The goal of this study was to determine whether use of postmenopausal estrogen (Premarin, Wyeth-Ayerst, Philadelphia, PA) in women with autosomal dominant polycystic kidney disease (ADPKD) increases liver, hepatic cyst, or kidney volume. We also determined whether clinical symptoms correlated with the volume of either the liver or kidneys. Eight women off estrogen (control, C) and 11 others on estrogen (Premarin, E) were studied basally and after 1 year. The two groups were similar in age, weight, age at menarche, and gravida. Volumes of total liver, hepatic cysts, hepatic parenchyma, and total kidney were measured by a validated computed tomography (CT) technique. Estrogen treatment was associated with a selective increase in total liver volume (E vs. C: delta = 7% +/- 12% vs. -2% +/- 8%, P < .03) and no change in kidney volume (E vs. C: delta = 0% +/- 6% vs. -2% +/- 6%, P = NS). Symptoms were common, regardless of estrogen treatment (abdominal pain 60%, shortness of breath 40%, or both 35%). Patients with symptoms of abdominal pain and shortness of breath had significantly increased hepatic volumes (P < .03) but similar kidney volume compared with patients without symptoms. We conclude that estrogen treatment of postmenopausal ADPKD women is associated with selective liver enlargement and that abdominal symptoms in ADPKD patients may be because of extensive hepatic cystic disease.
A B S T R A C T To study the events that might lead to an increased risk of cholesterol gallstones, we examined biliary lipid composition and secretion and bile acid composition and kinetics at different stages of pregnancy or ovulation in young, nonobese, healthy women.Lipid composition and bile acid distribution were determined in duodenal fluid obtained in percentage of cholic acid. The pool size of each major bile acid increased in the first trimester. Chenodeoxycholic acid and deoxycholic acid pools, but not cholic acid pools, subsequently decreased. The fractional turnover rate of both primary bile acids was slower during pregnancy. The synthesis rate of chenodeoxycholic but not cholic acid decreased in a linear manner during the first 20 wk of pregnancy. The rate of enterohepatic cycling of the bile acid pool was reduced throughout pregnancy.The volume of the fasting gallbladder and the residual volume after a physiologically stimulated contraction were directly correlated with bile acid pool size. The residual volume was also directly related to total bile acid synthesis.
Administration of the synthetic estrogen ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,173diol) decreases hepatic Na+,K+-ATPase (ATP phosphohydrolase; EC 3.6.1.3) activity and bile flow to 50% and alters the composition and structure of surface membrane lipid in rats. Although the content of phospholipids was not changed by treatment, free cholesterol (130%) and cholesterol esters (400%) were increased in liver surface membrane fractions. These observations correlate with changes in membrane viscosity, as shown by electron spin resonance probes. Both rotational correlation time, using the isotropic probe methyl (12-nitroxyl)stearate, and the order parameter, determined by the anisotropic probe 5-nitroxylstearic acid, were significantly increased in liver surface membrane fractions from rats treated with ethinyl estradiol. Administration of Triton WR-1339, a nonionic detergent that corrects hepatic and serum lipid changes caused by ethinyl estradiol treatment, restored toward normal elevated membrane lipids and viscosity as well as Na+,K+-ATPase activity and bile flow. Although restoration of normal liver surface membrane structure and function may be due to reversal of abnormal lipid composition, detergents also may directly alter membrane enzyme activity. Addition of Triton WR-1339 in vitro increased Na+,K+-ATPase activity and reduced membrane viscosity of surface membranes from rats treated with ethinyl estradiol. Triton had no effect on either parameter in normal membrane preparations. Studies of membrane structure and function both in vivo and in vitro suggest that alterations in lipid composition may alter Na+,K+-ATPase function and bile flow. Na+,K+-ATPase (ATP phosphohydrolase, EC 3.6.1.3) is a mammalian surface membrane that is sensitive to the lipid structure of the membrane bilayer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)). An important function of Na+,K+-ATPase in the hepatocyte may be the active secretion of sodium into the bile canaliculus, thus driving water across the canalicular membrane (8,9). This fraction has been called bile salt-independent bile flow, and recent studies have demonstrated a strong correlation between hepatic Na+, K+-ATPase activity and bile flow (10), supporting the hypothesis that this component of bile flow is regulated by the sodium pump. One drug consistently shown to reduce bile salt-independent bile flow is the synthetic estrogen derivative ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,17f3-diol) (10)(11)(12)(13).The aim of the present study was to examine whether Na+, K+-ATPase activity is reduced after ethinyl estradiol treatment and, if so, what possible mechanisms might be involved. We recently found that ethinyl estradiol significantly increases hepatic cholesterol ester concentrations by activating hepatic microsomal cholesterol acyl-CoA transferase (14).The possibility that altered membrane lipid composition was involved in the mechanism through which ethinyl estradiolThe publication costs of this article were defrayed in part by page charge payment. Thi...
