Zollinger-Ellison syndrome

The Zollinger-Ellison syndrome (ZES) is caused by mainly pancreatic, gastrin-producing tumours, which show a high rate of malignancy. The clinical picture is dominated by gastric hypersecretion, which results in the development of peptic ulcerations of the stomach and duodenum, reflux esophagitis, or diarrhea. The differentiation from other types of hypergastrinemia is done by provocative tests, mainly the secretin-test. Because of the high malignancy rate, therapeutically, a symptomatic treatment of gastric hypersecretion by H2-receptor antagonists or in cases of ineffective conservative treatment total gastrectomy is performed. In patients with duodenal gastrinomas or in the rare cases with benign pancreatic tumours resection of the tumours is the therapy of choice.     

Causal relationship between Helicobacter pylori infection and upper gastroduodenal diseases

Helicobacter pylori infection causes chronic gastritis (nonatrophic gastritis), which progresses to atrophic gastritis and intestinal metaplasia over a period of decades. Atrophy may result from inflammation and apoptosis caused by H. pylori infection. H. pylori is an important risk factor for peptic ulcer disease. Duodenitis in the gastric metaplasia of the duodenum, hypergastrinemia, and impaired proximal duodenal mucosal bicarbonate secretion are considered causal factors for duodenal ulcer disease. Low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) develops in response to H. pylori infection. Studies of Mongolian gerbil model demonstrated that H. pylori had an initiator or promoter effect on gastric carcinogenesis.     

Zollinger-Ellison syndrome

As clinical experience with patients with ZES has grown, increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy, including a thorough examination of the duodenum and perhaps intraoperative ultrasound, should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach, it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole, excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.     

Peptic ulcer pathophysiology

Despite extensive research, the etiology of peptic ulcer disease remains unclear. Given the multiple processes that control acid and pepsin secretion and defense and repair of the gastroduodenal mucosa, it is likely that the cause of ulceration differs between individuals. Acid and pepsin appear to be necessary but not sufficient ingredients in the ulcerative process. It is clear that the majority of gastric ulcers and a substantial number of duodenal ulcers do not have increased gastric acid secretion. Recent research has focused more on protection and repair of the stomach and duodenum. NSAIDs cause a significant number of gastric and duodenal ulcers; this is probably due to inhibition of prostaglandin production with loss of its protective effects. In the absence of NSAIDs and gastrinoma, it appears that most gastric ulcers and all duodenal ulcers occur in the setting of H. pylori infection. Evidence is mounting in support of H. pylori as a necessary ingredient in the ulcerative process, similar to acid and pepsin. It is not known whether the bacteria or the accompanying inflammation is the more important factor in the pathophysiology. Although the pathophysiology of gastric ulcer and duodenal ulcer is similar, there are clearly differences between the two groups. Duodenal ulcer is typified by H. pylori infection and duodenitis and in many cases impaired duodenal bicarbonate secretion in the face of moderate increases in acid and peptic activity. These facts suggest the following process: increased peptic activity coupled with decreased duodenal buffering capacity may lead to increased mucosal injury and result in gastric metaplasia. In the presence of antral H. pylori, the gastric metaplasia can become colonized and inflamed. The inflammation or the infection itself then disrupts the process of mucosal defense or regeneration resulting in ulceration. A cycle of further injury and increased inflammation with loss of the framework for regeneration may then cause a chronic ulcer. Gastric ulcer often occurs with decreased acid-peptic activity, suggesting that mucosal defensive impairments are more important. The combination of inflammation, protective deficiencies, and moderate amounts of acid and pepsin may be enough to induce ulceration. Many questions remain in understanding the pathophysiology of peptic ulcer disease. The physiology and pathophysiology of mucosal regeneration and the mechanisms by which H. pylori and inflammation disrupt normal gastroduodenal function will be fruitful areas of future investigation.     

