C, Mecsei R, Sandvik AK. Are diffuse gastric carcinomas neuroendocrine tumours (ECL-omas)? Eur J Gastroenterol Hepatol 1991;3: 245–9. Waldum HL, Aase S, Kvetnoi I, Brenna E, Sandvik AK, Syversen U, et al. Neuroendocrine differentiation in human gastric carcinoma. Cancer 1998;83:435–44. Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. APMIS 6: 209–222. Acta Pathol Microbiol Scand 1965;6: 64:31–49. Bakkelund K, Fossmark R, Nordrum I, Waldum H. Signet ring cells in gastric carcinomas are derived from neuroendocrine cells. J Histochem Cytochem 2006;54:615–21. Sordal O, Qvigstad G, Nordrum IS, Sandvik AK, Gustafsson BI, Waldum H. The PAS positive material in gastric cancer cells of signet ring type is not mucin. Exp Mol Pathol 2014;96:274–8. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311–15. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991; 325:1127–31. Hansson LE, Engstrand L, Nyren O, Evans DJ Jr, Lindgren A, Bergstrom R, et al. Helicobacter pylori infection: independent risk indicator of gastric adenocarcinoma. Gastroenterology 1993;105:1098–103. Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784–91. Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996;335:242–9. Testoni PA, Masci E, Marchi R, Guslandi M, Ronchi G, Tittobello A. Gastric cancer in chronic atrophic gastritis. Associated gastric ulcer adds no further risk. J Clin Gastroenterol 1987;9:298–302. Chuang CH, Sheu BS, Yang HB, Kao AW, Cheng HC, Yao WJ. Hypergastrinemia after Helicobacter pylori infection
[100]
[101] [102]
[103]
[104]
[105]
[106]
[107] [108]
[109]
[110]
is associated with bacterial load and related inflammation of the oxyntic corpus mucosa. J Gastroenterol Hepatol 2004;19: 988–93. Waldum HL, Hauso Ø, Sørdal ØF, Fossmark R. Gastrin may mediate the carcinogenic effect of Helicobacter pylori infection in mice. Dig Dis Sci 2014; Epub ahead of print. Berstad K, Berstad A. Helicobacter pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993;28:561–7. Lerang F, Moum B, Mowinckel P, Haug JB, Ragnhildstveit E, Berge T, et al. Accuracy of seven different tests for the diagnosis of Helicobacter pylori infection and the impact of H2-receptor antagonists on test results. Scand J Gastroenterol 1998;33:364–9. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455–60. Lassen AT, Hallas J, Schaffalitzky de Muckadell OB. Helicobacter pylori test and eradicate versus prompt endoscopy for management of dyspeptic patients: 6.7 year follow up of a randomised trial. Gut 2004;53:1758–63. Lindstrom CG. Gastric and duodenal peptic ulcer disease in a well-defined population. A prospective necropsy study in Malmo, Sweden. Scand J Gastroenterol 1978;13:139–43. Ostensen H, Gudmundsen TE, Bolz KD, Burhol PG, Bonnevie O. The incidence of gastric ulcer and duodenal ulcer in north Norway. A prospective epidemiological study. Scand J Gastroenterol 1985;20:189–92. Bonnevie O. The incidence of gastric ulcer in Copenhagen county. Scand J Gastroenterol 1975;10:231–9. Nyren O, Adami HO, Gustavsson S, Lindgren PG, Loof L, Nyberg A. The "epigastric distress syndrome". A possible disease entity identified by history and endoscopy in patients with nonulcer dyspepsia. J Clin Gastroenterol 1987;9:303–9. Bernersen B, Johnsen R, Straume B, Burhol PG, Jenssen TG, Stakkevold PA. Towards a true prevalence of peptic ulcer: the Sorreisa gastrointestinal disorder study. Gut 1990;31:989–92. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Changes in prevalence, incidence and spontaneous loss of gastrooesophageal reflux symptoms: a prospective populationbased cohort study, the HUNT study. Gut 2012;61: 1390–7.
REVIEW
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Upper gastrointestinal physiology and diseases
HELGE L WALDUM1,2, PER M KLEVELAND1,2 & REIDAR FOSSMARK1,2 1
Department of Medicine, Norwegian University of Science and Technology, and 2Department of Gastroenterology and Hepatology, St Olavs Hospital, Trondheim, Norway
Abstract Nordic research on physiology and pathophysiology of the upper gastrointestinal tract has flourished during the last 50 years. Swedish surgeons and physiologists were in the frontline of research on the regulation of gastric acid secretion. This research finally led to the development of omeprazole, the first proton pump inhibitor. When Swedish physiologists developed methods allowing the assessment of acid secretion in isolated oxyntic glands and isolated parietal cells, the understanding of mechanisms by which gastric acid secretion is regulated took a great step forward. Similarly, in Trondheim, Norway, the acid producing isolated rat stomach model combined with a sensitive and specific method for determination of histamine made it possible to evaluate this regulation qualitatively as well as quantitatively. In Lund, Sweden, the identification of the enterochromaffin-like cell as the cell taking part in the regulation of acid secretion by producing and releasing histamine was of fundamental importance both physiologically and clinically. Jorpes and Mutt established a center at Karolinska Institutet in Stockholm for the purification of gastrointestinal hormones in the 1960s, and Danes followed up this work by excelling in the field of determination and assessment of biological role of gastrointestinal hormones. A Finnish group was for a long period in the forefront of research on gastritis, and the authors’ own studies on the classification of gastric cancer and the role of gastrin in the development of gastric neoplasia are of importance. It can, accordingly, be concluded that Nordic researchers have been central in the research on area of the upper gastrointestinal physiology and diseases.