Rats treated with ethinylestradiol (5 mg kg-1 day-1 for 5 days) secrete de novo synthesized bile acids at a markedly reduced rate (-57%). Administration of the nonionic detergent Triton WR-1339 to estradiol-treated rats rapidly restored the rate of secretion of de novo synthesized bile acids to control levels. In contrast, when Triton was administered to control rats, the secretion rate of bile acids was unaffected. The reduction in bile acid synthesis displayed by estradiol-treated rats was similar to the 50% decrease in the activity of hepatic microsomal 7 alpha-hydroxylase. The activity of 7 alpha-hydroxylase was also restored to control levels by the administration of Triton to estradiol-treated rats. We examined the possibility that estradiol acts directly on the hepatic microsomes. Adding increasing amounts of estradiol to microsomes obtained from control rats resulted in decreasing activities of 7 alpha-hydroxylase. The inhibition by estradiol of 7 alpha-hydroxylase obtained in vitro occurred with amounts of estradiol that were found to accumulate in the liver via in vivo treatment. Double-reciprocal analysis showed that at and below 50 micrograms of estradiol/0.5 mg of protein uncompetitive inhibition was displayed. Additional experiments showed that adding Triton to microsomes obtained from estradiol-treated rats increased the activity of 7 alpha-hydroxylase to control levels. In contrast, Triton did not increase the activity of 7 alpha-hydroxylase when it was added to control microsomes. These data show for the first time that the estrogenic steroid estradiol acts directly on the microsomes and inhibits both the activity of 7 alpha-hydroxylase and the rate of bile acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Some patients with early-stage cirrhosis preserve hepatic function, whereas others have little hepatic reserve and rapidly deteriorate. The aim of this study was to use quantitative tests of liver function (QLFTs) to define the degree of functional hepatic impairment in patients with earlystage cirrhosis (Child-Pugh score 5-7) and to determine whether the tests predicted subsequent hepatic decompensation. We recruited 10 cirrhotic (Cr) patients and 10 healthy controls (Nl), who were well matched for race, age, weight, and gender. Clearances of caffeine (CF) and antipyrine (AP) after oral administration were measured from timed samples of saliva. Copyright r 1997 by the American Association for the Study of Liver Diseases C onventional liver tests (serum bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) do not quantitate hepatic function but only assess the presence or absence of hepatobiliary injury. 1 Chronic liver disease, especially early cirrhosis, is characterized by a compensated phase (Child' s class A) where clinical findings and standard routine biochemical parameters are relatively stable despite progression of the liver disease. During this phase some patients experience significant worsening of functional hepatic reserve and are at risk for clinical decompensation. For these reasons, we determined in a small group of cirrhotic patients whether quantitative tests could identify the degree of impairment in hepatic reserve and whether those with the greatest impairment had clinical progression in their liver disease.A number of model compounds have been shown to be useful in assessing the severity of liver disease: aminopyrine, antipyrine, phenacetin, caffeine, erythromycin, galactose, indocyanine green, lidocaine, and bile acids. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] These studies suggest that hepatic drug clearance offers more precise quantitation of hepatic function and reserve when compared with standard liver blood tests. Hepatic clearance of these model compounds is dependent on two major physiological variables: the rate of delivery of the drug to the liver and the intrinsic hepatic clearance. For compounds with a high intrinsic hepatic clearance, such as cholate, clearance is limited by liver blood flow. For compounds with a low intrinsic hepatic clearance, such as antipyrine and caffeine, clearance is relatively independent of liver blood flow but dependent upon hepatic metabolism.The specific aims of this study were to define the degree of functional hepatic impairment by comparing clearances of caffeine, antipyrine, and cholate in patients with early-stage cirrhosis to those of controls. In addition, we determined whether the
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