G. Nassuato

The Effect of Drugs on Bile Flow and Composition: An Overview

SummaryMany drugs are eliminated via the hepatobiliary route, after biotransformation in the liver. Some of them may affect bile flow and/or the hepatic secretion of biliary lipids such as bile acids, cholesterol and phospholipids.Bile acids are the most potent agents which increase bile flow, especially unconjugated bile acids. Other drugs which increase bile flow include phenobarbitone (phenobarbital), theophylline, glucagon and insulin. In contrast, ethacrynic acid, amiloride, ouabain, oestrogens and chlorpromazine are among those agents which decrease bile flow. Biliary bile acid secretion is altered by a variety of drugs, including cheno- and ursodeoxycholic acids (CDCA and UCDA), the bile acid sequestrants cholestyramine and colestipol, and ethinyloestradiol.The composition of bile can also be altered by drug therapy. Thus, clofibrate increases biliary cholesterol secretion, and reduces bile acid concentrations, without altering biliary phospholipid concentrations. However, other clofibrate derivatives may produce changes of a different pattern, suggesting that the risk of developing gallstones may differ for each derivative. Nicotinic acid and d-thyroxine also increase biliary cholesterol saturation, while CDCA and UDCA reduce biliary cholesterol concentration.The potential consequences of drug-induced changes in bile flow and composition extend to the liver, the gallbladder and the intestine. If adverse effects are to be avoided, further study in this often overlooked area is required.

Effect of Silibinin on biliary lipid composition experimental and clinical study

The effect of Silymarin, a natural flavonoid, on biliary lipid composition, was studied in rats and humans. Bile flow, biliary cholesterol, phospholipid and total bile salt concentrations were measured in 23 control rats and in 27 rats treated with Silibinin, the active component of Silymarin, at the dose of 100 mg/kg body weight i.p. (n = 21) or 50 mg/kg body weight i.p. (n = 6) for 7 days. Biliary cholesterol and phospholipid concentrations were significantly reduced after the higher Silibinin dose (60.9 and 72.9% of the control values), whereas bile flow and biliary total bile salt concentration were unchanged. After the lower Silibinin dose all parameters remained unchanged. Total liver cholesterol content was not affected by Silibinin. On the other hand, in vitro determination of rat liver microsomal 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity showed a significant dose-dependent inhibition by Silibinin (0.5-8 mg/kg). Biliary lipid composition was also assayed in four gallstone and in 15 cholecystectomized patients before and after Silymarin (420 mg per day for 30 days) or placebo administration. In both groups, biliary cholesterol concentrations were reduced after Silymarin treatment and the bile saturation index significantly decreased accordingly. These data suggest that Silibinin-induced reduction of biliary cholesterol concentration both in humans and in rats might be, at least in part, due to a decreased synthesis of liver cholesterol.

Gallstone disease in an elderly population: the Silea study.

BACKGROUND Little is known on gallbladder emptying and gallstone composition in the elderly. AIMS AND SUBJECTS: Cross-sectional survey on the prevalence of gallstone disease and associated factors, gallstone characteristics and gallbladder emptying in a population aged > or = 60 years. METHODS Gallstone number and size as well as gallbladder motor function were assessed by ultrasound. Gallstone composition and pattern were evaluated by conventional radiology and computed tomography (CT) based on Hounsfield units (HU). RESULTS Gallstones were found in 148/1,065 subjects (13.9%), while 136 subjects (12.8%) were cholecystectomized with an overall prevalence of gallstone disease of 26.7% (sex ratio: F > M). Multiple gallstones (62.7%) and small gallstones (52%, diameter < or = 15 mm) were seen; silent gallstones accounted for 93.9% of the total. Only diabetes mellitus in women was significantly associated with cholelithiasis. Gallbladder fasting volumes were larger in gallstone carriers than in controls (P < 0.01); residual and ejection volumes were also significantly greater in gallstone carriers, whereas ejection fractions were similar in the two groups (50.3% +/- 2.4 versus 54.9% +/- 3.0; not significant). Gallstone calcifications were detected in 29/91 gallstone carriers by X-ray and in another 20 by CT (HU > 90). Moreover, 35 gallstone carriers had a score < or = 50 HU and six had attenuation values between 50 and 90 HU. Six gallstone patterns were identified: hypo-isodense, homogeneously dense, rimmed, laminated, core-hyperdense, gas-containing. CONCLUSIONS In the elderly, the prevalence of gallstone disease is very high, especially in women, but gallstone size, number and pattern and gallbladder emptying do not differ from those reported in the middle-aged gallstone population. Advanced age is associated with a high rate of calcified, probably pigment stones.

