bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relationship Between Prostacyclin Activity and Pressure in the Portal Vein
Authors: Hamilton George , Phing Rose Chow Fung , Hutton Ronald A. , Dandona Paresh , Hobbs Kenneth E.F.
Published: July 2010

The effect of portal hypertension (induced by partial ligation) on the ability of the portal vein wall to produce prostacyclin (PGI2) was studied in rats over a period of 6 weeks. PGI2–like activity measured by bioassay was shown to be significantly increased in portal vein segments during established hypertension when compared to control groups. As a collateral circulation developed with consequent fall in portal venous pressure, PGI2–like activity decreased. A positive correlation between PGI2–like activity and portal pressure has been demonstrated. Parallel measurements of this activity by bioassay and radioimmunoassay to 6–keto–prostaglandin–F1 α showed a positive correlation (r = 0.88) and suggested that PGI2 is the inhibitory prostaglandin involved. The possible significance of these observations in relation to the hemorrhagic manifestations associated with portal hypertension in man is discussed.
Concanavalin A Reduces Liver Collagen Accumulation in Murine Schistosomiasis
Authors: Takahashi Shizuko , Kobayashi Michio
Published: July 2010

Mice infected with Schistosoma mansoni develop hepatic fibrosis associated with enhanced collagen synthesis that out–paces induced collagenase activity. Administration of one dose of concanavalin A [Con A (200 jug)] by i.p. injection to mice at 5 or 6 weeks after infection with 50 S. mansoni cercariae decreased liver collagen content by 50% compared to levels in control–infected mice injected with either homologous immunoglobulin (200 jug) or phosphate–buffered saline; additional doses of Con A had no further effect. The decrease in collagen content could not be attributed to either decreased egg deposition in the liver or inhibition of liver collagen synthesis, but was coincident with a greater solubility of granulomas. Collagen contents of skin and tail were unaffected. The relative solubilities of liver collagen in 8 M urea: 10 vaM dithiothreitol were greater in treated animals as compared to controls. However, the amounts of collagen solubilized were similar in both sets of animals, since the total collagen content of treated mice was 50% of the controls. A possible explanation for these results is that much of the synthesized collagen does not accumulate in treated animals, whereas it does accumulate in controls. Peak collagenase and neutral protease activities occurred at 7 weeks postinfection in treated animals, and were 2–fold greater than in controls. Similar effects were observed when succinylated Con A was administered. The results suggest that Con A may modulate host–immune responses influencing fibrogenesis in hepatic murine schistosomiasis.
Effects of Ticrynafen on Hepatic Excretory Function in the Isolated Perfused Rat Liver
Authors: Zimmerman Hyman J. , Abernathy Charles O. , Lukacs Lorinc , Ezekiel Mildred
Published: July 2010

Ticrynafen, a uricosuric diuretic agent which causes hepatocellular injury in man as an apparent idiosyncratic reaction, was found to impair the function of the isolated perfused rat liver. At concentrations in the perfusate equivalent to those produced in the blood of man by therapeutic doses, the drug led to a striking reduction in bile flow and sulfobromophthalein excretion and release of aspartate aminotransferase into the perfusate. These adverse effects were enhanced by treatment of rats with phenobarbital prior to removal of the liver, indicating that the adverse effect of ticrynafen is probably caused by a metabolite produced in the cytochrome P–450 system.
Chronic Lobular Hepatitis: A Clinicopathological and Prognostic Study
Authors: Liaw Yun-Fan , Chu Chia-Ming , Chen Tong-Jong , Lin Deng-Yn , Chang-Chien Chi-Sin , Wu Cheng-Shyong
Published: July 2010

A series of 80 patients with chronic lobular hepatitis (CLH) was reviewed clinically and histologically to demonstrate etiology, clinical presentation, course, and prognosis of this disorder. Data from our study indicate that CLH in Taiwan is a disease of viral origin, mostly hepatitis B (67.5%) and some non–A, non–B. It occurs predominantly in young males (81.3%); frequently commences as acute viral hepatitis (57.5%); and has clinical and laboratory features similar to convalescent viral hepatitis or even indistinguishable from full–blown acute viral hepatitis. Clinical and histological follow–up study indicate that CLH may extend for several years with remissions and relapses. No evidence of progression to cirrhosis was observed at least in a 4½–year period of follow–up. It is concluded that CLH is a persistent but nonprogressive disease although the number of non–A, non–B CLH is too small to ascertain its nonprogressive course. The prognosis is generally good, and no specific therapy is required.
Metabolic Coordination of Liver and Kidney in Mercapturic Acid Biosynthesis In Vivo
Authors: Inoue Masayasu , Okajima Kenji , Morino Yoshimasa
Published: July 2010

When S–carbamido(14C)methyl glutathione, a model compound of glutathione S–conjugate, was administered i.v. to mice, radioactivity accumulated in the kidney within 1 to 2 min and then decreased gradually during the following 10 to 15 min with concomitant increase in hepatic radioactivity. Most hepatic radioactivity was accounted for by S–carbamidomethyl cysteine and its N–acetyl derivative, a mercapturic acid. The i.v. administration of S–carbamido(14C)methyl cysteine resulted in rapid and predominant accumulation of radioactivity in the liver. In both cases, the radioactive urinary metabolites were fully accounted for by N–acetyl–S–carbamidomethyl cysteine. N–Acetyl–S–carbamido(14C)methyl cysteine administered to mice was accumulated preferentially in the kidney and was excreted into urine very rapidly. These results suggest the following series of events: glutathione S–conjugate accumulated mainly in the kidney and is hydrolyzed into its component amino acids, presumably by γ–glutamyl transferase and some peptidase(s) on the renal brush border membranes. The cysteine S–conjugate which is formed in the tubular lumen is reabsorbed and transferred to the liver, acetylated to form N–acetylcysteine S–conjugate, and excreted in the urine. Thus, renal hydrolysis of glutathione S–conjugates seems to be coordinated with acetylation in liver and with mercapturic acid biosynthesis in vivo.
Mast Cell Degranulation, Hepatic Glycogen Depletion, and Hyperglycemia in Compound 48/80 or Pilocarpine–Treated Rats
Authors: Dimlich Ruth V.W. , Townsend Samuel F. , Reilly Frank D.
Published: July 2010