Key Words: Gastritis, gastroduodenal-clinical, Helicobacter pylori, hormones and receptors
Introduction Most people have sometimes experienced reflux of sour gastric juice. Gastric acid has therefore naturally been ascribed to play an important role in the pathogenesis of symptoms from the upper gastrointestinal tract. It is also true that gastric acid plays a central role in gastroesophageal reflux disease and peptic ulcer disease, which previously was previously very prevalent, but now has become rarer. Accordingly, the regulation of gastric acid secretion has been of great interest. Combined with the relative ease with which gastric juice is collected from humans as well as animals, it is understandable that the regulation of gastric acid secretion is among the physiological processes most studied. In many ways, experimental animal research started with dogs provied
with fistula by Pavlov demonstrating the role of vagal nerves (acetylcholine) in regulating gastric acid secretion [1]. The hormonal concept was formulated by Bayliss and Starling based upon the stimulation of bicarbonate and water secretion from a denervated pancreas subsequent to acidification of the duodenal mucosa [2]. Shortly afterwards, Edkins postulated the presence of an antral hormone, gastrin, stimulating the oxyntic mucosa to secrete acid [3]. In 1920, Popielski described that histamine was an efficient gastric acid secretagogue [4], and for decades afterwards the interactions between these three (acetylcholine, gastrin and histamine) substances in the regulation of acid secretion was disputed. In the later elucidation of both the regulation of gastric acid secretion as well as identifying the cells producing the histamine, which stimulates gastric
Correspondence: Helge L Waldum, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway. E-mail: [email protected]
(Received 6 December 2014; revised 5 January 2015; accepted 8 January 2015) ISSN 0036-5521 print/ISSN 1502-7708 online Ó 2015 Informa Healthcare DOI: 10.3109/00365521.2015.1009157
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acid secretion, Nordic researchers have made major contributions. In the Nordic countries, science has had a strong position for a long time in Sweden and Denmark, whereas in Finland, Norway and Iceland, all three countries that became independent during the last century, the scientific tradition has been weaker. Sweden stayed out of the Second World War and continued to do medical research during that period. In all respects, including research on the gastrointestinal tract, Sweden was a great power in the first years after the war. The first decade after the war was used in Norway and Finland to rebuild the countries, but around 1960, science began to make its way into clinical medicine, including gastroenterology, also in these young countries. Siurala put Finland into a leading position within the research on gastritis [5], while the founder of Scandinavian Journal of Gastroenterology, Johs. Myren, together with another Editor-in-Chief, E. Gjone, initiated research within gastroenterology in Norway. Johs. Myren went to the inventor of the flexible endoscope, Basil Hirschowitz, in Birmingham, Alabama, to learn scientific methods, mainly related to the regulation of gastric acid secretion. Hirschowitz helped in many ways to establish Norwegian gastrointestinal research by later admitting professor Per Burhol and Arnold Berstad to his unit, and also contributed to Swedish science by accepting Prof Herbert Helander into his laboratory. During the same time period, Jorpes and Mutt were the leading scientists within gastrointestinal hormones [6], and during that decade, there was a tradition that ambitious researchers went to “Karolinska Institutet”, Stockholm, to identify and characterize a new gastrointestinal hormone. Thus VIP [7], GIP [8] and motilin [9] were found besides CCK and secretin, which were purified by Jorpes and Mutt themselves [6,10]. Nordic research on gastrointestinal hormones will be covered in a separate chapter by Prof Jens F. Rehfeld in this issue. Studies on the regulation of gastric acid secretion in animals and man: status in 1965 when Scandinavian Journal of Gastroenterology was founded The interaction between the three principal gastric acid secretagogues was still heavily disputed. Komarov had shown shortly before the Second World War that gastrin was not a histamine [11], and in 1961, Gregory and Tracy purified, sequenced and synthesized gastrin [12]. Kahlson and co-workers in Lund showed that food intake as well as (penta)- gastrin depleted the oxyntic mucosa of histamine and simultaneously stimulated histamine synthesis [13]. Nevertheless,
Leonard Johnson wrote in “Gastroenterology”: No room for histamine? [14]. This was, of course, abruptly changed by the description by Black of the histamine-2 (H-2)-receptor and the effect of H-2 antagonists on acid secretion [15]. The histamine producing enterochromaffinlike cell and the role of histamine in the regulation of gastric acid secretion Kahlson together with Rosengren [13] made important contributions to the study of regulation of release and synthesis of histamine at a time when the physiological role of histamine in the regulation of acid secretion [14] was disputed. Histamine research was continued in Lund by Håkanson and co-workers. In 1968, Håkanson and co-workers described the presence of histamine in a neuroendocrine cell in the oxyntic mucosa of the rat [16]. They named this cell the enterochromaffin-like (ECL) cell. Even then, many thought that mast cells produced the histamine participating in the regulation of acid secretion [17]. When immunohistochemistry with increased sensitivity was first used nearly 20 years later, showing histamine in a similar cell in many species including man [18], the ECL cell was generally accepted as central in the regulation of acid secretion. It is curious that so many for so long believed that the mast cell, a cell without a fixed position to the acidproducing parietal cell, took part in the regulation of acid secretion. Håkanson and his group continued their work related to histamine and acid secretion and described the regulation of decarboxylation of histidine, the most important step in histamine synthesis [19].Further elucidation of the regulation of histamine release was hampered for some time due to the lack of a sensitive method to determine histamine concentration, as well as histamine not being a hormone, but working locally as a paracrine substance. This was overcome when we used a sensitive radioimmunoassay for histamine [20], which was applied on the venous effluent from the totally isolated, acidproducing rat stomach [21]. These experiments proved that gastrin was a very potent stimulator of histamine release [22], resulting in histamine concentrations sufficient to explain the acid stimulatory effect of gastrin [23]. Later on, we were able to show that a functional CCK2/gastrin receptor was localized solely to the ECL cell in the oxyntic mucosa [24]. In isolated oxyntic mucosal cell fractions enriched by elutriation, we were able to show that gastrin released histamine [25]. However, not all cell preparations responded to gastrin by histamine release [25]. This method was improved by Prinz and co-workers by markedly increasing the percentage of ECL cells in