Regional peptic acid activity in gastroduodenal ulcers

The acid peptic activity in different parts of the gastroduodenal area using an original method was investigated in 25 patients with duodenal ulcer, 39 patients with gastric ulcer and 14 controls. Acidity and proteolytic activity in the gastroduodenal area were different and correlated with morphofunctional peculiarities of the mucosa. The acid peptic activity in the zone of ulceration in mediogastric and anthropyloric ulcers did not exceed that in persons without gastroduodenal pathology. The acid peptic activity in the proximal part of the duodenum was higher in the patients with duodenal ulcer than in the controls.     

Gastric Vagotomy in the Treatment of Peptic Ulcer

A hypersecretion of gastric juice, both in the empty stomach and in response to the stimulus of food-taking, is regularly found in patients with duodenal and gastrojejunal ulcers. When a similar hypersecretion of gastric juice is produced in experimental animals, ulcers will result. Of the total amount of gastric juice produced in 24 hours in normal animals, 45 per cent is due to the nervous phase, 45 per cent to the antral or hormonal phase, and 10 per cent to the intestinal phase of secretory stimulation. In duodenal ulcer patients, the nervous phase of stimulation is enormously exaggerated and may account for 80 per cent of the total acid output of the stomach. This nervous phase of secretion is permanently abolished by a complete supradiaphragmatic vagotomy. This operation is both practical and effective, and the side effects of the procedure can be controlled by a type of postoperative management that is also simple and effective.     

Helicobacter pylori in Peptic Ulcer: Have Koch's Postulates Been Fulfilled?

This brief review considers whether or not Koch's postulates have been fulfilled for Helicobacter pylori and peptic ulceration. The histological features of peptic ulcer disease in man are active chronic gastritis with antral predominance, duodenal gastric metaplasia and active duodenitis. Other features are hyperpepsinogenaemia, relative postprandial hypergastrinaemia and basal acid hypersecretion. The macroscopic features are duodenal bulb ulceration or lesser curve and antral gastric ulceration.

At present, gastric colonization with H. pylori has been produced in small animal species (rats and mice), but the infection is difficult to establish in immunocompetent animals, and histological gastritis is unconvincing. In larger animals the germ-free pig has been the most reliable model but the gastritis tends to be chronic with little activity.

The best examples of acute infection are in three ‘self-administration’ experiments in humans. In these cases acute gastritis with hypochlorhydria developed which, when it converted to active chronic gastritis, tended to be asymptomatic. Either the circumstances were incompatible with ulceration, or the experiments were not continued for the many years necessary to develop peptic ulceration. It is concluded that only one of the many steps required for the development of peptic ulceration has so far been fulfilled, i.e. the ability of H. pylori to produce histological gastritis in a susceptible host.     

The characteristics of duodenal peptic ulcer in obese persons]

Analysis was made of the rate of clinical manifestations and complications in 77 patients with overweight exceeding stage I obesity, suffering from duodenal ulcer. In the overwhelming majority of the patients, the disease ran with typical complaints and the diagnosis of peptic ulcer was not difficult. In subjects prone to and suffering from obesity, duodenal ulcer accounted for 2.3% among all the patients with duodenal ulcers. The patients were noted to be fairly prone to complications, particularly to the stenosing of the duodenum. Concomitant complications occurred frequently enough (36.3%). In obese patients, nontypical "low" localization of duodenal ulcer and a high proneness to hypersecretion were encountered more frequently.     

Functiono-morphologic substantiation of the diagnostic value of the atropine test in patients with duodenal ulcer

The basal production of hydrochloric acid, pepsin, the level of immunoreactive gastrin-17 in the blood serum and gastric juice, endocrine G-, EcI- and Ec-cells of the gastric mucosa were studied in 42 patients with duodenal peptic ulcer. Patients with a negative atropine test were characterized by a high production of hydrochloric acid, hypergastrinemia, an elevated secretion of gastrin with gastric juice, hyperplasia of G- and EcI-cells. In a positive atropine test these indices were lower with the exception of a great amount of Ec-cells in the antral mucosa. Thus the atropine test reflected the functional-morphological arrangement of the secretory apparatus of the gastric mucosa and was of diagnostic value.     