Blood glucose, hepatic glycogen, and mean carotid blood pressure were determined in anesthetized Sprague–Dawley rats receiving an i.v. infusion of Compound 48/80, pilocarpine, or Ringer's solution as a control. Histochemical determinations of the integrity and number of hepatic mast cells and hepatic glycogen content also were performed at the light microscopic level, and the results compared to those from rats whose livers were treated topically with each of these compounds. Compound 48/80 produced a marked decrease in mean carotid blood pressure, while pilocarpine produced a slight increase in this parameter. Injection of either Compound 48/80 or pilocarpine provoked an increase in blood glucose and a decrease in hepatic glycogen as well as in the number of hepatic mast cells. Infusion produced no change in glycogen within cardiac or skeletal muscle. The application of Compound 48/80 or pilocarpine to the surface of the liver evoked no alteration in the histochemical appearance of hepatic glycogen. However, the topical application of these substances elicited a significant decrease in the number of Falck–Hillarp–positive hepatic mast cells. Blood glucose was higher in rats that survived 30 min or more after injection of either compound. However, glucose levels were significantly higher in rats that survived 30 min or longer following Compound 48/80 infusion than in those surviving pilocarpine treatment. These results provide evidence that the i.v. injection of Compound 48/80 or pilocarpine causes: (a) hyperglycemia; (b) depletion of hepatic glycogen, and (c) a concomitant decrease in the number of Falck–Hillarp–positive mast cells. The degree of hyperglycemia appeared to correlate with the length of survival of the rats and to be independent of the hyper– or hypotensive effects elicited by either chemical.
Noninvasive Measurement of Nutrient Portal Blood Shunting: An Experimental Study With [14C]Ursodeoxyeholie Acid
Authors: Nordlinger Bernard , Parquet Michel , Infante Recaredo , Moreels Reginald , Blondiau Pol , Boschat Michele , Groussard Michèle , Huguet Claude
Published: July 2010

All of the methods proposed for measuring portal blood flow are either invasive, estimate total rather than nutrient flow, and none has proved reliable in cirrhotic patients. A method has been derived from pharmacokinetic principles used for the calculation of bioavailability of drugs according to the route of administration (i.v. or p.o.) and tested experimentally in 20 pigs. A tracer dose of [14C]ursodeoxycholic acid, a biliary acid with a high–liver first–pass effect, is administered in the duodenum, and serial peripheral blood samples are taken. Later, the same dose of the same drug is administered i.v. The shunt fraction of portal blood F is obtained by the ratio of the areas under the plasma level vs. time curves (“AUC”) after p.o. and i.v. administrations:

The pigs were divided into three experimental groups, (i) Group I: undisturbed portal flow; (ii) Group II: total diversion of portal blood with an end–to–side portacaval shunt, and (iii) Group HI: partial diversion of portal blood through a side–to–side portacaval shunt.

Portal flow was measured during surgery with an electromagnetic flowmeter above and below the shunt and the degree of shunting calculated.

Results show that the shunt fraction measured with ursodeoxycholic acid is well–correlated with hemodynamic data. No overlap between Groups I to III is observed.

It is concluded that the shunt fraction of nutrient portal blood can be measured with this noninvasive method. Minute amounts of ursodeoxycholic acid were used in order to be completely metabolized by the liver, even in spite of hepatocellular dysfunction. Therefore, this method should be valid in cirrhotic patients and be useful to decide the type of portosystemic shunt to propose for the decompression of gastroesophageal varices.
Hla in Chileans With Intrahepatic Cholestasis of Pregnancy
Authors: Reyes Humberto , Wegmann María E. , Segovia Nelly , Cuchacovich Miguel , Jadresic Enrique , Contador Mónica , Fuentes Cecilia , Melendez Mireya
Published: July 2010

A possible association between intrahepatic cholestasis of pregnancy (ICP) and human–leukocyte histocompatibility (HLA) antigens-used as genetic markers-was studied in 100 women with ICP compared to 100 multiparous women without a past history of the disease. Because we previously found a higher frequency of ICP in women with an overt Araucanian Indian descent than in Chilean Caucasoids, women from both ethnic groups were studied. Among the 37 specificities of the HLA system studied (17 of HLA–A, 16 of HLA–B, and 4 of HLA–C series), only HLA–BW16 showed a tendency to be more frequent in women with ICP rather than in control women. This finding appears to be related with ethnic origin and not ICP, HLA–BW16 was significantly more frequent in women with Araucanian Indian descent (43.4%) than in Chilean Caucasoids (16.3%) (p < 0.01). The high frequency of HLA–BW16 in the predominantly Caucasoid population in Chile, in comparison with Caucasians in Europe and in North America, may be another indicator of their ethnic admixture with aborigine groups. The high frequency of HLA–BW16 reported in North American Indian–admixed groups (16%) suggests that HLA–BW16 may be a genetic characteristic common to some aboriginal populations in North and South America.
Four Generations of Arteriohepatic Dysplasia
Authors: Labrecque Douglas R. , Mitros Frank A. , Nathan Radha J. , Romanchuk Ken G. , Judisch George F. , El-Khoury George H.
Published: July 2010