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Upper gastrointestinal physiology and diseases their cell fractions [26]. However, they were not able to correlate the stimulation of histamine release with the effect on acid secretion as we could [25]. Besides the isolated rat stomach and isolated oxyntic mucosal cells, Håkanson and co-workers introduced microdialysis to assess the regulation of histamine release [27]. There is a high degree of correlation between these three methods, and it may be concluded that gastrin is a potent stimulator of histamine release, which subsequently increases acid secretion through interaction with the CCK-2/gastrin receptor localized to the ECL cells. From the above achievements, it may be stated that Nordic researchers have been central in research on the role of histamine in regulation of acid secretion during the last 50 years. Studies on acid secretion in isolated organs, glands and cells Due to the relative ease with which gastric juice may be collected from animals and humans, gastric acid secretion has been extensively examined. However, the complexity of intact organisms has necessitated the development of methods to assess gastric acid secretion in less complex models. It was a major breakthrough when Öbrink and Berglindh with their co-workers in Uppsala developed methods allowing assessment of acid secretion in isolated oxyntic glands or parietal cells by measuring oxygen consumption and the accumulation of a radioactive weak base, aminopyrine [28,29]. They could not find any stimulation of acid secretion by gastrin in such preparations from rabbits [29]. On the other hand, Soll claimed that acid secretion was stimulated in isolated canine parietal cells by gastrin [30], a species very sensitive towards histamine with respect to stimulation of gastric acid secretion [31]. When we started with isolated rat stomachs, the belief was that they did not produce acid. However, previous studies on isolated stomachs had applied oxygenated buffers to perfuse the vascular bed. Considering that acid secretion produce an H+ gradient of more than 1 million, which is probably the most energy requiring process in the body, the oxygen supply by such an approach was obviously not sufficient. We therefore started to add erythrocytes to the perfusion buffer and used a membrane oxygenator developed at our university. At the same time, Short and co-workers [32] described success with ovine erythrocytes, which we adopted [33]. By this method, we could show that gastrin was very potent in stimulating histamine release [20], that gastrin in contrast to a cholinergic agent did not augment maximal gastrinstimulated acid secretion [21], and that from a functional point of view, stimulation of gastric acid secretion by gastrin could be solely due to stimulation
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of histamine [23]. Later studies in Lund on isolated ECL cells by the Håkanson group further elaborated the connection between the ECL cells and gastrin in the release and synthesis of histamine [34,35].Taken together, the long-term dispute about the interaction between the three secretagogues may be concluded by histamine and acetylcholine having a direct effect on the parietal cells, whereas gastrin has an indirect effect by stimulating the ECL cells to release histamine. Studies on the regulation of gastric secretion in animals and man Studying gastric acid secretion has been an old tradition in Sweden [36]. It was continued after the Second World War by studies in animals with pouches and vagal stimulation [37,38]. These studies were the background for the development of omeprazole [39], which binds covalently to the proton pump [40]. For more than a decade, the proton pump inhibitors (PPIs) were the top selling drugs. The development of omeprazole will be covered in a separate chapter in this issue by Lundell. In Norway, studies on the regulation of gastric acid secretion in man [41] started in the 1960s, followed by experimental studies on animals [42–44]. Berstad developed his own method to assess pepsin concentration in the gastric juice [45] and used it to study the regulation of pepsin secretion. Waldum studied pepsinogen in blood for use as a marker of gastric acid secretion [46] and Vatn studied the secretion of the intrinsic factor [47]. Since the time of experiments by Pavlov [1], the central role of the vagal nerves in the regulation of acid secretion has been known. Moreover, it was shown that patients with duodenal ulcer have increased acid secretion [48]. Accordingly, the reduction of gastric acid secretion by vagotomy was a possible treatment. However, due to inhibition of gastric emptying by truncal vagotomy, pyloroplasty as a drainage procedure had to be added. When proximal gastric vagotomy was introduced, the neural supply to the antrum was preserved and gastric emptying was less affected [49–51], so pyloroplasty could be avoided [52]. (Motility is covered in a separate chapter in this issue). Proximal gastric vagotomy markedly reduces gastric acid secretion [53]. It should also be added that we in Trondheim improved the insulin-test for testing the completeness of vagotomy by the glucose clamp technique [54]. Studies on gastrointestinal hormones Stockholm was, as previously stated, for a long period the center for detecting new gastrointestinal hormones
