The influence of oral contraceptives on the composition of bile.

The increased risk of cholelithiasis during intake of oral contraceptives may be due to estrogen-induced saturation of the bile with cholesterol. In a randomized, prospective, crossed-over double-blind study 20 healthy women after roentgenological exclusion of gall-stones received either 1.0 mg of norethindrone acetate and 50 microgram ethinyl estradiol daily - as usual in oral contraception - for 21 days with 7 days of placebo treatment in each cycle or one fifth of this hormone dose in form of a continuous daily medication. After a 4 month's treatment the medication form was crossed-over. At the beginning of the study, before the cross-over and after the study bile was collected by duodenal intubation after a 12-h fast and the lithogenic index as a measure for cholesterol saturation of the bile was determined. No correlation between the dose and the lithogenic index was demonstrated, neither in 15 women, who had used oral contraceptives before the study nor in five women without any previous hormonal contraceptives.

PIP: The increased risk of cholelithiasis during oral contraceptive (OC) intake may be due to the estrogen-induced saturation of the bile with cholesterol. In a randomized, prospective, crossover double-blind study, 20 healthy women after roentgenological exclusion of gallstones received either 1.0 mg of norethindrone acetate and 50 mcg of ethinyl estradiol daily for 21 days with 7 days of placebo treatment in each cycle or 1/5 of this hormone dose in the form of continuous daily medication. After 4 months of treatment, the medication form was crossed over. At the beginning of the study, before the crossover and after the study, bile was collected by duodenal intubation after a 12 hour fast and the lithogenic index as a measure for cholesterol saturation of the bile was determined. No correlation between the dose and the lithogenic index was demonstrated, neither in 15 women who had used OCs prior to the study nor in 5 women without any previous OC taking history. (author's)

[Indications for the medical gallstone dissolution]. / Indikationen zur medikamentösen Gallenstein-Auflösung.

The indications for gallstone dissolution have to consider different factors of the gallbladder and its stones. The bladder must be visualized in an i.v. cholecystogram and should well contract on meal. The gallstones should not be calcified and their diameter should not be greater than 2 cm. Dissolution is only possible for cholesterol gallstones. Until today their negative presentation on x-ray is the most important hint at their composition, but pigment stones often are negative on x-ray, too. This unsatisfactory diagnosis of cholesterol gallstones in vivo restricts the success rate of gallstone dissolution to approximately 70%, when the other factors of the treatment are observed. A comparison of cost of dissolution and operation shows that despite the restricted success rate dissolution of gallstones is also justified when indications are well observed.

Gallstone dissolution with chenodeoxycholic acid. A clinical study.

Out of 95 patients with radiolucent gallstones who enrolled in a clinical study with chenodeoxycholic acid (CDC) for gallstone dissolution 75 patients with cholecystolithiasis completed 12 months of treatment. As a side effect 31% of patients reported intermittent diarrhea which did not cause cessation of therapy or missing of work. The incidence of biliary colic was markedly decreased during treatment in comparison to the rate in the year before. From more than 20 laboratory values checked before start and every 3 months during therapy only aminotransferases increased up to 3 fold in 20% of patients. gamma-GT elevated in 31% of patients before treatment improved in half of these patients during therapy. Gallstone dissolution defined as 30% or more diminution of the gallstone area on comparable x-rays occurred in 40% of patients. Analysis of factors showed that gallstones above 2 cm in diameter did not dissolve. When the dose of CDC was retrospectively related to body weight a success rate of 68% was found in the group taking more than 13 mg CDC/kg/day. The lithogenic index determined at 6 and 12 months had significantly decreased after 6 months in patients with success. This study demonstrates that medical dissolution of gallstones with chenodeoxycholic acid should be performed in patients with radiolucent stones of less than 2 cm in diameter and with a dose above 13 mg CDC/kg body weight/day. Under these conditions the success rate is above 60% accompanied by minimal side effects.

Tupaias (tree shrews)--a new animal model for gallstone research. II. Influence of fat, sugar, and cholesterol on bile composition.

