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Neuroendocrine gastroenteropancreatic tumours are rare with an incidence of 2-4/100.000 per year. More than 75% of the patients develop hepatic metastases, which reduce the five year survival from 70-80% to 30-40%. In addition to chemo- and biotherapy, interventional therapy of liver metastases should be considered in order to prolong survival and reduce endocrine and local symptoms. Surgical resection is the only curative treatment, but possible in less than 10% of the patients. Curative and palliative resection, which is possible in less than 20-25% of the patients, relieve endocrine and local symptoms in 90% of the patients for more than two years, and the five year survival is prolonged to 40-85%, although metastases recur or progress in almost all patients. Tumour ablation by radiofrequency therapy has a palliative effect on endocrine symptoms in 70-90% of the patients for up to two years, but should not be a substitute for surgical treatment. When metastases are not eligible for surgical treatment or ablation, embolization or chemoembolization are alternative options with a reduction in tumour burden in about 50% and a five year survival of around 60% ofthe patients. The symptomatic response rate is 90% with a mean duration of two years. Liver transplantation should be restricted to very few and highly selected patients without extrahepatic disease. Recurrence is inevitable in nearly all patients.

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PURPOSE: To evaluate the potential of combined administration of the gastrointestinal hormones secretin (Secrelux) and c-terminal cholecystokinin (CCK-8 s) together with contrast-enhanced ultrasound (CE-US) to generate an extended contrast enhancement of healthy pancreatic tissue. MATERIALS AND METHODS: 14 anaesthetised pigs weighing 30-35 kg were studied. After laparotomy, the pancreas was located and a B-mode examination followed by a CE-US examination of the gland was made using SonoVue 1.5 ml. After an injection of Secrelux 1 U/kg and CCK-8 s 100 pmol/kg, a second CE-US examination was conducted. The hormones and the contrast agent were administered through a catheter in the superior vena cava. The sonographic images were stored for later evaluation. RESULTS: The study showed that CE-US increased the echogenicity of the pancreas by an average of 15.6 decibel (dB) (confidence intervals [CI]: 13.72, 17.42) p < 0.0001, an increase of 24%. The administration of Secrelux and CCK-8 s in combination with CE-US further increased the echogenicity of the pancreas by an average of 3% (CI: 0.36, 5.36) p = 0.028. A new sequence of hormones and CE-US 20 min after the previous injection did not induce further enhancement. The area under the curve (AUC) was significantly larger using both hormones and CE-US compared with CE-US alone by an average of 66 dBx sec (CI: 28,103) p = 0.002. CONCLUSION: It is possible to generate an extended contrast enhancement of healthy pancreatic tissue using CE-US combined with the administration of the gastrointestinal hormones secretin (Secrelux) and c-terminal cholecystokinin (CCK-8 s). Our results may improve the ability to discriminate between healthy pancreatic tissue and areas with a changed blood flow due to either neoplasm or other pathological lesions.

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A 54-year-old woman presented with extremely fluctuating and symptomatic blood glucose levels. Very high levels of somatostatin and low levels of insulin, C-peptide, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) in peripheral blood were constantly present. A benign somatostatinoma was localized by meta-iodobenzyl guanidine iodine 123 (MIBG-I(123)) scintigraphy and successfully removed encapsulated in an ovarian teratoma. The patient made a complete recovery. The case described is unique with regard to clinical symptomatology and anatomic localization of the tumor.

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The days of the autumn 1970 when a gastrin assay was developed have been revisited, and the research conditions then and now compared. No valid conclusions seem possible from such a study, but a lot of facts suggest that the good old days were better.

