Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.

BACKGROUND: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long-term morbidity and mortality is unclear. AIM: To investigate the long-term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. METHODS: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow-up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post-thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. RESULTS: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow-up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent triggering risk factor - especially with venous insufficiency at baseline - signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28-1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83; 95% CI 1.44-2.23) or from myocardial infarction or stroke (SIR 1.28; 95% CI 1.00-1.56). The duration of anticoagulation did not have a statistically significant effect on any of the long-term outcomes. CONCLUSION: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed.

Aspirin in the prevention of progressing stroke: a randomized controlled study.

OBJECTIVES: In acute stroke, progression has a severe impact on patient outcome and no effective treatment is known. The main objective was to evaluate the efficacy of aspirin for prevention of stroke progression thereby improving outcome. DESIGN: The trial was randomized, double-blind and placebo-controlled. SETTING: The patients were treated in stroke units of four hospitals in Sweden. SUBJECTS: Patients with ischaemic stroke but not complete paresis were included. No antiplatelet drugs were allowed within the last 72 h before onset. Delay until first trial dosage was maximized to 48 h. The trial was designed to detect a 20% reduction of the rate of stroke progression, which was estimated to take place in 20% of cases. Totally, 441 patients (220 aspirin, 221 placebo) completed the trial. Baseline comparisons between the groups showed no differences. INTERVENTIONS: Aspirin (325 mg) or placebo was given once daily for five consecutive days. MAIN OUTCOME MEASURES: Neurological assessments were carried out three times daily during the treatment period to detect progression of at least two points in the Scandinavian Stroke Supervision Scale. Patient outcome was followed up at discharge and at 3 months. RESULTS: Aspirin treatment did not significantly reduce the frequency of stroke progression. Amongst aspirin-treated patients, stroke progression occurred in 15.9% as compared with 16.7% in the placebo group, which is less frequent than expected. The relative risk was 0.95 (95% CI 0.62-1.45) in the treatment group. As regards patient outcome at discharge and after 3 months, aspirin treatment did not show any difference. CONCLUSION: No positive effect of aspirin, of the expected size, could be shown on the frequency of stroke progression or patient outcome.

Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT.

Forty-eight patients with acute proximal deep vein thrombosis (DVT) were randomised to intravenous infusions for 4 to 6 days with melagatran, a novel synthetic low molecular weight thrombin inhibitor, or unfractionated heparin adjusted by the activated partial thromboplastin time (APTT). The aim of the study was to investigate the pharmacokinetics, pharmacodynamics and the safety of melagatran therapy at three different doses. Steady-state plasma concentrations were rapidly achieved and maintained throughout the infusion period. The mean plasma concentrations in the low, medium and high dose groups were 0.17, 0.31 and 0.53 micromol/l, respectively. The prolongation of APTT was stable during the melagatran infusions and correlated to the plasma concentration. Phlebographically verified regression of thrombus size measured as decrease in Marder score was seen after 4 to 6 days in 8 of 12 patients, 6 of 12 patients and 5 of 11 patients in the low, medium and high dose groups of melagatran and in 5 of the heparin-treated patients. In the low dose group with melagatran, thrombus extension was seen in one patient. At the dose levels studied, melagatran was well tolerated with no clinically significant bleeding problems, suggesting that melagatran could safely be given to patients suffering from DVT.

A prospective follow-up study of acute deep venous thrombosis using colour duplex ultrasound, phlebography and venous occlusion plethysmography.

OBJECTIVE: To study the extent of deep venous thrombosis (DVT) and thrombus regression over time and to compare the results obtained with different diagnostic techniques. EXPERIMENTAL DESIGN: A prospective follow-up study with repeated examinations during a 6-month period. SETTING: Patients studied at clinical vascular laboratories. PATIENTS: Forty patients hospitalised for acute DVT. Thirty-six of these completed the follow-up period. MEASURES: The diagnosis of DVT was confirmed with phlebographic and/or ultrasonographic techniques. The patient were then re-examined with colour duplex ultrasound and venous occlusion plethysmography after one week, 3 months and 6 months and with phlebography after 1 week and 6 months. The extent of DVT and number of occluded segments were determined with phlebographic and ultrasonographic techniques. Venous occlusion plethysmography was used to evaluate the functional degree of outflow obstruction. RESULTS: Colour duplex scanning at 3 months' and 6 months' follow-up showed that 55% and 74% of initially occlusive thrombi, respectively, were recanalized, with thrombus resolution occurring faster and more completely in those initially limited to popliteal and/or calf level. Discrepancies between phlebography and duplex scanning were found in 6% (26/441) of venous segments investigated by both methods, primarily concerning flow in the veins below the knee. CONCLUSIONS: In comparison with phlebography, colour duplex scanning is an accurate method for evaluation and follow-up of patients with DVT. The non-invasive nature of colour duplex scanning makes this method extremely suitable for repeated studies and thus a potentially very valuable tool for both clinical and research studies of circulatory changes involved in acute and chronic DVT.

