A Test of Pancreatic Function in Man Based on the Analysis of Duodenal Contents after Administration of Secretin and Pancreozymin

Pancreozymin in man as in animals appears to act as a specific enzyme stimulant. The preparations of pancreozymin used in these experiments also contain cholecystokinin, which causes the gall bladder to contract, and a smooth muscle stimulant, possibly substance P.

The duodenal contents obtained in response to a standard dose of secretin and pancreozymin have been collected quantitatively in man and the volume and amount of bicarbonate, amylase, trypsin, and lipase measured in order to study pancreatic function. The results of 105 tests undertaken on a normal group, in pancreatic and biliary disease, and in non-pancreatic steatorrhoea have been analysed.

In localized pancreatic lesions and after recovery from acute pancreatitis, normal function is often retained. Mild functional impairment may be demonstrated only by a poor enzyme output in the post-pancreozymin fractions, while at a later stage bicarbonate output is affected and finally the volume of the duodenal contents is reduced. The secretin-pancreozymin test is most valuable, therefore, in the more chronic and advanced forms of pancreatic disease in which it gives a good assessment of residual pancreatic function. In diagnosis care must be taken in interpreting a functional test in terms of anatomical pathology. The test has proved useful not only in diagnosis but also as a guide to treatment and an index of prognosis.

     

Correlation Analysis of Duodenal Aspirates after Secretin Administration

In 12 experiments with 12 subjects, duodenal aspirates were analysed for flow rate, amylase, and six electrolytes, before and after secretin administration. Correlation analysis permitted the differentiation of two groups of constituents: the one comprising Na⁺ and HCO^-₃, the other K⁺, Ca⁺, Na⁺, Cl⁴, HPO⁼₄ and amylase. A modified version of the admixture hypothesis of exocrine pancreatic secretion is outlined in brief.     

Serum Amylase and Serum Lipase Levels in Man after Administration of Secretin and Pancreozymin

A simple evocative test has been used to study pancreatic function. Serial estimations of amylase and lipase in blood serum are made at intervals up to six hours and again at 24 hours after injecting intravenously standard doses of secretin and pancreozymin. The results of 213 tests on a normal group, in pancreatic disease, in biliary and hepatic diseases have been analysed and compared with the results of duodenal intubation and an oral glucose tolerance test. A combined evocative test and oral glucose tolerance test provide evidence of pancreatic dysfunction in the majority of cases of cancer of the pancreas and chronic pancreatitis. The conditions of the test are described and the pathological lesions in which false positive evocative tests may be found are indicated.

The simple evocative test provides the earliest biochemical evidence of pancreatic disease in some patients with cancer of the pancreas and chronic pancreatitis.

     

Intraductal Secretin Test Is as Useful as Duodenal Secretin Test in Assessing Exocrine Pancreatic Function

We assessed the clinical usefulness of theintraductal secretin test in order to ascertain whetherit can substitute for the conventional duodenal secretintest. Duodenal juice was obtained with a triple-lumen tube and pure pancreatic juice was obtained byretrograde cannulation of the main pancreatic duct usinga duodenofiberscope. Pancreatic secretion was stimulatedby a bolus intravenous injection of secretin (100 units). The two tests showed comparableinterindividual coefficients of variation, significantlygood correlations, and comparable diagnosticefficiencies. The intraductal secretin test showed noless reproducibility than that of the duodenalsecretin test as reported in the literature. In theintraductal secretin test, secretory volume, peak flowrate, bicarbonate output, and lipase output yielded the best diagnostic efficiency, followed by amylaseoutput and maximal bicarbonate concentration. In theintraductal secretin test, a 10-min collection providedas much information as a 20-min collection. We conclude, therefore, that the 10-minintraductal secretin test is as useful as theconventional duodenal secretin test in assessingexocrine pancreatic function and that the mostdiscriminatory parameters are secretory volume, bicarbonate output, andamylase (or lipase) output.     

Standard and Augmented Secretin Testing in Chronic Pancreatic Alcoholic Disease

Sequential standard (1.0 U./kg.) and augmented (4.0-5.0 U./kg.) secretin response to the pancreas has been briefly compared in normal subjects and in patients with combinations of alcoholism, cirrhosis and alcoholic pancreatitis. The results of sequential testing led to the conclusion that, for clinical purposes, the standard test is adequate for the diagnosis of well established pancreatic pathologies causing gross destruction of the parenchyma. The augmented test is of particular value when the response to 1 U./kg. produced equivocal results, inasmuch as augmented stimulation enhances the masked secretory deficiency. The administration of the augmented stimulus to alcoholic patients yielded data which suggest a new hypothesis of pathogenesis for alcoholic pancreatitis, e.g., the postsecretin response pattern of minimal pancreatic inflammatory pathology is hypersecretion. Alcohol is thought to induce fatty degeneration of the pancreatic cell initially. Continued injury leads to necrosis and fibrosis.     

