Effect of histamine on haemorrhagic mucosal lesions is related to vascular permeability in rats: studies with histamine, H1-, H2- and H3-agonists and bradykinin.

OBJECTIVE: To test the hypothesis that an early increase in vascular permeability is correlated with later gastric mucosal protection in the rat. METHODS: Histamine, its agonists (H1, H2, H3) and bradykinin, were either given subcutaneously or intragastrically before the intragastric administration of ethanol. The extravasation of intravenously injected 99mTc-glucoheptonate into the gastric wall and into the gastric contents was used as an indicator of increased permeability. Gastric haemorrhagic lesions where measured by computerized planimetry and ethanol absorption was determined by an ACA Clinical Analyzer. RESULTS: Histamine and bradykinin increased vascular permeability in the glandular stomach and provided significant gastroprotection, similar to H1-, H2- and H3-agonists, against ethanol-induced gastric haemorrhagic lesions. This gastroprotection was accompanied by low blood levels of ethanol, probably indicating decreased ethanol absorption and the creation of a histodilutional barrier in the stomach by histamine. CONCLUSIONS: These data indicate that an increase in vascular permeability dissipates the concentration, and may delay the absorption, of ethanol in gastric mucosa by creating a perivascular histodilutional barrier. Vascular injury, which is an early pathogenetic factor in the development of ethanol-induced gastric haemorrhagic erosions, may thus be prevented.

Lung damage aggravates gastric mucosal lesions induced by ethanol in the rat.

The hypothesis that severe lung damage generated by acid aspiration or a 50-hour exposure to 100% oxygen aggravates ethanol-induced hemorrhagic mucosal lesions in the stomach was examined in the rat. Animals were either given intratracheally with pyrogen-free saline or HCl (pH 1.75) or exposed for 50 h to 100% oxygen before the intragastric application of 1 ml of 50 or 75% ethanol. All rats receiving 50% ethanol were also given 3% monastral blue, 3 min before ethanol administration as a vascular tracer. Lung acid damage and inflammation as assessed by bronchopulmonary lavage were severe. We observed a significant increase in extracellular lactate dehydrogenase beta-glucosaminidase, albumin and the number of polymorphonuclear leukocytes in the lavage fluid. The number of resident macrophages decreased significantly. Blood gas analysis was not influenced. Hemorrhagic gastric mucosal lesions after 50 or 75% ethanol increased from 4.4 or 8.2% to 9.8 or 13.1% after HCl and from 6.7 or 18.2% to 10.6 or 21.6% of the glandular stomach following oxygen exposure. The area of mucosal vascular damage caused by 50% ethanol as revealed by monastral blue labelling was 3.3 and 2.6 times larger in rats with lung damage induced by HCl or hyperoxia, respectively. Thus, severe lung damage predisposes to microvascular damage and aggravates chemically induced hemorrhagic mucosal lesions.

"Endemic" idiopathic portal hypertension: report on 32 patients with non-cirrhotic portal fibrosis.

The clinical features, surgical management, and long term follow up of 32 patients from Iran with idiopathic portal hypertension are reported. Many features of the disease are similar to those reported from India and Japan. The unsuspected finding was a 46% history of marked pica of clay (geophagia) in a subset of 26 patients. In addition, 81% of our patients had a prolonged prothrombin time, despite otherwise normal to minimally abnormal liver function tests. Liver biopsies revealed intrahepatic periportal fibrosis with subintimal thickening of terminal branches, and in many specimens a striking peri-ductular fibrosis was seen in the adjacent bile ducts. The spleen was very large with a dilated artery (external diameter: 11 mm to 15 mm). Portal venous pressure (PVP) was measured intra-operatively before and after clamping the splenic artery (SA). Clamping the SA consistently caused a decreased in PVP which ranged from 2.0 to 18.2 cm water with the mean +/- SEM of 9.7 +/- 1.5 cm water (p < 0.001, paired t-test). It was equivalent to 32.3 +/- 3.6% decrease in PVP. Fifteen selected patients (Group I) were managed with splenectomy with excellent short and long term results. The selection criteria for splenectomy included a decrease in PVP to < 24 cm of water after clamping the SA. Three patients from this group were re-examined 10 to 12 years following splenectomy. Cirrhosis had not developed, but the minimal abnormalities in the liver function tests had persisted.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical aspects of gastroduodenal ulcer recurrence: an overview.