The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group.

BACKGROUND: A consensus has not been reached about the optimal duration of oral anticoagulant therapy after a second episode of venous thromboembolism. METHODS: In a multicenter trial, we compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had had a second episode of venous thromboembolism. Of 227 patients enrolled, 111 were randomly assigned to six months of anticoagulation and 116 were assigned to receive anticoagulant therapy indefinitely; for both groups, the target international normalized ratio was 2.0 to 2.85. The initial episodes of deep-vein thrombosis (n = 193) and pulmonary embolism (n = 34), as well as recurrent episodes, were all objectively confirmed. RESULTS: After four years of follow-up, there were 26 recurrences of venous thromboembolism that fulfilled the diagnostic criteria, 23 in the group assigned to six months of therapy (20.7 percent) and 3 in the group assigned to continuing therapy (2.6 percent). The relative risk of recurrence in the group assigned to six months of therapy, as compared with the group assigned to therapy of indefinite duration, was 8.0 (95 percent confidence interval, 2.5 to 25.9). There were 13 major hemorrhages, 3 in the six-month group, (2.7 percent) and 10 in the infinite-treatment group (8.6 percent). The relative risk of major hemorrhage in the six-month group, as compared with the infinite-treatment group was 0.3 (95 percent confidence interval, 0.1 to 1.1). There was no difference in mortality between the two groups. CONCLUSIONS: Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of venous thromboembolism was associated with a much lower rate of recurrence during four years of follow-up than treatment for six months. However, there was a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely.

No influence of simvastatin treatment on platelet function in vivo in patients with hypercholesterolemia.

Hypercholesterolemia is associated with platelet activation. Reduction of plasma cholesterol levels by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin has been found to improve certain aspects of platelet function in vitro and in vivo, but controlled trials are largely lacking. The present randomized, double-blind, crossover study was performed to evaluate whether 10- to 12-week treatment with simvastatin or placebo affects platelet function in vivo in 23 hypercholesterolemic men. Measurements were performed at rest and during mental stress. Simvastatin treatment reduced plasma total cholesterol levels by 18 +/- 2% and low density lipoprotein cholesterol levels by 26 +/- 2% (P < .001 for both), whereas high density lipoprotein cholesterol levels increased slightly (6 +/- 2%, P < .05). Platelet aggregability as assessed by filtragometry ex vivo was unaffected by simvastatin treatment both at rest and during mental stress. Plasma beta-thromboglobulin levels, which reflect platelet secretion, were also unaltered by simvastatin treatment both at rest (antilog of the mean: 20.2 versus 20.0 ng/mL during placebo) and during mental stress. Moreover, nocturnal excretion of 11-dehydrothromboxane B2 in urine did not differ between placebo and active treatment: 218 versus 216 ng/mmol creatinine, respectively. The corresponding values for urinary excretion of high-molecular-weight beta-thromboglobulin were 1.78 versus 1.92 ng/mmol creatinine. Thus, simvastatin treatment had no clear-cut effect on platelet function, as assessed by four different in vivo related platelet function variables, in hypercholesterolemic men.

Bile acid metabolism in familial dysbetalipoproteinaemia: studies in subjects with the apolipoprotein E-2/2 phenotype.

Bile acid kinetics and biliary lipid composition were determined in seven subjects with primary dysbetalipoproteinaemia. They were all homozygous for the apolipoprotein E isoform E-2 and six of them were hyperlipidaemic (type III hyperlipoproteinaemia). With or without hyperlipidaemia, the apo E-2/2 phenotype was associated with increased bile acid formation (mean increase compared with 32 normolipidaemic controls, 43%; P less than 0.025). The biliary lipid composition was not different from that seen in the controls. The results indicate that the uptake by the liver of apo E-containing remnant particles is of importance for the regulation of hepatic cholesterol metabolism in man. It is suggested that hepatic cholesterol synthesis is stimulated in dysbetalipoproteinaemia, and that this leads to a compensatory increase in bile acid synthesis.

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia.

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.