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[6–10]. The Nordic tradition of research on gastrointestinal hormones was maintained by JF Rehfeld in Copenhagen who was in the forefront of developing and characterizing radioimmunoassay for their determination, and particularly of the hormones belonging to the gastrin/CCK family [55–57]. Many other Danes studied other gastrointestinal hormones (see specific chapter by Rehfeld). Schrumpf in Oslo also developed a gastrin radioimmunoassay at an early stage [58]. Studies on gastric, duodenal and pancreatic bicarbonate secretion It had for long been presumed that the surface epithelium in the stomach and upper duodenum produced bicarbonate that diffused into the mucus layer to protect surface cells from destruction by acid and the proteolytic enzyme pepsin. Gastric bicarbonate secretion has been estimated by studying antral pouches, antral mucosa in Ussing chambers or in intact stomachs where acid secretion is heavily inhibited. Particularly, in the field of duodenal bicarbonate secretion, Flemström has been a pioneer [59]. Pancreatic bicarbonate secretion was studied by Petersen in Oslo [60]. By observing increased pancreatic bicarbonate secretion in a patient with gastrinoma, he got the idea of a positive trophic effect parallel to the functional effect, which resulted in a stay in Los Angeles and cooperation with Grossman [61]. Studies on gene-modified mice Duan Chen and his wife Chun Mei Zhao came from China to Lund to work with professor Håkanson. There, both wrote excellent theses in the field of gastric physiology [62,63]. Chen was called for professorship in Trondheim and they both have continued their work in the same area. In cooperation with different American groups, they have studied mice where gastrin and/or the CCK2 receptor have been knocked-out [64–66]. Of particular interest is their study of the role of the vagal nerves in gastric carcinogenesis [67]. Trophic effects of gastrointestinal hormones The positive trophic effect of gastrin on the oxyntic mucosa was indirectly shown by the succulent mucosa in patients with Zollinger–Ellison syndrome [68] and the atrophy of the oxyntic mucosa after removal of the antrum [69]. The development of ECL cell carcinoids after long-term hypergastrinemia either due to gastrinoma [70] or induced by hypoacidity secondary to atrophic gastritis [71] suggested a specific trophic effect on this cell. However, this was not focused on before
long-term, profound inhibition of acid secretion either by the insurmountable H-2 blocker loxtidine [72] or the PPI omeprazole [72] was reported to induce ECL cell neoplasia in rodents. It was soon realized that hypergastrinemia was the pathogenic factor for these tumors. Gastrin stimulates the proliferation of the ECL cells, a cell type that had been claimed not to divide [73]. We could show a close correlation between the stimulation of function (histamine release) and growth of the ECL cells and that maximal effects of gastrin were reached at much lower concentrations than anticipated [74]. Based upon our previous finding that the functional effect (stimulation of acid secretion) was indirect via simulation of histamine release [23] and that we could not find any binding of gastrin in the stem cell area [24], we postulated that the trophic effect on the oxyntic mucosa also was secondary to effects on the ECL cells. By differential counting of the oxyntic mucosal cells from hypergastrinemic rats, we found a disproportional increase in the ECL cells, whereas the number of parietal cells and the other mucosal cells only reflected the total number of mucosal cells [75]. This study thus shows that there is no specific trophic effect on other cell types than the ECL cells in the oxyntic mucosa, but does not exclude a direct effect on the stem cells. Anyhow, the trophic effect on the ECL cells by gastrin results in rebound hypersecretion of acid after a period with profound inhibition of acid secretion [76]. Maximal gastrin-stimulated acid secretion is inferior to maximal histamine-stimulated [21], and thus meal-stimulated acid secretion is restricted by the magnitude of histamine release, which depends of the ECL cell mass [77]. The clinical importance of rebound acid hypersecretion after a period of PPI dosing was shown by research groups from both Denmark [78] and Sweden [79]. Gastrin and neoplasia In studies on rats it was shown that ECL cells proliferate [80,81] and that long-term hypergastrinemia in that species induces ECL cell neoplasia whatever the cause of hypergastrinemia [72,82,83]. For the pharmaceutical company Astra that produced omeprazole, it was important to show that ranitidine could also induce ECL cell tumors in rats when given sufficient doses [84]. It could thus be concluded that the ECL cell tumors in rats after omeprazole was a consequence of its biological effect and not due to a specific carcinogenic effect. However, was the neoplastic effect of hypergastrinemia mainly confined to rats and without relevance for humans? We started to study gastric carcinomas from humans for ECL cell markers, and could find evidence for such origin in an important proportion of the tumors [85–89],
Upper gastrointestinal physiology and diseases particularly those described as being of diffuse type according to the Finnish pathologist Laurén [90]. In signet ring cell carcinomas, a subgroup of diffuse carcinomas, we found a high degree of neuroendocrine differentiation [91]and no sign of mucin expression when examined by in situ hybridization [92].
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Helicobacter pylori The identification of Helicobacter pylori (HP) as the main cause of gastritis and peptic ulcer [93] and the subsequent recognition of the major role of HP in gastric carcinogenesis [94] were major breakthroughs in the last two decades of the 20th century. Swedish research groups contributed within this new field of research from the early 1990s [95,96]. In spite of tremendous efforts, no definitive mechanism of the carcinogenic effect of HP infection has been reached. However, the protective effect of duodenal ulcer against gastric cancer was described by Hansson [97] and the carcinogenic effect of HP infection seems to be related to its induction of atrophic corpus gastritis [98] resulting in hypergastrinemia [99]. Quite recently we showed that the hypergastrinemic effect of HP infection could explain the carcinogenic effects of HP [100]. In Norway, Arnold Berstad was the first to grasp the clinical importance of HP infection [101]. Lerang in Fredrikstad, Norway, conducted important studies related to the diagnosis of HP infection [102]. In Denmark, Schaffalitzky de Muckadell investigated the effectiveness of a HP test-and-treat strategy in dyspeptic patients after both short- and long-term follow-up [103,104].
