Gallstones In Man Research Articles

Functional CT and MR Biliary Imaging in Patients With Unexplained Abdominal Pain and Controls

G A A b st ra ct s recruited into the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk) with 23 658 completing 7-DFDs at enrolment. The cohort was monitored for 14 years for new symptomatic gallstones, with diagnoses confirmed by review of the clinical notes. The 7-DFDs recorded one week's diet including drink type, brands and volumes consumed. A representative sample of 3 970 and also those with gallstone disease had their 7-DFDs coded by nutritionists using a computer program containing nutrient information on 11 000 food and drink items. A cohort analysis used Cox regression modelling to estimatehazard ratios (HR) for men and women, comparing 1, 2 or 3+ cups (1 cup=250mls) of caffeinated coffee and tea intake per day versus zero intake as well as a binary variable of any caffeinated coffee vs none and decaffeinated coffee vs none. The analyses were adjusted for the risk factors: age, body mass index, energy intake, alcohol intake and physical activity in men, and also parity and hormone replacement therapy use in women. Results: 177 women (mean age of diagnosis 66.5 yrs SD=9.5 yrs) and 90 men (64.2 yrs SD=9.2 yrs) developed symptomatic gallstones. In men, caffeinated coffee intake was associated with a decreased risk of symptomatic gallstones (3+ cups day vs zero intake HR=0.48, 95% CI=0.26-0.89) with a significant trend across categories (per 1 cup increase HR=0.79, p=0.022). Drinking any caffeinated coffee compared to zero consumption in men, the HR was 0.58 (95% CI= 0.38-0.90, p=0.015). If all men consumed three or more cups of caffeinated coffee a day, then 26% of symptomatic gallstones could be prevented. No effects were found for tea and decaffeinated coffee consumption in men and any drink intake in women (any caffeinated coffee vs zero consumption HR=0.84 95% CI=0.60-1.17, p=0.30). Conclusion: The data suggests that caffeinated coffee may reduce the risk of symptomatic gallstones in men but not in women. Coffee should be measured in future studies investigating the aetiology of gallstones in men.

Caffeinated Coffee is Associated With a Reduction of Symptomatic Gallstones in Men. Data From a UK Prospective Cohort Study (EPIC-Norfolk) Using 7-Day Food Diaries

Introduction: Low iron intake reduces nitric oxide synthase (NOS) activity, which impairs gallbladder motility and bile flow. Low iron intake decreases activity of cholesterol 7-αhydroxlase, an enzyme which converts cholesterol to bile acids. Niacin increases plasma high density lipoprotein and lowers plasma triglycerides, both of which are associated with a lower incidence of gallstone disease. This study investigated dietary iron and niacin intake and the risk of developing symptomatic gallstones, for the first time using seven-day food diaries (7-DFDs), the most accurate feasible method of estimating food intake in large epidemiological studies. Methods: 25 639 participants (56% women), aged 40-74 yrs were recruited into the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk) with 23 658 completing 7-DFDs at enrolment. The cohort was monitored for 14 years for new symptomatic gallstones, with diagnoses confirmed by review of the clinical notes. The 7-DFDs recorded one week's diet including food types, frequency of consumption, quantities and cooking methods. A representative sample of 3 970 and those with gallstone disease had their 7-DFDs coded by nutritionists using a computer program containing nutrient information on 11 000 food and 55 000 portion sizes. A cohort analysis used Cox regression to estimate sex specific hazard ratios (HR) for developing gallstones comparing fifths of dietary iron and niacin acid intake adjusted for age, body mass index, energy, alcohol and physical activity in men, and also parity and hormone replacement therapy use in women. Results: 177 women (mean age of diagnosis 66.5yrs SD=9.5yrs) and 90 men (64.2yrs SD= 9.2yrs) developed symptomatic gallstones. In women, increased dietary iron intake was associated with a decreased risk of symptomatic gallstones (highest vs lowest fifth, HR=0.36 95% CI=0.20-0.66; per fifth increase, HR=0.82 95% CI=0.72-0.94 p=0.003), although no effects were seen in men (per fifth increase, HR=0.97 95% CI=0.81-1.17). Increased dietary niacin intake was also associated with a decreased risk of disease in women (highest vs lowest fifth, HR=0.50 95% CI=0.30-0.83; per fifth increase, HR=0.86 95% CI=0.76-0.97 p=0.011), but no effects were found in men (per fifth increase, HR=0.96 95% CI=0.811.14). Conclusion: In women, gallstone disease may be prevented by increasing dietary iron and niacin intake, for which there are plausible biological mechanisms. No effects were found in men, although this could be due to a lack of power as only half the number of cases diagnosed and also that men are less likely to be iron deficient. These nutrients should be measured in future studies to confirm the association. Risk of developing symptomatic gallstones by fifths of dietary intake of iron and niacin in women and men.

