Prospective randomised comparison of adjustable gastric banding and vertical banded gastroplasty for morbid obesity.

OBJECTIVE: To compare the clinical results of adjustable gastric banding and vertical banded gastroplasty for morbid obesity. DESIGN: Prospective randomised trial. SETTING: University hospital, Sweden. PATIENTS: 59 morbidly obese patients, listed for obesity surgery. INTERVENTIONS: Adjustable gastric banding (n = 29) or vertical banded gastroplasty (n = 30). MAIN OUTCOME MEASURES: Weight loss, complications, need for revisional surgery, reflux symptoms and the patient's own evaluation. RESULTS: Five years after surgery the mean (SEM) weight reduction for adjustable gastric banding was 43 (3.0) kg and for vertical banded gastroplasty 35 (4.8) kg. One patient in each group died of unrelated causes during follow-up and 3 and 2 patients, respectively, were lost to follow-up. One patient in the vertical banded group required reoperation for an anastomotic leak on the third postoperative day. A total of 3 patients in the adjustable group required reoperation and 11 in the vertical banded group. CONCLUSIONS: Adjustable gastric banding carries a smaller risk of reoperation than vertical banded gastroplasty and the weight reduction is in the same order of magnitude.

Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin.

The effects of acylation-stimulating protein (ASP) and insulin on free fatty acid (FFA) release from isolated human fat cells and the signal transduction pathways to induce these effects were studied. ASP and insulin inhibited basal and norepinephrine-induced FFA release by stimulating fractional FFA re-esterification (both to the same extent) and by inhibiting FFA produced during lipolysis (ASP to a lesser extent than insulin). Protein kinase C inhibition influenced none of the effects of ASP or insulin. Phosphatidylinositol 3-kinase inhibition counteracted the effects of insulin but not of ASP. Phosphodiesterase 3 (PDE3) activity was stimulated by ASP and insulin, whereas PDE4 activity was slightly increased by ASP only. Selective PDE3 inhibition reversed the effects of both ASP and insulin on fractional FFA re-esterification and lipolysis. Selective PDE4 inhibition slightly counteracted the ASP but not the effect of insulin on fractional FFA re-esterification and did not prevent the action of ASP or insulin on lipolysis. Thus, ASP and insulin play a major role in regulating FFA release from fat cells as follows: insulin by stimulating fractional FFA re-esterification and inhibiting lipolysis and ASP mainly by stimulating fractional FFA re-esterification. For both ASP and insulin these effects on FFA release are mediated by PDE3, and for ASP PDE4 might also be involved. The signaling pathway preceding PDE is not known for ASP but involves phosphatidylinositol 3-kinase for insulin.

Hepatic cholesterol metabolism in human obesity.

Hepatic cholesterol metabolism was studied in operative liver biopsies from 17 morbidly obese subjects and compared with that in samples from 15 nonobese controls. The aim was to understand the mechanisms causing the hypersecretion of cholesterol into bile. The content of cholesteryl esters was increased threefold in the liver of obese subjects compared with that of the controls (P < .0001). The activity and the messenger RNA (mRNA) level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate limiting enzyme for cholesterol synthesis, were higher in the obese subjects compared with the nonobese subjects (75% and 140%, respectively; P < .01). In the obese subjects, the activity and mRNA level of cholesterol 7alpha-hydroxylase, which regulates the catabolism of cholesterol to bile acids, were also increased by 140% (P < .05) and 180% (P = .06), respectively, as compared with the controls. There was a significant correlation between the activities and the mRNA levels of cholesterol 7alpha-hydroxylase among the obese subjects (r = +0.65, P < .01). The activities of acyl-coenzyme A:cholesterol acyltransferase (ACAT), which governs cholesteryl ester formation, in obese and nonobese patients were 12.5 +/- 1.7 and 8.1 +/- 1.2 pmol/min/mg protein, respectively (P < .05), and the low-density lipoprotein (LDL) receptor mRNA levels were 5.3 +/- 0.7 and 4.5 +/- 0.9 molecules of mRNA/microg of RNA, respectively. We conclude that the activities of three key enzymes in hepatic cholesterol metabolism were increased in morbidly obese subjects compared with nonobese controls, as were mRNA levels of HMG CoA reductase and cholesterol 7alpha-hydroxylase. The mRNA level of the LDL receptor in the obese subjects was not significantly changed. The hypersecretion of cholesterol occurring in obesity is neither due to a reduced conversion of cholesterol to bile acids nor to a decreased esterification of hepatic cholesterol but may be due to an increased synthesis of cholesterol.