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gastrointestinal tract during this period of 50 years. Gastrointestinal hormones were identified by Jorpes and Mutt in Stockholm in the 1960s; Rehfeld and coworkers in Copenhagen developed immunoassays of a more sophisticated level and studied the heterogeneity and the synthesis, particularly of peptides belonging to the CCK family; in Lund, Kahlson started research on the role of histamine in the regulation of acid secretion that was followed by Håkanson describing the ECL cells as the cells producing the histamine that participates in the regulation of acid secretion; Flemström in Uppsala has been a leader within research on protective factors of the mucosae exposed to gastric juice; and Öbrink and Berglindh and we in Trondheim have made important contributions related to the interaction between the gastric acid secretagogues as well as the localization of the gastrin receptor. The clinical consequence of gastrin as a trophic hormone has also been an important topic for us. Moreover, the discovery and development of the first PPI, omeprazole, was a natural consequence of the strength of Swedish research in gastric physiology. Finally, it has to be realized that Nordic research within gastroenterology, including all aspects, would have been much weaker had we not had our own journal, Scandinavian Journal of Gastroenterology. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper
References Epidemiology The Nordic countries are well organized and have had a homogenous and stable population, and thus these countries have been ideal for epidemiological studies. These characteristics are particularly true for Iceland – see separate chapter by Bjørnsson and Ekbom. Also in the other Nordic countries, important epidemiological studies on peptic ulcer disease [105–107] as well as dyspepsia [108] have been done. Of particular importance is the study in Northern Norway where a whole community was examined with upper gastrointestinal endoscopy [109] and the epidemiology of gastrointestinal reflux disease as a part of the so-called HUNT study where the population of a whole county was followed longitudinally [110]. Conclusion It may be concluded that Nordic research has been in the forefront in all aspects related to the upper
[1] Pavlov IP. The centrifugal (efferent) nerves to the gastric glands and the pancreas. In The work of the digestive glands. Philadelphia: Griffin and Co., Ltd; 1910. p 48–59. [2] Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902;28:325–53. [3] Edkins JS. On the chemical mechanism of gastric acid secretion. Proc R Soc Med 1905;76:376. [4] Popielski L. Beta-imidazolyläthylamin und die Organextrakte. beta-imidazolyläthylamin als Mächtiger ereger der Magendrüsen. Pflugers Arch 1920;178:214–36. [5] Siurala M, Isokoski M, Varis K, Kekki M. Prevalence of gastritis in a rural population. Bioptic study of subjects selected at random. Scand J Gastroenterol 1968;3:211–23. [6] Mutt V, Jorpes JE. Structure of porcine cholecystokininpancreozymin. 1. Cleavage with thrombin and with trypsin. Eur J Biochem 1968;6:156–62. [7] Mutt V, Said SI. Structure of the porcine vasoactive intestinal octacosapeptide. The amino-acid sequence. Use of kallikrein in its determination. Eur J Biochem 1974;42:581–9. [8] Brown JC, Mutt V, Pederson RA. Further purification of a polypeptide demonstrating enterogastrone activity. J Physiol 1970;209:57–64. [9] Brown JC, Mutt V, Dryburgh JR. The further purification of motilin, a gastric motor activity stimulating polypeptide from
6
[10]
[11] [12]
Scand J Gastroenterol Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 04/15/15 For personal use only.
[13]
[14] [15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] [23]
[24]
[25]
[26]
[27]
[28]
[29]
H.L. Waldum et al. the mucosa of the small intestine of hogs. Can J Physiol Pharmacol 1971;49:399–405. Mutt V, Jorpes JE, Magnusson S. Structure of porcine secretin. The amino acid sequence. Eur J Biochem 1970; 15:513–19. Komarov SA. Gastrin. Soc Exp Biol Med 1938;38:514–16. Gregory RA, Tracy HJ. The preparation and properties of gastrin. J Physiol 1961;156:523–43. Kahlson G, Rosengren E, Svahn D, Thunberg R. Mobilization and formation of histamine in the gastric mucosa as related to acid secretion. J Physiol (Lond) 1964;174: 400–16. Johnson LR. Control of gastric secretion: no room for histamine? Gastroenterology 1971;61:106–18. