Assessment of gall bladder dynamics, cholecystokinin release and the development of gallstones during octreotide therapy for acromegaly.

The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.     

Identification and measurement of molecular variants of cholecystokinin in duodenal mucosa and plasma. Diminished concentrations in patients with celiac disease.

The amount and type of cholecystokinin (CCK) in duodenal extracts and plasma of celiac patients and normal subjects was studied by radioimmunoassay and gel filtration. In both groups there were similar patterns of molecular forms in extracts of duodenal biopsies, but concentrations in celiac disease were significantly depressed. In boiling water extracts of duodenal mucosa from both groups a factor with the properties of the COOH-terminal octapeptide of cholecystokinin predominated, but there were also significant amounts of a larger molecular weight form. In acid extracts of mucosa a factor with the properties of the 33 or 39 residue form was identified in amounts that were approximately 25% those of CCK8; there were also similar amounts of an acid-soluble form that had an apparent molecular weight higher than CCK39. Plasma immunoreactive cholecystokinin was studied after concentration by immunoaffinity adsorption and fractionation by gel filtration. In normal subjects fasting CCK-like immunoreactivity was less than 0.8 pmol/liter, and after a light breakfast increased to 2.0 +/- 0.7 (range 1.0 to 4.8) pmol/liter; CCK8-like activity accounted for all the increased immunoreactivity. In five of six celiac patients the concentrations of both fasting and postprandial CCK-like immunoreactivity in plasma were undetectable (less than 0.8 pmol/liter). We conclude that diminished production and release of CCK could account for the impaired pancreatic and gall bladder responses to intraluminal stimuli in celiac disease.     

Delayed postprandial plasma bile acid response in coeliac patients with slow mouth-caecum transit

Coeliac patients are known to have an expanded bile salt pool which recirculates slowly due, at least in part, to impaired gall bladder contractility. We have investigated the possibility that delayed small bowel transit of chyme and bile may also contribute to this sluggish recycling. Plasma cholylglycine, total bile acids and cholecystokinin concentrations were measured after a lactulose-labelled test meal whose mouth-caecum transit time (M-C TT) was assessed by the breath hydrogen technique. Overall there were no significant differences in plasma bile acid profiles between seven healthy controls and a group of 25 coeliac patients. However, when subjects were divided according to their M-C TT, the 10 with the slowest transit were found to have significant elevation of fasting levels when compared with the 10 with the fastest transit, fasting total bile acids being 3.4 +/- 1.3 versus 0.7 +/- 0.6 mumol/l (P less than 0.02) and fasting cholylglycine being 0.43 +/- 0.17 versus 0.06 +/- 0.04 mumol/l (P less than 0.05) respectively. Peak bile acid levels did not differ significantly between subjects with fast or slow transit. However, subjects with slow transit were found to have a delay in the return of plasma bile acid levels to fasting levels so that the 4 h postprandial levels were significantly elevated when compared with those observed in the subjects with fast transit (total bile acids 3.6 +/- 1.2 versus 0.19 +/- 0.1 mumol/l and cholylglycine 0.70 +/- 0.13 versus 0.24 +/- 0.07 mumol/l respectively, both P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

无钛夹腹腔镜胆囊切除术625例经验

目的探讨无钛夹法处理胆囊管及胆管动脉在腹腔镜胆囊切除术中的应用。方法回顾性分析腹腔镜无钛夹法胆囊切除625例，术中应用超声刀或单极电刀封闭切断胆囊动脉，丝线结扎、套扎器结扎或可吸收夹结扎疸囊管。结果术后无1例病人出现腹腔感染、胆漏和出血等并发症。术后随访1-12个月。未见有腹痛、肩背部疼痛、黄疸及发热等症状。结论腹腔镜胆囊切除术中无钛夹法处理胆囊管及胆管动脉安全、可靠。能避免使用钛夹所致的并发症。     

Immediate and long-term effects of endoscopic papillosphincterotomy in patients with cholelithiasis