The aetiology of gallstones – caffeinated coffee is associated with a reduction of symptomatic gallstones in men: data from a UK prospective cohort study (EPIC-Norfolk) using 7-day food diaries

IntroductionCaffeine and coffee may influence gallstone formation by stimulating gallbladder motility and reducing cholesterol saturation of the bile, although not all epidemiological studies have confirmed a protective effect of coffee....

Insulin Resistance is Associated with Gallstones Even in Non-obese, Non-diabetic Korean Men

It remains unclear as to whether insulin resistance alone or in the presence of well-known risk factors, such as diabetes or obesity, is associated with gallstones in men. The aim of this study was to determine whether insulin resistance is associated independently with gallstone disease in non-diabetic men, regardless of obesity. Study subjects were 19,503 Korean men, aged 30-69 yr, with fasting blood glucose level <126 mg/dL and without a documented history of diabetes. Gallbladder status was assessed via abdominal ultrasonography after overnight fast. Body mass index and waist circumference were measured. Insulin resistance was estimated by the Homeostasis Model Assessment of insulin resistance (HOMA-IR). The prevalence of obesity, abdominal obesity, and metabolic syndrome in the subjects with gallstones were higher than in those without. The prevalence of elevated HOMA (>75 percentile) in subjects with gallstones was significantly higher than in those without, and this association remained even after the obesity stratification was applied. In multiple logistic regression analyses, only age and HOMA proved to be independent predictors of gallstones. Insulin resistance was positively associated with gallstones in non-diabetic Korean men, and this occurred regardless of obesity. Gallstones appear to be a marker for insulin resistance, even in non-diabetic, non-obese men.

DNA synthesis, cell proliferation index in normal and abnormal gallbladder epithelium.

The observation of mitotic figures in the epithelium of the normal gallbladder is exceptional because cell renewal is occurring at a very slow rate. It is only after using 3H-thymidine and autoradiography to observe the cells in DNA synthesis that evidence of a significant epithelial cell replication has been provided. Because numerous mitotic figures and increased 3H-thymidine uptake have been observed after intraluminal introduction of foreign bodies or after ligation of the common bile duct in animals, mechanical distension has been supposed to represent an important trigger factor of cell proliferation in this hollow organ. An increased epithelial cell renewal was also observed in human gallbladders of patients with a complete obstruction of the common bile duct causing the distension. However, the absence of correlation between the degree of gallbladder distension and the proliferative response was suggesting that factors other than distension could be involved. In studies on experimental lithiasis cell proliferation appeared to be enhanced in the gallbladder epithelium of mice fed on a cholesterol-cholic acid-rich lithogenic diet. The fact that the increase in proliferative activity was preceding the formation of gallstones was another indication that factors other than mechanical stimulation by stretching or by the stones may stimulate cell renewal in this organ. Factors in the bile of animals receiving a lithogenic diet could be involved which might cause cellular death and, hence, a regenerative reaction. Direct mitogenic effect of an unknown factor in the bile of these animals is an alternative possibility. On the other hand the stimulating effect of postprandial hormones on gallbladder cell renewal suggested by the observation of a DNA synthesis peak after feeding has been established. Synthetic cholecystokinin analogues have been shown to increase the proliferative activity and to induce epithelial hyperplasia in this organ. In one recent study using fundusectomy to increase the serum gastrin levels, a significant proliferative stimulation in the gallbladder was also observed. In human gallbladder mitotic activity in gallbladders with gallstones in much higher than in the controls. No correlation between stone number, weight or volume and the proliferative activity was put in evidence, whereas cell renewal appeared to be more influenced by the composition of the stones than by their physical presence. Epithelial DNA synthesis activity was, namely, much higher in gallbladders with cholesterol stones than in those with pigment stones. Whether increased cell turnover and, hence, cellular shedding into the lumen could represent a nucleating factor for cholesterol stones is an attractive working hypothesis. Considering the very high frequency of gallstones in man and also the frequent association of gallbladder cancer and lithiasis, further studies on mitotic activity in this organ are required. In conclusion, data from animal experiments and in vitro studies on human gallbladders indicate that gallbladder epithelial cell proliferation may be influenced by several mechanical, chemical and hormonal factors. The list of these factors is still incomplete while their possible role in gallbladder disease is a fascinating exploration field for future research.