The Influence of Intraduodenal Administration of Pancreatic Juice on the Bile-Induced Pancreatic Secretion and Immunoreactive Secretin Release in Man

The exocrine pancreatic secretion of water, bicarbonate, amylase, and protein and the plasma levels of immunoreactive secretin (IRS) were studied after intraduodenal infusions of bile and pancreatic juice. Pancreatic secretion was obtained by endoscopic cannulation of the main pancreatic duct. Bile and pancreatic juice were infused into the duodenum through separate catheters attached to the outside of the duodeno-scope. The unstimulated secretion was collected for 20 min. After intraduodenal stimulation of the pancreatic secretion with a nearly neutral solution of dried cattle bile, juice was collected for another 20-min period. Then, pure pancreatic juice was infused into the duodenum. It was shown that pancreatic juice reduced the flow rate and output of bicarbonate, amylase, and protein significantly (p < 0.05). A significant reduction in plasma concentration of IRS (p < 0.05) was also found. In the controls, i.e., when no pancreatic juice was instilled into the duodenum, a further increase in flow rate, bicarbonate secretion, and IRS was found. It is concluded that the exocrine pancreatic secretion and IRS release induced by intraduodenal administration of bile may be depressed by reinfusions of pancreatic juice. The corresponding effect on bicarbonate secretion and IRS release found in this study supports the view that secretin may play an important role in the exocrine pancreatic secretion induced by intraduodenal infusion of bile.     

Evidence of a Stimulatory Effect of Cyclic AMP on Pancreatic Lipase and Colipase Synthesis in Rats

The effects of endogenous and exogenous cyclic AMP on the synthesis of pancreatic lipase, colipase, and amylase were studied. Pancreatic lobules were prepared and incubated with forskolin, dibutyryl cyclic AMP (dbcAMP), and dibutyryl cyclic GMP (dbcGMP), respectively, in the presence of “S-cysteine”. The individual pancreatic enzymes were isolated by polyacrylamide gel electrophoresis, and the incorporation of radioactive cysteine into lipase, colipase, and amylase was determined. Incubation with forskolin (25 uM) rapidly increased lipase synthesis rate within 30 min, followed by an increase in colipase synthesis rate after 60 min of incubation. Amylase synthesis rate did not change during the 1st h of incubation but decreased slightly when incubated for 2h. Incubation of pancreatic lobules with dbcAMP (1 mM) for 1 h also stimulated the incorporation of cysteine into lipase and colipase by 21% and 25%, respectively, whereas incubation with dbcGMP had no effect on the synthesis rates of lipase and colipase. Neither dbcAMP nor dbcGMP had any effect on synthesis rate of amylase. It is concluded that cyclic AMP might be an important intracellular signal for the synthesis of pancreatic lipase and colipase in the rat     

Stimulation of Biliary Secretion by Duodenal Acidification and Secretin

The volume and bicarbonate output of hepatic bile was observed in chronic biliary fistula dogs during intravenous infusion of varying doses of secretin or intraduodenal introduction of varying loads of acid. Secretin and acid produced a dose-related increase in bile flow and in bicarbonate output reaching a maximum at the dose of 16 units per kg per hr of secretin and 32 mEq per hr of acid. The maximal volume and bicarbonate output with secretin was about 25% higher than with acid. Closing the gastric fistula during the maximal gastric acid response to histamine or pentagastrin and thus permitting the gastric acid to pass the duodenum, resulted in the increase in bile flow and bicarbonate output comparable to that obtained with exogenous duodenal acidification.     

A Comparison of the Response to Secretin,Pancreozymin and a Combination of these Hormones,in Man

The effect of secretin and pancreozymin on the secretion of electrolytes and enzymes into the duodenum has been studied in human subjects. The reproducibility of the response to secretin alone and to secretin plus pancreozymin was excellent, providing a period of about one month was allowed to elapse between tests. With short intervals between tests, some subjects showed marked ‘hypersensitivity’ to low doses of secretin. Pancreozymin (16 units per kg each hour) combined with a barely suprathreshold dose of secretin (0.25 units per kg each hour) elicited a bicarbonate response as great as the response to a high dose rate (4 units per kg each hour) of secretin alone. The potentiation involved a change in the mechanism of secretion of bicarbonate, since the chloride response to the combination of hormones was significantly less than the chloride response to secretin alone.     