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2 -receptors. Nature 1972;236:385–90. Hakanson R, Lilja B, Owman C. Cellular localization of histamine and monoamines in the gastric mucosa of man. Histochemie 1969;18:74–86. Soll AH, Lewin K, Beaven MA. Isolation of histaminecontaining cells from canine fundic mucosa. Gastroenterology 1979;77:1283–90. Simonsson M, Eriksson S, Hakanson R, Lind T, Lonroth H, Lundell L, et al. Endocrine cells in the human oxyntic mucosa. A histochemical study. Scand J Gastroenterol 1988;23:1089–99. Hakanson R, Liedberg G. The role of endogenous gastrin in the activation of gastric histidine decarboxylase in the rat. Effect of antrectomy and vagal denervation. Eur J Pharmacol 1970;12:94–103. Sandvik AK, Waldum HL, Kleveland PM, Schulze Sognen B. Gastrin produces an immediate and dosedependent histamine release preceding acid secretion in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 1987;22:803–8. Kleveland PM, Waldum HL, Larsson H. Gastric acid secretion in the totally isolated, vascularly perfused rat stomach. A selective muscarinic-1 agent does, whereas gastrin does not, augment maximal histamine-stimulated acid secretion. Scand J Gastroenterol 1987;22:705–13. Sandvik AK, Waldum HL. Rat gastric histamine release: a sensitive gastrin bioassay. Life Sci 1990;46:453–9. Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrinhistamine sequence in the regulation of gastric acid secretion. Gut 1991;32:698–701. Bakke I, Qvigstad G, Sandvik AK, Waldum HL. The CCK-2 receptor is located on the ECL cell, but not on the parietal cell. Scand J Gastroenterol 2001;36:1128–33. Brenna E, Waldum HL. Studies of isolated parietal and enterochromaffin-like cells from the rat. Scand J Gastroenterol 1991;26:1295–306. Prinz C, Kajimura M, Scott DR, Mercier F, Helander HF, Sachs G. Histamine secretion from rat enterochromaffinlike cells. Gastroenterology 1993;105:449–61. Kitano M, Norlen P, Hakanson R. Gastric submucosal microdialysis: a method to study gastrin- and food-evoked mobilization of ECL-cell histamine in conscious rats. Regul Pept 2000;86:113–23. Bergqvist E, Obrink KJ. Gastrin-histamine as a normal sequence in gastric acid stimulation in the rabbit. Ups J Med Sci 1979;84:145–54. Berglindh T, Bergqvist E. Regulation of histamine release induced by gastrin and acetylcholine in isolated rabbit gastric glands. Gastroenterology 1984;86:1024.
[30] Soll AH, Amirian DA, Thomas LP, Reedy TJ, Elashoff JD. Gastrin receptors on isolated canine parietal cells. J Clin Invest 1984;73:1434–47. [31] Waldum HL, Sandvik AK, Brenna E. Gastrin: HistamineReleasing Activity. In Walsh JH, editor. Gastrin. New York: Raven Press Ltd; 1993. [32] Short GM, Wolfe MM, McGuigan JE. Pentagastrin-stimulated gastric acid secretion by the isolated perfused rat stomach. Life Sci 1984;34:2515–23. [33] Kleveland PM, Haugen SE, Sandvik S, Waldum HL. The effect of pentagastrin on the gastric secretion by the totally isolated vascularly perfused rat stomach. Scand J Gastroenterol 1986;21:379–84. [34] Andersson K, Cabero JL, Mattsson H, Hakanson R. Gastric acid secretion after depletion of enterochromaffin-like cell histamine. A study with alpha-fluoromethylhistidine in rats. Scand J Gastroenterol 1996;31:24–30. [35] Lindstrom E, Bjørkqvist M, Boketoft A, Chen D, Zhao CM, Kimura K, et al. Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. Regul Pept 1997;71:73–86. [36] Uvnäs B. The part played by the pyloric region in the cephalic phase of gastric secretion. Acta Physiol Scand 1942;4:Suppl. XIII. [37] Linde S. Studies on the stimulation mechanism of gastric secretion.Acta Physiol (Oxf) 1950;21:Supplementum74:1–94. [38] Olbe L. Significance of vagal release of gastrin during the nervous phase of gastric secretion in dogs. Gastroenterology 1963;44:463–8. [39] Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Sjostrand SE, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase. Nature 1981; 290:159–61. [40] Sachs G, Chang HH, Rabon E, Schackman R, Lewin M, Saccomani G. A nonelectrogenic H+ pump in plasma membranes of hog stomach. J Biol Chem 1976;251:7690–8. [41] Myren J, Semb LS. The number of parietal cells and the rates of gastric secretion before and after subcutaneous injection of large doses of histamine. Gastroenterologia 1962;98:207–16. [42] Burhol PG. Gastric secretion in the chicken. Scand J Gastroenterol 1971;6:Supplement 11:1–65. [43] Grabner P, Donahue PE, Grabner ET, Kalahanis NG, Bombeck CT, Nyhus LM. Non-gastrin, intestinal-phase secretion. Experimental confirmation in the dog. Scand J Gastroenterol 1980;15:165–70. [44] Guldvog I. Vagally innervated and denervated gastric pouch in one and the same dog–a new model. Scand J Gastroenterol 1980;15:921–8. [45] Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 1970;5:343–8. [46] Waldum HL, Burhol PG, Straume BK. Serum group I pepsinogens during prolonged infusion of pentagastrin and secretin in man. Scand J Gastroenterol 1979;14:761–8. [47] Vatn MH. Haemoglobin-coated charcoal for estimation of gastric intrinsic factor. Scand J Gastroenterol 1973;8:755–60. [48] Wormsley KG, Grossman MI. Maximal histalog test in control subjects and patients with peptic ulcer. Gut 1965; 6:427–35. [49] Moberg S, Carlberger G. The effect on gastric emptying of test meals with various fat and osmolar concentrations. Scand J Gastroenterol 1974;9:29–32. [50] Amdrup BM, Griffith CA. Selective vagotomy of the parietal cell mass: Part II: With suprapyloric ucosal antrectomy and suprapyloric antral resection. Ann Surg 1969;170:215–20.
Scand J Gastroenterol Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 04/15/15 For personal use only.