The subjects of the study were 164 patients, divided into two groups. Group I included 76 patients at the physicochemical stage of cholelithiasis, and 38 patients after cholecystectomy, who underwent endoscopic papillosphincterotomy (EPST). Group II (control) included 30 patients at the physicochemical stage of cholelithiasis, and 20 patients after cholecystectomy, who did not undergo EPST. Endoscopic retrograde pancreatocholangiography revealed type II Oddi's sphincter dysfunction in all the patients. Evaluation of the chemical composition of bile in Group I, performed 6, 12, 18, and 24 months after EPST, revealed its graduate stabilization. In Group II the dynamics of bile composition was negative--in 8 patients bile became more lithogenic. Long-term observations showed that 6 years after EPST bile was lithogenic only in 4 Group I patients, while at the same moment in 25 Group I patients bile lithogenicity did not disappear, but even worsened. Biliferous tract ultrasonography, performed long after EPST, found biliary sludge in 4 Group I patients. 6-year observation of Group Il patients, including ultrasonography, demonstrated that during the 4th year of observation biliary sludge occurred in as many as 28 patients, in 15 of whom small concrements on the bottom of the gall bladder were found during the 5-6th year of observation, and in 3 of whom a solitary concrement of 4 to 5 mm in diameter was found in the choledoch. The results demonstrate that it is appropriate to perform EPST as early as at the physicochemical stage of cholelithiasis, because this procedure results in stabilization of biliary colloid balance and thus prevents biliary sludge and forming of gall bladder concrements. At the same time, 36% of patients with cholelithiasis at various stages who did not undergo EPST, formed gall bladder concrements. EPST is also appropriate in some patients after cholecystectomy, in order to prevent repeating gall bladder concrement formation.     

Biliary excretion of ceftizoxime in humans

Biliary concentrations of a new cephalosporin, ceftizoxime, were measured in bile collected in 8 cholecystectomized patients provided with T-tube drainage and in 14 patients where bile was obtained by puncture of the gall bladder and choledochus during cholecystectomy. In patients with external biliary drainage, a mean biliary peak of 150.3 +/- SEM 49.8 micrograms/ml has been observed 2 h after intravenous injection of 2 g of ceftizoxime; the antibiotic activity amounted still to 17.3 +/- 6.0 micrograms/ml after 6 h. Assays performed during operation showed the following simultaneous concentrations 1 h after 2 g of ceftizoxime given intravenously: serum: 85.3 +/- 8.1 micrograms/ml; main duct bile: 279.8 +/- 40.0 micrograms/ml; gallbladder bile: 119.9 +/- 19.4 micrograms/ml. These findings were compared with the biliary excretion of 8 other cephalosporins studied previously under the same conditions. The results of the present study suggest that administration of ceftizoxime may be effective in the treatment of biliary tract infections.     

Intraabdominal tissue concentration of ertapenem

OBJECTIVES: Ertapenem, a class I carbapenem, is approved for the treatment of mild to severe intraabdominal infections, but its in vivo concentrations in intraabdominal tissues are unknown. The purpose of this study was to determine the concentration of ertapenem in intraabdominal tissue. PATIENTS AND METHODS: After informed consent 48 patients, 23 female and 25 male with a median age of 58 years (34-81), requiring surgical intervention at intraabdominal organs were enrolled. Patients received 1 g of ertapenem intravenously for perioperative prophylaxis. Tissue samples were taken after resection of parts of the organs. Plasma samples were taken when tissue samples were taken. Drug concentrations were determined by liquid chromatography/mass spectrometry. An ANCOVA test (analysis of covariance) was performed to assess organ-specific differences in ertapenem concentration and penetration ratios. RESULTS: Mean+/-SD ertapenem tissue concentration (mg/kg) was 16.0+/-8.8 in the gall bladder, 12.1+/-5.3 in the colon, 7.0+/-5.7 in the small bowel, 4.5+/-2.3 in the liver and 3.4+/-2.9 in the pancreas. The mean tissue/plasma ratio was 0.19 (colon), 0.17 (small bowel), 0.17 (gall bladder), 0.088 (liver) and 0.095 (pancreas). The ANCOVA test revealed statistically significant organ-specific differences in ertapenem tissue concentration in the gall bladder versus liver/pancreas and in tissue penetration for the colon versus liver/pancreas. CONCLUSIONS: These pharmacokinetic results support the assumption that ertapenem is suitable for the treatment of intraabdominal infections.     

