Effects of cholecystectomy on the kinetics of primary and secondary bile acids.

Removal of the gallbladder is thought to increase formation and pool size of secondary bile acids, mainly deoxycholic acid (DCA), by increased exposure of primary bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA]) to bacterial dehydroxylation in the intestine. We have tested this hypothesis by simultaneous determination of pool size and turnover of DCA, CA, and CDCA in nine women before and at various intervals after removal of a functioning gallbladder. An isotope dilution technique using marker bile acids labeled with stable isotopes (2H4-DCA, 13C-CA, 13C-CDCA) was used. After cholecystectomy, concentration and output of bile acids relative to bilirubin increased (P less than 0.02) in fasting duodenal bile and cholesterol saturation decreased by 27% (P less than 0.05) consistent with enhanced enterohepatic cycling of bile acids. Three months after removal of the gallbladder bile acid kinetics were in a new steady state: pool size and turnover of CDCA were unchanged. Synthesis of CA, the precursor of DCA, was diminished by 37% (P = 0.05), probably resulting from feedback inhibition by continuous transhepatic flux of bile acids. The fraction of CA transferred after 7 alpha-dehydroxylation to the DCA pool increased from 46 +/- 16 to 66 +/- 32% (P less than 0.05). However, this enhanced transfer did not lead to increased input or size of the DCA pool, because synthesis of the precursor CA had decreased.     

Serum unconjugated bile acids in patients with small bowel bacterial overgrowth

Concentrations of total and unconjugated bile acids in serum were measured fasting and 2 h postprandially in 9 patients with a positive [14C]glycocholate breath test consistent with small bowel bacterial overgrowth and in 13 controls. Gas-liquid chromatography-mass spectrometry (GLC-MS) and enzymatic-fluorometric assays were both used. In contrast to previous work, total serum bile acids were only occasionally elevated in patients with bacterial overgrowth. Total 2 h postprandial unconjugated bile acids, however, were elevated in 7/9 patients when measured by GLC-MS and in 6/9 when measured by the enzymatic-fluorometric method. The best separation between patients and controls was achieved by GLC-MS determinations of 2 h postprandial unconjugated cholic acid or primary bile acids, which were abnormal in 8/9 patients. This study indicates that measurement of serum bile acids may be a useful approach to the diagnosis of bacterial overgrowth, but would require accessible methods for separating and measuring cholic acid or unconjugated primary bile acids in post-prandial sera.     

Variations in colonic H2 and CO2 production as a cause of inadequate diagnosis of carbohydrate maldigestion in breath tests

BACKGROUND: Lactose maldigestion is usually diagnosed by means of the H2 breath test. When 13C-lactose is used as substrate, a 13CO2 breath test can be performed simultaneously. In an earlier publication we described the relation between both the H2 and 13CO2 exhalation in breath and the measured intestinal lactase activity after consumption of 13C-lactose. We found a discrepancy between both breath test results in 36% of the cases. To investigate the possible cause of these incongruous breath test results, we studied gas production from carbohydrate in the colon, using 13C-lactulose as a non-absorbable substrate. METHODS: Experiments were performed in 21 subjects, by applying 5 different doses of 13C-lactulose. Repeatability studies were performed in six of these subjects, using 10 g substrate (three tests with 1-week intervals). RESULTS: Both the H2 and the 13CO2 excretion in breath varied strongly interindividually and intraindividually after consumption of 13C-lactulose. In both cases no dose-response relation was observed. A significant positive linear relationship was found between H2 and 13CO exhalation (r = 0.45, P < 0.005). Extrapolation of these results to 13C-lactose breath tests indicates that the colonic contribution of 13CO2 production to the total 13CO2 excretion in breath varies but is on the average large enough to cause false-negative 13CO2 breath test results. CONCLUSIONS: Excretion in breath of 13CO2 produced in the colon during a 13C-lactulose breath test correlates with the breath H2 excretion. This could explain the occurrence of false-negative 13CO2 lactose breath tests when colonic gas production is high and false-negative lactose H2 breath test results when gas production is low. It can also explain the improved sensitivity of the combined H2/13CO2 lactose breath test compared with both breath tests alone.     

Bile acid metabolism in human hyperthyroidism

Decreased levels of serum cholesterol are a well-recognized finding in hyperthyroidism. Since the conversion to bile acids is an important pathway for the elimination of cholesterol, we studied primary bile acid kinetics in seven hyperthyroid patients before and after medical treatment. Pool sizes, fractional turnover and synthesis rates of cholic acid and chenodeoxycholic acid were determined after oral administration of 50 mg [13C]cholic acid and 50 mg [13C]chenodeoxycholic acid. 13C/12C isotope ratios in serum were measured by capillary gas chromatography/electron impact mass spectrometry. Compared with the euthyroid state, serum cholesterol levels were distinctly lower in hyperthyroidism (150 +/- 33 vs. 261 +/- 51 mg per dl, p less than 0.01). Thyroid hormone excess caused a 34% reduction in cholic acid synthesis (5.8 +/- 2.8 vs. 7.9 +/- 4.2 mu moles per kg per day, p less than 0.02), which was associated with a 47% decrease in cholic acid pool size (11.7 +/- 3.4 vs. 22.0 +/- 5.2 mu moles per kg, p less than 0.01). Chenodeoxycholic acid kinetics exhibited no apparent changes. Thus, total primary bile acid synthesis was diminished by 20% in hyperthyroidism. After normalization of thyroid function, the ratio of cholic acid/chenodeoxycholic acid pool size increased in all patients. This was paralleled by a rise in the ratio of concentrations of cholic acid/chenodeoxycholic acid in serum. The depression of cholic acid synthesis in the presence of unaltered subjects is compatible with an inhibition of hepatic 12 alpha-hydroxylation by thyroid hormone. Furthermore, evidence is provided that, in man, the low serum cholesterol levels found during hyperthyroidism are not caused by an increased conversion of cholesterol to bile acid.     