Duodenal ulcer is a disease characterized by very high rates of recurrence: up to 80% at 1 year, 95% at 2 years. Maintenance therapy will reduce relapse rates. However, when therapy directed against gastric acid is stopped, the slope of the recurrence curve is identical whether therapy is stopped after 6 weeks, 8 weeks, 3 months, 6 months, 1 year, or 2 years. This suggests that therapy directed against acid does nothing to change the natural history of ulcer disease. Cytoprotective therapy is equally successful as H2-blockers at healing ulcer or reducing relapse rates, but the time to recurrence is significantly prolonged after either acute or maintenance cytoprotective therapy is stopped. This suggests that cytoprotective therapy has a beneficial effect that does improve the natural history of ulcer disease. The mechanism by which maintenance therapy reduces ulcer relapse could be masking symptoms (analgesic), accelerated healing, or true prevention of ulcer recurrence. By using frequent endoscopic assessment combined with complex statistical evaluation (calculating traditional ulcer prevalence, point prevalence, and maximal ulcer prevalence), we showed that sucralfate cytoprotection genuinely prevents ulcer recurrence. The incidence of asymptomatic ulcer recurrence after sucralfate is 10% but is up to 40% after H2-blocker therapy.

Maintenance therapy with sucralfate in duodenal ulcer: genuine prevention or accelerated healing of ulcer recurrence?

We sought to compare the efficacy of sucralfate to placebo for the prevention of duodenal ulcer recurrence and to determine that the efficacy of sucralfate was due to a true reduction in ulcer prevalence and not due to secondary effects such as analgesic activity or accelerated healing. This was a double-blind, randomized, placebo-controlled, parallel groups, multicenter clinical study with 254 patients. All patients had a past history of at least two duodenal ulcers with at least one ulcer diagnosed by endoscopic examination 3 months or less before the start of the study. Complete ulcer healing without erosions was required to enter the study. Sucralfate or placebo were dosed as a 1-g tablet twice a day for 4 months, or until ulcer recurrence. Endoscopic examinations once a month and when symptoms developed determined the presence or absence of duodenal ulcers. If a patient developed an ulcer between monthly scheduled visits, the patient was dosed with a 1-g sucralfate tablet twice a day until the next scheduled visit. Statistical analyses of the results determined the efficacy of sucralfate compared with placebo for preventing duodenal ulcer recurrence. Comparisons of therapeutic agents for preventing duodenal ulcers have usually been made by testing for statistical differences in the cumulative rates for all ulcers developed during a follow-up period, regardless of the time of detection. Statistical experts at the United States Food and Drug Administration (FDA) and on the FDA Advisory Panel expressed doubts about clinical study results based on this type of analysis. They suggested three possible mechanisms for reducing the number of observed ulcers: (a) analgesic effects, (b) accelerated healing, and (c) true ulcer prevention. Traditional ulcer analysis could miss recurring ulcers due to an analgesic effect or accelerated healing. Point-prevalence analysis could miss recurring ulcers due to accelerated healing between endoscopic examinations. Maximum ulcer analyses, a novel statistical method, eliminated analgesic effects by regularly scheduled endoscopies and accelerated healing of recurring ulcers by frequent endoscopies and an open-label phase. Maximum ulcer analysis reflects true ulcer recurrence and prevention. Sucralfate was significantly superior to placebo in reducing ulcer prevalence by all analyses. Significance (p less than 0.05) was found at months 3 and 4 for all analyses. All months were significant in the traditional analysis, months 2-4 in point-prevalence analysis, and months 3-4 in the maximal ulcer prevalence analysis. Sucralfate was shown to be effective for the prevention of duodenal ulcer recurrence by a true reduction in new ulcer development.

Practice patterns and costs of hospitalization for upper gastrointestinal hemorrhage.

