Helge Worning

Symptomatic Effect of Pancreatic Enzyme Therapy in Patients with Chronic Pancreatitis

The symptomatic effect of pancreatic enzyme substitution therapy was examined in a 4-week double-blind crossover study. Twenty patients, 11 with and 9 without steatorrhoea, were examined. Pancreatic steatorrhoea was reduced from a median of 24 g/day to 10 g/day by the enzyme therapy (P less than 0.01). No significant pain reduction was found in either of the two groups, although there was a tendency to reduction in pain and analgetic consumption in the patients with steatorrhoea when treated with pancreatic enzymes. It is concluded that pancreatic steatorrhoea is still the only indication for pancreatic enzyme therapy.

pH and Pancreatic Enzymes in the Human Duodenum during Digestion of a Standard Meal

Seventy-seven healthy subjects were given a standardized meal and the duodenal contents were aspirated during four consecutive periods of 20 minutes. The volume, pH, and the concentration of α-amylase, trypsin, chymotrypsin, and lipase of the aspirates were determined. The stabilities of the enzymes in the aspirates and the reproducibility of the procedures were recorded.All results were statistically evaluated. Parameters were established for the different populations of pH, enzyme concentrations and relations of enzyme concentrations, and the corresponding normal ranges were defined (95 per cent probability). The variations in repeated tests in one subject were considerably smaller than those observed among different subjects. Hypochlorhydria was correlated with a higher duodenal pH. Male subjects with gastric acid secretion provided a pH which was lower than those obtained from female subjects. The concentrations of the enzymes reached the highest values in the first collection and remained constant at...

The effect of the cholecystokinin receptor antagonist MK-329 on meal-stimulated pancreaticobiliary output in humans

To determine the physiological role of circulating cholecystokinin (CCK), the effect of the CCK receptor antagonist MK-329 on upper digestive processes was investigated in six normal volunteers after a mixed meal. In a double-blind, two-period, randomized crossover design, the subjects received either 10 mg MK-329 or placebo orally 3 hours 15 minutes before the meal, which contained 51CrCl3 as food marker. A five-lumen tube with the tip in the distal duodenum allowed continuous marker infusion (57Co-B12) and duodenal aspiration as well as recordings of antral and duodenal motility patterns via three pressure sensors. Postprandially, MK-329 caused a significant reduction of 30%-60% (P less than 0.05) in pancreatic trypsin output during the initial three 15-minute periods; thereafter, the output was virtually the same than after placebo. Thus, the integrated enzyme response was only reduced by 15% (NS) during the 3-hour period beginning 15 minutes after the meal. In contrast, gallbladder contraction, determined by total bile acid excretion, was inhibited by 77% (P less than 0.05), indicating a crucial role of CCK in regulating gallbladder motility. Except for the initial 30 minutes postprandially, MK-329 also induced a significant reduction in duodenal pH with mean values ranging from 3.5 +/- 0.2 to 4.1 +/- 0.3 compared with 4.5 +/- 0.3 to 5.0 +/- 0.4 after placebo (P less than 0.05), probably because of lowered secretion of pancreatic bicarbonate. Gastric emptying rate was significantly accelerated by MK-329 during the initial 75 minutes after the meal, but the time for 50% emptying did not differ from placebo [127.5 +/- 7.7 vs. 140.0 +/- 9.0 minutes (NS)]. No changes were observed in the motility pattern of the proximal duodenum after feeding. Whereas MK-329 only caused a slight increase of the basal plasma CCK concentrations, the postprandial levels were markedly enhanced. Peak concentrations were 10.0 +/- 1.3 vs. 4.0 +/- 0.5 pmol/L after placebo (P less than 0.001), and the integrated response exceeded the control value by 175% (P less than 0.01). The results suggest that circulating CCK is not an essential mediator of the postprandial pancreatic enzyme secretion in humans, whereas it plays a critical role in gallbladder emptying.