The effect of vitamin C in high doses on plasma and biliary lipid composition in patients with cholesterol gallstones: prolongation of the nucleation time.

Vitamin C deficiency in guinea pigs leads to cholesterol supersaturation of bile and formation of cholesterol gallstones. It has been suggested that there may also exist an association between vitamin C and cholesterol gallstones in man, but such a relationship has not been studied in gallstone patients. In order to study the possible effects of vitamin C on gallstone disease in humans, plasma lipid levels, hepatic cholesterol metabolism, biliary lipid composition, cholesterol saturation and nucleation time of gallbladder bile were analysed in 16 consecutive gallstone patients, who were planned for laparoscopic cholecystectomy and were treated with vitamin C (500 mg, four times a day) for 2 weeks before surgery. The plasma concentration of vitamin C increased by 42% in the treatment group. The concentrations of plasma lipids did not differ before and after vitamin C treatment; nor did the plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one, reflecting cholesterol and bile acid synthesis respectively. The relative concentrations of cholesterol, bile acids and cholesterol concentration of bile did not differ significantly between the two groups, but the relative concentration of phospholipids was slightly higher in the treated group. The bile acid composition was changed; the percentage of cholic acid being lower and those of deoxycholic acid, ursodeoxycholic acid and lithocholic acid higher in the vitamin C-treated patients compared with the untreated group. The nucleation time was significantly longer in the treatment group (7 days) compared with the untreated group (2 days). Our findings indicate that vitamin C supplementation may also influence the conditions for cholesterol gallstone formation in humans.

GALLSTONES AND GALLBLADDER CANCERS AT PATHOLOGICAL AUTOPSY CASES

In order to study the recent incidence of gallstones or gallbladder cancer in autopsy cases, 103, 454 pathological autopsy cases from the Annual of the Pathological Autopsy Cases in Japan (1991-1993) in which autopsied stillborn infants, neonates, age-and sex-unknown cases were excluded, were subjected. Gallstones were detected in 2, 478 cases (2.4%) including 2, 204 cases (2.1%) of cholelithiasis, 268 cases (0.3%) of bile duct stones and 104 cases (0.1%) of intrahepatic gallstones. Cholecystectomy had been already performed in 187 cases (7.8%) among 2, 391 cholecystolithiasis. Gallbladder cancer was encountered in 1, 516 cases (1.5%), and 52 cases (9.3%) in men and 124 cases (13.0%) in women of them were complicated with cholecystolithiasis. On the contrary, the incidences of cholelithiasis associated with gallbladder cancer were 4.5% in men and 11.7% in women, totally 8.0%. Fifty-three cases (4.1%) of gallstones in men had intrahepatic gallstones and 51 cases (4.3%) in women. These percentages of intrahepatic gallstones were higher than those encountered in clinical cases. A ratio of man to woman in intrahepatic gallstones was 1 to 1.05, and there was no significant difference on incidence of intrahepatic gallstones between both sexes.

Development of biliary sludge in patients on intensive care unit: results of a prospective ultrasonographic study.