Status of the bicarbonate-mucous barrier in patients with gastroduodenal pathology

An important role in the protection of the gastric and duodenal mucosa is played by bicarbonates. Gastric secretion of bicarbonates was examined in 42 patients with gastroduodenal pathology. Basal secretion of bicarbonates by the stomach was approximately the same (0.84 +/- 0.07 mmol/h) in patients with chronic gastritis, gastroduodenitis and peptic ulcer. After stimulation of gastric glands with a 5% alcoholic solution gastric secretion of bicarbonates increased in patients with chronic gastritis whereas in patients with peptic ulcer and gastroduodenitis, it significantly reduced. A inverse relationship was discovered between bicarbonate production and hydrochloric acid secretion. In patients with peptic ulcer, the reduction of bicarbonate and mucus output by the stomach is viewed as one of the mechanisms of ulcerogenesis.     

Prostaglandin therapy for peptic ulcer disease

The demonstration of inhibition of acid secretion in man or cytoprotection in animals is not proof of efficacy in clinical disease. Indeed, there has been continued debate up to now as to whether any of our previous standard therapies for peptic ulcer disease did more than alleviate symptoms. The use of the fiberoptic endoscope to locate and measure ulcers precisely and evaluate the progress of ulcer healing may finally allow us to assess the efficacy of new therapy. Several endoscopically controlled studies abroad have found PG analogs to be effective in both gastric and duodenal ulcer disease. Clearly, well-controlled, large clinical trials are needed to assess the efficacy of these compounds when compared to placebo and other modes of therapy. A close watch must be kept to detect the possible development of toxicity or other unwanted effects. We are still at an early stage in the development of the specific PG molecule that will affect only the stomach and duodenum in a favorable way, while having no effect on other tissues. When we come close enough to this goal, a PG may be the drug of choice for peptic ulcer disease in man.     

Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.     

Diagnostic value of secretin provocation test.

Plasma gastrin response to the intravenously administered secretin was investigated in various clinical entities. The marked increase of plasma gastrin was found in response to secretin in a case of suspected Zollinger-Ellison syndrome in contrast to various degrees of plasma gastrin decrease seen in patients with ordinary or postoperative recurrent peptic ulcer. The diagnostic value of secretin provocation test was stressed especially in relation to differentiation between Zollinger-Ellison syndrome and recurrent ulcer due to retained pyloric antrum kept away from the food-passing route, both of which are characterized by hypergastrinemia and acid hypersecretion.     

Reverse diffusion of hydrogen ions and its correlation with acid secretion and proliferative activity of gastric mucosal epithelium in patients with variants of chronic gastritis and peptic ulcer

Eighty-one patients with chronic gastritis and 124 patients with peptic ulcer were examined. It was discovered that in chronic gastritis, the concomitant gastritis included, in patients with peptic ulcer, the degree of enhancement of reverse diffusion of hydrogen ions depended on the intensity of atrophy of the fundal and antral mucosa as well as on the extent of gastric lesions. The duodenogastral reflux promoted the increase of reverse diffusion of hydrogen ions. In mediogastral ulcer site, reverse diffusion of hydrogen ions was, at the height of exacerbation, enhanced to a greater degree than in the stage of ulcer healing. In atrophic variants of chronic gastritis and in peptic ulcer patients with an ulcer sited in the stomach, a close positive correlation was noted between reverse diffusion of hydrogen ions and proliferative activity of the gastric mucosa epithelium and a negative correlation between the diffusion and hydrochloric acid secretion. In patients with peptic ulcer of the duodenum without gastritis or the duodenogastral reflux, the characteristics of reverse diffusion of hydrogen ions did not differ from those seen in normal subjects.     