Cholecystokinetic and Pancreozymic Effect of O-Sulfated Gastrin Compared With Nonsulfated Gastrin and Cholecystokinin

To assess whether sulfated gastrin contributes to the cholecystokinetic and pancreozymic activity of plasma in humans, 8 healthy subjects on separate days received a mixed meal, graded i.v. infusions of synthetic human tyrosine-O-sulfated gastrin 17 (10.9, 32.7, and 98.1 pmol/kg X h), which was compared with nonsulfated gastrin 17 (12.2, 36.6, and 109.8 pmol/kg X h) and O-sulfated cholecystokinin-octapeptide (5.5, 16.5, and 49.5 pmol/kg X h). Gallbladder volumes were measured by ultrasonography, and the concentrations of gastrin and cholecystokinin in the circulation were determined by specific radioimmunoassays. Neither of the gastrins induced changes in gallbladder volume at serum concentrations occurring postprandially, whereas cholecystokinin-octapeptide produced a significant reduction in gallbladder volume even at a plasma cholecystokinin concentration lower than observed postprandially. Another 8 subjects received the same infusions in combination with a background infusion of synthetic secretin (0.3 CU/kg X h). Gastric and duodenal juice was continuously aspirated using a double-marker perfusion technique. Neither of the gastrins caused an increase in the output of amylase, lipase, trypsin, chymotrypsin, or bilirubin, but both induced a modest increase in the output of bicarbonate and duodenal juice, the former only significantly during infusion of sulfated gastrin 17. The output of all parameters was significantly elevated during all doses of cholecystokinin-octapeptide. The results indicate that neither of the gastrins stimulates gallbladder contraction and pancreatic enzyme secretion in humans under physiologic conditions. However, gastrin may, like cholecystokinin, potentiate the effect of secretin on pancreatic secretion of juice and bicarbonate.

Plasma cholecystokinin concentrations in patients with advanced chronic pancreatitis

Plasma concentrations of cholecystokinin (CCK) have been reported to be elevated in patients with chronic pancreatitis. The elevations are suggested to be due to increased release of CCK from the upper small intestine secondary to the absence of protease activity (trypsin and chymotrypsin) in the intestinal lumen. We have studied plasma CCK levels before and after liquid as well as solid meals in eight patients with pancreatic insufficiency due to advanced chronic pancreatitis and in eight healthy controls. CCK concentrations were measured with a sensitive and specific radioimmunoassay using an antibody directed against the sulfated tyrosyl region of CCK. No differences in basal or maximal postprandiel plasma CCK levels between patients and controls were observed. In the liquid meal study, basal CCK concentrations in patients and controls were 2.2 ± 0.7 and 2.5 ± 0.4 pM, respectively, with maximal postprandial concentrations of 9.6 ± 2.2 and 11.2± 1.4 pM. In the solid meal study, basal CCK concentrations in patients and controls were 2.5 ± 0.6 and 2.6 ± 0.4 pM, respectively, with maximal postprandial concentrations of 9.4 ± 1.6 and 8.6 ± 1.4 pM. The only difference observed was a significantly longer time interval to maximal plasma CCK levels in patients as compared with controls after the liquid meal. Two patients with no detectable trypsin activity in the small intestinal lumen during a Lundh test meal had basal CCK levels of 1.3 and 1.8 pM. Thus, the present study does not support the hypothesis that trypsin is involved in the regulation of CCK release. It is concluded that both basal and postprandial plasma CCK concentrations are normal in patients with pancreatitis insufficiency due to advanced chronic pancreatitis.

Inhibition of Cholecystokinin-Stimulated Pancreaticobiliary Output in Man by the Cholecystokinin Receptor Antagonist MK-329

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.

Chronic pancreatitis and extrapancreatic cancer: a retrospective study among 181 patients with chronic pancreatitis.

