Lipase Output Research Articles

Temporal relationships of cholecystokinin release, pancreatobiliary secretion, and gastric emptying of a mixed meal

The influence of gastric emptying of nutrients on plasma cholecystokinin and pancreatobiliary functions is poorly understood. We therefore temporally related the emptying of fat, protein, and glucose of a mixed meal to release of the gut hormones cholecystokinin, pancreatic polypeptide, and peptide YY and outputs of trypsin, lipase, bilirubin, and bile salts. Five healthy volunteers with a multilumen duodenal tube ingested a mixed meal with phasespecific markers for the aqueous phase, liquid fat, solid fat, and solid protein phases. Duodenal passage was determined by intraduodenal infusion of a second set of phase-specific nonabsorbable markers. Plasma cholecystokinin levels and pancreatobiliary secretions rose to a maximum at 30–60 min and then gradually declined (p < 0.01) despite continued entry of protein and fat into the duodenum throughout the whole 4-h experimental period. High levels of both pancreatic polypeptide and peptide YY were observed in the last 2 h of the experiment. Release of factors capable of inhibiting cholecystokinin release and subsequently pancreatobiliary secretion may be responsible for the observed time-course.

Cholecystokinin release and biliopancreatic secretion in response to selective perfusion of the duodenal loop with aminoacids in man.

The aim of this study was to measure the role of the duodenal loop in biliopancreatic secretion in man by infusing various stimuli at the ampulla of Vater and collecting duodenal contents at the ligament of Treitz, above an occluding balloon. Perfusion at 10 ml/min of a first mixture of aminoacids - phenylalanine (47.2 mmol), methionine (38.2 mmol), tryptophan (11 mmol), valine (61.6 mmol) - increased cholecystokinin (CCK) plasma concentrations and duodenal bile salt output (p less than 0.005) as compared with a control electrolyte solution, but did not change pancreatic enzyme secretion significantly; duodenal infusion of another aminoacid mixture - arginine (32.4 mmol), histidine (14.1 mmol), leucine (36 mmol), isoleucine (21.5 mmol), lysine (31 mmol), threonine (23 mmol) - did not change CCK plasma concentrations, bile salt or pancreatic enzyme output. The respective role of duodenal distension and endogenous CCK was investigated by perfusing the first aminoacid solution and the control solution at 2, 5, and 10 ml/min. Changing the perfusion rate of control solution from 2 to 5 ml/min led to a significant increase (p less than 0.01) in pancreatic secretion with no further increase at 10 ml/min. Bile salt output was not influenced by the perfusion rate of control solution. During the perfusion of the aminoacid solution, despite a stepwise increase in CCK release, the only significant change in pancreatic secretion was an increase of lipase output (p less than 0.05) when the infusion rate was raised from 2 to 5 ml/min. Our results suggest that duodenal CCK release (1) depends on the nature of aminoacids (2) has predominant role in the regulation of pancreatic secretion at low perfusion rate but is less effective when superimposed on a mechanical stimulus caused by duodenal distension (3) is a major stimulus for gall bladder contraction which is not influenced by duodenal distension.

Feedback regulation of stimulated pancreatic enzyme secretion during intraduodenal perfusion of trypsin in man

The pancreatic enzyme secretion in several species is controlled by a negative feedback mechanism induced by the presence of active proteases in the duodenum. The existence of this mechanism in man is controversial. The purpose of the present study was to evaluate the effect of tryptic activity in the duodenum on phenylalanine-stimulated pancreatic enzyme secretion in healthy volunteers. A double-balloon, multi-lumen tube was used for the collection of duodenal juice containing pancreatic enzymes. The continuous infusion of phenylalanine (100 mM) into the duodenum evoked an almost constant secretion of trypsin, amylase and lipase for 160 min. The infusion of trypsin (150 mg h-1; 1.25 g l-1) caused a reduction of phenylalanine-stimulated amylase and lipase output by 25%. The subsequent infusion of aprotinin at a dose of 1.5 X 10(6) KIU for 30 min led to an almost complete inhibition of trypsin. Simultaneously, the amylase and lipase output returned to the values seen before trypsin perfusion. Infusion of a higher dose of trypsin (300 mg h-1; 2.5 g l-1) caused a more pronounced decrease in phenylalanine-stimulated amylase and lipase output by 45%. These data indicate that active trypsin in the duodenum is responsible for the inhibition of phenylalanine-stimulated pancreatic enzyme secretion in man in a dose-dependent fashion, thus confirming the existence of a feedback control of pancreatic secretion regulated by the amount of proteases in the gut.