Plasma cholesterol esterification rate in hyperlipoproteinaemia: relation to cholesterol elimination.

The present study was undertaken to determine the relationship between plasma lecithin: cholesterol acyl transfer (LCAT) rate and cholesterol and bile acid turnover in hyperlipidaemia. Nineteen healthy controls, 19 patients with hyperlipoproteinaemia (HLP) type IIa and 12 patients with HLP type IV were studied under standardized dietary conditions. Bile acid kinetics was determined with the aid of [14C]labelled cholic acid and chenodeoxycholic acid. In the hyperlipidaemic patients, cholesterol balance was calculated as the sum of bile acid synthesis plus daily faecal excretion of neutral C27 steroids minus dietary intake of cholesterol. The plasma LCAT rate was determined simultaneously. The mean values of bile acid formation, cholesterol balance, and LCAT rate in HLP type IV patients exceeded those in HLP type IIa patients or in the controls. An increased plasma LCAT rate was found among HLP type IV patients with and without evidence of cardiovascular disease. Plasma LCAT rate correlated positively with bile acid formation (Rs = +0.78, p less than 0.01) and cholesterol balance (Rs = +0.88, p less than 0.002) in HLP type IV. No such relationships were obtained in the controls or in HLP type IIa. It is suggested that an increased production and/or flux of VLDL in HLP type IV is linked to an enhanced plasma LCAT rate and to an increased formation and metabolism of cholesterol in the liver.

Interindividual variability in biliary excretion of ceftriaxone: effects on biliary lipid metabolism and on intestinal microflora.

Ceftriaxone is a broad spectrum parenteral cephalosporin that is eliminated through renal as well as biliary excretion. In order to characterize factors influencing the biliary excretion of ceftriaxone, and possible effects of this organic anion on biliary lipid transport, we studied six healthy volunteers before and during ceftriaxone infusion. The biliary secretion rates of cholesterol, bile acids, phospholipids and ceftriaxone were determined using a duodenal perfusion technique, and the biliary lipid composition and cholesterol saturation of stimulated hepatic bile were determined. Changes in the intestinal microflora induced by ceftriaxone treatment were also analysed. There was a three-fold interindividual variation in biliary excretion of ceftriaxone, and this was correlated with the secretion rate of bile acids (rs = 0.83, P = 0.05). During ceftriaxone infusion, the secretion rate of cholesterol was reduced by 32% (P less than 0.05), which resulted in a reduction of cholesterol saturation of bile, from 107 +/- 11 to 75 +/- 12% (SEM, P less than 0.05). The suppression of intestinal Escherichia coli and Bacteroides, and the proliferation of enterococci and lactobacilli were related to the biliary excretion of ceftriaxone. We conclude (i) that biliary excretion of ceftriaxone is of major importance for its effects on intestinal microflora, (ii) that secretion of this organic anion into bile is largely dependent on bile acid secretion, and (iii) that ceftriaxone inhibits the biliary secretion of cholesterol.

On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment.

Thrombotest (TT) values were studied in patients fed an ordinary diet and on continuous and well controlled warfarin therapy because of deep venous thrombosis or pulmonary embolism. The aim was to characterize the effect of single and multiple administrations (daily during one week) of vitamin K1 (Konakion), vitamin K-rich vegetables such as spinach and broccoli, and table wine. Single administration of 250 micrograms vitamin K1, 250 g spinach, 250 g broccoli and 37.5 cl wine did not result in TT-values outside the therapeutic range. However, when Konakion, broccoli and spinach were given daily during one week the TT-values tended to rise above the therapeutic limit, requiring dose adjustment. On the basis of this study it appears that excessive intake of vitamin K-rich food and a moderate intake of alcohol on one occasion may be permitted during anticoagulant therapy.

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.

Effect of ciprofibrate treatment on biliary lipids in patients with hyperlipoproteinaemia.

