bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis B surface antigen binds to human serum albumin cross-linked by transglutaminase†
Authors: Thung Swan N. , Wang De-Fa , Fasy Thomas M. , Hood Andrew , Gerber Michael A.
Published: March 2007

It has been postulated that polymerized human serum albumin may play a role in the infection of hepatocytes by hepatitis B virus, because both the envelope of hepatitis B virus (HBsAg) and hepatocytes exhibit binding activity for human serum albumin after cross-linking by glutaraldehyde. Since glutaraldehyde-dependent cross-linking of albumin molecules is not likely to occur in vivo, we considered the possibility that albumin may be polymerized by the action of transglutaminase enzymes present in plasma as activated factor XIII or released into plasma from tissues. Guinea pig liver transglutaminase covalently cross-linked human serum albumin molecules into dimers, trimers and polymers up to hexamers as shown by polyacrylamide gel electrophoresis in sodium dodecyl sulfate. HBsAg particles bound transglutaminase-cross-linked as well as glutaralde-hyde-cross-linked human serum albumin as demonstrated by radioimmunoassay and immunoelectron microscopy. The binding was blocked by preincubation of HBsAg with transglutaminase-or glutaraldehyde-cross-linked human serum albumin, anti-HBs or monoclonal anti-pre-S2, but not by polymerized bovine or rat serum albumin or by monomeric human serum albumin. These data indicate that HBsAg particles contain specific binding sites for transglutaminase-cross-linked human serum albumin, but it remains to be determined whether the albumin polymers play a role in the attachment of hepatitis B virus to hepatocytes.
Expression of different members of heat shock protein 70 gene family in liver and hepatomas
Authors: Cairo Gaetano , Schiaffonati Luisa , Rappocciolo Emilia , Tacchini Lorenza , Bernelli-Zazzera Aldo
Published: March 2007

The levels of expression of some genes of the HSP 70 family have been assessed in rat liver and in a series of transplantable hepatomas with different growth rates, subjected to heat shock in vivo. For this purpose, the mRNAs for the constitutive cognate HSC 73, the heat-inducible HSP 70 and the glucose-regulated GRP 78 have been analyzed by: (i) translation in reticulocyte lysates; (ii) hybrid-selected translation, and (iii) Northern blot analysis. In comparison with the liver, the fastgrowing 3924A hepatoma has an increased constitutive amount of HSC 73 mRNA and a lower induction of HSP 70 mRNA after heat shock. The behavior of the 9618A slow-growing hepatoma is more similar to that of the liver, indicating that the changes detected in the fastgrowing hepatoma are correlated to the high growth rate of the tumor rather than to carcinogenesis. This conclusion is reinforced by the results obtained with Yoshida AH-130 cells, growing at two different rates imposed by the environment in which they develop. When the Yoshida hepatoma grows rapidly in the peritoneal cavity, constitutive expression of HSC 73 mRNA is high and the inducibility of HSP 70 mRNA is poor: the opposite occurs when the tumor grows slowly in the subcutaneous compartment.

The amount of GRP 78 mRNA increases progressively from the liver to the fast-growing hepatoma.

The level of HSC 73 mRNA seems to correlate with the methylation state of the corresponding gene.
Do transplanted human livers regenerate?
Authors: Koch Katherine S. , Leffert Hyam L.
Published: March 2007

Two individuals undergoing orthotopic hepatic transplantation received livers from donors who were on average 10 kg smaller than themselves based on recipient ideal body weight. As a result, the donor livers in these 2 cases were 29%-59% smaller than would be expected had the donor liver and recipient been matched ideally. The liver grafts in the recipients steadily increased in size, as determined by serial computed tomography scanning, to achieve new volumes consistent with those that would have been expected in a normal individual of the recipient’s size, sex, and age. Fasting plasma levels of amino acids, glucagon, insulin, and standard liver injury tests were monitored to determine which measure best reflected the changes observed in the size of the grafts over time. No relationship between the changes observed in any of these parameters and hepatic growth was apparent. In both cases, the liver increased in volume at a rate of ˜ 70 ml/day. These data demonstrate that a small-for-size liver transplanted into a larger recipient increases in size at a rate of ˜ 70 ml/day until it achieves a liver volume consistent with that expected given the recipient’s size, age, and sex.
Hepatic vascular toxicity of dacarbazine (DTIC): Not a rare complication
Authors: Marsh John C.
Published: March 2007