A pathogenic role of visceral fat beta 3-adrenoceptors in obesity.

Increased release of free fatty acids (FFA) from visceral fat cells to the portal venous system may cause several metabolic disturbances in obesity. However, this hypothesis and the underlying mechanism remain to be demonstrated. In this study catecholamine-induced lipid mobilization through lipolysis in omental adipose tissue was investigated in vitro in 25 markedly obese subjects (body mass index range 35-56 kg/m2) undergoing weight reduction surgery and in 19 nonobese subjects (body mass index range 20-28 kg/m2) undergoing cholecystectomy. Release of FFA and glycerol, induced by norepinephrine or adrenergic receptor subtype-specific agonists, were determined in isolated omental fat cells. The obese subjects had higher fat cell volume, blood pressure, plasma insulin levels, blood glucose, plasma triglycerides, and plasma cholesterol than the controls. There was evidence of upper-body fat distribution in the obese group. The rate of FFA and glycerol response to norepinephrine was increased twofold in the cells of obese subjects; no significant reutilization of FFA during catecholamine-induced lipolysis was observed in any of the groups (glycerol/FFA ratio near 1:3). There were no differences in the lipolytic sensitivity to beta 3- or beta 2-adrenoceptor specific agonists between the two groups. However, beta 3-adrenoceptor sensitivity was approximately 50 times enhanced (P = 0.0001), and the coupling efficiency of these receptors was increased from 37 to 56% (P = 0.01) in obesity. Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001). In conclusion, catecholamine-induced rate of FFA mobilization from omental fat cells is accelerated due to elevated rate of lipolysis in obesity, mainly because of an increased beta 3-adrenoceptor function, but partly also because of a decreased alpha 2-adrenoceptor function. This promotes an increased release of FFA to the portal system, which may contribute to the parallel metabolic disturbances observed in upper-body obesity.

Vertical Banded Gastroplasty with Adjustable Silicone Band: Preliminary Experience.

A series of ten patients operated on with vertical banded gastroplasty (VBG) with an adjustable silicone band at the outlet is presented. The loss of body weight and complication rate is evaluated. Preoperative mean excess overweight of the patients was 94% and mean BMI was 42.6. The loss of body weight at one year's follow-up was 38 kg or 59% of excess weight. Complications were one case of infection at the subcutaneous injection port and one case of a nonfatal pulmonary embolus. The results so far are thus comparable with VBG with a conventional fixed band, but the adjustable band actually simplifies the operative procedure since no exact calibration of the collar size is necessary at the time of surgery and should diminish the need for reoperations due to misalignment of collar size. The possibility of better weight control in the long-term perspective remains to be proven.

Bile acid pool size and gallbladder storage capacity in gallstone disease.

Gallstone patients have a reduced total bile acid pool size. To analyze mechanisms behind this, the relation between gallbladder storage capacity and bile acid pool size was studied in 20 gallstone patients, 15 women and 5 men. At cholecystectomy bile was aspirated from the gallbladders, and the volume of bile and concentration of bile acids were recorded. The total bile acid pool size was at the same time estimated by an isotope dilution technique. A significant positive correlation between gallbladder volume and bile acid pool size was found (r = 0.45). The correlation between bile acid concentration in the gallbladders and pool size was, however, not significant (r = 0.24). It is suggested that gallbladder storage capacity may be a determinant of bile acid pool and that a diminished pool size, as seen in gallstone disease, may to some extent be caused by gallbladder fibrosis and shrinkage.

Increased oxidoreduction of deoxycholic acid in cholecystectomised patients.