We conducted an observational study at three hospitals in Boston to examine the patterns of practice and the costs involved in the medical management of noncirrhotic, upper gastrointestinal bleeding. A total of 111 patients were identified and studied: 42 from hospital 1, 38 from hospital 2, and 31 from hospital 3. There were no significant differences in the management of the patients, except for the more frequent use of upper gastrointestinal radiography at hospital 3 and the more frequent use of cimetidine at hospital 2. Only a small percentage (3-7%) of patients required surgery, and overall mortality (0-8%) was low. The average cost of hospitalization, determined by using the New England Medical Center cost model, was calculated for direct costs ($3,180). The majority of costs incurred were for hospital bed or intensive care unit stay (63%) and transfusion of blood products (14%), with costs for physicians' services (9%), endoscopy (2%), and upper gastrointestinal radiography (1%) accounting for only a small percentage. This study demonstrates remarkable similarity in practice patterns and resource utilization at three different hospitals and provides data on the actual costs involved in hospitalization for noncirrhotic, upper gastrointestinal hemorrhage.

Non-acid mechanisms of gastric and duodenal ulcer formation.

The pathophysiology of gastric and duodenal ulcer disease has two sides: the aggressive attack, principally by the highly corrosive gastric acid; and the defending forces of mucus, mucosal resistance, and other protective substances and functions. This report reviews the roles of both the attacking and defending forces in the pathophysiology of ulcer disease. It also discusses how an early notion of ulcer formation (e.g., the Schwarz dictum of "no acid, no ulcer," first published in 1910) became the slogan by which ulcer disease was understood and from which therapy took its cue. Subsequent work has since found that the Schwarz dictum holds for duodenal ulcer, but not for gastric ulcer. Non-acid mechanisms of ulcer formation--i.e., impairment of at least one of the defending or protective forces--are also described, as are treatment approaches to ulcer disease. Although suppression of acid secretion is a mainstay of treatment, agents that safely and effectively strengthen the defense are being used more frequently. There are signs that the safe limits for acid-suppressing therapy have been reached or passed. On the other hand, the search for therapy that strengthens the defensive factors has only begun.

Sucralfate tablets 1 g twice a day for the prevention of duodenal ulcer recurrence.

Sucralfate 1 g twice daily was found to be significantly better than placebo for the prevention of duodenal ulcer recurrence. This was a double-blind, randomized, placebo-controlled, parallel groups study. A total of 254 patients with a history of two or more duodenal ulcers, the most recent event diagnosed within three months of study entry, were entered into the trial after healing was documented. Patients received sucralfate 1 g twice daily or placebo for four months, or until recurrence. Endoscopies and symptom assessments were scheduled monthly and at investigator discretion upon symptom development. Treatment groups were comparable with regard to number of patients, age, sex, smoking status, and ulcer history. Traditional ulcer prevalence and point prevalence analyses were performed. Traditional ulcer prevalence included all ulcers found at scheduled visits and interim recurrences. Point prevalence included only ulcers found at scheduled visits. In the traditional analysis, sucralfate was significantly better than placebo in reducing ulcer recurrence for all months of the study. The life table estimate of the cumulative percent with ulcer at four months was 42 percent for the sucralfate group and 63 percent for the placebo group (p = 0.002). At four months, there were 49 recurrences among 122 patients in the sucralfate group and 71 among 117 patients for the placebo group. In the point prevalence analysis, sucralfate was significantly better than placebo in reducing ulcer recurrence at Months 2 through 4. The life table estimate of the cumulative percent with ulcer at four months was 36 percent for the sucralfate group and 55 percent for the placebo group (p = 0.005). At four months, there were 38 recurrences among 114 patients in the sucralfate group and 54 among 104 patients for the placebo group. Both analyses demonstrated that sucralfate 1 g twice daily was significantly better than placebo for the prevention of duodenal ulcer recurrence. Symptom development was associated with recurrence in both treatment groups. Smoking was associated with a greater tendency to recur in placebo-treated patients only.

Hemobilia in a patient with multiple hepatic artery aneurysms: a case report and review of the literature.

