Pancreatic enzyme secretion and pancreatic pseudocysts in patients with chronic pancreatitis.

CONCLUSIONS: Pseudocyst contents are not indicative of pancreatic function. We presume that the nonresolving pseudocysts did not resolve because they were noncommunicating. The question of the kinetics of secretion into pancreatic pseudocysts is still unresolved. BACKGROUND: Pseudocysts are one of the complications of chronic pancreatitis. We wanted to investigate whether it is of any value to measure enzyme activities (amylase and lipase) in pseudocyst contents, in order to answer the following questions: Is the enzymatic activity: 1. Reproducible in consecutive punctures of the same cyst; 2. Related to cyst age; 3. Indicative for the risk of relapse; and 4. Representative of exocrine pancreatic function. METHODS: In a retrospective study we examined 28 patients with chronic pancreatitis complicated with pancreatic pseudocysts. RESULTS: Reproducibility of enzyme activity in cyst juice in consecutive punctures of the same cyst was poor. We did not observe any correlation between enzyme activity and cyst age defined as the time between two cyst punctures. Enzyme activity in cyst juice was without indication for the risk of relapse. No correlation between enzyme activity and exocrine pancreatic function was found. The pseudocyst contents are not pancreatic juice in the common sense of the word

Gastric emptying of pancreatin granules and dietary lipids in pancreatic insufficiency.

AIM: To investigate the emptying of enzyme granules and dietary lipids in patients with pancreatic insufficiency secondary to chronic pancreatitis. PATIENTS AND METHODS: Seven patients with chronic pancreatitis and exocrine pancreatic insufficiency ingested a test meal including colloidal 99m-technetium-radiolabelled liver paté, and swallowed two pancreatin capsules, in which half of the granules had been replaced with 111-indium-radiolabelled plastic particles of comparable physical dimensions. The passage of the two isotopes was followed simultaneously by gamma camera imaging for direct visual judgement and calculation of mean gastric emptying time. RESULTS: Pancreatin granules and dietary lipids were observed to empty simultaneously. In the duodenum the particles and the test meal were well mixed. Mean gastric emptying time of radiolabelled liver paté and radiolabelled plastic particles could be calculated in six patients. The median of these values were 47 and 43 min, respectively (P = 0.69). CONCLUSION: Pancreatin granules sized 1.0-1.5 mm seem to empty together with dietary lipids.

Chronic pancreatitis.

Chronic pancreatitis is a serious disease with many yet unsolved problems, e.g. pathogenesis, cause of pain and treatment. Danish gastroenterologists have for many years participated actively in the investigation of the disease and have produced many internationally recognized results, especially regarding secretion physiology and pathophysiology, epidemiology, cause of pain and characterization of the secondary diabetes mellitus. In the past 25 years more than 60 Danish papers about chronic pancreatitis have been published in international, reviewed journals. Furthermore six theses on subjects related to chronic pancreatitis have been produced. In this article the Danish contribution to the literature on chronic pancreatitis during the past 25 years is reviewed.

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

The 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.

Low doses of pentagastrin stimulate gastric lipase secretion in man.

BACKGROUND: Gastric lipase is an important enzyme for dietary triglyceride digestion in normal subjects. Its regulation is unknown, as is the relation between the quantity and activity of the enzyme. METHODS: In a dose-response study we investigated the effect of low doses of pentagastrin (less than 1000 ng/kg/h) on the output of gastric lipase measured by a kinetic assay and an enzyme-linked immunosorbent assay (ELISA). RESULTS: In five healthy volunteers stepwise intravenous pentagastrin infusions of 0, 50, 100, 500, and 1000 ng/kg/h resulted in a stepwise increase in the lipase output, as measured with ELISA. However, the lipolytic activity, measured with a kinetic assay, decreased as the pH of the gastric contents decreased. CONCLUSION: We conclude that secretion of the gastric lipase is stimulated by pentagastrin, but the simultaneous secretion of acid counteracts the lipolytic activity of the enzyme when food is not present.

[Acute pancreatitis in Denmark]. / Akut pancreatitis i Danmark.