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The antral hormone gastrin is synthesized by processing progastrin into different peptides that stimulate gastric secretion. The effect on acid secretion depends mainly on the metabolic clearance rate of the peptides, but some of them may differ in potency and maximum acid output at similar concentrations in plasma. Sulfated and nonsulfated gastrin-6 are the smallest circulating bioactive gastrins in humans. Their effect and metabolism have now been investigated in nine normal subjects and compared with nonsulfated gastrin-17, a main product of progastrin. Maximum acid output after stimulation with gastrin-17, sulfated gastrin-6, and nonsulfated gastrin-6 were 28.3 +/- 2.0, 24.5 +/- 2.0 (P < 0.02), and 19.3 +/- 2. 3 (P < 0.05) mmol H(+)/50 min, respectively, and the corresponding EC(50) values were 43 +/- 6, 24 +/- 2 (P < 0.01), and 25 +/- 2 (not significant) pmol/l. The half-life of gastrin-17 was 5.3 +/- 0.3 min, the metabolic clearance rate (MCR) was 16.5 +/- 1.3 ml. kg(-1). min(-1), and the apparent volume of distribution (V(d)) was 124.3 +/- 9.6 ml/kg. The half-lives of sulfated and nonsulfated gastrin-6 were 2.1 +/- 0.3 and 1.9 +/- 0.3 min, the MCRs were 42.8 +/- 3.7 and 139.4 +/- 9.6 ml kg(-1) min(-1) (P < 0.01), and the V(d) were 139.0 +/- 30.5 and 392.0 +/- 81.6 (P < 0.01) ml kg(-1). All pharmacokinetic parameters differed significantly from gastrin-17 (P < 0.01). We conclude that gastrin 6 has a higher potency but a lower efficacy than gastrin-17. The efficacy of gastrin-6 is increased by tyrosine O-sulfation, which also enhances the protection against elimination.

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The kinetics and metabolism in various organs of three bioactive products of progastrin, the small sulfated and nonsulfated gastrin-6 and the large nonsulfated gastrin-52, were examined during intravenous administration in anesthetized pigs. The kidney, hindlimb, liver, head, and gut eliminated the hexapeptides efficiently, with a fractional extraction ranging from 0.50 to 0.28 (P<0.001-0.05). No metabolism was recorded in the lungs, and sulfation was without influence on the extraction of gastrin-6. Gastrin-52 was eliminated only in the kidney and the head, with a fractional extraction between 0.23 and 0.11 (P<0.01-0.05). The half-life of sulfated and nonsulfated gastrin-6 was 1.5+/-0.4 and 1.4+/-0.3 min, the metabolic clearance rate (MCR) was 80.8+/-7.6 and 116.0+/-13.5 ml x kg(-1) x min(-1) (P<0.05), and the apparent volume of distribution (V(dss)) was 199.3+/-70.1 and 231.4+/-37.3 ml/kg, respectively. The decay of gastrin-52 in plasma was biexponential. The half-lives of this biexponential after a bolus injection were 3.9+/-0.5 (T(1/2alpha)) and 25.7+/-1.4 (T(1/2beta)) min, and the MCR and V(dss) were 4.2+/-0.4 ml. kg(-1) x min(-1) and 116.2+/-16.2 ml/kg(1). We conclude that there is a differential elimination of progastrin products in splanchnic and nonsplanchnic tissue, which depends on the chain length of the peptides. Sulfation of gastrin-6 had no influence on the organ-specific extraction but reduced the MCR. Our results are in keeping with previous studies of nonsulfated gastrin-17, which is extracted in the kidney, head, limb, and gut but not in the liver.

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The renal handling of carboxyamidated gastrins, NH2-terminal progastrin fragments, and glycine-extended gastrins was examined in healthy volunteers. The respective urinary clearances after a meal amounted to 0.09 +/- 0.02%, 0.17 +/- 0.04% (P < 0.05), and 0.04 +/- 0.01% (P < 0.01) of the glomerular filtration rate. During intravenous infusion of carboxyamidated gastrin-17, progastrin fragment-(1-35), and glycine-extended gastrin-17, the respective urinary clearances amounted to 0.08 +/- 0.02, 0.46 +/- 0.08, and 0. 02 +/- 0.01%, respectively, of the glomerular filtration rate. The metabolic clearance rate of the three peptides was 24.4 +/- 1.3, 6.0 +/- 0.4, and 8.6 +/- 0.7 ml. kg-1. min-1. A maximum rate for tubular transport or degradation of the peptides could not be determined, nor was a renal plasma threshold recorded. Plasma concentrations and urinary excretion rates correlated for gastrin-17 and progastrin fragment-(1-35) (r = 0.94 and 0.97, P < 0.001), whereas the excretion of glycine-extended gastrin diminished with increasing plasma concentrations. We conclude that renal excretion of progastrin products is negligible compared with renal metabolism and that renal handling of the peptides depends on their molecular structure. Hence, the kidneys exhibited a higher excretion of NH2-terminal progastrin fragments than of carboxyamidated and especially glycine-extended gastrins.