Absorption of bile acids from the large bowel in man

The absorption of bile acids from the human large bowel was studied in eight patients. All patients had cholecystitis and cholelithiasis and had to undergo cholecystectomy. Cholic acid-¹⁴C was injected during surgery into the lumen of the cecum, hepatic flexure of the colon, or transverse colon in six patients, under the visual control of the surgeon. Common duct bile was collected by T tube daily for 5 days, and bile acids were extracted. Significant amounts of radioactivity appeared in T tube bile in each patient. T tube bile acids contained a total of 43.6-84.6% of the administered radioactivity; the average for the six patients was 58.9%. The majority of the tracer was excreted during the first 24 hr. In an additional patient cholic acid-¹⁴C was given in the form of an enema 5 days postoperatively. In this subject 30.8% of the retained radioactivity was excreted through the T-tube in 48 hr. The labeled cholic acid was recovered as both cholic and deoxycholic acid from T tube bile. Thin-layer chromatographic analysis of the bile acid samples indicated that the fraction of radioactivity recovered as deoxycholate increased with time during the postoperative period. Gas-liquid chromatographic analysis showed that the daily total quantity of excreted bile acids increased significantly from the 1st-5th days of the experiment. The amount of cholate excreted in T tube bile increased markedly with time, that of chenodeoxycholate increased moderately, and that of deoxycholate decreased sharply during the 5 days of the experiment. In three patients, injection of radiopaque material mixed with the tracer showed no evidence of regurgitation into the small bowel by serial X-rays. In an additional patient, tube aspirate from the terminal ileum contained no radioactivity. The results indicate that cholic acid is converted to deoxycholic acid in the human colon, and both of these bile acids are absorbed from the human large bowel in significant amounts. These data establish the previously unproved concept that significant absorption of bile acids takes place from the large bowel of man.     

Influence of cholic and chenodeoxycholic acid on biliary cholesterol secretion in man

The interrelationships between biliary bile acid, lecithin and cholesterol secretion rates were studied druing depletion of the bile acid pool and during duodenal administration of cholic or chenodeoxycholic acid in thirteen patients 7-12 days after operation for uncomplicated gallstone disease. The mean lecithin secretion rate was signigicantly higher during cholic acid than during chenodeoxycholic acid infusion. The relationship between bile acid and cholesterol secretion rates was curvilinear, y = x/(a + bx) during bile acid pool depletion and during duodenal cholic acid infusion. At low bile acid secretion rates, during bile acid pool depletion and during cholic acid infusion, the lecithin secretion rate was significantly correlated to the cholesterol secreation rate. The bile acid and cholesterol secretion rates were not significantly correlated during chenodeoxycholic acid infusion. However, under this experimental condition a significant curvilinear relationship between lecithin and cholesterol secretion rates was found. The hepatic bile became unsaturated in cholesterol at significantly lower bile acid secretion rate during chenodeoxycholic acid infusion (10.7 +/- 0.3 mumol min-1) than during cholic acid infusion (15.6 +/- 0.5 mumol min-1).     

Pathogenesis of steatorrhea in chronic diseases of the small intestine

Altogether 150 patients with chronic enteritis and celiac disease with a history of resection of a part of the ileum were examined. It was established that in patients with chronic enteritis, of importance for the pathogenesis of steatorrhea was the deficiency of bile acids during digestion because of hypokinesia of the gallbladder and partial deconjugation of bile acids in the presence of bacterial dissemination of the small intestine. During celiac disease, steatorrhea was caused by the decreased enzymatic function of the pancreas, asynchronism of the food and bile supply to the intestinal lumen, disorders of absorption of lipolysis products. In patients with large resection of the ileum, steatorrhea was associated with abnormality of the enterohepatic circulation of bile acids, bacterial dissemination of the small intestine and reduction of the absorption surface. A schedule of differentiated therapy is offered.     