Exocrine pancreatic function test by endoscopic retrograde aspiration of pure pancreatic juice.

The validity of endoscopic retrograde aspiration of pure pancreatic juice (PPJ) as an exocrine pancreatic function test was evaluated in terms of coefficients of variation in control subjects, reproducibility on repeated examinations, and sensitivity for detecting patients with chronic pancreatitis (CP). PPJ was obtained from, nine control subjects, four patients with suspected CP and 13 with CP. PPJ was collected from within the pancreatic duct by endoscopic retrograde catheterization of the papilla at 2-min intervals for 20 minutes after a bolus intravenous injection of secretin (1U/kg) and then for further 20 minutes after a bolus intravenous injection of CCK-PZ (1U/kg). It was recognized that endoscopic aspiration of PPJ was at least as useful and reliable as the traditional pancreozymin secretin test. Useful parameters included 10-min secretory volume and 10-min bicarbonate output after secretin stimulation, and 10-min enzyme output after CCK-PZ stimulation (lipase output showed higher sensitivity than amylase output). Maximal bicarbonate concentration showed poorer reproducibility and sensitivity despite better coefficients of variation. Lower limits in controls (mean-1.5SD) were 22.5ml for 10-min secretory volume, 2.7mEq for 10-min bicarbonate output, 24.5 x 10(3)U for 10-min amylase output and 3.4 x 10(3)IU for 10-min lipase output.

Human Gastric Lipase: Variations Induced by Gastrointestinal Hormones and by Pathology

Secretin and cholecystokinin-pancreozymin had no effect on the secretion of human gastric lipase, in contrast to pentagastrin, which increased the gastric lipase output but not the enzyme concentration in gastric juice. The secretion of gastric lipase was not significantly different in patients with duodenal ulcer or chronic pancreatitis and in controls. In contrast, basal gastric lipase concentration was significantly lower in children with cystic fibrosis than in normal children. This shows that neither in adults nor in children is there a compensation for a decreased lipase secretion by an increased gastric lipase secretion.

Effects of sex and age on pancreatic secretion

The secretory response of the exocrine pancreas to an intravenous bolus of secretin (1.0 U/kg) was studied in healthy men and women below and above 45 years of age. We studied the secretory pattern, i.e., electrolyte and enzyme secretion in 8 sequential, 10-min collections and cumulative values for each parameter. Within the male group, no significant changes were observed, except for higher amylase and lipase secretions in the older subjects. On the other hand, females over 45 yr old had secretory patterns that showed a decline of flow and of bicarbonate concentration and output. No significant secretory differences were observed in the groups of younger males and females. When the over-45 groups of men and women were compared, the women exhibited a significant decrease in bicarbonate concentration and output. Moreover, this group of women had a cumulative 80-min output of bicarbonate and lipase significantly below these parameters in the men. Possible mechanisms are discussed.

Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin.

Feedback regulation of pancreatic enzyme secretion occurs in rats. Whether such a system exists in man remains unsettled and the responsible mechanism is unknown. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Intraduodenal perfusion of trypsin-inhibited phenylalanine-, oleic acid-, and meal-stimulated chymotrypsin and lipase outputs in a dose-related manner. The minimal concentration of bovine trypsin needed to inhibit pancreatic enzyme secretion was 0.5 g/liter. 1 g/liter caused a maximal suppression of 35 +/- 4% of the phenylalanine-stimulated chymotrypsin release. This inhibitory effect was protease-specific. Intraduodenal perfusion of phenylalanine and oleic acid increased plasma cholecystokinin (CCK) from a basal level of 0.9 +/- 0.06 to 5.3 +/- 0.9 pM and 7.2 +/- 1.3 pM, respectively. Addition of bovine trypsin to the perfusates significantly reduced the plasma CCK level to basal values. This inhibitory effect of trypsin on CCK release was dose dependent and specific to proteases. Therefore, the present studies indicate that feedback regulation of pancreatic enzyme secretion is operative in man and it is mediated by release of CCK.