Treatment with hypolipidaemic drugs such as clofibrate increases secretion of biliary cholesterol and induces supersaturation of bile, leading to an increased risk of gallstone formation. Ciprofibrate is a phenoxyisobutyrate derivative with lipid-lowering effects in hyperlipoproteinaemia. We analysed serum lipid levels and biliary lipid composition and cholesterol saturation of gallbladder bile in nineteen hyperlipoproteinaemic patients before and after 6 weeks treatment with ciprofibrate, 100 mg daily. In addition, hepatic secretion rates of biliary lipids were determined in eight of the patients. Ten of the patients were also studied after 1 year of treatment. Short-term treatment reduced the serum cholesterol levels by about 20% (P less than 0.001) and the serum triglycerides by about 40% (P less than 0.001). The relative cholesterol concentration and cholesterol saturation of bile were not significantly increased for the group as a whole, nor in patients with familial hypercholesterolaemia (n = 9), or with other types of hyperlipidaemia (n = 10). During treatment, however, fourteen patients had saturated bile compared with nine before treatment. An increase in cholesterol saturation was the consequence of an increased hepatic secretion of cholesterol whereas the secretion rates of bile acids and phospholipids were unaffected. After 1 year of treatment the serum lipid concentrations were reduced to about the same level as after 6 weeks, whereas biliary lipid composition and cholesterol saturation had returned to pre-treatment values. In contrast to clofibrate ciprofibrate exerts hypolipidaemic effects without consistently increasing the relative cholesterol concentration in bile. In some patients it leads to a transient rise in cholesterol saturation of gallbladder bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid on bile acid kinetics and biliary lipid secretion in humans. Evidence for different modes of action on bile acid synthesis.

The effects of ursodeoxycholic acid on biliary lipid secretion and bile acid kinetics were determined in 12 men. For comparison, eight of the subjects were also treated with chenodeoxycholic acid using a crossover study design. The daily dose of each bile acid was 15 mg/kg body wt; each treatment period lasted for 5-6 wk. Kinetics of cholic acid and chenodeoxycholic acid, hepatic secretion rates of biliary lipids, and lipid composition of concentrated fasting duodenal bile were determined before and at the end of each treatment period. The synthesis rates of cholic acid and chenodeoxycholic acid were increased by approximately 80% and 40%, respectively, during treatment with ursodeoxycholic acid. The fractional catabolic rates of the two bile acids were increased by approximately 50%, whereas the pool sizes remained unchanged. Under similar conditions, administration of chenodeoxycholic acid reduced the pool size as well as the synthesis rate of cholic acid by approximately 70%. Ursodeoxycholic acid reduced the hepatic secretion of cholesterol to a higher extent (approximately 50%) than did chenodeoxycholic acid (approximately 30%). The secretion rates of bile acids and phospholipids remained essentially unchanged during the two treatment periods. Fasting duodenal (gallbladder) bile was unsaturated with cholesterol during both regimens. It is concluded that the two bile acids exert different effects on bile acid metabolism. The enhanced conversion of cholesterol to bile acids observed during ursodeoxycholic acid treatment may at least partly explain why ursodeoxycholic acid can reduce the biliary output of cholesterol without suppressing hepatic cholesterol synthesis.

Bile acid metabolism in hypothyroid subjects: response to substitution therapy.

Bile acid kinetics and biliary lipid composition were determined in ten hypothyroid patients before and after treatment with L-thyroxine. Hypothyroid patients had normal synthesis rates of cholic acid and chenodeoxycholic acid. Hormone treatment, which lowered plasma cholesterol by about 35%, stimulated the formation of chenodeoxycholic acid by about 40% but did not significantly change the synthesis of cholic acid or total primary bile acids. The mean relative biliary concentration of deoxycholic acid was decreased from 30% to 19% and that of chenodeoxycholic acid was concomitantly increased. Cholesterol saturation of bile was decreased by treatment in six of the patients, but the mean value before treatment (135 +/- 13%) was not significantly different from that obtained after treatment (108 +/- 9%). It is suggested that the hypocholesterolaemic effect of thyroid hormones is not primarily due to an increased degradation of cholesterol to bile acids. Similar to what is observed in heterozygous familial hypercholesterolaemia, the defective receptor mediated degradation of plasma low density lipoproteins in hypothyroidism is thus apparently associated with a quantitatively normal catabolic rate of cholesterol to bile acids.

The effect of weight reduction on biliary lipid metabolism in patients with hyperlipoproteinemia type IV.

Nine slightly obese patients with hyperlipoproteinemia type IV were studied, before and after a mean weight reduction of about 15 kg, with respect to bile acid kinetics, cholesterol balance and biliary lipid composition. The bile acid pool size was not consistently changed. The synthesis of cholic acid and chenodeoxycholic acid was decreased by about 65% and 50%, respectively. The net steroid balance, calculated as bile acid synthesis plus fecal excretion of neutral steroids minus dietary cholesterol intake, was reduced by about 50%. In all but one of the patients bile was supersaturated with cholesterol but weight reduction was not associated with any change in cholesterol saturation. The results indicate that hyperlipoproteinemia type IV may be associated with some metabolic defects which are not corrected for by weight reduction.