Arteriohepatic dysplasia (AHD) is a multisystem disorder which is characterized by liver, heart, eye, and bony abnormalities. A characteristic facies is also present. The etiology is not clear, and some authors have favored an in utero toxin or infection as the cause. Other reports have shown parent–to–child transmission suggesting an autosomal dominant form of inheritance. This study documents the presence of AHD characteristics in four successive generations of a single kindred. Overall, 15 of 24 members had at least some characteristics of AHD. In addition to the usual findings, renal disease, a small flat face on lateral X–ray, and mild conductive hearing loss were frequently noted in this kindred. Physiological studies on one member revealed a normal bromo–sulfophthalein Tm and S but a late rise in plasma bromosulfophthalein and indocyanine green.

This study strongly supports an autosomal dominant form of transmission for the AHD syndrome. The ease of determining the eye, bone, and heart abnormalities should simplify genetic studies of other patients' families. In addition, because these characteristics are recognizable at birth, documenting their presence in a jaundiced neonate should spare the infant unnecessary and potentially dangerous surgery to rule out extrahepatic obstruction, especially if one or more family members demonstrate the same abnormalities.
The Effect of Propranolol on Portal Hypertension in Patients With Cirrhosis: A Hemodynamic Study
Authors: Lebrec Didier , Hillon Patrick , MuńOz Cristina , Goldfarb Gerard , Nouel Olivier , Benhamou Jean-Pierre
Published: July 2010

The gradient between wedged and free hepatic venous pressures was measured in patients with alcoholic cirrhosis before and 1, 3, and 9 months after continuous oral administration of propranolol at doses reducing the heart rate by 25% or after administration of a placebo. The gradient between wedged and free hepatic venous pressures decreased throughout the duration of propranolol administration, and it did not significantly change in the patients receiving placebo. Since the gradient between wedged and free hepatic venous pressures closely reflects portal venous pressure in alcoholic cirrhosis, it is concluded that continuous oral administration of propranolol produced sustained reduction in portal venous pressure in these patients.
The Role of Hepatocyte Enlargement in Hepatic Pressure in Cirrhotic and Noncirrhotic Alcoholic Liver Disease
Authors: Blendis Laurence M. , Orrego Hector , Crossley Ian R. , Blake Joan E. , Medline Alan , Israel Yedy
Published: July 2010

The relationship between hepatocyte enlargement and intrahepatic and portal pressures was studied in a group of 163 patients with alcoholic liver disease presenting liver biopsy abnormalities, including 91 cirrhotics. For the complete group, hepatocyte surface areas were significantly correlated (r = 0.73, p < 0.0001) with pressure. Cirrhotics as a group had a mean average pressure of 20.4 ± 0.9 mm Hg, while that for noncirrhotics was 11.7 ± 0.8 mm Hg (p < 0.0001). The corresponding values for mean hepatocyte surface areas were 2,308 ± 76 μm2 and 1,692 ± 63 /μm2. In cirrhotics with corrected sinusoidal pressures (wedged hepatic vein pressure–free pressure), or intrahepatic pressures below 10 mm Hg, mean hepatocyte surface area 1,405 ± 51 μm2 was in the same area range as that of the group of noncirrhotics with similar pressures (1,410 ± 46 μm2). It is postulated that higher pressures often seen in cirrhotics are due to the existence of larger cells in these patients, rather than the existence of “regenerative” nodules. Cirrhosis per se was not a good indicator of portal hypertension and 23% of cirrhotics were shown to have pressures below 10 mm Hg. On the other hand, when hepatocyte enlargement was used as an indicator of portal pressure, it was found that pressures below 10 mm Hg occurred in only 6.8% of individuals with cell surface areas exceeding 1,700 μm2. In patients with or without cirrhosis in whom two pressure determinations were carried out simultaneously with the biopsies, it was observed that changes in pressures were followed remarkably closely by changes in cell surface areas in the same direction (91% of cases, p < 0.001). Elevated portal pressure could also be found in a group of 43 chronic alcoholics in whom 50 liver biopsies were reported as “normal.” In these, correlation between hepatocyte area and intrahepatic pressure was also highly significant (r = 0.88, p < 0.0001) with an abrupt increase in intrahepatic pressure above 10 mm Hg, for hepatocyte areas greater than 1,500 μm2. Collagen accumulation in the space of Disse has been proposed as a cause of portal hypertension. While we have confirmed that a correlation exists between Disse collagen scores and intrahepatic or corrected sinusoidal pressures, when measured at a single point in time, (r = 0.63, p < 0.0001), collagen did not follow the changes in pressure in 65% of the cases. While these observations firmly support our earlier postulation of a strong correlation between hepatocyte enlargement and the production of intrahepatic or portal hypertension, further studies should be conducted to establish causality in the association between these two factors.
Rosette Inhibitory Factor: T–Lymphocyte Subpopulation Specificity and Potential Immunoregulatory Role in Hepatitis B Virus Infection
Authors: Sanders Gary , Perrillo Robert P.
Published: July 2010

We have observed the disappearance of rosette inhibitory factor (RIF) from the serum of 19 patients with acute hepatitis B virus infection. This occurred at a time coinciding with the detection of anti–HBs. In addition, levels of RIF activity were significantly greater (p < 0.001) in 35 HBsAg carriers who lacked anti–HBs when compared to 15 carriers who regularly demonstrated this antibody. In all instances, RIF effect was partial affecting some, but not all, T–lymphocytes from forming erythrocyte rosettes.