Dissociation between pancreatic enzyme secretory and synthetic dose-responses to cholecystokinin in man.

The effect of varying the intensity of pancreatic stimulation on the synthesis of human pancreatic enzymes has not previously been studied. We have measured the secretion and synthesis of pancreatic enzymes in response to either secretin alone (1 CU.kg-1.h-1) or secretion plus increasing doses of cholecystokinin (CCK) (0.25, 0.5 or 1.0 IDU.kg-1.h-1). Enzyme synthesis was measured using the incorporation of 75Se-methionine (0.15 mCi (5.6 kBq).kg-1.h-1) into the trichloracetic acid-insoluble fraction of the duodenal aspirate. Outputs of trypsin, chymotrypsin, lipase and protein showed a bell-shaped dose response to increasing doses of cholecystokinin, with maximal outputs occurring in response to secretin plus cholecystokinin 0.5 IDU.kg-1.h-1. The rate of incorporation of 75Se-methionine increased with increasing doses of cholecystokinin and was maximal in response to secretion plus cholecystokinin 1.0 IDU.kg-1.h-1. There was therefore dissociation between the secretory and synthetic responses to increasing doses of cholecystokinin.

Pathogenesis of Steatorrhea in Primary Biliary Cirrhosis

To investigate the pathophysiology of steatorrhea in primary biliary cirrhosis, the severity of steatorrhea, small bowel histology and function, cholestasis, exocrine pancreatic secretion and liver histology were studied. Twenty-four primary biliary cirrhotic patients had a quantitative stool fat collection, serum bilirubin and alkaline phosphatase and liver biopsies. From this group, ten had further studies: a small bowel biopsy (n = 7); a D-xylose test (n = 9); measurement of pancreatiobiliary concentrations and outputs after intravenous cholecystokinin (n = 10); essential amino acid perfusion of the duodenum (n = 9), and eating a test meal (n = 7). D-xylose absorption was normal, and only one patient had a minimal small bowel mucosal abnormality. Pancreatic lipase outputs in response to cholecystokinin were low in two primary biliary cirrhotic patients, but were greater than 10% of normal. Postprandial lipase outputs were normal except in one patient who had abnormal duodenal acidification. Mean enzyme outputs in primary biliary cirrhotic patients were normal in response to essential amino acid perfusion; but 6 had low lipase and 5 had low trypsin outputs which were associated with decreased bile acid outputs (p less than 0.03). Severity of steatorrhea was associated with reduced bile acid outputs and concentrations (r = 0.82; p less than 0.0001), degree of cholestasis (serum bilirubin; r = 0.88; p less than 0.001) and advanced histologic stages (p less than 0.005). Severe intraluminal bile acid deficiency combined with a submaximal intraluminal stimulus (essential amino acids) may be associated with decreased exocrine pancreatic secretion in primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of parenteral amino acids on human pancreatic exocrine secretion.

Parenteral administration of amino acids has been utilized for the nutritional support of patients with a variety of gastrointestinal disorders including protracted pancreatitis and pancreatic fistulae. However, the effect of parenteral amino acid administration alone on human pancreatic secretion has not been studied. We have studied the short-term effect of parenteral administration of amino acids on pancreatic exocrine secretion in seven healthy men. A double-lumen tube was placed in the duodenum and polyethylene glycol was perfused into the proximal duodenum at the rate of 10 ml/min. A second double-lumen tube was placed in the stomach and bromsulfthalein was perfused into the cardia. Samples of duodenal contents were aspirated and gastric contents recovered during one hour of intravenous saline infusion followed by two hours of an amino acid mixture infusion. Hourly outputs of protein and pancreatic enzymes were determined, correcting for duodenogastric reflux based on concentrations of both markers in the samples. Despite an average increase of 72% in the plasma concentration of the infused amino acids, the outputs of protein, trypsin and amylase did not change significantly during amino acid infusion; the output of lipase decreased significantly during amino acid infusion. Two subjects were given intravenous secretin and cholecystokinin following amino acids; this resulted in increased outputs of protein, trypsin, and amylase in both. We conclude that the parenteral administration of amino acids to healthy young men does not stimulate pancreatic enzyme secretion as measured by the method using duodenal marker perfusion at the rate of 10 ml/min.