The incidence, etiology, severity and mortality of acute pancreatitis in Denmark were investigated by examining published material from Denmark from the period 1979-1992 and information from the central registry of diagnoses from the period 1981-1990. The incidence of acute pancreatitis increased from 26.8 to 35.4 per 100,000 inhabitants per year from 1981 to 1990. An increase in the incidence among males was solely responsible for this total increase in incidence. Acute pancreatitis is significantly more frequent in men than in women, in men the frequencies in the age-group 15-64 and the age-group > 65 were the same. In contrast, acute pancreatitis was nearly twice as common among women of 65 or older as it was among the 15-64 year-old women. Oedematous pancreatitis accounted for 95% of the total number of cases registered, with minimal yearly variations (94.0-96.0%). The total mortality was low, with no systematic variation in the period studied (3.2%, yearly variations between 2.6 and 4.2%). Hospitalization time decreased over the period from an average of 12.8 to nine days.

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.

Scintigraphic determination of gastrointestinal transit times. A comparison with breath hydrogen and radiologic methods.

A scintigraphic method for determination of gastrointestinal transit times was compared with the breath hydrogen test and a multiple-bolus, single-radiograph technique. A close temporal association was found between the caecal appearance of radioactivity and the onset of breath hydrogen excretion in eight healthy subjects. Neither mean small-intestinal nor mean orocaecal transit times of the radiolabelled marker were correlated with the magnitude of hydrogen peak, hydrogen peak time, or the area under hydrogen curve. No correlation was noted between whole-gut transit time of the radiolabelled marker and mean whole-gut transit time calculated from a 6-day administration of the radiopaque marker in 16 healthy subjects. The stool weight was inversely correlated with the mean colonic (r = -0.46, p = 0.009) and the mean whole-gut (r = -0.45, p = 0.011) transit times of the radiolabelled marker. In conclusion, inadequate delineation of the caecal region seems to be an unimportant drawback of the scintigraphic measurements, whereas day-to-day variation in gastrointestinal transit rates may influence the reliability of the assessments. Probably, quantitative transit data cannot be obtained from the breath hydrogen concentration profiles.

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.

The effect of insulin withdrawal on intermediary metabolism in patients with diabetes secondary to chronic pancreatitis.

Insulin was withdrawn from 7 patients with Type I (insulin-dependent) diabetes and 4 patients with insulin-dependent diabetes secondary to chronic pancreatitis, both groups without residual beta-cell function. Median plasma glucagon concentrations rose slightly, but significantly after withdrawal of insulin in Type I diabetic patients (from 14 (range: 11-16) to 19 (14-25) pmol/l by 6 h), but not in the patients with secondary diabetes. This was accompanied by a significantly higher increase in blood glucose concentration from 5.1 (4.9-5.7) to 15.2 (12.9-18.1) mmol/l by 6 h in Type I diabetic patients compared with patients with secondary diabetes (from 4.9 (4.3-6.7) to 13.1 (10.9-13.5) mmol/l) (p less than 0.01). Beta-hydroxybutyrate increased to a similar extent in the two groups, whereas no significant increases were found in glycerol and lactate in any of the groups. Increased secretion of glucagon is not essential for the development of hyperglycemia and ketonemia in patients with diabetes secondary to chronic pancreatitis, but may augment the degree of hyperglycemia in Type I diabetic patients compared with patients having secondary diabetes.

Short report: lipid and vitamin B12 malassimilation in pancreatic insufficiency.

Patients with exocrine pancreatic insufficiency have steatorrhoea as well as vitamin B12 malassimilation. To investigate whether this is caused by the pancreatic insufficiency per se or whether intestinal bacterial overgrowth contributes to the condition, 10 patients with pancreatic steatorrhoea were studied. Intestinal culture was done. Lipid and vitamin B12 assimilation was estimated from faecal spot tests, using 14C-triolein and 58Co-vitamin B12 as tracers and 51CrCl3 as marker. Out of the 10 patients, 9 had either vitamin B12 malassimilation (n = 8), and/or bacterial overgrowth (n = 5). These 9 patients were retested with pancreatic enzyme therapy, with and without addition of the antibiotics metronidazole and cefalexin. The lipid assimilation was significantly increased by enzyme therapy but did not improve further on additional antibiotic treatment. The vitamin B12 assimilation did not improve significantly on enzyme therapy nor with additional antibiotic treatment.