Biliary sludge may be a precursor of gall stones in man. The aim of this study was to determine the incidence of biliary sludge in a prospective study of 36 patients admitted to the intensive care unit for longer than two days. The presence of biliary sludge was determined by ultrasonography. Biliary sludge developed in 17 patients (47%), after a mean of 5.5 days in the intensive care unit. Patients who developed biliary sludge spent longer in the intensive care unit (14.2 d (1.3)), compared with patients who did not (8.3 d (1.4)); (p = 0.003). Ten of the patients with biliary sludge had a recognised risk factor: total parenteral nutrition (five), abdominal surgery (two), or both (three). All neurosurgical patients (four) who required total parenteral nutrition developed biliary sludge. Seven patients with biliary sludge had no previously recognised risk factor, five of whom had severe head trauma or neurosurgery. In conclusion, biliary sludge develops frequently and rapidly in patients admitted to an intensive care unit. Neurosurgical procedures are associated with biliary sludge formation. (Sludge is commonly associated with the development of cholestatic liver biochemistry.)

Longitudinal study of gall stone prevalence at necropsy.

A prospective study of the prevalence of gall stone disease at necropsy in a stable population has been undertaken over a 10 year period up to June 1988. In women, the prevalence of gall stone disease remained static but in men aged 50-59 years it rose from 7% (n = 148) in the first three years to 18% (n = 138) in the last three years (p less than 0.01) and in men aged 60-69 it rose from 12% (n = 370) to 20% (n = 366, p less than 0.01). In the latter age group the female: male ratio fell from 2:1 to 0.8:1. The proportion of deaths from coronary heart disease in men fell slightly in those over 70 during the study period. There was a fall in deaths from coronary heart disease in all age groups in women. Men with gall stones were less likely to have had a cholecystectomy than women, and overall 88% of gall stones remained in situ. In a parallel clinical study, the number of cholecystectomies carried out in the same district fell by 18% over the 10 years without any apparent change in the provision of resources. Cholecystectomy remained almost three times more frequent in women. National data indicate that there have been major changes in the average diet before and during the period of study in favour of reducing coronary heart disease. There has been no change in mortality from coronary heart disease in young men but if the observed increase in the prevalence of gall stones in men and the decrease in deaths from coronary heart disease in women are real phenomena, it seems likely that they are diet related.

Immunoglobulins as nucleating proteins in the gallbladder bile of patients with cholesterol gallstones

The gallbladder bile of patients with cholesterol gallstones contains pronucleating proteins which accelerate precipitation of cholesterol crystals from bile. In this study we have improved the purification procedure developed earlier for these nucleating proteins and have now identified the nature of these proteins. Gallbladder bile from patients with cholesterol gallstones was applied to concanavalin A affinity columns. The ConA-binding glycoprotein fractions containing the nucleating proteins were then separated by FPLC (fast protein liquid chromatography) using a Superose 12 gel filtration column. Nucleating activity was detected in the high molecular weight (FPLC-1) as well as in the low molecular weight fractions (FPLC-3). Investigation of the high molecular weight fraction by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by electroelution and amino acid sequencing suggested that these proteins were immunoglobulins. Immunostaining of Western blots with specific monoclonal antibodies identified the presence of immunoglobulin (Ig) M and IgA in the FPLC-1 fraction. These immunoglobulins were further purified by affinity chromatography employing an antibody exchanger (ABx) column which specifically binds immunoglobulins. There was no reduction in the cholesterol nucleating activity in the Abx-bound fraction compared to FPLC-1. Additional studies showed that the FPLC-1 fraction was significantly more potent than the ConA glycoproteins from either rapid and slow nucleating biles. Also the number of crystals formed was significantly greater in the FPLC-1 fraction isolated from cholesterol gallstone biles than from the FPLC-1 fraction from control patient biles. Commercially obtained IgM and IgA had no effect on nucleation, but IgM isolated from the serum of patients with Waldenstrom's macroglobulinemia did accelerate the nucleation of cholesterol. We conclude that the IgM and possibly IgA are pronucleating proteins and may be important in the pathogenesis of cholesterol gallstones in man.

Quantitative ultrastructural studies of gall bladder epithelium in gall stone free subjects and patients with gall stones.

