Helicobacter pylori and gastric acid: an intimate and reciprocal relationship.

Helicobacter pylori (Hp) is the main cause of gastritis, peptic ulcer disease and gastric cancer. There are still unanswered questions related to the interaction between Hp and man, like what determines the susceptibility for the initial infection and the mechanisms for the carcinogenic effect. The initial infection seems to require a temporal gastric hypoacidity. For Hp to survive in the gastric mucous layer, some acidity is necessary. Hp itself is probably not directly carcinogenic. Only when inducing oxyntic mucosal inflammation and atrophy with hypoacidity, Hp predisposes for gastric cancer. Gastrin most likely plays a central role in the Hp pathogenesis of duodenal ulcer and gastric cancer.

Upper gastrointestinal physiology and diseases.

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.

Difficult cannulation as defined by a prospective study of the Scandinavian Association for Digestive Endoscopy (SADE) in 907 ERCPs.

BACKGROUND: The definition of a "difficult" cannulation varies considerably in reports of endoscopic retrograde cholangiopancreatography (ERCP). AIMS: To define a difficult cannulation, which translates into higher risk of post-ERCP pancreatitis. PATIENTS AND METHODS: Prospective consecutive recording of 907 cannulations in Scandinavian centers done by experienced endoscopists. Inclusion: indication for biliary access in patients with intact papilla. Exclusion: acute non-biliary and chronic pancreatitis at time of procedure. RESULTS: The primary cannulation succeeded in 74.9%, with median values for time 0.88 min (53 s), with two attempts and with zero pancreatic passages or injections. The overall cannulation success was 97.4% and post-ERCP pancreatitis (PEP) rate was 5.3%. The median time for all successful cannulations was 1.55 min (range 0.02-94.2). If the primary cannulation succeeded, the pancreatitis rate was 2.8%; after secondary methods, it rose to 11.5%. Procedures lasting less than 5 min had a PEP rate of 2.6% versus 11.8% in those lasting longer. With one attempt, the PEP rate was 0.6%, with two 3.1%, with three to four 6.1%, and with five and more 11.9%. With one accidental pancreatic guide-wire passage, the risk of the PEP was 3.7%, and with two passages, it was 13.1%. CONCLUSIONS: If the increasing rate of PEP is taken as defining factor, the wire-guided cannulation of a native papilla can be considered difficult after 5 min, five attempts, and two pancreatic guide-wire passages when any of those limits is exceeded.

How to cannulate? A survey of the Scandinavian Association for Digestive Endoscopy (SADE) in 141 endoscopists.

Cannulation of the papilla vateri represents an enigmatic first step in endoscopic retrograde cholangiopancreaticography (ERCP). In light of falling numbers of (diagnostic) ERCP and novel techniques, e.g. short-wire system, we were interested in the approach novice and experienced endoscopist are taking; especially, what makes a papilla difficult to cannulate and how to approach this. We devised a structured online questionnaire, sent to all endoscopists registered with SADE, the Scandinavian Association for Digestive Endoscopy. A total of 141 responded. Of those, 49 were experienced ERCP-endoscopists (>900 ERCPs). The first choice of cannulation is with a sphincterotome and a preinserted wire. Both less experienced and more experienced endoscopists agreed on the criteria to describe a papilla difficult to cannulate and both would choose the needle-knife sphincterotomy (NKS) to get access to the bile duct. The less experienced used more "upward" NKS, whereas the more experienced also used the "downward" NKS technique. This survey provides us with a database allowing now for a more differentiated view on cannulation techniques, success, and outcome in terms of pancreatitis.

Gastric neuroendocrine carcinoma after long-term use of proton pump inhibitor.

We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

Rebound acid hypersecretion from a physiological, pathophysiological and clinical viewpoint.

OBJECTIVE: The recent description of dyspepsia in healthy individuals after stopping treatment with proton-pump inhibitors (PPIs) indicates that reflux disease may worsen due to this treatment. The aim of this paper is to review current knowledge of the regulation of gastric acid secretion, including maximal acid secretion, and to improve understanding of the pathogenesis of acid-related conditions. MATERIAL AND METHODS: We reviewed our findings from three decades of studies on gastric acid secretion in the isolated rat stomach and in humans as well as studies by the group of Robert Jensen involving gastrinoma patients. RESULTS: The parietal cell has receptors for histamine and acetylcholine, whereas the gastrin receptor is localized to the enterochromaffin-like (ECL) cell. Gastrin-stimulated histamine release depends on the ECL cell mass, which is regulated by gastrin. The parietal cell mass is also influenced by gastrin. All conditions with hypergastrinemia concomitant with a normal oxyntic mucosa result in an increase in acid secretion. Helicobacter pylori infection in the antral mucosa may induce duodenal ulcers by its effect on acid secretion, as in patients with gastrinoma. Whereas PPIs induce clinically important rebound acid hypersecretion, histamine-2 blockers do not, since they also induce tolerance. CONCLUSION: From a biological and physiological point of view, patients should be given treatment that disturbs the normal physiology as little as possible.

The cellular localization of the cholecystokinin 2 (gastrin) receptor in the stomach.

The role of the gastric acid secretagogues acetylcholine, gastrin and histamine has been debated for decades. Initially, the mast cell was considered the source of acid stimulatory histamine. Later, Håkanson & Owman (1969) showed that the entero-chromaffinlike (ECL) cell produces and stores histamine in several species, including rat and man. Kahlson et al. (1964) showed that food and gastrin stimulated oxyntic mucosal histamine synthesis and release, Berglindh et at. (1976) that histamine and cholinergics but not gastrin induced acid secretion in isolated oxyntic glands and parietal cells, and Rangachari (1995) that acetylcholine or gastrin released histamine in isolated mucosa. These findings suggested that gastrin stimulates acid secretion through release of ECL cell histamine. Studying simultaneous histamine release and acid secretion in isolated oxyntic mucosal cells, we found that gastrin stimulated acid secretion only in preparations releasing histamine. Moreover, in the isolated rat stomach, gastrin stimulated both histamine release and acid secretion. Maximal acid output was higher with histamine than with gastrin, and augmented by acetylcholine but not by gastrin. These findings strongly suggested that gastrin acts by releasing histamine. Finally, a fluorescein-labelled gastrin analogue bound to the ECL cell, not to the parietal or stem cell regions. This is interesting, recalling that gastrin has a potent and specific trophic effect on the ECL cell and only a general effect on all other oxyntic cell types. In conclusion, physiological observations are best explained by localising the CCK2 receptor only to the ECL cell, the other effects of gastrin on the gastric mucosa being secondary to the release of mediators from the ECL cell.