Hepatic artery aneurysm is a rare vascular lesion that accounts for nearly 10% of hemobilia cases. Its etiology is most often atherosclerosis, trauma, or infection. Autoaggressive disorders are rarely associated with hepatic artery aneurysm as is thyroid dysfunction. Presented here is a case of hemobilia secondary to a rupture of one of multiple aneurysms of both right and left hepatic arteries in a women with a history of rheumatoid arthritis, hypothyroidism, and hypertension. Surgical intervention has been the rule in the past. Selective transcatheter embolization has gained clinical application in recent years, especially in the treatment of intrahepatic aneurysms. Its efficacy and safety are demonstrated by this case.

Cure of hemophilia A by orthotopic liver transplantation.

A patient with hemophilia A and transfusion-associated end-stage chronic liver disease underwent orthotopic liver transplantation. He had no requirement for exogenous factor VIII replacement during the 27 mo he survived. Although his hemophilia was cured, he had antibodies to the human immunodeficiency virus; ultimately he died of complications arising from acquired immunodeficiency syndrome. Liver transplantation for cirrhotic hemophiliacs can free them of the need for antihemophilic-factor therapy; however, application of this approach may be limited by the high prevalence of human immunodeficiency virus infection in multitransfused hemophiliacs.

Diagnosis of cholestasis: an analytic view.

The authors analyzed two invasive procedures used to visualize the biliary tree, endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC), and also explored the utility of preinvasive workups for patients with suspected cholestasis. For this analysis they used published ranges for success, fatality, complications, diagnostic accuracies of the procedures, and prognostic information about the underlying diseases. The choice between ERCP and PTC was found to be a "close call," but ERCP was generally favored as the first-choice procedure. The results suggest that noninvasive imaging does not help decide between ERCP and PTC. Although noninvasive imaging may identify those patients with common duct dilation, the higher success rate with PTC in these patients is offset by a slightly higher mortality rate. Consequently, the choice between ERCP and PTC remains close even if ultrasound has shown that biliary ducts are dilated. Furthermore, it is shown that these noninvasive tests are most useful when they can conclusively determine the presence or absence of biliary obstruction. For many patients, noninvasive imaging will not obviate the need for invasive tests.

Alternatives to the acid-oriented approach to ulcer disease: does 'cytoprotection' exist in man? A new classification of antiulcer agents.

This review summarizes the historical contradictions and inconsistencies that form the labile arguments advocating neutralization or inhibition of secretion of gastric acid for the prevention or treatment of gastroduodenal ulcers. Re-evaluation of old concepts is needed in the wake of recognition that even the most potent antisecretory agents do not change the natural history of ulcer disease; that is, the recurrence is high after termination of treatment. New biochemical, functional, and structural targets are listed for pharmacologic intervention in ulcer disease. As a supplement or alternative to the antisecretory agents, we should now consider prosecretory agents (for example, for bicarbonate and mucus secretion) and antioxidants (for example, free radical scavengers). Gastroduodenal motility, smooth muscle, the vascular endothelial cell, and the basement membrane seem to represent additional pharmacologic targets toward which new gastroprotective drugs can be directed even though the biochemical mechanism of action of these new agents may not be fully understood. New results suggest that these elements have a role in the pathogenesis of ulcer disease, and their modulations seem to exert a beneficial effect without inhibiting gastric secretion in rodents. In man, the acid antisecretory and cytoprotective doses seem to overlap, but arguments are presented to shift defining gastric 'cytoprotection' by the dose of drugs to the characterization of the phenomenon (for example, events such as the ethanol-induced hemorrhagic erosions which cannot be decreased by antisecretory agents). Furthermore, non-prostaglandin and non-H2-receptor antagonist drugs are available that exert acid-independent gastroprotection both in animals and humans. The future is thus bright for the development of new antiulcer agents.

Clinical interpretation of recurrence data.

High rates of recurrence of peptic ulcer disease have been demonstrated in numerous studies. Maintenance drug therapy can successfully reduce the rate of recurrence and probably should be given during the first year after healing, when complications are more likely to be serious. After the first year, serious complications such as perforation, bleeding, and death are not likely. The most appropriate candidates for maintenance therapy are patients older than age 50 and those who are at high risk for relapse (e.g., those who smoke, have a family history of ulcer disease, or a history of ulcer relapse). The currently available cytoprotective agent sucralfate may be the most appropriate agent to use for maintenance therapy because it is locally acting and low in toxicity, as well as effective.