To define if RIF exhibits an effect on specific T–lymphocyte subpopulations, lymphocytes from healthy donors were separated into TM (helper), TG (suppressor), and To (null) subpopulations by an immunoglobulin–ox–cell rosette depletion method. The effect of RIF on erythrocyte rosette formation and Fc–receptor expression in these subpopulations was assessed. TG–lymphocytes were found to be refractory to RIF–mediated suppression of erythrocyte rosette formation while TM–lymphocytes demonstrated an enhanced sensitivity to RIF. Incubation of TG– and To–lymphocytes, potential TM–precursor cells, with RIF resulted in a decreased expression of new IgM–Fc receptors.

In order to determine if any functional significance could be derived from these findings, the effect of RIF on in vitro immunoglobulin secretion was tested. Using pokeweed mitogen–stimulated mononuclear cell cultures, purified RIF–low density lipoprotein was shown to suppress IgM, IgG, and IgA secretion by 75.3, 74.3, and 59.3%, respectively.

These data are consistent with the hypothesis that RIF is a potential immunoregulatory protein which could contribute to the lack of anti–HBs noted during the acute phase of hepatitis B and in the majority of HBsAg carriers.
Taurocholate Transport by Rat Liver Sinusoidal Membrane Vesicles: Evidence of Sodium Cotransport
Authors: Inoue Masayasu , Kinne Rolf , Tran Thao , Arias Irwin M.
Published: July 2010

To elucidate the first step in the vectorial transport of bile acids by the liver, plasma membrane vesicles were isolated from rat liver by differential and sucrose–Ficoll density gradient centrifugation. The membranes were selectively enriched 20–fold in Na+,K+-ATPase activity, a marker of sinusoidal plasma membranes. Electron microscopy of pellets from sinusoidal membrane fraction did not reveal other organelles.

The initial rate of taurocholate uptake by the membrane vesicles was stimulated by a sodium gradient but not by a potassium gradient (Naoutside> Nainside). Sodium–dependent uptake of taurocholate was inhibited at low temperature (0oC), reduced by decreasing intravesicular space, and showed transstimulation in tracer exchange experiments indicating that uptake into vesicles, rather than binding to membranes, was occurring. Sodium–dependent taurocholate transport by the vesicles exhibited saturation kinetics with respect to taurocholate (apparent Km = 56 μM, Vmax = 0.65 nmoles per mg × 15 sec at 100 mM NaNO3 and 25oC) and sodium (apparent Km = 48 mM at 50 μM taurocholate). Other cations, such as lithium and choline, did not replace sodium in its stimulatory action. Sodium–dependent taurocholate uptake was selectively inhibited by cholic acid and probenecid. When the electrical potential difference across the vesicle membrane was altered by anion replacement, a more negative intravesicular potential inside the vesicles stimulated and a more positive potential inhibited sodium–dependent taurocholate transport. These data indicate the presence of a taurocholate–sodium cotransport system in the sinusoidal membranes of rat hepatocytes. This sodium–cotransport system probably participates in sodium–dependent uptake of bile acids into the hepatocyte. Bile acid secretion in the liver can be classified as secondary active transport.
Importance of Solvent Drag and Diffusion in Bile Acid–Dependent Bile Formation: Ion Substitution Studies in Isolated Perfused Rat Liver
Authors: ANWER Sawkat M. , Hegner Dietmar
Published: July 2010

Ion substitution studies were carried out in the isolated perfused rat liver to define the importance of solvent drag and diffusion in bile acid–dependent bile formation. Two different methods, namely single injection (20 μmoles) and continuous infusions at 0.4, 0.8, 1.2, and 1.6 μmoles per min taurocholate (TC), were used to determine the bile acid–dependent bile flow (BADF). Both methods gave essentially the same results. Replacement of Na+ (146 mM) by 120 or 146 mM Li+ and Cl- (127 mM) by 120 mM NO3
- increased BADF significantly. On the other hand, replacement of Na+ by 120 mM choline and Cl- by 120 mM isethionate decreased the BADF. The osmolarity of TC solution was not different when Na+ was replaced by 120 mM Li+ or choline and TC did not affect the osmotic activity of NaCl, LiCl, and choline–Cl differently. Thus, the observed effect of Na+ replacement on BADF is not due to any change in the osmotic activity of the secreted TC. Substitution of HCO3
- by equimolar tricine also decreased BADF. Under this condition, BADF increased when NaCl was replaced by equimolar NaN03. Thus, HCO3” does not seem to be essential for TC choleresis. Since Li+ and NO3” are more permeable, and choline and isethionate are less permeable than Na+ and Cl-, respectively, these results suggest that the BADF is dependent on the permeability of the substituting cations and anions and thus support the hypothesis that solvent drag and diffusion play an important role in BADF.
Discrepancy Between Ultrasound and Oral Cholecystography in the Assessment of Gallstone Dissolution
Authors: Shapero Theodore F. , Rosen Irving E. , Wilson Stephanie R. , Fisher Murray M.
Published: July 2010