Clofibrate treatment and bile cholesterol saturation: short-term and long-term effects and influence of combination with chenodeoxycholic acid.

In order to determine whether the clofibrate-induced increase in bile cholesterol saturation is transitory, duodenal bile samples were analysed from sixteen hyperlipoproteinaemic patients before and after 6 months to 2 years treatment with clofibrate, 2 g daily. Standardized dietary and weight conditions were obtained. In all but two subjects cholesterol saturation remained elevated (150 +/- 7%, mean +/- SEM) compared to pretreatment values (112 +/- 6%, P less than 0.01). In nine of the patients, duodenal bile was obtained also after 6 weeks of treatment. Although two patients with increased saturation at 6 weeks displayed a return to basal values at 2 years, the majority showed no consistent changes between these two occasions. Addition of chenodeoxycholic acid to clofibrate medication led to a normalization of cholesterol saturation (from 145 +/- 9 to 89 +/- 18%, P less than 0.01) in eight out of nine patients studied. The serum levels of total cholesterol and triglycerides, very low density lipoprotein and high density lipoprotein cholesterol were not significantly changed. However, the low density lipoprotein (LDL) cholesterol concentration was increased by 15--20% (from 4.8 +/- 0.3 to 5.7 +/- 0.4 mmol/l, P less than 0.01). It is concluded that clofibrate induces changes in biliary lipid composition which are consistent over at least 2 years of treatment. Possible measures to avoid these effects must therefore also be taken over a prolonged time. Chenodeoxycholic acid prevents the lithogenic effect of clofibrate but it cannot presently be recommended as an adjunct to clofibrate treatment since it simultaneously causes a rise in the serum concentration of LDL-cholesterol.

Plasma cholesterol esterification rate in type IV hyperlipoproteinemia. Relation to bile acid kinetics and triglyceride metabolism.

The LCAT rate, VLDL triglyceride turnover, and bile acid kinetics were determined under standardized conditions in 10 patients with primary type IV HLP. Bile acid and plasma VLDL triglyceride kinetics were determined with the aid of [14C]-labeled cholic and chenodeoxycholic acid and [3H]glycerol, respectively. The LCAT rate was simultaneously determined in fasting-state plasma. The mean values of total bile acid formation (21.2 +/- 2.6 mumol kg-1 day-1), apparent VLDL triglyceride production (19.6 +/- 2.0 mumol kg-1 hr-1), and LCAT rate (6.0 +/- 0.6 mumol kg-1 hr-1) exceeded those reported previously for healthy controls. Plasma LCAT rate correlated positively with bile acid synthesis (R = 0.85, p less than 0.01) and with apparent plasma VLDL triglyceride production (R = 0.75, p less than 0.02). The results suggest that parallel disturbances in the regulation of cholesterol, bile acid, and lipoprotein metabolism occur in some patients with type IV HLP.

Biliary lipid composition in obesity.

Fasting gallbladder bile was obtained under standardized conditions from 15 gallstone-free obese subjects (greater than 130% of ideal weight) and 23 healthy control subjects matched for age, sex, and serum lipid levels. The proportion of cholesterol, expressed as molar percentage of total biliary lipids, was increased in obesity (10.8 +/- 0.6 versus 6.8 +/- 0.4 M % (mean +/- S.E.M.), P less than 0.001), whereas that of bile acids was decreased (64.7 +/- 1.3 versus 71.0 +/- 1.0 M %, P less than 0.001). The cholesterol saturation of bile was higher in obesity (141 +/- 7%) than in controls (96 +/- 5%, P less than 0.001). The results provide an explanation of the enhanced frequency of cholesterol gallstones in obese subjects.

Cholesterol and bile acid metabolism in obesity.

1. The present study was undertaken to determine the influence of obesity on bile acid kinetics and cholesterol balance in man. 2. Fourteen obese and normolipidaemic patients (160 +/- 6% of ideal body weight, mean +/- SEM) were studied under standardized dietary conditions. Bile acid kinetics, were determined with the aid of 14C-labelled cholic acid and chenodeoxycholic acid. Cholesterol balance was calculated as the sum of bile acid synthesis plus daily faecal excretion of neutral C27 steroids minus dietary intake of cholesterol. The results obtained were compared with previously published data on control subjects (n = 13). 3. The cholesterol balance was higher in the obese patients (2.61 +/- 0.27 mmol/day) than in the control subjects (1.78 +/- 0.22 mmol/day), owing to a higher excretion of neutral steroids. When expressed per kg of body weight the cholesterol balance was quite normal in the obese patients.