P. M. Kleveland

The Predictive Value of History in Dyspepsia

Symptomatic patients referred to an open-access upper gastrointestinal endoscopy completed a detailed, self-administered questionnaire aimed at assessing the predictive value of history in dyspepsia. Nine hundred and thirty patients were suitable for analysis. Of these, 29% were found to have organic dyspepsia. A substantial overlap of symptoms and demographic data was found among the various endoscopic diagnoses. Discriminating variables were identified by stepwise logistic regression analysis and included in predictive score models. Pain relieved by antacids, age above 40 years, previous peptic ulcer disease, male sex, symptoms provoked by berries, and night pain relieved by antacids and food were found to predict organic dyspepsia with a sensitivity and specificity of approximately 70%, when applied on the observed material. Similar probabilities were found for score models of peptic ulcer and esophagitis. In general, the low prevalence of organic diseases resulted in low positive and high negative predictive values. Accordingly, the main impact of the predictive models may be to reduce the number of negative endoscopies rather than to predict a precise diagnosis. Independent of disease category and age, 41% of the subjects expressed a fear of malignancy, emphasizing the value of reassurance from a negative endoscopy.

Relationship between Endoscopic Hiatus Hernia and Gastroesophageal Reflux Symptoms

Little is known about the relationship between hiatus hernia (HH) and gastroesophageal reflux symptoms (GERS). Nine hundred and thirty patients submitted to gastroscopy because of symptoms completed a self-administered questionnaire. Fourteen per cent showed esophagitis (ES) and 17% HH. Forty-nine per cent of the patients with HH had endoscopic ES, and 60% of those with ES had HH. The severity of ES was dependent (p less than 0.05) on both the presence and the size of HH. After exclusion of patients with peptic ulcer and malignancy, patients with and without HH and ES were compared with regard to the presence of single symptoms and a weighted GERS score based on symptoms proven to be typical for ES. Only borderline differences were found between patients with ES and HH and those with ES and no HH. The former group, however, presented with significantly (p less than 0.001) more GERS than the patients with HH only. Nevertheless, the patients with HH as the only pathologic finding had significantly (p less than 0.01) more GERS than the patients with no major endoscopic abnormality. This study indicates a close association between HH and gastroesophageal reflux disease and supports the clinical significance of an endoscopically detected HH.

Cimetidine Responders in Non-Ulcer Dyspepsia

The effect of cimetidine and placebo was examined in 123 patients with non-ulcer dyspepsia (NUD) by means of a 12-day multi-crossover model with 5 regular interchanges between cimetidine and placebo. The evaluation of effect in individual patients was based on the number of times cimetidine was associated with less symptoms than the preceding or following placebo period. If cimetidine had no effect, the probability of being defined as a cimetidine responder was 25%. In general, cimetidine was associated with less symptoms than placebo (p less than 0.0001). Forty patients were identified as cimetidine responders (R) and the remaining patients were termed non-responders (NR). Symptoms compatible with gastroesophageal reflux were significantly more frequent in R than in NR, whereas the opposite was true for symptoms of the irritable colon syndrome. The ability of symptoms selected by stepwise logistic regression to predict response to cimetidine showed at best a sensitivity of 75% and a specificity of about 65%. No differences were found between R and NR with regard to acid secretion, endoscopic and histologic findings, or the result of an acid perfusion test. The present study supports the existence of a subgroup of cimetidine responders among patients with NUD characterized by symptoms suggestive of gastroesophageal reflux disease in the absence of confirmatory objective evidence.

The Clinical Benefit of Routine Upper Gastrointestinal Endoscopy

In a prospective study including 1526 consecutive endoscopies, attempts were made to characterize the benefit of upper gastrointestinal endoscopy. Before endoscopy judgements were made about the most likely diagnosis and treatment and about the degree of suspicion of upper gastrointestinal malignancy. After endoscopy the same types of judgement were made again. The study showed that about half of the endoscopies disclosed clinically significant abnormalities. Furthermore, about every third endoscopy led to unpredicted diagnostic and diagnostic and therapeutic consequences. The benefit was comparably small in patients below the age of 40 years and particularly great in patients above the age of 65, in patients submitted to endoscopy because of barium meal pathology or general suspicion of malignancy, and in patients with upper gastrointestinal bleeding. In general, the present study supports the widespread use of upper gastrointestinal endoscopy in clinical practice.

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

Abstract 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.