Effect of Secretin, Glucagon and Duodenal Acidification on Bombesin-induced Hypergastrinemia in Man

The action of duodenal acidification, of continuous I.V. infusion of secretin and glucagon and of a one bolus I.V. administration of secretin and glucagon at maximal doses on BBS-induced gastrin secretion has been studied in a group of 18 healthy subjects.
Continuous infusion of secretin and glucagon and the acidification of the duodenum did not alter significantly the levels of gastrin stimulated by BBS. Secretin and glucagon administered by a single I.V. bolus paritially inhibit the effect of BBS on gastrin levels.
On the basis of these results it is not possible to affirm or to exclude the possibility that BBS is a hormone physiologically present in man.     

Pancreatic Function Tests: Comparison of Standard and Augmented Secretin

The results of standard and augmented secretin tests have been compared in the diagnosis of pancreatic exocrine disease. Eighty-six patients had a standard secretin test utilising 1 unit per kg body weight secretin. Mean peak bicarbonate concentration was 104 mEq/ litre in 43 normal subjects compared with 64 mEq/litre in 30 patients with chronic pancreatitis. Of these 30 patients, seven had normal peak bicarbonate concentration giving a diagnostic error of 23%. Assessment of other parameters of pancreatic secretion, namely total bicarbonate output and fluid output, did not improve this figure. Ninety-six patients had an augmented secretin test of 2–3 units per kg body weight. Mean peak bicarbonate concentration in normals was 97 mEq/litre compared with 51 mEq/ litre in 36 patients with chronic pancreatitis. Of the latter group, four had peak bicarbonate concentration in the normal range (11% diagnostic error) but only two had total bicarbonate output in the normal range (5–6%diagnostic error). However, in six patients who were subsequently shown to have a normal pancreas, four had abnormal peak bicarbonate concentration and five an abnormal bicarbonate output. These results indicate that augmented secretin correctly diagnoses chronic pancreatitis more frequently than a standard test but at the expense of incorrectly indicating chronic pancreatitis when this is not present.     

Proliferative Response of Different Exocrine Pancreatic Cell Types to Hormonal Stimuli: II. Effects of Long-Term Secretin Administration

The effect of graded doses of secretin on exocrine pancreatic growth and cell proliferation was studied in a long-term experiment. After 16.5 and 150μg/kg/24h of secretin, each administered as two subcutaneous injections daily for 14 days, the pancreatic wet weight decreased, whereas the protein and DN A content of the gland was uninfluenced. When administered as described above for 14 days, 16.5, 50, 150, and 450μg/kg/24 h of secretin did not affect the proliferation rate of ductal, acinar, or centroacinar cells as measured by a labeling index after 7 days of continuous ³H-thymidine administration. In the control groups a higher labeling index was found for ductal cells (19.9%) than for acinar cells (11.0%). During the 7 days of ³H-thymidine administration 80–90% of ductal and acinar cells remained in the GO phase. There was a significantly higher labeling index in interlobular than in intralobular duct cells.     

Treatment with Secretin and a Cholecystokinin-Like Peptide in Patients with Pancreatic Cancer

Secretin and cholecystokinin (CCK) have trophic effects on the pancreas and may therefore have a place in the treatment of pancreatic cancer. The present study was performed to examine whether these hormones may cause harm in patients with pancreatic cancer receiving cytostatics. The cytostatics were 5-fluorouracil, adriamycin, and mitomycin C (FAM). Secretin plus Thr²⁸Nle³¹CCK25-33, in doses stimulating pancreatic secretion to about 60% of maximal, were given as a continuous 6-day intravenous infusion just before (four patients) or immediately after (five patients) starting treatment with FAM. Five patients received FAM only. When considering symptoms, laboratory findings, abdominal CT scans, and survival, no evidence was found that secretin and CCK may cause serious or unpleasant side effects in patients with pancreatic cancer receiving cytostatics.     

Urinary Cyclic AMP in Diagnosis and Management of Hypercalcaemia: Studies of Patients without Primary Hyperparathyroidism

Summary: Urinary adenosine-3', 5'-cyclic monophosphate was measured in 14 patients with hypercalcaemia not caused by primary hyperparathyroidism. Increased levels were found in patients with malignant disease without bone metastases and believed to be examples of paraendocrine syndrome. Decreased levels were found in patients with meta-static carcinoma involving bone, and in patients with multiple myeloma, lymphoma and immobilisation after fracture. Results obtained during treatment for hypercalcaemia are described in three patients.
In two hypercalcaemic patients (one with hyperthyroidism and one with breast cancer with bone metastases) normal levels were found.
This measurement is a useful substitute for assay of serum parathyroid hormone and is of value in the diagnosis of hypercalcaemia, in monitoring effects of treatment and in revealing underlying mechanisms.     