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Renal handling of postprandial and intravenously administered gastrin was investigated in anaesthetised pigs. The fractional extraction of postprandial carboxyamidated and glycine-extended gastrin in the kidneys was 0.21 +/- 0.01 and 0.16 +/- 0.02, but the respective urinary clearance comprised only 0.57 +/- 0.03 and 0.44 +/- 0.05% of the GFR (P < 0.02). The respective total body clearance of carboxyamidated and glycine-extended gastrin-17 (gastrin-17 and gastrin-17Gly) during continuous infusion was 22.9 +/- 1.5 and 19.6 +/- 1.4 mL kg-1 min-1 (NS), and the renal fractional extraction of the peptides was 0.31 +/- 0.03 and 0.29 +/- 0.05, respectively. The kidneys accounted for 8% of total body clearance of gastrin-17. Renal filtration rate of gastrin-17 exceeded renal extraction rate (9.739 +/- 0.487 vs. 6.407 +/- 0.321 pmol min-1). Urinary clearance of gastrin-17 and gastrin-17Gly amounted only 0.91 +/- 0.16 and 0.13 +/- 0.03%, respectively, of the GFR (P < 0.01), but urinary excretion rate correlated with the filtered amount of the peptides (r = 0.93, P < 0.01). Neither was a renal plasma threshold recorded nor was a Tm value for tubular uptake or degradation of gastrin achieved in spite of supraphysiological plasma levels of the peptides. The results indicate that filtered gastrin is almost completely removed in the renal tubules, primary by metabolism although part of the absorbed peptides may be returned to the circulation in intact form. The process for uptake or metabolism has a high capacity but varies with the molecular form of gastrin.

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OBJECTIVE: Gastric lipase and gastric acid are secreted simultaneously. The aim of this study was to investigate whether the acid interferes with the lipase secretion. The secretion of human gastric lipase was studied during blockade of gastric acid secretion and modified sham feeding to estimate the impact of these conditions on both gastric lipase enzyme activity and immunoreactivity. METHODS: Eight healthy volunteers were intubated with a nasogastric tube. We examined gastric aspirates for the amount and activity of lipase secretion during basal conditions, after blockade of acid secretion with a proton pump inhibitor (omeprazole iv. infusion), and in response to sham feeding (chewing gum) during the blockade. RESULTS: The amount of secreted gastric lipase was unaffected by blockade of acid secretion and increased significantly after sham feeding (169.9+/-35.7 microg/15 min to 348.1+/-79.2 microg/15 min; p < 0.01). Likewise, the output of enzyme activity increased after sham feeding (0.63+/-0.09 kU/15 min to 1.52+/-0.36 kU/15 min; p < 0.03). The concentration of enzyme activity remained unchanged by blockade of acid secretion, whereas the output of enzyme activity was decreased, probably because of reduced volume secretion or denaturation and conformational changes of the enzyme. Plasma concentrations of gastrin increased in response to blockade of acid secretion (basal 9.6+/-1.4 pmol/L to 13.3+/-2.9 pmol/L; p < 0.02). CONCLUSIONS: Gastric acid secretion is not a prerequisite for gastric lipase secretion. Lipase enzyme activity, though, is sensitive to anacidic conditions.