The Sunnybrook Medical Centre Gallstone Study is a randomized, controlled, double–blind study of chenodeoxycholic acid for dissolution of radiolucent gallstones. Of the first 22 patients whosestones were apparently totally dissolved on oral cholecystography, seven were found to have residual small stone fragments on ultrasound examination of the gallbladder. Continuing chenotherapy was unsuccessful in dissolving these fragments. The possibility that the residual stones represent insoluble nuclei of the original calculi must be considered. Responses to cholelitholytic therapy and subsequent stone recurrences need to be reevaluated using ultrasound.
Liver Transplantation in Adults
Authors: Van Thiel David H. , Schade Robert R. , Starzl Thomas E. , Iwatsuki Shunzaburo , Shaw Byers W. , Gavaler Judith S. , Dugas Marcus
Published: July 2010

Human liver transplantation has been possible since 1967. We report our experience in 32 adult patients who received liver transplants at the University of Pittsburgh over a 16–month period. Survival data, method utilized for patient selection, costs, and morbidity of the procedure are discussed.
Hepatic Fibrosis After Long–Term Administration of Ethanol and Moderate Vitamin A Supplementation in the Rat
Authors: Leo Maria Anna , Lieber Charles S.
Published: July 2010

Rats were fed up to 9 months diets supplemented with vitamin A in an amount that, by itself, had no apparent adverse effect on the liver. When associated with chronic ethanol administration, vitamin A supplementation strikingly exacerbated ethanol–induced abnormalities: fat accumulation was increased and numerous giant mitochondria were observed. Furthermore, lesions appeared which ethanol alone does not produce in rats, namely necrosis, inflammation, and fibrosis. Vitamin A supplementation increased the number of fat storing cells (lipocytes) which positively correlated with vitamin A accumulation in the liver. However, when vitamin A supplementation was combined with ethanol administration, vitamin A levels in the liver and the number of fat storing cells decreased and numerous myofibroblasts appeared in association with abundant collagen fibers. There was also hepatic inflammation and necrosis, accompanied by a rise in serum glutamate dehydrogenase, SGOT, and SGPT and a decrease in retinol binding protein and vitamin A. We conclude that amounts of vitamin A, which by themselves appear harmless, may produce severe liver lesions when associated with chronic ethanol consumption.
Modulation by S–Adenosyl–L–Methionine of Hepatic Na+, K+–Atpase, Membrane Fluidity, and Bile Flow in Rats With Ethinyl Estradiol–Induced Cholestasis
Authors: Boelsterli Urs A. , Rakhit Gopa , Balazs Tibor
Published: July 2010

Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug–induced cholestasis. To elucidate the mechanism by which S–adenosyl–L–methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague–Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (25 mg per kg, 3 times per day, for 3 days). Na+, K+–ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE–treated rats resulted in a marked increase in Na+, K+–ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic Mg2+–ATPase and y–glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in vivo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+, K+–ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+, K+–ATPase was associated with SAMe–induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE–induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE–induced impairment of bile secretory function.
Effect of (+)–Cyanidanol–3 in Acute Hav, Hbv, and Non–A, Non–B Viral Hepatitis
Authors: Piazza Marcello , Guadagnino Vincenzo , Picciotto Ludovico , Mercato Renato De , Chirianni Antonio , Orlando Raffaele , Golden Gerard
Published: July 2010

A double–blind trial was carried out on 124 randomized patients with acute viral hepatitis, of whom 58 were treated with (+)–cyanidanol–3 in a dose of 3 gm per day and 66 with placebo. The treatment was given for 50 days. At 5–day intervals, SGPT, SGOT, and total serum bilirubin levels were tested. For the total group of patients, the levels of SGPT and SGOT activity were significantly lower in the cyanidanol group than in the control group from 30th to 50th day of treatment (with exception of SGOT at Day 35) (Student's t test: p between 0.01 and 0.05).

In 35 patients with acute hepatitis caused by hepatitis A virus, 17 treated with cyanidanol and 18 controls, no significant differences for either SGPT and SGOT were observed. In 58 patients with acute hepatitis caused by hepatitis B virus, 27 treated with cyanidanol and 31 controls, a trend in favor of the cyanidanol group was observed after 30 days of treatment in SGPT activity, the difference being statistically significant after 45 days of treatment (p < 0.05). There was also a trend in favor of the cyanidanol group for SGOT activity from the 30th to 45th day of treatment (p between 0.05 and 0.10). In 31 patients with acute hepatitis caused by hepatitis non–A, non–B virus, 14 treated and 17 controls, a significant difference between the groups, in favor of the cyanidanol group was observed for both SGPT and SGOT after 40 and 45 days of treatment (p < 0.05). The effect of cyanidanol on the transaminases appeared to be a suppression of the “rebounds” occurring from Day 30 onward. There were no significant differences in the evolution of levels of total serum bilirubin.

Among the patients with acute hepatitis caused by hepatitis B virus, 10 of the 27 patients treated with cyanidanol became HBsAg negative after 50 days of treatment compared to 16 of 31 in the control group. This difference is not statistically significant. Cyanidanol had no effect on carrier state. Since patients who show rebounds in levels of serum transaminase activity after apparent recovery from the initial phase usually undergo a more prolonged convalescence, it appears that treatment with (+)–cyanidanol–3 could be useful in shortening the total duration of their illness. It is essential that the investigations of the effects of drugs in viral hepatitis be performed on well–defined etiological homogeneous subgroups.
Plasma Norepinephrine, Weak Neurotransmitters, and Renin Activity During Active Tilting in Liver Cirrhosis: Relationship With Cardiovascular Homeostasis and Renal Function
Authors: Bernardi Mauro , Trevisani Franco , Santini Costanza , Zoli Giorgio , Baraldini Mario , Ligabue Amedeo , Gasbarrini Giovanni
Published: July 2010

Derangements in cardiovascular homeostasis are well–known features of liver failure. To evaluate the role of possible alterations in adrenergic and reninangiotensin systems in this context, tilting–induced changes in plasma norepinephrine, octopamine, β–phenylethanolamine, and plasma renin activity were related to modifications in blood pressure, heart rate, plasma volume, and renal function in 10 healthy controls and 20 patients with liver cirrhosis.