Action of secretin on pancreatic enzyme secretion in man. Studies on pure pancreatic juice.

The action of pure, natural secretin on the pancreatic secretion of enzymes was investigated in six patients with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery. Secretin infused for five successive 50 minute periods at increasing doses of 0.03, 0.1, 0.3, 0.9 and 2.7 clinical units (CU)/kg/h, produce a dose dependent increase in protein and lipase output. A weak but significant (p less than 0.02) increase of enzyme output above the fasting level was already observed with the lowest dose. The maximal output of protein and lipase, observed with the highest dose of secretin infused, corresponded to about 50% of that induced by maximal doses of cerulein (100 ng/kg/h) plus secretin (1 CU/kg/h). As far as bicarbonate is concerned, the lowest dose of secretin (0.03 CU/kg/h) significantly (p less than 0.001) stimulated bicarbonate output. The dose of 0.9 CU/kg/h of secretin evoked a bicarbonate output of 526 +/- 49 micromol/min; trebling the dose of secretin did not significantly increase the output of bicarbonate above this value. Increasing doses of secretin induced a dose related increase in calcium output. There was a close parallel between calcium and protein outputs, suggesting that the increase in calcium output reflected primarily an increase in the enzyme-associated fraction of pancreatic juice calcium. It is concluded that secretin stimulates pancreatic enzyme secretion in man probably by a direct action on the acinar cells.

Oral Foy in the treatment of chronic pancreatitis

Oral Foy decreases the elevated lipase/trypsin ratio in 3 out of 4 patients PABA serum test is improved in all patients, the effect on chymotrypsin output in duodenal juice has still to be investigated. The duodenal output of lipase, trypsin and bicarbonate were not significantly changed and this may be due to the non-homogeneous group of patients. These results encourage us to continue the investigation on the effects of oral Foy in patients with chronic pancreatitis by a controlled double-blind study.

Effects of Wheat Bran on the Exocrine Pancreas and the Small Intestinal Mucosa in the Dog

Five Beagle dogs, equipped with duodenal and gastric fistulae, were fed a standard diet before receiving the same diet supplemented with wheat bran for 1 month. Pancreatic secretory investigations performed in conscious animals before and 1 month after bran administration showed a significant parallel increase in the flow rate of pancreatic secretion and the outputs of bicarbonate and amylase both in basal and secretin-stimulated conditions. The outputs of protein and chymotrypsin increased only in unstimulated secretions, while the output of lipase was strongly reduced in response to secretin. However, the small intestinal mucosa was not affected by bran administration. Dietary fiber did not alter the height of the villi or the activity of sucrase, maltase and aminopeptidase in mucosal homogenates or isolated brush border membranes from intestinal biopsies. These data suggest that wheat bran supplemented to the standard diet affects the exocrine pancreatic secretion but not intestinal enzyme activities involved in the absorption of carbohydrates and proteins in the dog.

Colipase and lipase secretion in childhood-onset pancreatic insufficiency: Delineation of patients with steatorrhea secondary to relative colipase deficiency

Pancreatic lipase and colipase secretion was assessed in 64 patients with pancreatic disease, 24 of whom had steatorrhea, and in 14 control subjects. A wide range of lipase and colipase secretion was seen in patients both with and without steatorrhea. Considerable loss of pancreatic lipase and colipase secretion had to occur before steatorrhea developed, as the highest hourly secretion of lipase and colipase in this group of patients was < 4% and < 2%, respectively, of the lowest values recorded in normal subjects. Colipase and lipase outputs were very strongly correlated (r = 0.96) throughout the range of pancreatic function. Lipase was always unsaturated with respect to colipase, but in only a limited number of patients with relatively low pancreatic secretion was the degree of unsaturation > 2 standard deviations below the mean. The importance of low saturation or low colipase secretion was evident in a group of 11 patients with a narrow range of lipase secretion in a transitional zone between secretion rates associated with steatorrhea and with normal fat excretion. In this group, 7 patients were identified in whom colipase deficiency appeared to be the sole cause of steatorrhea. The correlation of colipase secretion with the level of fecal fat excretion was highly significant (p < 0.001) and indicated that fat digestion and subsequent fat absorption depended on colipase secretion up to at least a level of 25% fecal fat excretion. Nonpancreatic factors could well govern the extent of fat absorption above this level, as colipase secretory values in this range were uniformly low.