Upper gastrointestinal physiology and diseases [51] Amdrup BM, Griffih CA. Selective vagotomy of the parietal cell mass: Part I: With preservation of the innervated antrum and pylorus. Ann Surg 1969;170:207–14. [52] Amdrup E, Jensen HE. Selective vagotomy of the parietal cell mass preserving innervation of the undrained antrum. A preliminary report of results in patients with duodenal ulcer. Gastroenterology 1970;59:522–7. [53] Roland M, Berstad A, Liavag I. Acid and pepsin secretion in duodenal ulcer patients in response to graded doses of pentagastrin or pentagastrin and carbacholine before and after proximal gastric vagotomy. Scand J Gastroenterol 1974;9:511–18. [54] Qvigstad G, Bjorgaas M, Eide I, Sandvik AK, Waldum HL. Vagal stimulation augments maximal (penta) gastrinstimulated acid secretion in humans. Acta Physiol Scand 1999;165:277–81. [55] Rehfeld JF, Stadil F, Rubin B. Production and evaluation of antibodies for the radioimmunoassay of gastrin. Scand J Clin Lab Invest 1972;30:221–32. [56] Stadil F, Rehfeld JF. Determination of gastrin in serum. An evaluation of the reliability of a radioimmunoassay. Scand J Gastroenterol 1973;8:101–12. [57] Rehfeld JF, Schwartz TW, Stadil F. Immunochemical studies on macromolecular gastrins: evidence that "big big gastrins" are artifacts in blood and mucosa, but truly present in some large gastrinomas. Gastroenterology 1977; 73:469–77. [58] Schrumpf E, Sand T. Radioimmunoassay of gastrin with activated charcoal. Scand J Gastroenterol 1972;7:683–7. [59] Flemström G. Gastric and duodenal mucosal secretion of bicarbonate. In Johnson LR, editor. Physiology of the Gastrointestinal Tract. New York: Raven Press; 1994. p 1285–309. [60] Petersen H. The relationship between the gastric and pancreatic secretion in man. Scand J Gastroenterol 1969;4: 345–51. [61] Petersen H, Grossman MI. Pancreatic exocrine secretion in anesthetized and conscious rats. Am J Physiol 1977;233: E530–6. [62] Chen D. The biology of the rat stomach ECL cells: Responses to gastrin and cholecystokinin. Sweden: University of Lund; 1994. [63] Zhao C-M. Exocytic and crinophagic pathwaysin ECL cells of the rat stomach. Sweden: University of Lund; 1999. [64] Chen D, Zhao CM, Al-Haider W, Håkanson R, Rehfeld JF, Kopin AS. Differentiation of gastric ECL cells is altered in CCK(2) receptor-deficient mice. Gastroenterology 2002;123: 577–85. [65] Chen D, Zhao CM, Håkanson R, Samuelson LC, Rehfeld JF, Friis-Hansen L. Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology 2004;126:476–87. [66] Zhao CM, Martinez V, Piqueras L, Wang L, Tache Y, Chen D. Control of gastric acid secretion in somatostatin receptor 2 deficient mice: shift from endocrine/paracrine to neurocrine pathways. Endocrinology 2008;149:498–505. [67] Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT, et al. Denervation suppresses gastric tumorigenesis. Sci Transl Med 2014;6:250ra115. [68] Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955;142:709–23; discussion 24-8. [69] Lees F, Grandjean LC. The gastric and jejunal mucosae in healthy patients with partial gastrectomy. AMA Arch Intern Med 1958;101:943–51.
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[70] Solcia E, Capella C, Buffa R, Usellini L, Frigerio B, Fontana P. Endocrine cells of the gastrointestinal tract and related tumors. Pathobiol Annu 1979;9:163–204. [71] Wilander E, El-Salhy M, Pitkanen P. Histopathology of gastric carcinoids: a survey of 42 cases. Histopathology 1984;8:183–93. [72] Havu N. Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion. Digestion 1986;35:42–55. [73] Barrett P, Hobbs RC, Coates PJ, Risdon RA, Wright NA, Hall PA. Endocrine cells of the human gastrointestinal tract have no proliferative capacity. Histochem J 1995;27:482–6. [74] Brenna E, Waldum HL. Trophic effect of gastrin on the enterochromaffin like cells of the rat stomach: establishment of a dose response relationship. Gut 1992;33:1303–6. [75] Bakke I, Qvigstad G, Brenna E, Sandvik AK, Waldum HL. Gastrin has a specific proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell: a study by elutriation centrifugation. Acta Physiol Scand 2000;169:29–37. [76] Waldum HL, Arnestad JS, Brenna E, Eide I, Syversen U, Sandvik AK. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut 1996;39:649–53. [77] Waldum HL, Lehy T, Brenna E, Sandvik AK, Petersen H, Sognen BS, et al. Effect of the histamine-1 antagonist astemizole alone or with omeprazole on rat gastric mucosa. Scand J Gastroenterol 1991;26:23–35. [78] Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009;137:80–7. [79] Niklasson A, Lindstrom L, Simren M, Lindberg G, Bjornsson E. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebocontrolled trial. Am J Gastroenterol 2010;105:1531–7. [80] Ryberg B, Tielemans Y, Axelson J, Carlsson E, Håkanson R, Mattson H, et al. Gastrin stimulates the self-replication rate of enterochromaffin-like cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats. Gastroenterology 1990;99:935–42. [81] Tielemans Y, Willems G, Sundler F, Håkanson R. Self-replication of enterochromaffin-like cells in the mouse stomach. Digestion 1990;45:138–46. [82] Mattsson H, Havu N, Brautigam J, Carlsson K, Lundell L, Carlsson E. Partial gastric corpectomy results in hypergastrinemia and development of gastric enterochromaffin-like cell carcinoids in the rat. Gastroenterology 1991;100:311–19. [83] Poynter D, Pick CR, Harcourt RA, Selway SA, Ainge G, Harman IW, et al. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut 1985;26:1284–95. [84] Havu N, Mattsson H, Ekman L, Carlsson E. Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine. Digestion 1990;45:189–95. [85] Qvigstad G, Falkmer S, Westre B, Waldum HL. Clinical and histopathological tumour progression in ECL cell carcinoids. APMIS 1999;107:1085–92. [86] Qvigstad G, Sandvik AK, Brenna E, Aase S, Waldum HL. Detection of chromogranin A in human gastric adenocarcinomas using a sensitive immunohistochemical technique. Histochem J 2000;32:551–6. [87] Qvigstad G, Qvigstad T, Westre B, Sandvik AK, Brenna E, Waldum HL. Neuroendocrine differentiation in gastric
8
[88]
[89]
Scand J Gastroenterol Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 04/15/15 For personal use only.