The extent of oxidoreduction of deoxycholic acid in the enterohepatic circulation was studied in seven healthy subjects and seven patients after cholecystectomy. (12 beta-3H) Deoxycholic acid was given orally together with (24-14C) labelled bile acid. The rate of oxidoreduction of the 12 alpha-hydroxyl group of deoxycholic acid was calculated from the decay in ratio between 3H and 14C. In spite of a normal proportion of deoxycholic acid and other secondary bile acids in bile, patients after cholecystectomy had more than two-fold higher degree of oxidoreduction of the 12 alpha-hydroxyl group than healthy controls. The high extent of oxidoreduction is probably because of an increased exposure of the bile acid pool to intestinal bacteria and may have physiological implications.

Occurrence of cholesterol monohydrate crystals in gallbladder and hepatic bile in man: influence of bile acid treatment.

The occurrence of cholesterol monohydrate crystals was examined and related to the degree of cholesterol saturation in gallbladder bile and hepatic bile of gallstone (GS) patients (n = 34), gallstone-free (GSF) subjects (n = 33) and GS patients treated with chenodeoxycholic acid (CDCA (n = 7) or ursodeoxycholic acid (UDCA) (n = 11) for 3 weeks prior to cholecystectomy. Twenty-five untreated GS patients (74%) and four UDCA-treated patients (40%) displayed cholesterol crystals in the gallbladder bile. Only two GSF subjects (6%) and none of the CDCA-treated patients had crystals. Half of the patients with crystals in the gallbladder bile had crystals also in the hepatic bile. Cholesterol saturation of the gallbladder bile was higher in GS (142 +/- 15%, mean +/- SEM) than in GSF patients (74 +/- 5%). Saturation was also higher in GS patients with crystals (157 +/- 20%) than in those without crystals (99 +/- 12%). Gallbladder bile was unsaturated in all CDCA- and UDCA-treated patients. The results underline the importance of the degree of cholesterol saturation for the formation of cholesterol crystals. The data also give further support to the concept that the mechanism for inducing gallstone dissolution is different for CDCA and UDCA.

Cuff abscesses and ileoanal anastomotic separations in pelvic pouch surgery. An analysis of possible etiologic factors.

In many reports, mucosal proctectomy and ileoanal anastomosis has been reported as a procedure afflicted with a considerably high frequency of cuff abscesses and ileoanal anastomotic separations. In order to find the predisposing factors the charts of 20 early pouch patients were reviewed; ten of these patients had these complications and ten constituted a control group. There were two striking findings about the complication group: a tendency toward more severe rectal gross inflammation and troublesome mucosectomy, and consistently very long, greater than or equal to 7 cm, acute angulated, efferent conduits, and severe evacuation difficulties. Reconstruction of the pouch, with shortening of the efferent limb, was necessary for definite cure in all but one patient. The cuff abscess seemed to be either a descending infection, or an infection ascending from a disrupted anastomosis, a rupture provoked by a long, kinked efferent conduit. After introduction of the S-pouch with short spout and the J-pouch, this feared complication did not appear.

Ursodeoxycholic acid treatment in humans: effects on plasma and biliary lipid metabolism with special reference to very low density lipoprotein triglyceride and bile acid kinetics.

Ursodeoxycholic acid reduces biliary saturation with cholesterol and may induce dissolution of cholesterol gallstones in man. In order to characterize the effects of this potentially useful bile acid on plasma lipid metabolism, we determined lipoprotein levels and very low density lipoprotein (VLDL) triglyceride kinetics in six hypertriglyceridaemic and three normolipidaemic subjects before and after 4-6 weeks of ursodeoxycholic acid treatment at a daily dose of 15 mg kg-1 body weight. The plasma levels of low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol were not significantly affected by therapy. Nor were the plasma level and apparent formation of VLDL triglycerides changed. In five subjects, the effects of a low dose (7.5 mg kg-1 body weight day-1 for 4-6 weeks) of ursodeoxycholic acid on biliary lipid composition and kinetics of cholic acid and chenodeoxycholic acid were determined. The relative concentration of cholesterol in bile was reduced to the same level as during treatment with a high dose of ursodeoxycholic acid. The synthesis rates of bile acids were not suppressed with ursodeoxycholic acid. It is concluded that, unlike chenodeoxycholic acid, ursodeoxycholic acid does not suppress endogenous bile acid production. The efficiency at lower doses, and the lack of effects on plasma lipid metabolism, may make ursodeoxycholic acid a more attractive alternative for clinical attempts of gallstone dissolution.