经腹腔镜逆行胆囊切除术在临床中的应用分析

目的探讨经腹腔镜胆囊切除术中采取逆行胆囊切除在临床中的应用。方法回顾总结我院100例手术，均采取腹腔镜下逆行切除胆囊。结果经采取该术式均无胆瘘、胆管损伤等并发症的发生。结论经采取腹腔镜逆行胆囊切除术对于复杂性胆囊是一种行之有效的方法，降低了胆管损伤及中转开腹率。     

Bile Acid Kinetics in Relation to Sex, Serum Lipids, Body Weights, and Gallbladder Disease in Patients with Various Types of Hyperlipoproteinemia

Bile acid kinetics were determined in 15 normolipidemic and 61 hyperlipidemic subjects with the aid of [(14)C]cholic acid and [(3)H]chenodeoxycholic acid. The diet was standardized and of natural type. The total bile acid formation was within normal limits in patients with hyperlipoproteinemia types IIa and IIb. On the average the production of cholic acid (C) represented less than 50% of the total bile acid synthesis in both groups. The corresponding value recorded for the controls was 64+/-2% (mean+/-SEM). The synthesis of C in hyperlipoproteinemia type IIa was significantly below normal. Of the 27 patients with the type IV pattern, 18 had a synthesis of C and C + chenodeoxycholic acid (CD) that exceeded the upper range recorded for the controls. In these subjects the C formation represented 73+/-3% of the total bile acid synthesis. Similar findings were also encountered in the five patients with the type V lipoprotein pattern studied. The bile acid pool size of the 11 patients with hyperlipoproteinemia type IV, who had been cholecystectomized or suffered from cholelithiasis, was 900 mg smaller on the average than that of the other subjects with the same type of hyperlipoproteinemia. However, the pool size in the former subjects still tended to be higher than that of the control subjects without evidence of gallbladder "disease". In all groups of subjects the formation of bile acids tended to be higher in the male than in the female subjects. Bile acid synthesis showed no linear correlation to actual body weight, relative body weight, or body surface area. A moderate weight reduction in five patients (one with type IIb and four with type IV pattern) was followed by a 50% reduction of the C and CD synthesis.     

The concentration of latamoxef achieved in the bile and gallbladder wall of patients with cholecystitis

This study reports the clinical and pharmacokinetic results following an injection of latamoxef (moxalactam disodium) in patients undergoing cholecystectomy for symptomatic cholelithiasis. Two groups were involved in the study. Group A consisted of 22 patients who received 1 g of intramuscular latamoxef at the time of premedication prior to surgery, and group B consisted of 12 patients each of whom received an intravenous dose of 0.5 g of latamoxef at the time of anaesthetic induction. Latamoxef levels were then measured in peripheral blood, gall bladder bile, common bile duct (CBD) bile and gall bladder wall. Despite a significant difference in the sampling times, inhibitory levels were obtained in the majority of samples in both groups, singularly high levels being assayed in CBD bile. We conclude that an intravenous dosage of latamoxef (0.5 g) given with anaesthetic induction is as effective as 1 g intramuscular dosage given with the pre-medication.     

Conversion of 7 alpha-hydroxycholesterol to bile acid in human subjects: is there an alternate pathway favoring cholic acid synthesis?