Effects of dietary fiber on pancreatic enzyme activities of ileostomy evacuates and on excretion of fat and nitrogen in the rat.

Ileostomized rats were fed diets with different fiber content. The addition of 5% pectin to the diet caused an increase in the wet weight, fat content, amylase activity per gram, and lipase output of the ileostomy evacuates. Twenty percent wheat bran in the diet increased weight, fat and nitrogen content, and trypsin output of the evacuates. In normal rats pectin added to a meal containing 3H-labeled triolein increased the isotope activity of the feces, indicating an impaired fat absorption. In rats operated on with occlusion of the pancreatic ducts with a tissue glue, the fat absorption was, however, not significantly affected by pectin. The results of the study show that fiber can cause a change in the intestinal enzymatic milieu of ileostomized rats and can cause steatorrhea, which can be explained, at least partly, by malabsorption.

Colonic inhibition of pancreatic and biliary secretion

The purpose of this study was to determine whether or not nutrients in the colon influence pancreatic and biliary secretion in humans. In six healthy subjects, similar caloric loads (117 cals) of oleic acid, essential amino acids, and glucose in isomolar (280 mosmol/L), similar pH (7.4) solutions were infused into the right colon at 10 ml/min through a colonic tube passed by mouth. A background of submaximal pancreatic and biliary secretion was maintained by continuous intravenous infusion of the octapeptide of cholecystokinin. Biliary and pancreatic secretions were quantitated using the gastroduodenal intubation perfusion technique. Among the three nutrients tested, only oleic acid in the colon decreased pancreatic enzymes and bicarbonate outputs. The mean trypsin output decreased from 26.3 ± 2.6 kU/h to 12.3 ± 1.9 kU/h (46% ± 6% of control), while the lipase output decreased from 62 ± 6.6 kU/h to 36 ± 5.6 kU/h (58% ± 6% of control). Similarly, the output of bicarbonate in the duodenal aspirate decreased from 31 ± 7.2 mEq/h to 16.3 ± 3.1 mEq/h (61% ± 5% of control). Intracolonic perfusion of essential amino acids or glucose had no effect on pancreatic enzymes and bicarbonate secretion. In contrast, all three nutrients in the colon inhibited biliary secretion. The mean output of bilirubin decreased from 56 ± 6 mg/h to 19 ± 2 mg/h (35% ± 5% of control) during intracolonic perfusion of oleic acid. Essential amino acids lowered the output of bilirubin from 54 ± 12 mg/h to 31 ± 8.6 mg/h (65% ± 6% of control), whereas glucose lowered it from 53 ± 12 mg/h to 22 ± 4 mg/h (45% ± 5% of control). This differing response of pancreatic and biliary output to intracolonic perfusion of nutrients suggests differential sensitivity of the pancreas and gallbladder to these inhibitory influences. In malabsorption states, unabsorbed nutrients in the colon may inhibit pancreatic and biliary secretion, further contributing to the loss of nutrients from the gastrointestinal tract.

The influence of diet on the exocrine pancreatic secretion of growing pigs.