Oxidoreduction of different hydroxyl groups in bile acids during their enterohepatic circulation in man.

The extent of oxidoreduction of the 3 alpha-, 7 alpha- and 12 alpha-hydroxyl groups in bile acids during the enterohepatic circulation in man was studied with the use of [3 beta-3H]-labeled deoxycholic acid and cholic acid, [7 beta-3H]-labeled cholic acid, and [12 beta-3H]-labeled deoxycholic acid and cholic acid. Each [3H]-labeled bile acid was given per os to healthy volunteers, together with the corresponding [24-14C]-labeled bile acid. The rate of oxidoreduction was calculated from the decrease in the ratio between 3H and 14C in the respective bile acid isolated from duodenal contents collected at different time intervals after administration of the labeled bile acids. The mean fractional conversion rate was found to be 0.29 day-1 for the 3 alpha-hydroxyl group in deoxycholic acid (n = 2), 0.18 day-1 for the 12 alpha-hydroxyl group in deoxycholic acid (n = 6), 0.09 day-1 for the 3 alpha-hydroxyl group in cholic acid (n = 3), 0.05 day-1 for the 7 alpha-hydroxyl group in cholic acid (n = 2), and 0.03 day-1 for the 12 alpha-hydroxyl group in cholic acid (n = 2). The extent of oxidoreduction of the 12 alpha-hydroxyl group in [12 beta-3H]-labeled deoxycholic acid given to two patients operated with subtotal colectomy and ileostomy was markedly reduced (less than 20% of normal).(ABSTRACT TRUNCATED AT 250 WORDS)

Proximal gastric vagotomy and segmental gastrectomy in duodenal ulcer disease--a preliminary report.

The clinical and acid secretory results of 3 patients operated upon with proximal gastric vagotomy associated with a segmental gastrectomy for duodenal ulcer are presented. The outcome of surgery was favourable with cure of the ulcer disease, without dumping, diarrhoea or retention symptoms. The maximal acid output was reduced by 82% and the basal acid output by 62%. However, one patient developed a nonfatal anastomotic leak postoperatively and was reoperated upon. As this might be due to inadequate blood supply following proximal gastric vagotomy we plan to study the microcirculation in this area before proceeding with this combined procedure.

Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by isotope dilution-mass spectrometry.

The present work describes an accurate assay of the rate-limiting enzyme in bile acid synthesis, the cholesterol 7 alpha-hydroxylase, in human liver. The assay is based on isotope dilution-mass spectrometry, and endogenous microsomal cholesterol is used as the only substrate for the enzyme. Operative liver biopsies were obtained from patients undergoing elective cholecystectomy under highly standardized conditions. In ten gallstone patients, the enzyme activity of the microsomal fraction averaged 9.6 +/- 1.4 (mean +/- SEM) pmol X min-1 X mg protein-1 corresponding to a daily synthesis of about 0.5 mmol of bile acids. Three cholestyramine-treated patients displayed a four-fold higher enzyme activity. No evidence was obtained supporting the concept that the cholesterol 7 alpha-hydroxylase is modulated by phosphorylation-dephosphorylation.

Influence of age on secretion of cholesterol and synthesis of bile acids by the liver.

Supersaturation of bile with cholesterol predisposes to the development of cholesterol gallstones. To identify the factors determining cholesterol saturation of bile, we analyzed the lipid composition of stimulated duodenal bile in 60 healthy subjects of various ages (31 men and 29 women) who were not obese and were free of gallstones. A positive correlation between age and cholesterol saturation of bile was found (P less than 0.001). To analyze the relation between age and cholesterol saturation, we studied the rates of hepatic secretion of biliary lipids and the kinetics of cholic acid and chenodeoxycholic acid in 22 and 18 of the subjects, respectively. Age was positively correlated with the cholesterol secretion rate (r = 0.48) and negatively correlated with bile acid synthesis (r = -0.60) and the size of the cholic acid pool (r = -0.54). We conclude that cholesterol saturation of bile increases with age as a consequence of enhanced hepatic secretion of cholesterol and decreased bile acid synthesis. These findings may explain why age is a risk factor for the development of cholesterol gallstones.