Despite the fact that most human subjects synthesize about twice as much cholic acid as chenodeoxycholic acid, available evidence suggests that 7 alpha-hydroxycholesterol, the first intermediate in the major pathway for bile acid synthesis, is converted about equally to these two bile acids. Synthesis through the main alternate pathway can not explain this discrepancy because 27-hydroxycholesterol, the first intermediate in that pathway, is converted preferentially to chenodeoxycholic acid. To examine the validity of these contradictory observations, we administered (24-(14)C)-cholic acid and (24-(14)C)-chenodeoxycholic acid together with (7 beta-(3)H)-7 alpha-hydroxycholesterol on one occasion and (22,23-(3)H)-27-hydroxycholesterol on a separate occasion to eight normal human subjects. Synthesis of the two primary bile acids was determined by means of standard isotope dilution kinetics of the carbon 14-specific activities of biliary bile acids. Conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol and (22,23-(3)H)-27-hydroxycholesterol to bile acid was calculated from the tritium/carbon 14 ratio in cholic and chenodeoxycholic acid. For synthesis, the mean +/- SEM cholic/chenodeoxycholic ratio was 1.82 +/- 0.26. For apparent conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol to bile acid, the mean +/- SEM cholic/ chenodeoxycholic ratio was 1.02 +/- 0.09, whereas for (22,23(3)H)-27-hydroxycholesterol, the mean +/- SEM cholic/chenodeoxycholic ratio was 0.38 +/- 0.03. These data imply that, on average, more than 40% of cholic acid in these subjects was synthesized through a pathway that bypassed initial 7 alpha-hydroxylation. However, consideration of all potential candidates for such a pathway raises doubts that any of them contributes substantially to bile acid synthesis.     

Bile salt malabsorption in regional ileitis,ileal resection and mannitol-induced diarrhea

Fecal bile salt excretion was studied in healthy volunteers, patients with regional ileitis, and patients with ileal resection. 10 muc of carboxyl-(14)C-cholic acid was given orally. Stools and urine were collected daily for 5-10 days, the bile salts extracted, and the radioactivity assayed. Urinary excretion was negligible. All patients with ileal resection excreted bile salts in the feces significantly faster than controls, and five of the six excreted 50% of the radioactivity within 24 hr. Their mean intestinal transit time was 5.6 hr compared to 26 hr for the controls. Two of the three patients with regional ileitis excreted bile salts almost as rapidly as patients with ileal resection. Vitamin B(12) absorption was also defective in those patients, but the intestinal transit time was not decreased.To study the effect of rapid intestinal transit on bile salt excretion, four of the control subjects were given orally 1200 ml of 10% mannitol for 7 days, and the labeled cholic acid excretion rate was again studied. The mean intestinal transit time was markedly shortened, mild steatorrhea developed, and the fecal bile salt excretion rate increased slightly.It is concluded that ileal resection and ileal disease are major factors and rapid intestinal transit is a minor factor in causing excessive fecal bile salt loss. The relevance of bile salt wastage to lipid malabsorption is unknown because of insufficient information about compensatory jejunal absorption, maximum rate of hepatic bile salt synthesis, and the minimum necessary intraluminal concentration of conjugated bile salt.     

Biliary penetration of cefbuperazone in the presence and absence of obstructive jaundice

In thirteen patients with normal liver function, the mean concentrations of cefbuperazone in hepatic bile, gall bladder bile and gallbladder tissue 30 min after injection were 1134.8 +/- 36.8 (mean +/- S.E.M.) mg/l, 6.6 +/- 3.0 mg/l and 26.1 +/- 7.6 mg/l, respectively. In patients with obstructive jaundice, cefbuperazone concentrations in bile were 99 +/- 29.2 mg/l (mean +/- S.E.M.) 1 h post-dose and decreased to 13.9 +/- 5.1 mg/l 6 h post-dose. In both groups of patients biliary concentrations of cefbuperazone were higher than the MICs of most organisms causing biliary infection.     