Gall bladder dysmotility: a risk factor for gall stone formation in hypertriglyceridaemia and reversal on triglyceride lowering therapy by bezafibrate and fish oil

BACKGROUND AND AIM: The aim of this study was to unravel the mechanisms responsible for the increased risk of gall stone disease in hypertriglyceridaemia (HTG) and to compare the effects of triglyceride lowering therapy by bezafibrate and fish oil on determinants of cholelithiasis (biliary lipid composition and gall bladder motility) in HTG patients. PATIENTS AND METHODS: Gall bladder motility (ultrasonography) was studied postprandially and during infusion of cholecystokinin (CCK). Determinants of cholelithiasis and serum lipids were compared between nine HTG patients and 10 age, sex, and body mass index matched normolipidaemic controls. The effects of bezafibrate and fish oil in HTG patients were studied in a randomised cross over trial. RESULTS: HTG patients showed 14-fold higher serum triglyceride (TG) levels than controls. Biliary lipid composition, fasting gall bladder volumes, and CCK levels did not differ between HTG patients and controls. Gall bladder emptying was reduced in HTG patients compared with controls during CCK infusion (-22%) as well as in response to a meal (-37%; both p<0.001). Postprandial CCK levels were significantly higher in HTG patients. Both bezafibrate and fish oil reduced serum TG levels (-68% and -51% v baseline, respectively; both p<0.01). Fasting CCK levels were not affected whereas CCK induced gall bladder emptying increased during bezafibrate (+29%; p<0.001) and tended to increase on fish oil therapy (+13%; p=0.07). Postprandial gall bladder motility improved on bezafibrate and fish oil (+47 and +25% v baseline, respectively; both p<0.02) at least partly due to increased gall bladder sensitivity to CCK (both p<0.05 v baseline). Bezafibrate but not fish oil increased the molar ratio of cholesterol to bile acids (+40%; p相似文献   

Cafestol increases serum cholesterol levels in apolipoprotein E*3-Leiden transgenic mice by suppression of bile acid synthesis

Cafestol, a diterpene present in unfiltered coffee, potently increases serum cholesterol levels in humans. So far, no suitable animal model has been found to study the biochemical background of this effect. We determined the effect of cafestol on serum cholesterol and triglycerides in different mouse strains and subsequently studied its mechanism of action in apolipoprotein (apo) E*3-Leiden transgenic mice. ApoE*3-Leiden, heterozygous low density lipoprotein-receptor (LDLR+/-) knockout, or wild-type (WT) C57BL/6 mice were fed a high- (0.05% wt/wt) or a low- (0.01% wt/wt) cafestol diet or a placebo diet for 8 weeks. Standardized to energy intake, these amounts are equal to 40, 8, or 0 cups of unfiltered coffee per 10 MJ per day in humans. In apoE*3-Leiden mice, serum cholesterol was statistically significantly increased by 33% on the low- and by 61% on the high-cafestol diet. In LDLR+/- and WT mice, the increases were 20% and 24%, respectively, on the low-cafestol diet and 55% and 46%, respectively, on the high-cafestol diet. These increases were mainly due to a rise in very low density lipoprotein (VLDL) and intermediate density lipoprotein cholesterol in all 3 mouse strains. To investigate the mechanism of this effect, apoE*3-Leiden mice were fed a high-cafestol or a placebo diet for 3 weeks. Cafestol suppressed enzyme activity and mRNA levels of cholesterol 7alpha-hydroxylase by 57% and 58%, respectively. mRNA levels of enzymes involved in the alternate pathway of bile acid synthesis, ie, sterol 27-hydroxylase and oxysterol 7alpha-hydroxylase, were reduced by 32% and 48%, respectively. The total fecal bile acid output was decreased by 41%. Cafestol did not affect hepatic free and esterified cholesterol, but it decreased LDLR mRNA levels by 37%. The VLDL apoB and triglyceride production rates, as measured after Triton injection, were 2-fold decreased by cafestol, indicating that the number of particles secreted had declined and that there was no change in the amount of triglycerides present in the VLDL particle during cafestol treatment. However, the VLDL particles contained a 4-times higher amount of cholesteryl esters, resulting in a net 2-fold increased secretion of cholesteryl esters. The decrease in triglyceride production was the result of a reduction in hepatic triglyceride content by 52%. In conclusion, cafestol increases serum cholesterol levels in apoE*3-Leiden mice by suppression of the major regulatory enzymes in the bile acid synthesis pathways, leading to decreased LDLR mRNA levels and increased secretion of hepatic cholesterol esters. We suggest that suppression of bile acid synthesis may provide an explanation for the cholesterol-raising effect of cafestol in humans.