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In anaesthetized pigs, clearances of 51Cr-EDTA (EDTA) and endogenous creatinine were compared with renal clearance of inulin measured during constant infusion after bolus injection. Creatinine was determined by enzymatic (Kodak Ektachem) as well as conventional (Jaffé) methods. In saline-loaded pigs, renal clearance of constantly infused EDTA was 97.0 +/- 6.7 mL min-1 and identical to the clearance of inulin (94.1 +/- 9.1 mL min-1). There was good agreement between individual clearances. The extraction fractions of the two markers were indistinguishable (0.26 +/- 0.02 and 0.28 +/- 0.03, respectively). In other experiments the clearance of EDTA calculated from the first 4 h of the time course of the plasma concentration after single injection was 64.4 +/- 3.7 mL min-1, correlating well with inulin clearance (63.0 +/- 1.2 mL min-1). When calculated only from the monoexponential phase of the disappearance curve ('slope clearance'), significantly higher results were obtained (+33%, P < 0.001). Renal clearance of EDTA after single injection was 7.5 +/- 1.5 mL min-1 (approximately 12%) lower than inulin clearance (P < 0.001). Values of creatinine clearances determined by the two analytical methods showed a poor agreement with inulin clearance. It is concluded that, in pigs, glomerular filtration rate may be estimated by the clearance of EDTA using constant infusion or single injection of EDTA and that the renal clearance of endogenous creatinine is a less useful a measure of GFR.

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BACKGROUND: Glucagon-like peptide-1 (GLP-1)(7-36) amide is an intestinal incretin hormone which also inhibits gastric acid secretion in humans. Its mechanism of action is unclear, but it strongly inhibits vagally induced secretion (sham feeding), suggesting that it could influence vagal activity. AIM/METHODS: The effect of intravenous GLP-1 (7-36 amide) (1 pmol/kg/min) was studied on pentagastrin induced acid secretion in otherwise healthy subjects, previously vagotomised for duodenal ulcer (n = 8) and in a group of young (n = 8) and old (n = 6) healthy volunteers. RESULTS: Pentagastrin increased acid secretion significantly in all three groups, but the plateau concentration in the vagotomised subjects was lower than in controls. Infusion of GLP-1 (7-36 amide) significantly inhibited acid secretion in the control groups (to 67 (SEM 6) and 74 (SEM 3)% of plateau concentrations in young and old controls, respectively) but had no effect in the vagotomised subjects. Differences in plasma concentrations of GLP-1 (7-36 amide), recovery of gastric marker, duodenal regurgitation, or Helicobacter pylori status could not explain the lack of effect. Blood glucose was lowered equally by GLP-1 (7-36 amide) in all subjects. CONCLUSION: The inhibitory effect of GLP-1 (7-36 amide) on acid secretion depends on intact vagal innervation of the stomach.

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The elimination of carboxyamidated gastrin-17 and its glycine-extended precursor was studied in anesthetized pigs during constant-rate infusion. Extraction of amidated gastrin-17 was recorded in the hindlimb (42%), kidney (40%), head (32%, P < 0.001), and the gut (13%, P < 0.01). Elimination was not recorded in the liver, lungs, or heart. Extraction of glycine-extended gastrin-17 was measured in the kidney (36%), hindlimb (31%, P < 0.001), head (26%), and the gut (16%, P < 0.01), but not in the liver or the lungs. Glycine-extended gastrin-17 was not processed to amidated gastrin during infusion. The half-life, metabolic clearance rate, and apparent volume of distribution for amidated gastrin-17 were 3.5 +/- 0.4 min, 15.5 +/- 1.1 ml.kg-1.min-1, and 76.5 +/- 9.9 ml/kg, respectively, and for glycine-extended gastrin-17 were 4.3 +/- 0.6 min, 17.4 +/- 0.9 ml.kg-1.min-1, and 104.7 +/- 11.9 ml/kg, respectively. We conclude that extraction of amidated and glycine-extended gastrin-17 varies in the vascular beds, with elimination mainly confined to nonorgan tissues and the kidneys.