Serum concentrations of unconjugated and conjugated cholic acid in portal venous and systemic venous blood of fasting man

The fasting concentrations of unconjugated and conjugated cholic acid were determined in the peripheral venous serum of 15 healthy subjects, eight patients with ileal resection and six patients with known bacterial overgrowth of the upper small intestine. In addition, the estimated hepatic uptake of unconjugated and conjugated cholic acid was determined in 15 gallstone patients undergoing cholecystectomy. A highly accurate and specific mass-fragmentographic technique with high sensitivity was used. The proportion of unconjugated cholic acid averaged 34% in the healthy subjects. The estimated fractional hepatic uptake of unconjugated cholic acid was lower than that of conjugated cholic acid, 71% and 87%, respectively (means). Patients with ileal resection had an increased proportion of unconjugated cholic acid in their peripheral venous serum, 49% (mean). The patients with bacterial overgrowth of the upper small intestine also displayed a high proportion of unconjugated cholic acid, 63% (mean). It is suggested that determination of the proportion of unconjugated cholic acid in peripheral venous blood may possibly be used for detection of bacterial contamination of the upper small intestine.     

Determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates by means of stable isotope dilution technique, making use of deuterated cholic acid and chenodeoxycholic acid

A procedure is described for the simultaneous determination of cholic acid and chenodeoxycholic acid pool sizes and fractional turnover rates. After oral administration of known amounts of 11,12-dideuterated chenodeoxycholic acid and 2,2,4,4-tetradeuterated cholic acid, the ratios of chenodeoxycholic acid-D2/chenodeoxycholic acid and cholic acid-D4/cholic acid are measured in consecutive serum samples, after which fractional turnover rates and pool sizes of chenodeoxycholic acid and cholic acid are determined arithmetically. In 7 healthy volunteers pool sizes for chenodeoxycholic acid and cholic acid were 22.9 +/- 7.8 and 24.1 +/- 11.7 mumol/kg, respectively. The corresponding values for the fractional turnover rates were 0.23 +/- 0.10 and 0.29 +/- 0.12/day. After oral administration of the labelled bile acids in capsule, the obtained pool sizes were significantly higher than after administration in a bicarbonate solution. Bile acid kinetics were also performed in a patient suffering from a cholesterol synthesis deficiency and in a patient very likely suffering from a bile acid synthesis deficiency. Furthermore, the kinetics of the intestinal absorption and hepatic clearance of unconjugated bile acids have been investigated in 2 healthy subjects.     

Galstena efficacy in patients with biliary dyskinesia, chronic cholecystitis and cholelithiasis]

The response of inflammation, bile secretion, lipid metabolism, LDL sensitivity to oxidation was studied in patients with bile duct dyskinesia (BDD), chronic cholecystitis (CC) and cholelithiasis (CL) before and after a course of therapy with galstena. The treatment improved general condition in 90% of the patients, dyspeptic symptoms relieved or stopped. Galstena relieved general or local inflammation, reduced mean levels of total cholesterol and LDL cholesterol, raised HDL cholesterol. In patients with BDD and cholelithiasis galstena did not change normal sensitivity of LDL to oxidation. A galstena course in BDD and CC patients significantly diminished bile lithogenicity and improved gall bladder contractility.     

Possibilities of the treatment of biliary dyskinesia by laser irradiation

The examination of 68 patients with biliary dysfunction determined hypokinesia of the gallbladder in 40, sphincter of Oddi spasm in 15 and combination of the two conditions in 13 patients. Blood biochemical indices showed no differences in patients with biliary dyskinesia compared to normal subjects except for alkaline phosphatase levels elevated in 35.3% of patients. This suggests the development of biliary hypertension and cholestasis. All the patients demonstrated disturbed colloid stability of the bile, in those with combined dyskinesia it became lithogenic. Helium-neon and semiconductor laser radiation of biologically active points and the hepatic region, respectively, improved the patients' performance status. The pain and dyspepsia discontinued. The function of the gallbladder and sphincter of Oddi recovered. Positive changes occurred in the blood and bile biochemistry. Laser therapy promoted bilirubin and bile cholesterol decrease. Cholic acid concentration grew, lithogenic characteristics of the bile returned to normal. It is inferred that laser therapy of biliary dyskinesia proved effective.