After 2 hr of bed rest, the patients had higher norepinephrine (p < 0.05), octopamine, β–phenyl–ethanolamine (p < 0.001), plasma renin activity (0.1 ± p ± 0.05), heart rate (p < 0.05), and lower mean arterial pressure (0.1 ± p ± 0.05). Renal function was characterized by reduced creatinine clearance and filtered sodium (p < 0.001); tubular rejection fraction of sodium and sodium excretion were not significantly reduced. After the change in posture (observation period of 1 hr), tilting–induced tachycardia was abolished in patients who also showed a significant drop in blood pressure after a transient initial increase at 10 min, whereas a steady state was observed in normal subjects. Norepinephrine and plasma renin activity increases were greater and more prolonged in cirrhotics than in controls; octopamine and β–phenylethanolamine did not change in the latter and increased in the former, where they correlated with plasma norepinephrine in basal conditions and after tilting (r ± 0.49). Creatinine clearance, filtered sodium, and tubular rejection fraction of sodium underwent a greater decrease in cirrhotics. Although plasma volume reduction was more evident in cirrhotics, it remained steady after 10 min in both groups. In basal conditions and after tilting (60 min), plasma renin activity inversely correlated with arterial pressure (p < 0.05) and creatinine clearance (p < 0.01) in cirrhotic patients.

In conclusion, the adrenergic system, although hyper stimulated, did not achieve an adequate cardiovascular response which could be due, at least in part, to hyperproduction of weak neurotransmitters. The renin–angiotensin system played a compensatory role and its activation appears to be mainly dependent on intrarenal mechanisms.
Relationship of Pretransplant Hepatobiliary Disease to Bile Duct Damage Occurring in the Liver Allograft
Authors: Fennell Robert H. , Shikes Robert H. , Vierling John M.
Published: July 2010

Histopathological features of nonsuppurative destructive cholangitis have been described in primary biliary cirrosis, chronic graft–vs.–host disease, and chronic rejection of human liver allografts. To determine whether or not susceptibility to injury of interlobular bile ducts was related to the original hepatobiliary disease requiring transplantation, we compared the histopathology of allografts transplanted into two groups of patients. The first group consisted of patients whose original hepatobiliary diseases primarily affect bile ducts: primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. The second group consisted of patients whose original hepatobiliary diseases do not result in injury to interlobular bile ducts. In 32 liver allografts studied histopatho–logically, the original disease did not recur. Interlobular bile duct damage occurred, however, in 17 of the 32 and resembled that seen in primary biliary cirrhosis. The spectrum of bile duct injury included mononuclear inflammation of the bile duct epithelium, destruction of the bile duct epithelium, and dissolution of the bile duct. There was no relationship between the frequency or severity of bile duct damage and original hepatobiliary disease, age, sex, duration of allograft survival, or cause of death. We conclude that nonsuppurative destructive cholangitis occurs frequently in liver allografts and represents one component of allograft rejection. This lesion resembles, in many respects, that seen in primary biliary cirrhosis so that histopathological differentiation may be difficult.
In Vivo And Electron Microscopic Observations of the Hepatic Micro Vasculature in the Rat Following Portacaval Anastomosis
Authors: Mccuskey Robert S. , Vonnahme Franz J. , Grun Martin
Published: July 2010

The livers of rats subjected to end–to–side portacaval anastomoses were studied 3 to 5 months postoperatively by in vivo and electron microscopy. Compared with sham–operated controls, the livers of portacaval anastomoses animals contained dilated, tortuous networks of sinusoids. The velocity of blood flow in these vessels tended to be slower and more variable than controls, but always progressed toward the hepatic venules. Blood entered the sinusoids from portal venules and from arteriosinus twigs which terminated in the initial segments of some of the sinusoids at the periphery of the lobule. Together, the arteriosinus twigs and the short, initial segments of these sinusoids formed functional arterioportal anastomoses. These, in combination with the lack of portal venous inflow, resulted in retrograde blood flow in portal venules. Nevertheless, blood still flowed from these portal venules into the sinusoids unless the sinusoid was fed by an arteriosinus twig. In addition to these microcireulatory alterations, the number of Kupffer cells that phagocytized latex particles was less in the animals with portacaval anastomoses, as was the number of particles ingested by these cells. Scanning and transmission electron microscopy confirmed the paucity of Kupffer cells. Those seen appeared inactive since they were flattened, exhibited few microplicae and filopodia and contained few latex particles. The endothelial cells of the sinusoid lining were perforated by increased numbers of large fenestrae which may be a reflection of elevated intrasi–nusoid pressures generated by the expanded arterialization of the sinusoid bed. The observed dilated sinusoid network interspersed by narrowed plates of hepatocytes is also consistent with this hypothesis. Finally, scattered nodular foci were observed which contained enlarged hepatocytes, narrow sinusoids, active Kupffer cells, and more normal rates of blood flow. Such sites may represent attempts by the liver to regenerate its normal architecture.
Efficacy of Hepatitis B Immune Globulin for Prevention of Perinatal Transmission of the Hepatitis B Virus Carrier State: Final Report of A Randomized Double–Blind, Placebo–Controlled Trial
Authors: Beasley Palmer R. , Hwang Lu-Yu , Stevens Cladd E. , Lin Chia-Chin , Hsieh Fon-Jou , Wang Kwei-Yu , Sun Tsu-Shen , Szmuness Wolf
Published: July 2010