The present study aimed at a further evaluation of the role of glycoproteins in the formation of cholesterol gall stones in man. An electron microscopic morphometric study of the gall bladder epithelium was performed in six gall stone free subjects and 12 gall stone patients. Six of the gall stone patients were treated with ursodeoxycholic acid three weeks before cholecystectomy. The number and the volume density of the mucin containing secretory granules, were not significantly increased in gall stone patients compared with gall stone free subjects. Treatment with ursodeoxycholic acid did not affect the number or volume density of the secretory granules. Thus, these results do not give evidence for that the degree of cholesterol saturation influences mucin content in the gall bladder wall of man. A major new finding was that gall stone patients had a markedly reduced total lysosome area and volume density of lysosomes compared with gall stone free subjects, a finding which may be related to a decreased intracellular degradation of protein and/or mucin.

The epidemiology of gallstone disease in Rome, Italy. Part II. Factors associated with the disease

The epidemiological associations of gallstone disease were evaluated in a population of 2,325 civil servants (1,244 men and 1,081 women) in Rome, Italy, which was enrolled in a cross-sectional survey on cholelithiasis. Participants were screened for the presence of gallstones by gallbladder ultrasonography, completed a questionnaire on family and personal history and underwent a physical examination and blood chemistry. Statistically significant associations were established by univariate analysis of the age-standardized data and by step-wise multiple logistic regression. At univariate analysis, increasing age, serum triglycerides and number of cigarettes smoked per day, and decreasing high-density lipoprotein-cholesterol were the conditions associated with the presence of gallstones in men. Age and parity were the correspondent associations in women. After controlling by multiple logistic regression, a different pattern of associated conditions emerged. In men, only age and serum triglycerides showed a significant positive association with gallstones, which was independent of other variables. In women, the presence of gallstones was independently associated with increasing age, number of pregnancies, body mass index and serum triglycerides, and with decreasing total (and low-density lipoprotein) cholesterol. The latter association was curvilinear in shape. The conditions associated with a history of cholecystectomy differed from those observed in subjects with gallstones, with the exceptions of age, in both sexes, and high serum triglycerides, in women. Fasting blood glucose levels were higher in women with a history of cholecystectomy than in those with or without gallstones, both at univariate and multiple logistic regression analyses. The ongoing prospective evaluation of the populations under study will elucidate the potential role of the epidemiological associations found in men and women as risk factors for the development of gallstones.

β-Muricholic acid; potentiometric and cholesterol-dissolving properties

Some physicochemical properties of β-niuricholic acid (3α,6β,7β-trihydroxyβ-cholanic acid), a major bile acid biosynthesized by rat liver, were determined and compared to those of ursodeoxycholic and chenodeoxycholic acids. From potentiometric studies, the following characteristics of β-muricholic acid were shown: a low monomer solubility (13 μM), a high equilibrium precipitation pH (7.92 for 30 mM solution), an apparent critical micellar concentration of 4 mM, and a very low micellar capacity of the bile salt to dissolve the protonated bile acid. Sodium β-muricholate solution (30 mM) poorly solubilized cholesterol, as indicated by a bile salt/cholesterol molar ratio of 1430, whereas saturation ratios obtained with chenodeoxycholate and ursoseoxycholate were 24 and 384, respectively. Sodium β-muricholate (30 mM)/phosphatidylcholine/cholesterol mixtures contained non-micellar aggregates from very low cholesterol concentrations. At physiological phosphatidylcholine concentrations, sodium β-muricholate (100 mM) dissolved cholesterol crystals via essentially lamellar liquid-crystal formation. These solubilizing properties might have important physiological relevance to the dissolution of cholesterol gallstones in man.

Absorption of Urso- and Chenodeoxycholic Acid and Their Taurine and Glycine Conjugates in Rat Jejunum, Ileum, and Colon