The lipid composition of bile obtained from the gallbladder and from the liver of tupaias was determined. Compared to the gallbladder bile of man, the gallbladder bile of tupaias contains the same percentage of phospholipids (PL), one third of the cholesterol (CH), and 50% more total bile acids (TBA). The lithogenic index (LI) of the bile is about 0.2--0.3. No significant sex differences or diurnal variations are found in the composition of bile. The concentration of PL, CH, and TBA is found 5 to 8 times higher in the gallbladder bile than in the liver bile. The bile acid spectrum in tupaias equals that in man qualitatively and is similar quantitatively. In a feeding experiment, the influences of butter, cholesterol, butter plus cholesterol and sucrose on bile composition, clinicochemical serum values, and liver and gallbladder histology were studied. Groups of six animals each were fed the different diets over a 10-week period. In group A: 20% butter added to the standard diet, PL content was higher, the LI was unchanged. In group B: 2% cholesterol added to the standard diet, the CH value and the LI were elevated, CH crystals but no stones were found. In group C: 2% cholesterol and 20% butter in the standard diet, stone formation was observed. PL and CH values were higher than in group A and B, TBA values were lower. In group D: 50% sucrose added to the standard diet very low PL and TBA values were determined in the liver bile, resulting in elevated LIs. It is concluded that all three components of a diet, which had proven lithogenic in a preceding experiment (Schwaier, 1979a), contribute to gallstone formation.

The interaction of various control mechanisms in determining the rate of hepatic cholesterogenesis in the rat.

In these studies rats were subjected to diurnal light-cycling, stress, fasting and the feeding of cholestyramine, beta-sitosterol and cholesterol in various combinations. In control animals exposed to light cycling for 2 weeks the rate of hepatic cholesterogenesis was 3.7 fold higher in the mid-dark than in the mid-light phase of the light cycle. The magnitude of this difference varied with the duration of light cycling and the size of the animals. Similarly, enhanced rates of cholesterol synthesis were seen in the mid-dark phase relative to the mid-light phase of the light cycle in rats where the base-line level of hepatic cholesterogenesis was increased by feeding cholestyramine (1.6-fold) or beta-sitosterol (2.9-fold) or was depressed by fasting (19-fold) or cholesterol feeding (2.1-fold). Restraining animals for 48 h also increased the rate of cholesterol synthesis in the liver; in control animals, this stress enhanced the level of cholesterogenesis seen at both the mid-light and mid-dark phases of the light cycle. In addition, both the effects of stress and of diurnal light cycling could be identified in groups of animals where base-line cholesterogenic activity was varied by fasting or by feeding cholestyramine, beta-sitosterol or cholesterol. These studies illustrate the complexity of the control of hepatic cholesterol synthesis and suggest that the final rate of cholesterogenesis may be the result of several different effectors modifying by different mechanisms the activity of beta-hydroxy-beta-methylglutaryl-CoA reductase.

The kinetic characteristics of inhibition of hepatic cholesterogenesis by lipoproteins of intestinal origin.

In these studies intestinal lipoproteins were injected intravenously into recipient rats in order to study the kinetic characteristics of cholesterol uptake by the liver cell and inhibition of the cholesterol synthetic pathway. Net cholesterol uptake from circulating intestinal lipoproteins took place only in the liver, and only this tissue manifested inhibition of cholesterol syntheses. Cholesterol uptake by the liver, quantified by a rise in the cholesterol ester content, was a linear function of time and of the amount of lipoprotein cholesterol administered to the animals. Using groups of rats that were either fed cholesterol or injected intravenously with intestinal lipoproteins as a bolus or as a continuous infusion, there was generally a correlation between inhibition of the rate of cholesterol synthesis and the cholesterol ester content of the liver. However, there was no consistent quantitative relationship between these two variables suggesting either that cholesterol ester was not the immediate effector of the inhibition or, alternatively, that there was intracellular localization of the effector at the site of control of the rate-limiting enzyme in the cholesterogenic pathway.