Biliary lipid output and bile acid kinetics in cholesterol gallstone disease. Evidence for an increased hepatic secretion of cholesterol in Swedish patients.

Sweden has one of the highest incidences of gallstone disease in the Western world. It is therefore important to characterize the mechanisms responsible for the formation of cholesterol gallstones in this population. In the present study, we have determined the kinetics of the two primary bile acids, cholic acid and chenodeoxycholic acid, and the hepatic secretion rates of the biliary lipids in 21 normolipidemic, nonobese gallstone patients (13 with functioning and 8 with nonfunctioning gallbladder) and in 23 healthy controls. The cholesterol saturation of fasting gallbladder bile averaged 110% in the gallstone patients with functioning gallbladder and 82% in the controls. The pool sizes of cholic acid and chenodeoxycholic acid were reduced by about 40% in the two groups of gallstone patients, whereas the rates of synthesis were close to normal. The fractional catabolic rate of both bile acids was increased in both groups of gallstone patients. The gallstone patients with functioning gallbladder had an increased (about 50%) cholesterol secretion but normal bile acid and phospholipid secretion rates. In the gallstone patients with nonfunctioning gallbladder the secretion rates of biliary lipids were not significantly different from those of the controls. The ratio between cholesterol and bile acids was about 50% higher in the gallstone patients with functioning gallbladder than in the controls or in those with nonfunctioning gallbladder. The results indicate that the hepatic secretion of cholesterol is an important determinant for the development of saturated gallbladder bile in Swedish gallstone patients.

Serum concentrations of ursodeoxycholic acid in portal venous and systemic venous blood of fasting humans as determined by isotope dilution-mass spectrometry.

The fasting concentrations of ursodeoxycholic acid were determined in peripheral and portal venous serum of untreated (n = 12) and ursodeoxycholic acid-treated (n = 7) patients undergoing cholecystectomy. The levels of ursodeoxycholic acid were also determined in peripheral venous serum of 9 healthy subjects before and during treatment with ursodeoxycholic acid. Ursodeoxycholic acid, as well as cholic, chenodeoxycholic, and deoxycholic acids, were analyzed by a highly specific method based on isotope dilution-mass spectrometry. The fasting peripheral venous serum concentration of total (unconjugated plus conjugated) ursodeoxycholic acid averaged 0.14 mumol/L in the untreated gallstone patients and 0.19 mumol/L in the healthy subjects. The corresponding value in portal venous serum was 0.44 mumol/L. Treatment with ursodeoxycholic acid raised the level of this bile acid about 25-fold in portal as well as in peripheral venous serum. The proportion of unconjugated ursodeoxycholic acid was 34% in portal and 49% in peripheral venous serum of treated subjects. The mean hepatic uptake of ursodeoxycholic acid was calculated to be about 60% both in untreated and treated subjects. This uptake was significantly lower than that of cholic acid (83%). The hepatic uptake of ursodeoxycholic acid also tended to be lower than that of chenodeoxycholic acid (68%). This was mainly due to a lower hepatic uptake of unconjugated ursodeoxycholic acid (34%) compared with unconjugated chenodeoxycholic acid (49%). The relatively low hepatic uptake of unconjugated ursodeoxycholic acid explains why serum levels of the administered bile acid are higher during treatment with ursodeoxycholic acid than during treatment with chenodeoxycholic acid. Our results also give evidence that the hepatic uptake of ursodeoxycholic acid cannot be saturated under physiologic conditions.