Chenodeoxycholic acid (cheno) and ursodeoxycholic acid (urso) dissolve cholesterol gallstones in man. Comparative studies of the absorption of cheno and urso are not available. The absorption of urso and cheno and their glycine and taurine conjugates in jejunum, terminal ileum, and colon of the rat were therefore determined in an open in situ perfusion system. Absorption of unconjugated urso and cheno in jejunum, ileum, and colon was similar. In the jejunum conjugated urso and cheno were absorbed only in minimal amounts. In the ileum glycine-conjugated urso was absorbed to a lower extent than glycine-conjugated cheno (6.5 +/- 0.4 vs. 8.6 +/- 0.6 nmol/cm X h at 25 mumol/l bile acid concentration, p less than 0.05) and taurine-conjugated urso was absorbed less than taurine-conjugated cheno (6.4 +/- 0.5 vs. 8.1 +/- 0.7 nmol/cm X h, p less than 0.05). In the colon glycourso and taurourso were not absorbed, while glycocheno and taurocheno were absorbed in small amounts. The low reabsorption rates of urso conjugates in ileum and colon may contribute to the relatively low urso content in bile during urso treatment.

The possible role of free fatty acids in the pathogenesis of cholesterol gallstones in man

The lipid composition of hepatic and gallbladder bile was examined in 20 patients with cholesterol gallstones and in 20 control subjects. Lipid fractions other than bile salts, phospholipids and cholesterol were found to be present, i.e., sterol esters, non-identified fractions and, above all, free fatty acids. The latter probably originated from biliary phospholipids via activity of phospholipases, present in the gallbladder wall. No significant difference in amount and pattern of free fatty acids and phospholipids was found in hepatic bile between patients with gallstones and controls. On the contrary, we observed relevant differences in the lipid composition of gallbladder bile. In this way, we consider that the bile becomes lithogenic inside the gallbladder as a consequence of release of free fatty acids, particularly if these are constituted by saturated chains. In fact, these can compete with cholesterol in the solubilization in biliary micelles. On the other hand, free fatty acids can be directly toxic for the gallbladder wall and produce a cholecystitis.

Effect of female sex hormones on lithogenicity of bile

Effect of female sex hormones on lithogenicity of bile was investigated in an attempt to explain the female preponderance of cholesterol gallstones in man. Estrogen in a form of Estradiol valerate or progesterone in a form of 17 alpha-Hydroxy-progesterone caproate was administered to female dogs oophorectomized to negate influence of endogenous sex hormones from the gonads. Gallbladder bile was puncture aspirated at intervals before, during and after the administration. Lithogenicity of the bile increased markedly during the administration of estrogen. The increase was not so pronounced during the progesterone administration. The increase of lithogenicity is apparently mainly due to increase in the absolute concentration of cholesterol. Differences in the effect of estrogen and progesterone suggest the presence of fluctuation of lithogenicity of bile during the menstrual cycle and pregnancy.

Ursodeoxycholic acid versus chenodeoxycholic acid: Comparison of their effects on bile acid and bile lipid composition in patients with cholesterol gallstones

Chenodeoxycholic acid (cheno) and ursodeoxycholic acid (urso) dissolve cholesterol gallstones in man. In the present study the effects of cheno and urso were investigated in a prospective study in 10 patients in which every patient served as his own control. Five patients were first treated with cheno and subsequently with urso, and 5 patients were first treated with urso and subsequently with cheno. Each of the treatment periods lasted for 3 months. Cheno and urso were administered in daily doses of 12.7 to 17.9 mg per kg. In the control period biliary bile acids consisted of 40.7 ± 4.0% cheno, 1.4 ± 0.2% urso, 1.1 ± 0.1% lithocholic acid, and 0.7 ± 0.2% lithocholic acid sulfate. During treatment with cheno this bile acid increased in bile to 84.3 ± 1.6%, urso to 4.6 ± 1.2%, lithocholic acid to 2.0 ± 0.2%, and lithocholic acid sulfate increased to 1.6 ± 0.2%. In plasma cheno, lithocholic acid and lithocholic acid sulfate were increased. During treatment with urso this bile acid increased in bile to 57.1 ± 3.5% while cheno decreased to 17.9 ± 1.3%, lithocholic acid to 0.6 ± 0.1%, and lithocholic acid sulfate to 0.5 ± 0.1% of total biliary bile acids. In plasma only urso increased. Cholesterol saturation of bile decreased during both treatment periods but was significantly lower during urso treatment (0.6 ± 0.1) than during cheno treatment (0.8 ± 0.1). In 4 patients maximal SGPT values were elevated during the cheno treatment period in comparison to the control period and urso treatment period. All other liver function tests and also serum lipids were unchanged during both treatment periods.