Abstract 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 effect of cimetidine in non-ulcer dyspepsia: experience with a multi-cross-over model

The symptomatic effect of cimetidine was examined in 27 patients with non-ulcer dyspepsia (NUD) by means of a multi-cross-over model (MCO model) for testing the symptomatic effect of drugs in individual patients. None of the patients showed an ulcer at the time, but 20 patients had evidence of previous peptic ulcer disease. The variant of the MCO model used included six treatment periods and three regular interchanges between cimetidine and placebo. Treatment periods lasted 2 or 4 days. The individual results were evaluated on the basis of the number of times (X score) cimetidine was associated with less symptoms than the preceding or following placebo. In general, cimetidine was associated with significantly (p less than 0.02) less symptoms than placebo. The X-score distribution was therefore skew in favour of high scores. Five patients showed the maximal X score of 5. The chance of getting an X score of 5 when cimetidine is not better than placebo is about 9%. Accordingly, the risk of being wrong when defining these five patients as cimetidine responders is 9%. The present study confirms that the MCO model may identify individual cimetidine responders among patients with NUD.

Muscarinic M2 stimulation releases histamine in the totally isolated, vascularly perfused rat stomach.

The present study examines the role of histamine in the stimulation of acid secretion induced by vagal nerve stimulation and by the muscarinic M1 agonist McN-A-343 in the totally isolated, vascularly perfused rat stomach. The stimuli were combined with an agent stimulating the cAMP system (isobutyl methylxanthine (IMX) or forskolin), a muscarinic antagonist (atropine or pirenzepine), or a histamine H2 antagonist (ranitidine). IMX and forskolin potentiated McN-A-343-stimulated acid secretion, yielding acid outputs of 280% and 260% of the sum of McN-A-343- and IMX-, or McN-A-343- and forskolin-stimulated outputs, respectively. Ranitidine inhibited acid secretion stimulated by McN-A-343 alone or in combination with IMX, whereas the forskolin-stimulated secretion was not influenced by the H2 antagonist. This strongly indicates that endogenous histamine potentiates muscarinic M1-stimulated acid secretion by increasing parietal cell cAMP. Vagal nerve stimulation with IMX increased acid output from 12.2 +/- 3.0 to 49.2 +/- 9.3 mumol/60 min (mean +/- SEM). The M1 antagonist pirenzepine and the M1/M2 antagonist atropine both significantly (p less than 0.01) inhibited vagally stimulated acid secretion. Histamine output as measured in the venous effluent was unchanged by McN-A-343, whereas nerve stimulation induced a clear increase in venous histamine output, from 101 +/- 21 before to 212 +/- 28 pmol/min (mean +/- SEM) after initiation of nerve stimulation. Histamine release was reduced to base-line levels by atropine but only insignificantly inhibited by pirenzepine, indicating a muscarinic M2 stimulation of histamine release in the rat stomach.

The intensity and variability of symptoms in dyspepsia

During the waiting time for upper gastrointestinal endoscopy 165 patients with dyspepsia completed a questionnaire and a diary for daily measurements of the symptoms pain, heartburn, and global complaints. 23 patients (14%) had peptic ulcer disease (PUD), 18 oesophagitis (11%), and the rest were labelled nonulcer dyspepsia (NUD). NUD was further subdivided into ulcer-like, reflux-like, dysmotility, and essential NUD by means of predefined symptom profiles. 39 (24%) patients were on H2 receptor antagonist treatment. In general, the intensity of the daily symptoms was rather low, and except for a higher rating of heartburn in oesophagitis, there were no significant differences between PUD, oesophagitis, and NUD--treated or untreated. NUD patients with reflux-like dyspepsia had significantly more heartburn than the group with essential NUD; otherwise there were no differences between the subgroups of NUD. The individual daily ratings for abdominal pain, heartburn, and global symptoms varied by an average standard deviation of 64%, 97% and 47% of the mean values, respectively, and were independent of treatment or diagnoses. There was an approximately 40% probability that two successive days had different levels of symptoms. Only 10% of the patients showed stable symptoms, and the patients were completely symptom-free for 20% of the observation period. Symptoms in dyspepsia patients disclosed low intensity and high variability in this study. Such factors may be important sources of bias in clinical trials.

The Benefit of Colonoscopy

In a prospective study involving 833 consecutive outpatient and open-access colonoscopies, attempts were made to characterize the benefit of colonoscopy in terms of both predicted and unpredicted findings and therapeutic procedures. The endoscopist therefore predicted the endoscopic findings before the endoscopy. The results were compared for the different indications for colonoscopy. The overall agreement between the predictions and the colonoscopic findings was 61%. Clinically significant abnormalities were found in about half the examinations. The most frequent abnormal findings were benign polyps (24%), inflammatory bowel disease (17%), and malignancy (5%). In about half the patients with a malignancy the indication for colonoscopy was rectal bleeding, and half of the malignancies were not predicted. The greatest benefit of colonoscopy was found in patients referred because of overt rectal bleeding or occult faecal blood, and abnormal barium enema or endoscopy findings. The importance of complete colonoscopy in connection with operation for colorectal carcinoma is emphasized.