1. Pancreatic juice was collected from six pigs of 48 kg initial weight fitted with a collection catheter in the pancreatic duct and a return catheter in the duodenum. 2. Measurements of flow and composition of the juice were made during 24 h periods after adaptation to isonitrogenous diets based on barley, wheatings and fish meal (diet BWF) or starch, sucrose, casein, maize oil and cellulose (diet SSC), given in a change-over design. Measurements were also made during the periods of adaptation to a change from one diet to the other. 3. Mean flow-rates for pigs adapted to diets showed a highly significant four-fold difference between diets; values were 4962 ml/d for diet BWF and 1273 ml/d for diet SSC. The hourly volumes of juice were very variable and showed no clear response to feeding and no consistent diurnal pattern for either diet. 4. There were no significant differences between diets in the specific activities of the proteases. Average values were (units/mg protein) trypsin (EC 3.4.21.4) 29.6, chymotrypsin (EC 3.4.21.1) 7.7, carboxypeptidase A diet BWF than with diet SSC. The specific activities and total outputs of alpha-amylase (EC 3.2.1.1) and lipase (EC 3.1.1.3) were significantly higher for diet BWF than for diet SSC; specific activities for the two diets respectively were: (units/mg protein) alpha-amylase 95-6 and 42.3, lipase 59.0 and 14.5. 5. The higher daily volume of juice with diet BWF was associated with significantly (but only slightly) higher levels of both sodium and potassium, compared with diet SSC. 6. The results are discussed in relation to previous studies on digestion at this Institute, in which pigs with intestinal cannulas were given the same diets.

Influence of Adrenal Cortex on Exocrine Pancreatic Function

The exocrine pancreatic function of 8 patients with chronic adrenocortical insufficiency was studied and compared with 12 control subjects. The secretion of bicarbonate, lipase, and chymotrypsin in response to secretin and caerulein was significantly reduced in patients with adrenocortical insufficiency. The mean reduction in bicarbonate, lipase, and chymotrypsin output compared with the control values was 42%, 66%, and 53%, respectively. Chronic glucocorticoid substitution therapy restored pancreatic function almost to normal. It is concluded that the adrenal cortex plays an important role in maintaining the function of the exocrine pancreas in humans. The possible mechanisms are discussed.

Pancreatic exocrine function in severe human chronic renal failure.

Patients with chronic renal failure have an abnormal immunoreactive gastrointestinal hormone profile, which is characterised by raised fasting serum concentrations of hormones that have antagonistic effects on exocrine pancreatic function. In addition, in this present study we have found that in renal insufficiency cholecystokinin disappears slowly from the plasma after a constant intravenous infusion of the hormone (p = 0.05 compared with healthy subjects). To evaluate whether the stimulatory or inhibitory hormones have a predominant effect, pancreatic exocrine function under conditions of mannitol perfusion of the duodenum and continuous intravenous cholecystokinin stimulation was studied in eight patients who had severe chronic renal failure and eight age-matched and sex-matched control subjects. Compared with healthy subjects, patients with renal insufficiency had hypersecretion of trypsin in response both to mannitol perfusion of the duodenum and to cholecystokinin stimulation (p less than 0.05). No significant differences in lipase secretion were noted between the patients with renal insufficiency and control subjects. These findings are consistent with the hypothesis that, of the abnormally raised fasting serum concentrations of gastrointestinal hormones found in renal insufficiency, hormones that stimulate rather than inhibit pancreatic exocrine function predominate. Secondly, the dissociation between trypsin and lipase outputs in chronic renal failure may suggest a differential trophic influence of stimulatory hormones -- that is, hypercholecystokininaemia -- on pancreatic exocrine enzyme secretion.

Exocrine pancreatic function in insulin-dependent diabetes mellitus.

Exocrine pancreatic function was studied in patients with long-standing insulin-dependent diabetes mellitus using the secretin-pancreozymin test (n = 53), and estimation of immunoreactive trypsin (n = 43) and pancreatic isoamylase (n = 43). The secretin-pancreozymin test was abnormal in 23 patients (43%). The abnormalities found were a decreased output of lipase (37%), amylase (36%) or trypsin (26%) and bicarbonate (15%). Serum immunoreactive trypsin was below normal in only 6 (14%) and pancreatic isoamylase in 29 (67%) patients. There was no correlation between impairment of the secretin-pancreozymin test and decreased serum enzyme levels. It is concluded that an impairment of exocrine pancreatic function is frequent in insulin-dependent diabetics but that a decrease in serum enzymes, especially in pancreatic isoamylase, does not reflect an impairment of pancreatic function in these patients.