Metabolism of Ursodeoxycholic Acid in Man

The metabolism of ursodeoxycholic acid was investigated in 7 subjects during treatment with ursodeoxycholic acid, 1 g per day and chenodeoxycholic acid, 1 g per day for 2 weeks. The molar proportions of biliary cholesterol, lecithin, and bile salts were determined before and during bile acid treatment and the pool sizes and daily turnover of ursodeoxycholic acid were measured by isotope dilution techniques after administration of [24-14C]ursodeoxycholic acid. Ursodeoxycholic acid became the major biliary bile acid (56%) during ursodeoxycholic acid treatment while the proportions of chenodeoxycholic acid declined from 32 to 18%, and cholic acid from 38 to 17%. Deoxycholic acid and lithocholic acid were virtually absent from the bile. During chenodeoxycholic acid administration, chenodeoxycholic acid became the major biliary bile acid (59%), cholic acid declined to 22% of the biliary bile acids, while the proportion of lithocholic acid rose from 1.3 to 3.4%, and an additional 4% were sulfated. Ursodeoxycholic acid increased to 8% of the total bile acids. The molar percent of biliary cholesterol decreased from 8 to 5% during both ursodeoxycholic acid and chenodeoxycholic acid administration. After [24- 14C]ursodeoxycholic acid was administered intravenously the biliary specific activity- time curves of ursodeoxycholic acid decayed exponentially during both bile acid treatment periods. In the ursodeoxycholic acid-treated subjects, the ursodeoxycholic acid decay curve intersected with the rising specific activity curve of chenodeoxycholic acid and revealed a precursor-product relationship. The average ursodeoxycholic acid pool measured 938 ± 458 mg with a daily production rate of 900 ± 438 mg per day (absorption). The average ursodeoxycholic acid pool during chenodeoxycholic acid treatment measured 123 ± 82 mg and the production rate was 91 ± 35 mg per day (synthesis). These studies demonstrate that substantial quantities of ursodeoxycholic acid are absorbed when this bile acid is fed or are synthesized when chenodeoxycholic acid is given. The reduction in bile lithogenicity during ursodeoxycholic acid administration implies that this bile acid like chenodeoxycholic acid may be effective in dissolving cholesterol gallstones in man.

Effect of lysine acetylsalicylate on biliary lipid secretion in dogs.

1. The influence of lysine acetylsalicylate on bile flow, erythritol clearance and bile salt, phospholipid and cholesterol secretion in bile was studied in unanaesthetized dogs fitted with a Thomas duodenal cannula. 2. Lysine acetylsalicylate induced a marked increase in bile flow and a parallel increase in erythritol clearance although the bile salt secretion remained unchanged; this suggests that the compound stimulated the formation of the canalicular (hepatocytic) bile salt-independent fraction of bile flow. 3. Lysine acetylsalicylate induced a significant decrease in biliary phospholipid and cholesterol secretion and the cholesterol saturation of bile was significantly reduced. 4. It is postulated that the decrease in phospholipid and cholesterol secretion resulted from the dilution of intracanalicular bile salts. This effect of lysine acetylsalicylate, and possibly of other bile salt-independent choleretics, may be of value in the treatment of cholesterol gallstones in man.

Biliary lipid output during three meals and an overnight fast. II. Effect of chenodeoxycholic acid treatment in gallstone subjects.

Oral treatment with chenodeoxycholic acid causes dissolution of cholesterol gallstones in man. In order to determine the mechanism of this effect, we have measured 24-hour biliary lipid output, lipid composition of fasting gallbladder bile, and bile acid pool sizes before and during such treatment in six patients with radiolucent gallstones in functioning gallbladders. In all six patients, the degree of cholesterol saturation of fasting-state gallbladder bile was decreased during treatment to a level below the thermodynamic solubility line. This effect was due to a decrease in biliary cholesterol output, associated with conversion of more than 90% of the total bile acid pool to chenodeoxycholic acid. It could not be attributed to an increase in total bile acid pool size nor to an increase in biliary bile acid or phospholipid output.