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During the last quarter of this century gastrointestinal endocrinology has grown explosively. In 1970, three hormones (secretin, gastrin, and cholecystokinin) were identified and by authorities in the field considered sufficient to explain the entire hormonal regulation of digestion. That was some underestimation. Today the gut is known to express more than 20 different hormonal/regulatory peptide systems. Their widespread cellular occurrence, gene expression cascades, secretory mechanisms, receptors and receptor binding, as well as normal and pathophysiological effects are now also fairly well known owing to the marked progress in basic sciences and biochemical technologies (immuno and peptides chemistry, molecular and cell biology). Thus, the gut is now recognized as the largest endocrine organ of the body; and a substantial part of the gastroenterologic research over the latest decades has been devoted to gut hormones. The following review describes the recent development, with emphasis on gastrointestinal peptide systems that have been studied and even discovered in Denmark. Hence, as reflected by the number of doctoral theses and PhD studies (> 50 since 1974), gastrointestinal endocrinology has been a major research area in this country in the past 25 years.

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Glycine-extracted gastrins are the immediate precursors of the bioactive carboxyamidated gastrins. The effect on gastric acid secretion and the pharmacokinetics of glycine-extended gastrin-17 were studied in 8 normal subjects. The elimination in plasma after bolus injection was biexponential, the half-lives being 4.1 +/- 0.2 and 21.8 +/- 0.9 min, and clearance and apparent volume of distribution being 7.9 +/- 0.6 ml/kg/min and 69.5 +/- 2.7 ml/kg, respectively. Infusion of the peptide at three consecutive dose rates did not stimulate gastric acid secretion, although plasma concentrations reached supraphysiological levels. Nor did glycine-extended gastrin-17 influence submaximal acid secretion induced by amidated gastrin-17. In contrast to amidated gastrins, the concentration of glycine-extended gastrins in peripheral venous plasma did not increase significantly after a meal. The postprandial rise in amidated gastrin was unaffected by concomitant infusion of glycine-extended gastrin-17. A reduction in glycine-extended gastrin-17 concentrations in plasma during constant-rate infusion of the peptide was observed after a protein meal (p < 0.05). This reduction was reflected by an increase in glycine-extended gastrin-17 is without immediate effect on gastric output in man. The postprandial increase in clearance might be due to increased splanchnic blood flow with subsequently increased peptide elimination.

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The elimination of endogenous carboxyamidated and glycine-extended gastrins in liver and gut was studied before and after feeding in 14 anesthetized pigs. Before the meal, liver and gut extractions were nonsignificant. After feeding, the release rate of amidated gastrin increased from 7.5 +/- 2.6 to 21.9 +/- 5.3 pmol/min (p < 0.02), and the liver extracted significant amounts of amidated gastrin, while the intestinal extraction remained nonsignificant. The postprandial hepatic extraction ratio increased from 0.09 +/- 0.04 to 0.18 +/- 0.04 (p < 0.01). Before feeding, the hepatic and extrahepatic clearance rates were 80.0 +/- 38.7 and 232.3 +/- 77.7 ml/min. Clearance rates after feeding were 144.8 +/- 29.5 (p < 0.01) and 326.4 +/- 75.3 ml/min (NS), respectively. Portal plasma displayed a small postprandial increase in the concentration of glycine-extended gastrin, but extraction over the liver and gut remained nonsignificant. Gel chromatography of portal plasma showed that the fraction of postprandial amidated gastrin corresponded to gastrin-17. The concentration of glycine-extended gastrin was too low for chromatographic analysis. We conclude that endogenous amidated gastrin is eliminated in the liver after feeding in pigs.