The Pancreatic β-Cell Recognition of Insulin Secretagogues: Does Cyclic AMP Mediate the Effect of Glucose?

Insulin release and the content of cAMP were studied in microdissected pancreatic islets of noninbred ob/ob (obese) mice. In the absence of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, 20 mM glucose had no effect on cAMP save a very small initial rise detectable by a freeze-stop perifusion technique only. However, combined with this methylxanthine, 20 mM glucose produced significant increases of cAMP both in perifused islets and in islets conventionally incubated in closed vials. Glucose shared this capacity to raise the cAMP level with D-glyceraldehyde and 1,3-dihydroxyacetone. Isobutylmethylxanthine (0.05-1.0 mM) or 5 mug/ml of cholera toxin, an activator of adenylate cyclase, also increased the islet cAMP level; the effects of the methylxanthine, whether or not combined with cholera toxin, were potentiated by glucose. Isobutylmethylxanthine (0.05-1.0 mM) or 5 mug/ml of cholera toxin potentiated insulin release in response to 20 mM glucose. However, only 0.5-1.0 mM isobutylmethylxanthine stimulated insulin release in the presence of 3 mM glucose, whereas 0.05-0.1 mM isobutylmethylxanthine or 5 mug/ml of cholera toxin had no effect on secretion at the low glucose concentration. These discrepancies between cAMP-promoting and insulin-releasing activities suggest that glucose does not initiate insulin release by activating the beta-cell adenylate cyclase. By being metabolized in the beta-cells, glucose may both create a release-initiating signal not identical with cAMP and enhance cAMP formation, leading to potentiation of the effect of the initiator signal.     

Pharmacokinetics of Famotidine after Intravenous Administration in Liver Disease

The pharmacokinetics of famotidine were studied after the administration of a single intravenous dose of 20-mg to seven normal volunteers, six patients with chronic hepatitis, 14 patients with compensated cirrhosis, and seven patients with decompensated cirrhosis. The plasma terminal elimination half-life of famotidine was significantly prolonged and famotidine total body clearance was significantly reduced in patients with decompensated cirrhosis, whose creatinine clearance was 57.2 +/- 6.7 ml/min/1.48 m2, but these changes were not significant in patients with chronic hepatitis (creatinine clearance: 109.2 +/- 10.5 ml/min/1.48 m2) or in patients with compensated cirrhosis (creatinine clearance: 72.2 +/- 26.5 ml/min/1.48 m2 in comparison with normal volunteers. The total volume of distribution at steady state was not significantly different between the normal volunteers and the three groups of patients. Famotidine total body clearance showed a weak but significant correlation with the creatinine clearance (r = 0.66, p less than 0.001), serum albumin level (r = 0.51, p less than 0.01), and serum total bilirubin level (r = 0.36, p less than 0.05), which suggested that the reduction in clearance was due in part to the concomitant renal impairment, as well as hepatic dysfunction in these patients. In conclusion, famotidine total body clearance was reduced in decompensated cirrhosis, indicating that the dose schedule requires modification in patients with this condition.     

Effect of Atropine on Pancreatic Bicarbonate Output and Plasma Concentrations of Immunoreactive Secretin in Response to Intraduodenal Stimulants

In conscious dogs with gastric and pancreatic Thomas fistulas we studied the effect of atropine (50 μg kg^-1 intravenously) on pancreatic bicarbonate output and plasma concentrations of immunoreactive secretin in response to intraduodenal bolus injections of HCl (0.75 mmol), L-tryptophan (1 mmol), and sodium oleate (1 mmol). The 10-min integrated bicarbonate response to HCl was 1.7 times greater than the response to oleate and 2.8 times greater than that to tryptophan. Atropine significantly (p < 0.05) depressed the 10-min integrated bicarbonate response to HCl, oleate, and tryptophan by 67%, 79%, and 61%, respectively. HCl and oleate, but not tryptophan, significantly increased plasma secretin concentrations over basal levels. Atropine did not significantly alter basal plasma concentrations of secretin or the 10-min integrated plasma secretin response to HCl and oleate. We conclude that 1) intraduodenal tryptophan stimulates pancreatic bicarbonate secretion by an atropine-sensitive mechanism, release of secretin not being involved, and 2) in the presence of atropine the depressed pancreatic bicarbonate response to HCl and oleate is not due to decreased release of endogenous secretin.     

Combined Endoscopic Ultrasound and Secretin Endoscopic Pancreatic Function Test in Patients Evaluated for Chronic Pancreatitis

Background  

Endoscopic ultrasound and endoscopic secretin pancreatic function test may be combined in a single endoscopic session (EUS/ePFT) to diagnose chronic pancreatitis (CP).