慢性肺源性心脏病合并消化性溃疡的原因探讨

目的 探讨慢性肺源性心脏病合并消化性溃疡的原因,为早期防治提供依据.方法 回顾了1998年1月至2005年1月8年间共236例慢性肺源性心脏病患者的病历,对已经作了胃镜检查,提示有确切消化性溃疡病变的病人的病史、临床表现、用药、治疗措施以及其他辅助检查的结果进行了分析.结果 236例中有68例作了胃镜检查,36例提示有活动期消化性溃疡病变,其发病率为15.25%,检出率为52.94%.36例中胃溃疡22例,十二指肠溃疡14例,临床上均缺乏消化性溃疡的典型表现.结论 慢性肺心脏病容易合并消化性溃疡,且临床表现不典型,应该早期防范与处理.     

Misoprostol: discovery, development, and clinical applications

Misoprostol is a synthetic 15-deoxy-16-hydroxy-16-methyl analog of PGE1, and the first prostaglandin to be registered for the treatment of peptic ulcer disease. Misoprostol is a safe and well-tolerated drug that exerts potent gastric antisecretory effects and mucosal protective actions on the gastric and duodenal mucosa. In a dosage of 800 micrograms daily in two or four divided doses, misoprostol produced rates of complete ulcer healing in both gastric and duodenal ulcer patients significantly superior to placebo and comparable to H2 receptor antagonists. The major adverse effect is diarrhea in about 10% of patients, but this is usually mild and self-limiting. Misoprostol possesses uterotonic activity and should not be used in pregnant women or those who wish to become pregnant. Misoprostol effectively heals and prevents NSAID-induced gastropathy, a therapeutic need previously unserved. Due to its mucosal protective properties, misoprostol may have advantages over antisecretory drugs in the compromised patient who is a chronic smoker or alcohol user, in refractory duodenal ulcer patients, in recurrent ulcer, and in emergency use for acute upper GI bleeding. Misoprostol's tissue-protective effects may also extend to other therapeutic areas.     

Basal and food-stimulated blood gastrin in duodenal ulcer

It has been demonstrated that the basal gastrin level in the blood of patients with peptic ulcer of the duodenum is similar to that in normal subjects. Food stimulation raises blood gastrin in normal subjects and patients. However, in patients, the peak of the blood hormone rise is higher, with this rise lasting for a longer time. Besides, the total output of the hormone is greater. These changes are most marked during an incomplete disease remission, being less remarkable when exacerbation gets attenuated and during a complete remission. A correlation has been noticed between the acid-forming function of the stomach and basal blood gastrin level that increases as the acid content in gastric juice descends. In patients experiencing a complete remission and in those in the stage of an incomplete remission and attenuated exacerbation, a direct correlation was ascertained between the stimulated hypergastrinemia and duration of the intragastral pH elevation in response to food intake. It is suggested that in peptic ulcer of the duodenum, hypergastrinemia occurs as a defence reaction aimed at the activation of trophic processes in the mucous membrane of the gastroduodenal zone.     