Monitoring the effect of substitution therapy in patients with exocrine pancreatic insufficiency.

Twenty-three outpatients with chronic pancreatitis and severe exocrine insufficiency were studied for the purpose of comparing the effect of Pancrease, Pankreon, and Pankreatin by estimation of duodenal enzyme activity, the faecal fat excretion, and the faecal 14C-triolein-3H-oleic acid test and, at the same time, to evaluate these tests when monitoring outpatients. The three preparations did not disclose any significant difference in treating steatorrhoea. Pankreatin increased the meal-stimulated duodenal enzyme activity (p less than 0.01) and caused reduction in the faecal fat excretion (p less than 0.05), whereas no change in these variables were observed with Pankreon or Pancrease. The faecal 14C-triolein-3H-oleic acid test showed significant improvement in the 14C-triolein digestion with all three preparations (p less than 0.01). The faecal 14C-triolein-3H-oleic acid test was the most reliable when monitoring outpatients.

Pancreatic secretion of zinc and copper in normal subjects and in patients with chronic pancreatitis.

Pancreatic secretion of zinc and copper in duodenal juice were measured in 7 healthy persons and in 9 patients with chronic pancreatitis. Stimulation with cholecystokinin and secretin increased secretion of zinc in healthy persons but not in patients. Copper secretion was not influenced. In patients with chronic pancreatitis, the correlations between zinc secretion, and amylase and trypsin secretion were significant while in healthy subjects they were not. Possibly pancreatic zinc secretion in the duodenal juice might be used as a measure of exogenic pancreatic function, and determination of zinc in duodenal juice may replace enzyme determinations in the diagnosis of chronic pancreatitis.

A comparative study of microvascular complications in patients with secondary and type 1 diabetes.

The prevalence of retinopathy, albuminuria, and neuropathy were assessed in 25 patients with insulin-requiring diabetes secondary to chronic pancreatitis and in 25 patients with Type 1 (insulin-dependent) diabetes, matched for age at diabetes onset (secondary, 39 +/- 11 (+/- SD) years vs Type 1, 38 +/- 11 years) and duration of diabetes (10 +/- 6 vs 10 +/- 7 years). The prevalence of retinopathy was significantly higher in Type 1 diabetic patients (52%) than those with secondary diabetes (20%) (p less than 0.02). Median urinary excretion of albumin was 9 (range 1-206) mg 24-h-1 in patients with Type 1 diabetes and 7 (1-90) mg 24-h-1 in patients with secondary diabetes (NS). One secondary diabetic patient and five Type 1 diabetic patients had microalbuminuria (NS). Vibration perception threshold (measured at the big toe) was identical in the two groups of patients, and no patient had a threshold indicating somatic neuropathy (biothesiometry greater than 20 V). Retinopathy is more frequent in patients with Type 1 diabetes than in patients with insulin-requiring diabetes secondary to chronic pancreatitis. Retinopathy is so frequent in the latter group, however, that regular ophthalmoscopic examination is still required.

Insulin-dependent diabetes mellitus secondary to chronic pancreatitis is not associated with HLA or the occurrence of islet-cell antibodies.

We assessed HLA-DR types and investigated serum samples for islet-cell cytoplasmic antibodies (ICA) in 31 Danish patients with chronic pancreatitis. The antigen frequencies were compared with those in 1177 unrelated healthy Danish controls. Twenty patients had insulin-dependent diabetes and 11 had normal intravenous glucose tolerance. No significant differences in the frequencies of DR3, DR4, or DR2 were found between patients with insulin-dependent diabetes and patients with normal glucose tolerance or between any of these groups and controls. ICA were negative in all patients with chronic pancreatitis. It is concluded that the beta-cell dysfunction in insulin-dependent diabetes in chronic pancreatitis differs from that of classical insulin-dependent diabetes.