A randomized double–blind, placebo–controlled efficacy trial of hepatitis B immune globulin (HBIG) for prevention of the mother–to–infant transmitted HBsAg carrier state was conducted in Taiwan where the carrier rate in the general population is 15 to 20%. HBIG was given immediately after birth to infants of e antigen positive HBsAg carrier mothers, and all infants were followed for at least 15 months. Among 61 placebo recipients, the carrier rate was 92%; compared with 26% among 57 infants who received 0.5 ml HBIG at birth, 3 months, and 6 months, and 54% among 67 infants who received a single 1.0 ml dose of HBIG at birth only. Efficacy was 71 and 42%, respectively, for the two treatment schedules. The most common response of HBIG–treated infants was passive–active immunization which was 27% in the single–dose group and 61% in the three–dose group. Some of the infants who became carriers were probably infected as HBIG protection waned, and we expect that higher efficacy can be achieved by hepatitis B vaccine in conjunction with HBIG.
Elevated Circulating Immune Complexes in Primary Sclerosing Cholangitis
Authors: Bodenheimer Henry C. , Larusso Nicholas F. , Thayer Walter R. , Charland Colette , Staples Parker J. , Ludwig Jurgen
Published: July 2010

Primary sclerosing cholangitis (PSC) is a syndrome of unknown etiology characterized by an association with inflammatory bowel disease in 50% or more cases. Since altered immunity, including circulating immune complexes, has been implicated in the pathogenesis of inflammatory bowel disease, we postulated that humoral immune mechanisms might also be important in the development of PSC. Therefore, as an initial step in testing this hypothesis, we examined sera of patients with PSC for the presence of circulating immune complexes by two independent methods: Clq binding and Raji cell assays. Twenty–four patients with PSC, 16 of whom had coexisting chronic ulcerative colitis, were prospectively selected by predefined biochemical, histologic, and radiographic criteria. Sixteen patients with inflammatory bowel disease and normal liver tests as well as six patients with extrahepatic biliary obstruction served as disease controls. Sera were positive for circulating immune complexes by at least one method in 80% (16/20) of patients with PSC; 70% (14/ 20) were positive by the Raji cell assay, 58% (14/24) by the Clq binding assay, and 45% (9/20) by both methods. Levels of circulating immune complexes by each assay were higher in sera from patients with PSC than in sera from healthy controls or patients with inflammatory bowel disease alone (p < 0.01). There were no differences in the levels of circulating immune complexes or in the frequency of positive tests in PSC patients with or without associated inflammatory bowel disease. In addition, there was no difference between the Raji cell binding of sera from six patients with extrahepatic biliary obstruction and six healthy controls tested concurrently. These data are consistent with the hypothesis that immunologic mechanisms may be important in the pathogenesis of PSC.
Analysis of Bilirubins in Biological Fluids by Extraction and Thin–Layer Chromatography of the Intact Tetrapyrroles: Application to Bile of Patients With Gilbert's Syndrome, Hemolysis, or Cholelithiasis
Authors: Fevery Johan , Blanckaert Norbert , Leroy Pol , Michiels Roger , Heirwegh Karel P.M.
Published: July 2010

A method was developed to extract quantitatively the bilirubins from bile, urine, serum, stool, and preparations from liver with a chloroform–ethanol mixture at pH 1.8 in the presence of ascorbic acid and NaCl. Extracted pigment was submitted to thin–layer chromatography, and the separated bilirubins were either immediately eluted and determined spectrophotometrically or individually converted to ethyl anthranilate azo derivatives for thin–layer chromatographic analysis of each isolated pigment band. Bilirubins in duodenal bile of eight healthy adults comprised 1.5 ± 1.3% unconjugated bilirubin–IXα, 69 ± 6% bilirubin diglucuronide, and 16 ± 4% bilirubin monoglucuronides. Mixed diconjugates containing one glucuronosyl moiety and either one xylosyl or one glucosyl group amounted to 10 ± 3%. Most samples (6 of 8) contained trace amounts (0.6 ± 0.6%) of unconjugated bilirubin–IXβ, in agreement with nearly exclusive cleavage of heme at the α–meso position. The composition of the bilirubins in bile was normal in 6 patients with cholesterol gallstones, 4 with chronic hepatitis, and 3 with hemolysis. In duodenal bile of individuals with Gilbert's syndrome (n = 10), the concentration of bttirubin conjugates was comparable to that in healthy adults, but the proportion of bilirubin diglucuronides (52 ± 8%) was decreased. The concentration of unconjugated bilirubin–IXα showed a fair positive correlation with that of bilirubin monoglucuronide and was increased in half of the patients with Gilbert's syndrome.
Effect of Euglycemic Insulin Infusion on Plasma Levels of Branched–Chain Amino Acids in Cirrhosis
Authors: Marchesini Giulio , Forlani Gabriele , Zoli Marco , Dondi Cristina , Blanchi Glampaolo , Bua Vlncenzo , Vannini Pletro , Plsi Emilio
Published: July 2010