Diet and nutrition in ulcer disease

In this era of H2-inhibitors, the available evidence does not support the need to place peptic ulcer disease patients on restrictive diets. The major goal of diet is to avoid extreme elevations of gastric acid secretion and the direct irritation of gastric mucosa. In view of this, only slight modifications in the patient's usual diet are recommended. Table 1 depicts a sample menu for chronic peptic ulcer disease. Frequent milk ingestion as previously prescribed is not encouraged. This is owing to the transient buffering effect and significant gastric acid secretion effect of milk. The fat content of milk has no influence on these effects. Spices, in particular black pepper, red pepper, and chili powder, may produce dyspepsia. One study shows red chili powder to have no detrimental effect on duodenal ulcer healing. It has also been proposed that daily pepper ingestion may have a beneficial adaptive cytoprotective response. While still controversial and under evaluation, peptic ulcer patients should avoid any spice that causes discomfort, especially during exacerbation of peptic disease. Currently, studies indicate that it is prudent to avoid alcohol. This is especially true for the concentrated forms, such as 40% (80 proof) alcohol. Coffee should be avoided on the basis of its strong acid secretagogue property. Coffee can induce dyspepsia. Whether noncoffee caffeine-containing beverages (tea, soft drinks) induce peptic ulcer is unknown, but they are acid secretion stimulators. Decaffeinated coffee has an acid stimulating effect as well. It is reasonable to have peptic ulcer patients restrict decaffeinated coffee and all caffeine-containing beverages. There appears to be no evidence to restrict dietary fiber. Some fiber-containing foods may possess factors that are protective against ulcer disease. According to the Mayo Clinic Diet Manual, previously recommended small frequent feedings have not been shown to be more effective than three meals per day in the treatment of chronic peptic ulcer disease. This reference cites authorities advising against extra feedings because of increased acid secretion and unnecessary complication of eating patterns. However, some patients claim to be relieved of symptoms with more frequent feedings, especially during acute phases. Citric acid juices may induce reflux and cause discomfort in selective patients. Stomach distention with large quantities of food should be discouraged. Although there is now little role for dietary therapy, one should note that bland and ulcer diets probably are not detrimental to most persons if they are used for a short time and may have some psychological benefit.(ABSTRACT TRUNCATED AT 400 WORDS)     

Elimination of glycosaminoglycans in duodenal peptic ulcer and problems of its pathogenesis

Changes in the excretion and composition of proteoglycans specific for duodenal ulcer were studied in 50 patients with duodenal ulcer, 30 patients with gastric ulcer, 30 patients with chronic endogenous gastroduodenitis and in 35 healthy persons. In all the examinees proteoglycans were isolated from daily urine, their carbohydrate components--glycosaminoglycans (GAG)--were separated and divided into fractions (keratan sulfate, hyaluronic acid, heparan sulfate, chondroitin sulfate-4, chondroitin sulfate-6, dermatan sulfate, and heparin) by column chromatography on unmodified cellulose. It has been established that only peptic ulcer is characterized by disorders in GAG excretion differing in the period of exacerbation and remission. Changes in the composition of proteoglycans excreted with urine resulted probably from a deficiency of chondroitin sulfate-6 in patients with chronic duodenal ulcer. The deficiency was more marked during exacerbation but did not disappear in the period of remission of duodenal ulcer either.     

The content of gastrin, bombesin and somatostatin in the blood and gastric juice of patients with duodenal and gastric peptic ulcer]

Ninety patients suffering from peptic ulcer and 25 healthy subjects were examined for the content of gastrin, bombesin and somatostatin in blood and gastric juice. Among patients with duodenal ulcer, 2 groups were distinguished: group I included patients in whom peptic ulcer occurred before 30 years; the majority of the patients manifested blood hypergastrinemia, a decrease of bombesin concentration and normal somatostatin concentration; gastric juice was characterized by a lowering of somatostatin concentration and unchanged gastrin concentration; group II was made up of patients who developed peptic ulcer after 30: in the majority of the patients, gastrin concentration was reduced under basal conditions, after loading it was unchanged; in part of the patients, blood somatostatin concentration was elevated, in 16 in exacerbation and in 19 in remission; in the remainder, it was unchanged. The concentration of bombesin in blood remained unchanged. In gastric juice, gastrin concentration was increased only after histamine administration, somatostatin concentration was unchanged whatever the disease stage. In patients with gastric ulcer, gastrin concentration in blood was elevated only under basal conditions, being unchanged in gastric juice irrespective of the disease stage. Meanwhile, the concentration of bombesin was lowered both under basal conditions and after insulin administration, the concentration of somatostatin was decreased both in blood and gastric juice whatever the disease stage.