Glucose counterregulation in diabetes secondary to chronic pancreatitis.

Glucose counterregulation and hormonal responses after insulin-induced hypoglycemia were investigated in six patients with diabetes mellitus secondary to chronic pancreatitis, in seven with insulin-dependent (type I) diabetes mellitus, and in seven healthy subjects. Glucose counterregulation was identical in type I patients and in the patients with chronic pancreatitis, whereas both groups had impaired glucose recovery compared with the healthy subjects. The patients with chronic pancreatitis had no glucagon response to hypoglycemia, whereas epinephrine increased significantly. In an additional experiment, glucose recovery did not occur after hypoglycemia during concomitant beta-adrenoceptor blockade in these patients. In conclusion, glucose counterregulation is preserved but slightly impaired in patients with diabetes secondary to chronic pancreatitis, and the combination of total glucagon deficiency and pharmacological blockade of the metabolic actions of circulating epinephrine abolishes glucose counterregulation after hypoglycemia.

Monitoring of celiac plexus block in chronic pancreatitis.

Pharmacological, percutaneous celiac plexus blockade is often inefficient in the treatment of pain in chronic pancreatitis. Lack of efficiency could be due to incomplete denervation of the plexus; however, a method for measuring the completeness of celiac plexus blockade is not yet available. We have, therefore, monitored the physiological completeness of pharmacological percutaneous celiac blockade with 40 ml 25% ethanol by measuring the effect of posture on heart rate, blood pressure, hepato-splanchnic vascular resistance, and pancreatic hormone concentrations before and after celiac plexus block in 6 patients with chronic pancreatitis. Blood pressure decreased and heart rate increased after the block (P less than 0.025), whereas no significant change was found in hepato-splanchnic vascular resistance nor in the change of these parameters during transition from the supine to standing position. Pancreatic hormones (C-peptide, free insulin, glucagon, pancreatic polypeptide and somatostatin) did not change in response to standing, either before or after the block. The cardiovascular variables were normalized the day after the block, and all the patients were in their habitual state regarding pain after 1 week. In conclusion, pancreatic hormone concentrations in response to standing are not useful for monitoring celiac plexus block, whereas heart rate, blood pressure and hepato-splanchnic blood flow may yield useful information. From such measurements it was concluded that permanent denervation of the celiac plexus was not achieved in our patients after injection of 40 ml 25% ethanol.

Exocrine pancreatic function in patients with progressive systemic sclerosis.

The exocrine pancreatic function was investigated in 16 patients with progressive systemic sclerosis by means of a meal test (Lundh test) and in 9 of the patients by the secretin-cholecystokinin test as well. Gastrointestinal involvement with progressive systemic sclerosis was evaluated by esophageal manometry and by routine roentgenographic series of the small bowel. Fecal fat excretion measurement, the D-xylose absorption test, and a small-intestinal biopsy procedure were carried out. Duodenal juice was cultured and bacterial counts were estimated. One-third of the patients had reduced exocrine pancreatic function, but only four patients had unequivocally a reduction that could be of clinical importance. The results obtained with the meal test were in accordance with the secretin-cholecystokinin test, indicating a preserved capacity for endogenous stimulation.

Etiologic aspects of chronic pancreatitis. Review of current theories and experimental evidence.

The recent increase in incidence of chronic pancreatitis is difficult to explain. Alcohol consumption, although the prime precipitating factor, is not the only factor involved in the etiology. Differences in risk, presentation, and mortality in various areas of the world warrant investigation of the basic pathophysiologic mechanisms that are operative, and studies to determine if they are identical in all cases of chronic inflammatory diseases of the pancreas. Satisfactory animal models for human chronic pancreatitis have not yet been produced and it is still not known if the basic mechanism(s) leading to chronic pancreatitis are identical in all cases. The only theory concerning the etiopathogenesis of chronic pancreatitis that seems to have therapeutic merit involves the aberrant effects of mixed function oxidases, cytochrome P-450 induction, free radicals of oxygen, lipid peroxidation, and so on.