Hepatitis C virus infection and related chronic liver disease in a resident elderly population: the Silea study

The prevalence of hepatitis C virus (HCV) infection increases with advancing age, but the disease has been poorly studied in the elderly. A population‐based study was therefore carried out to investigate the prevalence of HCV infection and the severity of HCV‐related chronic liver disease in the elderly. One thousand and sixty‐three people (≥60 years of age) were screened for antibodies to HCV (anti‐HCV) and for possible abnormalities of common liver function tests. Positive subjects and sex and age‐matched anti‐HCV‐ negative controls were recalled 12 months later for measurements of liver enzymes, confirmatory testing of anti‐HCV, HCV RNA analysis and HCV genotyping. All subjects answered a specific questionnaire concerning medical history and possible risk factors. Forty‐four subjects were positive for anti‐HCV, the prevalence being 4.1%. Thirty‐five positive subjects and 35 controls were investigated further. Risk factors for acquiring HCV were found to be: blood transfusion, surgical intervention and the use of non‐disposable syringes. Abnormal alanine aminotransferase levels were found in 13 patients (37.1%). HCV RNA genotyping showed type 1b in three (15.8%), type 2a in 13 (68.4%) and not classified in three (15.8%) patients. There was no relationship between abnormalities of serum aminotransferase, the rate of HCV RNA positivity and HCV genotypes. Ultrasound abnormalities were present in 13 (37.1%) patients. In this elderly population the relatively high prevalence of HCV infection was thought to be caused by previous parenteral exposure. The low incidence of liver disease could be related to the prevalence of HCV genotype 2a in the majority of these patients, and hints at the possibility of an HCV carrier state in elderly individuals.

Epidemiology of Gallstone Disease in an Older Italian Population in Montegrotto Terme, Padua

allstone disease (GD), which includes the presence of G stones in the gallbladder and cholecystectomy, has a higher prevalence in females than in males.’-8 Prevalence increases with age,’-’ and environmental factors seem to be of etiological importance.” Most estimates of the prevalence of GD have been obtained from autopsy and from clinical series.s76 The real prevalence of the disease in a general population is debated because of limitations in investigative methods and biased sampling. With the advent of ultrasonography, epidemiological studies have been carried out with some degree of reliability on a large number of subjects.” However, many published studies include only people between 20 and 60 years of and therefore, only limited information is available on subjects older than 60.l3-I6 The clinical presentation of GD in older subjects is similar to that seen in younger patients, but often symptoms do not correlate with the severity of the disease.” Gallstone disease is associated with higher mortality and a higher complication rate in older adults than in younger adults,”*18 even if GD is commonly considered a benign condition.’’ In this epidemiological study, carried out in an older resident population, we investigated the prevalence of GD by ultrasonography. The clinical features and biochemical indices reported to be associated with GD were also evaluated in order to characterize the condition in this age group.

Effect of Silybin on biliary lipid composition in rats.

The authors studied the influence of Silybin in rats, administered i.p. for 7 days (daily dose of 100 mg/kg/b.w.) on the biliary lipid composition and on the maximal excretory rate of bile salts. Following this treatment, biliary cholesterol excretion was reduced, while the other lipids and bile flow were not significantly modified. After sodium cholate infusion (1.6 mumol/min/100 g b.w. i.v. for 80 minutes), the Tm of bile salts and bile flow remained unchanged in Silybin pretreated rats. The mechanism by which Silybin treatment reduces cholesterol excretion, is discussed.

Ionophore A 23187: Some Effects on Platelet Aggregation and Clot Retraction

The ionophore for divalent cations, A 23187, induces plate aggregation and clot retraction. Acetylsalicyclic acid has a potentiating effect on the aggregation induced by A 23187 in platelet-rich plasma, while it inhibits the aggregation of washed platelets. Acetylation of plasma proteins could be the reason of the increased platelet aggregation induced by A 23187 in the presence of acetylsalicyclic acid. Platelet aggregation by A 23187 is probably activated by the passage of Ca2+ through the platelet membrane(s); the aggation, clot retraction by A 23187 requires increased availability in the intracellular space of both Ca2+ and Mg2+.

Antipyrine Clearance: Evaluation of Simplified Methods in Chronic Liver Diseases

Antipyrine exhibits unique kinetic properties: given orally it is rapidly and completely absorbed, its binding to plasma proteins is negligible and its distribution volume equals total body water (Soberman et al. 1949; Stevenson 1977; Vessell 1979). Moreover, the drug is extensively metabolized by hepatic microsomal enzymes, its disposal can be described by a one-compartment model, and it is not influenced by hepatic blood flow (Stevenson 1977; Vessell 1979; Danhof and Tennissen 1984). Therefore, the determination of antipyrine clearance is being increasingly used to assess hepatic drug metabolism and as a quantitative test of liver function (Branch et al. 1973; Andreasen et al. 1974; Vessell 1979; Bircher 1983; Tygstrup and Vilstrup 1983). Due to a number of factors, antipyrine clearance shows a large interindividual variation, therefore the test is not useful for the diagnosis of liver disease. However, its use in clinical hepatology seems to be promising for prognostic purposes, for the assessment of surgical risk, and for the follow-up of liver patients (e. g., to assess the need and timing of transplantation; Andreasen and Ranek 1975; Ramsoe et al. 1980; Poulsen 1985; Poulsen and Loft 1986).

Platelet aggregation following electrical stimulation

It was demonstrated that the previous in vitro electrical stimulation of human and rat platelet-rich plasma does not modify the subsequent response of platelets to the aggregating activity of ADP, thrombin, thrombofax or adrenaline. This is interesting in view of the fact that the electrical stimulation can induce clot retraction.

Clinical significance of serum bilirubins:recent advances.

The potential clinical value of serum bilirubin cannot be fully exploited because of analytical problems affecting in particular the determination of the conjugated pigment fraction. In this review, some recent methodological advances are described which now allow direct quantitation of unconjugated bilirubin, bilirubin monoconjugate, and bilirubin diconjugate in human serum. This novel methodology has greatly improved our understanding of the mechanisms determining the levels of conjugated bilirubin in serum, and of changes occurring in pathological conditions.