[90]
[91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
H.L. Waldum et al. adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia. APMIS 2002;110:132–9. Waldum HL, Haugen OA, Isaksen C, Mecsei R, Sandvik AK. Are diffuse gastric carcinomas neuroendocrine tumours (ECL-omas)? Eur J Gastroenterol Hepatol 1991;3: 245–9. Waldum HL, Aase S, Kvetnoi I, Brenna E, Sandvik AK, Syversen U, et al. Neuroendocrine differentiation in human gastric carcinoma. Cancer 1998;83:435–44. Laurén P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. APMIS 6: 209–222. Acta Pathol Microbiol Scand 1965;6: 64:31–49. Bakkelund K, Fossmark R, Nordrum I, Waldum H. Signet ring cells in gastric carcinomas are derived from neuroendocrine cells. J Histochem Cytochem 2006;54:615–21. Sordal O, Qvigstad G, Nordrum IS, Sandvik AK, Gustafsson BI, Waldum H. The PAS positive material in gastric cancer cells of signet ring type is not mucin. Exp Mol Pathol 2014;96:274–8. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311–15. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 1991; 325:1127–31. Hansson LE, Engstrand L, Nyren O, Evans DJ Jr, Lindgren A, Bergstrom R, et al. Helicobacter pylori infection: independent risk indicator of gastric adenocarcinoma. Gastroenterology 1993;105:1098–103. Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784–91. Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996;335:242–9. Testoni PA, Masci E, Marchi R, Guslandi M, Ronchi G, Tittobello A. Gastric cancer in chronic atrophic gastritis. Associated gastric ulcer adds no further risk. J Clin Gastroenterol 1987;9:298–302. Chuang CH, Sheu BS, Yang HB, Kao AW, Cheng HC, Yao WJ. Hypergastrinemia after Helicobacter pylori infection
[100]
[101] [102]
[103]
[104]
[105]
[106]
[107] [108]
[109]
[110]
is associated with bacterial load and related inflammation of the oxyntic corpus mucosa. J Gastroenterol Hepatol 2004;19: 988–93. Waldum HL, Hauso Ø, Sørdal ØF, Fossmark R. Gastrin may mediate the carcinogenic effect of Helicobacter pylori infection in mice. Dig Dis Sci 2014; Epub ahead of print. Berstad K, Berstad A. Helicobacter pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993;28:561–7. Lerang F, Moum B, Mowinckel P, Haug JB, Ragnhildstveit E, Berge T, et al. Accuracy of seven different tests for the diagnosis of Helicobacter pylori infection and the impact of H2-receptor antagonists on test results. Scand J Gastroenterol 1998;33:364–9. Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455–60. Lassen AT, Hallas J, Schaffalitzky de Muckadell OB. Helicobacter pylori test and eradicate versus prompt endoscopy for management of dyspeptic patients: 6.7 year follow up of a randomised trial. Gut 2004;53:1758–63. Lindstrom CG. Gastric and duodenal peptic ulcer disease in a well-defined population. A prospective necropsy study in Malmo, Sweden. Scand J Gastroenterol 1978;13:139–43. Ostensen H, Gudmundsen TE, Bolz KD, Burhol PG, Bonnevie O. The incidence of gastric ulcer and duodenal ulcer in north Norway. A prospective epidemiological study. Scand J Gastroenterol 1985;20:189–92. Bonnevie O. The incidence of gastric ulcer in Copenhagen county. Scand J Gastroenterol 1975;10:231–9. Nyren O, Adami HO, Gustavsson S, Lindgren PG, Loof L, Nyberg A. The "epigastric distress syndrome". A possible disease entity identified by history and endoscopy in patients with nonulcer dyspepsia. J Clin Gastroenterol 1987;9:303–9. Bernersen B, Johnsen R, Straume B, Burhol PG, Jenssen TG, Stakkevold PA. Towards a true prevalence of peptic ulcer: the Sorreisa gastrointestinal disorder study. Gut 1990;31:989–92. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Changes in prevalence, incidence and spontaneous loss of gastrooesophageal reflux symptoms: a prospective populationbased cohort study, the HUNT study. Gut 2012;61: 1390–7.