To test the hypothesis that hyperinsulinism is responsible for reduced branched–chain amino acids in cirrhotics, plasma amino acids were sequentially determined in 8 controls and 8 matched cirrhotics during continuous i.v. insulin infusion. An artificial endocrine pancreas which infused glucose was used to sustain euglycemia. Basal plasma insulin levels were high and branched–chain amino acids were reduced in cirrhotics. Insulin infusion raised insulin levels to 3 to 4 times basal values. During the test, the decline in branched–chain amino acids was markedly higher in controls who had similar steady–state insulin levels. Not only did the level of branched–chain amino acids in controls reach the values seen in cirrhotics after 60 min, but the levels continued to fall at a significantly higher rate throughout the second hour. Glucose consumption and the ratio of glucose infused/steady–state insulin—a measure of tissue sensitivity to insulin—were markedly reduced in cirrhotics and positively correlated with the decline in branched–chain amino acids. In cirrhotics, insulin effects on carbohydrate and branched–chain amino acid metabolism were reduced. Low branched–chain amino acid levels in cirrhotics are not likely to depend only on hyperinsulinism.
Role of the Liver in Endotoxin–Induced Hyperinsulinemia and Hyperglucagonemia in Rats
Authors: Cornell Robert P.
Published: July 2010

The intravenous administration of bacterial endotoxin to fasted rats elicited basal portal and systemic venous hyperinsulinemia and hyperglucagonemia. Enhanced pancreatic secretion of insulin and glucagon was implied by the elevated portal venous hormonal levels. Elevated insulin and glucagon levels were present at 4 hr after a 33 m¨g/100 gm intravenous endotoxin dose despite no fluctuation of the plasma glucose concentration. The role of the liver in the pancreatic hormonal response to endotoxin was investigated by infusing lipopolysaccharide slowly into the portal vein or systemic inferior vena cava. At doses of 33 and 100 m¨g per 100 gm, endotoxin administered via the systemic route stimulated significantly greater insulin and glucagon responses than did portal administration. Furthermore, rats with acute liver injury induced by partial (67%) hepatectomy, which depressed Kupffer cell phagocytosis, did respond to the 33 m¨g per 100 gm intraportal endotoxin dose with significantly greater hyperinsulinemia and hyperglucagonemia. These data suggest that hepatic Kupffer cells normally function to remove lipopolysaccharideo from the portal venous blood and that at least at low pharmacological doses the pancreatic hormonal response to endotoxin is mediated by an unknown systemic mechanism.
Gallbladder Glycoprotein Secretion in Mice With Hemolytic Anemia and Pigment Gallstones
Authors: LaMont Thomas J. , Turner Bradley S. , Bernstein Seldon E. , Trotman Bruce W.
Published: July 2010

The nb/nb mouse with hereditary hemolytic anemia provides an animal model for the study of pigment gallstone disease. We measured glycoprotein synthesis and secretion in gallbladder neck and fundus of 6–month–old mice without stones, and in 12–month–old mice with and without stones in order to determine the effect of age and presence or absence of stones on mucin release. We observed that the gallbladder necks of 12–month–old nb/nb mice with pigment stones secreted more 3H–glucosamine–labeled glycoprotein (68.2 dpm per m¨g protein) than did the gallbladder necks of mice without pigment stones (31.1 dpm per m¨g protein).

When expressed as a percentage of total glycoprotein synthesis in the gallbladder neck, secretion of glycoprotein was 23.4% in 6–month–old hemolytic mice and 28.7% in 12–month–old hemolytic mice without pigment stones. However, in the presence of pigment stones, the percentage of secreted glycoprotein rose to 40.8%, which differed significantly from both 6–month–old (p < 0.02) and 12–month–old mice without stones (p < 0.05). Our results suggest that the presence of gallstones in nb/ nb mice was associated with a localized increase in glycoprotein release from gallbladder neck. The mechanism for this increase may be precipitation of pigment–mucin concretions in the gallbladder neck glands which has been previously described in this animal model.
Early Morphologic and Enzymatic Changes in Livers of Rats Treated With Chenodeoxycholic and Ursodeoxycholic Acids
Authors: Shefer Sarah , Zaki George F. , Salen Gerald
Published: July 2010

The effect of high doses of chenodeoxycholic and ursodeoxycholic acids on hepatic morphology and on cholesterol and hile acid metabolism was examined in the rat. After 2 weeks of either cheno or ursodeoxycholic acid feeding, the livers of the treated rats revealed marked proliferation of the smooth endoplasmic reticulum which appeared as an adaptation phenomenon of the microsomal enzyme system in response to bile acid intake. However, the livers of the chenodeoxycholic acid–treated rats showed early alteration that included mild triaditis, swelling of the bile canalicular microvilli, distended Golgi vesicles, whorling of the mitochondria, and presence of large vacuoles bound by single membranes. During cheno– or ursodeoxycholic acid treatment, the administered bile acid predominated in the bile and amounted to 79 or 67% of the biliary bile acids, respectively. At the same time, the concentration of the muricholic acids was also increased. Biliary cholic acid content dropped significantly, but no change in lithocholic acid concentration was observed. In addition, the activity of HMG–CoA reductase as well as that of cholesterol–7a–hydroxylase was reduced by either of the administered bile acids, while no change in hepatic cholesterol content was detected, and intestinal cholesterol absorption was not significantly different from that of controls.

These results show that cheno– and ursodeoxycholic acids inhibited hepatic cholesterol and bile acid synthesis but did not increase either intestinal cholesterol absorption or hepatic microsomal cholesterol content. Since the amounts of biliary lithocholic acid were similar in the bile acid–treated animals, the morphologic abnormalities detected in the chenodeoxycholic acid–fed rats are probably due to an increased pool of chenodeoxycholic acid. However, lithocholic acid–induced liver injury cannot be excluded.