Diet and other risk factors for cancer of the pancreas.

The findings of a case - control study of cancer of the pancreas, which was conducted in the Baltimore metropolitan area, are reported. Two hundred one patients with pancreatic cancer were matched on age (+/- 5 years), race, and sex to hospital and non-hospital controls, the latter selected by random-digit-dialing (RDD). All subjects were interviewed regarding diet, beverage consumption, occupational and environmental exposures, and medical and surgical history. Significantly decreased risks were associated with consumption of raw fruits and vegetables and diet soda, and significantly increased risks were associated with consumption of white bread when cases were compared with hospital and RDD controls. A significantly reduced risk was associated with consumption of wine when cases were compared to RDD controls. Risk ratios for consumption of coffee were not significantly different from one, although there appeared to be a dose - response relationship in women. A moderate but statistically nonsignificant increase in relative odds was found for cigarette smoking, and cessation of smoking was associated with a marked reduction in risk. No significant associations were found with particular occupational exposures. Tonsillectomy was associated with a significantly reduced risk, a finding that has been observed for other cancers as well. The current evidence indicates that pancreatic cancer is likely to result from a complex interaction of factors and suggests that the study of its etiology requires a multidisciplinary approach involving both laboratory and epidemiologic components.

Selection criteria for upper gastrointestinal examinations: attempts at improvement.

An attempt was made to improve upon selection criteria for the performance of upper gastrointestinal (UGI) series in three settings: a teaching hospital, a community hospital, and a health maintenance organization. Two statistical techniques, the polychotomous logistic model (to develop predictive algorithms for the identification of specific diseases) and the maximum attainable discrimination technique, were used to show the relationship between the percentage of patients with any disease detected and the percentage of UGI examinations performed. Results showed that neither technique improved significantly upon selection criteria for identifying patients with abnormal UGI series.

Effect of digitalis on estimated splanchnic blood flow.

Digitalis causes vasoconstriction of peripheral vasculature and has been shown to markedly decrease splanchnic blood flow in experimental animals in doses that are comparable to therapeutic doses in man. The effect of digitalis on splanchnic blood flow in heart failure in experimental animals and in man has been controversial. We found that i.v. ouabin reduced ESBF by 30% to 40% (p less than 0.001) in normal volunteer human subjects, that i.v. digoxin reduced ESBF by 15% to 25% (p less than 0.01) in normal subjects, and that oral digoxin had no discernible effect on ESBF in normal subjects. The difference between the effects of i.v. and oral administration appeared to be due to differences in peak blood levels, which were almost 10 times higher after i.v. administration. Glucagon prevented the effect of i.v. digoxin on ESBF in normal subjects. For patients in heart failure, the effect of i.v. digoxin on ESBF was variable: some patients had decreased ESBF but two had increased ESBF that seemed to be associated with a greater increase in cardiac output.

Hepatic artery response to vasopressin.

As vasopressin began to be used widely to control gastrointestinal hemorrhage, there was concern over the effect of vasopressin on the hepatic circulation. Although an initial vasoconstrictor effect of the drug has been described on the hepatic artery, a secondary increase in blood flow ensues. This increase has been attributed to the accompanying decrease in portal blood flow produced by vasopressin. The present study was done to investigate the mechanism of the response of hepatic artery to vasopressin in dogs. Anesthetized dogs were studied with flow probes placed on hepatic, superior mesenteric, femoral, and renal arteries, and the animals were prepared so that portal blood was diverted into jugular vein, with portal inflow to liver delivered at varying rates with blood pumped from a femoral artery. Vasopressin (0.5-1.0 U/kg) was administered intravenously. Results in dog indicate the biphasic response of hepatic artery blood flow to vasopressin is not dependent on changes in portal blood flow. Rather, it appears to be a characteristic response of this vessel. The biphasic response was not observed in other vascular beds studied and was not modified by atropine. beta-Adrenergic blockade enhanced the vasoconstrictor portion of the response, but this did not significantly alter the secondary blood flow increase.