3-hydroxy-3-methylglutaryl coenzyme A reductase in human liver microsomes: active and inactive forms and cross-reactivity with antibody against rat liver enzyme.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the rate-limiting step in cholesterol biosynthesis, exists in one active (dephosphorylated) and one inactive (phosphorylated) form in liver microsomes obtained from several animal species. The present study was undertaken in order to determine a) whether the human enzyme also exists in active and inactive readily interconvertible forms; b) whether the large inter-individual variation in HMG-CoA reductase activity observed in normal man can be explained by variations in the activation state of the enzyme; and c) to characterize the reactivity of antibodies raised against rat liver HMG-CoA reductase with the intact human microsomal enzyme. HMG-CoA reductase activity, assayed in microsomes prepared in the presence of 50 mM NaF, was only 17 +/- 3% of the activity observed in microsomes prepared from the same liver in the absence of fluoride. Preincubation of microsomes prepared in NaF with alkaline phosphatase resulted in a tenfold increase of enzyme activity, while the activity of microsomes prepared without fluoride was increased also (by about 45%) with this treatment. On the other hand, the activated enzyme could be inactivated by incubation of microsomes with Mg-ATP. In eleven normal weight, normolipidemic gallstone patients, the HMG-CoA reductase activity determined in microsomes prepared without NaF ("standard procedure") reflected well both the "expressed" activity (in microsomes prepared with NaF) and the "total" (fully activated) enzyme activity; correlation coefficients were +0.80 and +0.84, respectively. Preincubation of human liver microsomes with rabbit antiserum against partially purified HMG-CoA reductase from rat liver resulted in a 72 +/- 6% inhibition of enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Triglyceride metabolism in human liver: studies on hepatic phosphatidic-acid phosphatase in obese and non-obese subjects.

According to current concepts, soluble phosphatidic-acid phosphatase, converting phosphatidic acid into a diglyceride, is a rate-limiting enzyme in the hepatic biosynthesis of triglycerides. The present paper is the first report on this enzyme in human liver. The enzyme activity was assayed in ammonium sulphate precipitates of cytosol obtained from human liver biopsies. The activity was stimulated by preincubation with alkaline phosphatase and inhibited by Mg-ATP, suggesting that phosphorylation-dephosphorylation may be of some importance for the expression of the activity of the enzyme. When assayed under optimal conditions, the activity obtained in liver biopsies from normal-weight gallstone patients averaged 12.8 +/- 2.0 nmol min-1 (mg protein)-1 (mean +/- SEM) (n = 17). The enzyme activity was slightly higher in liver biopsies from morbidly obese subjects 16.4 +/- 2.8 nmol min-1 (mg protein)-1 (n = 14). The difference between the two groups of subjects was probably in part sex-dependent and was not statistically significant. A similar small and insignificant difference between the two groups of subjects was found when the enzyme activity was assayed in the maximally stimulated state--i.e. after incubation with alkaline phosphate. These findings suggest that an increased capacity of the soluble phosphatidic-acid phosphatase is not of major importance for the increased triglyceride synthesis known to occur in obesity. Other factors (i.e. availability of substrate and cofactors) may be of greater importance.

Effect of ursodeoxycholic acid treatment on intestinal absorption of triglycerides in man.

The aim of the present study was to evaluate whether treatment with ursodeoxycholic acid (UDCA) may affect the absorption of dietary fat in man. Fifteen healthy subjects volunteered for the study. They were treated with UDCA in a daily dose of 15 mg/kg body weight for 4 weeks. Before and during treatment fat absorption was measured with a 14C-triolein breath test. In addition, fasting serum bile acids were measured in 11 of the subjects. The maximum specific activity of 14CO2 was not significantly changed during the treatment period. However, the cumulative output of 14CO2 during a 6-h period was decreased by about 25% (p less than 0.03). Several subjects with decreased outputs also lost 1-2 kg of body weight during the study period. UDCA treatment raised the serum level of this bile acid from 0.18 +/- 0.11 mumol/l to 5.98 +/- 1.08 mumol/l. The concentrations of the other bile acids were not significantly changed. It is suggested that UDCA treatment may in some patients be associated with an impaired fat absorption. Whether this effect is of any clinical importance remains to be elucidated.