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It has been shown recently that the two largest alpha-carboxyamidated progastrin products are gastrin-71 and gastrin-52. Human gastrin-52 has now been synthesized, and the effect on gastric acid secretion and elimination from plasma was examined and compared with gastrin-17 in 12 normal subjects. The peptides were infused separately in four consecutive doses; the maximum response of gastrin-17 and gastrin-52 was 25.2 +/- 2.8 and 22.2 +/- 2.8 mmol H+/50 min, respectively (P < 0.01). This difference in efficacy was presumably related to nonequilibrium of gastrin-52 between plasma and receptor. The elimination of gastrin-17 was monoexponential with a half-life of 4.7 +/- 0.3 min; clearance and apparent volume of distribution were 16.7 +/- 1.5 ml.kg-1.min-1 and 106.0 +/- 9.2 ml/kg, respectively. The elimination of gastrin-52 was biexponential, the half-lives were 4.9 +/- 0.7 and 49.9 +/- 4.2 min, and clearance and apparent volume of distribution were 1.9 +/- 0.2 ml.kg-1.min-1 and 106.3 +/- 10.1 ml/kg, respectively. Gel chromatography of plasma samples drawn during infusion of gastrin-52 revealed that most of the immunoreactivity eluted in the position of the intact peptide. Small peaks in the positions of gastrin-34 and the NH2-terminal pentapeptide fragment of gastrin-52 indicate that a minor part of gastrin-52 is degraded to smaller peptides in vivo. It is concluded that gastrin-52 is bioactive with an efficacy close to or similar to that of gastrin-17. A minor fraction of gastrin-52 undergoes postsecretory cleavage either in plasma or after capillary transit.

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PURPOSE: An evaluation of the importance of gastrin in the colorectal carcinogenesis in patients with familial adenomatous polyposis was conducted. METHODS: Blood samples from 168 family members of 26 families were investigated for circulating gastrin. Blood was drawn from 65 affected patients, 66 clinically unaffected first-degree relatives, and 37 spouses. RESULTS: We did not find any difference in distribution of serum gastrin among these groups. CONCLUSION: Our results seem to exclude gastrin from being relevant in early carcinogenesis in patients with familial adenomatous polyposis.

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A consecutive series of patients with Zollinger-Ellison syndrome (ZES) is reported. A total of 53 cases were diagnosed, treated, and followed by one department during the period 1971-1990. Curative surgery was considered in all cases after suppression of acid secretion and after localization of the tumors. Exploratory laparotomy was not employed. Of the 53 patients 13 (24%) died from metastatic gastrinoma during the study. Tumors were ultimately located in 31 of the patients, and 21 of these patients were operated. A total of 12 patients (21%) were cured. The best results were obtained after Whipple pancreaticoduodenectomy in patients with small tumors located after percutaneous transhepatic portography with blood sampling for gastrin assay. In this group 9 of 10 operated patients were cured. Multiple endocrine neoplasia type I did not seem to preclude curative resection. The findings support an aggressive attitude toward local diagnosis and surgical treatment in ZES patients, but they also stress the need for improvements in methods for localizing tumors.

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OBJECTIVE: To compare the morbidity after stapled compared with handsewn J-pouch ileoanal anastomoses. DESIGN: Retrospective study. SETTING: University Hospital, Copenhagen, Denmark. SUBJECTS: 144 consecutive patients who underwent either handsewn or stapled J-pouch ileoanal anastomosis between November 1983 and December 1991. MAIN OUTCOME MEASURES: Length of operation; operative blood loss; incidence of anastomotic breakdown, fistula and stenosis; and number of pouches that were excised as a result of complications. RESULTS: Ninety-six patients had handsewn, and 48 patients had stapled, anastomoses. There were no differences between the groups except in the length of operation (median (range) 270 (155-420) in the handsewn group compared with 197 (135-300) in the stapled group, p < 0.001), and the incidence of later stenosis of the anastomosis (22/96, 23%, compared with 3/48, 6%, p = 0.02). Patients who developed anastomotic breakdown lost significantly more blood during operation (median 2300 ml, range 1100-7500, compared with 1600 ml, range 600-6000, p = 0.02), and women were more likely to develop anastomotic leaks than men (15/70 compared with 3/74, p = 0.009). CONCLUSION: We conclude that so far the stapled anastomoses have given superior results, but it remains to be seen whether other differences will emerge as length of follow up increases.

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