SummaryThe relationship between chronic pancreatitis (CP) and extrapancreatic cancer has been debated in the recent years. In prospective studies, it has been found that pancreatic cancer develops in 0–5% of patients with chronic pancreatitis. Many papers describe an increased relative risk for developing extrapancreatic cancer in patients suffering from chronic pancreatitis. In this study including 181 patients with CP, we found 14 patients with extrapancreatic cancer (three of these had two different types of cancer). No patient had pancreatic cancer. It was found that the respiratory airways and upper gastrointestinal tract were the dominating locations (five and four cases, respectively), but also genital and hemolymphopoietic cancers were represented (four and two cases, respectively). Two patients had metastatic cancer with unknown primary tumor. The patients with cancer tended to be older than those without cancer. The patients with CP had a 2.43 times greater risk of developing cancer than the general Danish population (age and sex standardized comparison). The relatively large number of cancers in the upper gastrointestinal tract and respiratory airways suggest that tobacco and alcohol may be responsible, as these organs have the highest exposure to these compounds, which are well known carcinogens.

AMYLASE CONCENTRATION OF DUODENAL ASPIRATES AFTER STIMULATION OF THE PANCREAS BY A STANDARD MEAL. CLINICAL EVALUATION IN GASTROINTESTINAL DISORDERS.

Summary A pancreatic function test based upon pancreatic stimulation with a fluid standard meal is described. After the stimulation the duodenal contents were aspirated in 4 collection periods, and volume, pH, and the concentration of amylase were determined. The results from 40 normal subjects and 118 patients with various gastrointestinal disorders are presented. The volume and pH of the aspirates were of little diagnostic significance. The amylase concentrations varied considerably, but the individual maximal values showed a characteristic pattern. The lower normal limit was 100 millienzymes per liter, and values below 30 millienzymes per liter indicated a severe reduction. Severely reduced values were observed in all 12 patients with chronic pancreatitis. Reduced values were observed in 12 of 16 patients with cancer of the head of the pancreas, the reduction being severe in 5 of these. Subnormal enzyme concentrations were found in 9 out of 15 patients with primary malabsorption, the reduction being severe in 2. Reduced values were found in 6 of 13 patients with duodenal ulcer, in 19 of 37 patients after subtotal gastrectomy and in 7 of 25 patients with different hepatic and biliary diseases.

Results of Long-Term Treatment with Cimetidine

Forty-two patients, 35 with duodenal ulcer, 6 with prepyloric ulcer, and 1 with gastric ulcer, were, in accordance with their own choice, allocated to either maintenance therapy with cimetidine or intermittent therapy in connection with symptoms and endoscopically proven relapse. Dosage during maintenance therapy was kept as low as possible to keep patients free of symptoms. Patients receiving maintenance therapy were mostly free of symptoms, but 6 out of 24 patients had from one recurrence every 2nd year to 3 recurrences per year. Patients receiving intermittent therapy had two recurrences per year (median). The yearly dose of cimetidine in maintenance therapy was high (219 g; range, 73-292 g) compared with 59 g (range, 42-84 g) in intermittent therapy. To conclude, we cannot recommend the use of maintenance therapy for years in the routine management of ulcer patients.

Exocrine Pancreatic Substitution: Facts and Controversies

The effect on intraluminal postprandial concentrations of different pancreatic enzymes and on fat absorption were studied in 35 patients with advanced chronic pancreatitis with pancreatic insufficiency. Different regimes were studied: commercial Pankreatin (III) alone or in combination with Cimetidine, Pancrease, dispensed in microspheres, and commercial Pankreatin III compared to an equivalent uncoated preparation (Pankreatin I). Pankreatin induced significant increase in the intestinal concentration of amylase, lipase, and trypsin. Pretreatment with Cimetidine did not increase the enzyme concentrations further. The amount of enzymes in Pancrease capsules are rather small, no effect on concentrations of enzymes could be detected but treatment with Pancrease decreased significantly the fat excretion in faeces. The uncoated Pankreatin I induced a significantly higher increase in enzyme concentrations in the intestine compared to Pankreatin III but the overall effect tested on faecal fat excretion was identical with the two preparations. The results indicate that the estimation of concentration of enzyme at one level of the small intestine without and with enzyme substitution not necessarily gives information on the therapeutical effect of the enzymes.