A fatal massive hepatic necrosis with widespread thrombotic occlusion of the small hepatic veins developed in two of 68 patients treated with DTIC for advanced melanoma in a randomized study. Thirteen similar reactions, in patients treated with single-agent DTIC, are reported in the literature. Several clinical and pathologic features distinguish this DTIC toxicity from Budd-Chiari syndrome and veno-occlusive disease (both well-known types of possibly drug-related hepatic vascular disease) and make it a distinctive syndrome. We were impressed by the repeated occurrence of this complication in a relatively small set of patients, in contrast with the rarity of the literature reports. We suggest that this dramatic complication could occur more frequently than commonly thought. Therefore, caution should be used with DTIC particularly in curable patients.
Cirrhotics with variceal hemorrhage: The importance of the time interval between admission and the start of analysis for survival and rebleeding rates
Authors: Burroughs Andrew K. , Mezzanotte Guerrino , Phillips Andrew , McCormick Aiden P. , McIntyre Neil
Published: March 2007

The importance of variable time of entry for analysis of survival following variceal bleeding has recently been disputed. In a study of 194 cirrhotic patients with bleeding esophageal varices in whom 2-day mortality was 3%, statistically significant differences in both survival and rebleeding rates were obtained by shifting the starting point for analysis of survival by 2 weeks following admission to hospital or by 5 days for the analysis of rebleeding. In addition, the curve of hazard function for death or for failure to control bleeding following admission clearly showed that any change in entry time in a study of variceal bleeding would introduce bias and alter survival or rebleeding rates. Thus, the starting point for analysis following variceal hemorrhage is an important confounding variable when calculating both survival and rebleeding. It should always be taken into account, particularly in clinical trials, which are often performed in centers where patients are referred from other hospitals at different times following bleeding.
Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: Influence of the extent of portal-systemic shunting
Authors: Kravetz David , Bosch Jaime , Arderiu Maite , Pizcueta Pilar M. , Rodés Juan
Published: March 2007

The present study investigated whether, in rats with portal hypertension due to cirrhosis of the liver induced by carbon tetrachloride, blood volume restitution following a hemorrhage produces an increase of portal pressure beyond control values, as observed in rats with prehepatic portal hypertension. Since carbon tetrachloride-induced cirrhosis caused mild portal-systemic shunting, in some of the cirrhotic rats (12 of 29 rats) portal-systemic shunting was enhanced by a transient (4 days) partial constriction of the portal vein, which was removed 1 week prior to the study. After baseline measurements of portal pressure and arterial pressure, 15 ml per kg of blood were withdrawn at a rate of 0.3 ml per min and reinfused 15 min later. After blood reinfusion, portal pressure and arterial pressure were measured again, and cardiac output, regional blood flows and portal-systemic shunting were determined using radioactive microspheres. Portal-systemic shunting was 78 ± 11% of total blood flow in the cirrhotic rats that had temporary portal vein constriction, but only 5 ± 2% (p < 0.001) in those that did not. Blood volume restitution in low-portal-systemic shunting rats did not produce any significant modification in splanchnic or systemic hemodynamics. However, in rats with high portal-systemic shunting, blood volume restitution produced a significant increase in portal pressure (from 9.9 ± 0.9 to 13.5 ± 0.9 mmHg, p < 0.02). This increase in portal pressure after blood reinfusion was due to a significant increase in portal vascular resistance (from 1.3 ± 0.2 to 1.9 ± 0.2 mmHg per ml per min per 100 gm, p < 0.05), since no significant changes were observed in either portal blood flow or systemic hemodynamics. Our results show that blood volume restitution after a hemorrhage worsens the portal hypertension syndrome in cirrhotic rats with high portal-systemic shunting but not in those with low portal-systemic shunting, thus demonstrating that the extent of portal-systemic shunting is an important mediator of this deleterious effect.
Effect of vasodilators on hepatic microcirculation in cirrhosis: A study in the isolated perfused rat liver
Authors: Marteau Philippe , Ballet François , Chazouillères Olivier , Chrétien Yves , Rey Colette , Petit Danielle , Poupon Raoul
Published: March 2007

We studied the effects of a series of vasodilators on intrahepatic vascular resistance of isolated perfused cirrhotic rat livers in basal conditions and during norepinephrine-induced vasoconstriction. Cirrhosis was induced by repeated intraperitoneal injections of carbon tetrachloride. The vasodilators were a nonselective β-adrenergic antagonist (propranolol), an α1-adrenergic antagonist (prazosin), a nonselective β-adrenergic agonist (isoproterenol), an α2-agonist (clonidine), nitrovasodilators (nitroglycerin and nitroprusside), calcium channel blockers (verapamil, diltiazem, nifedipine), papaverine, diazoxide and pentoxifylline. In basal conditions, isoproterenol, nitroglycerin, papaverine, pentoxifylline and nitroprusside demonstrated significant vasodilatory activity. However, the response was weak and isoproterenol was the only drug active in the therapeutic range of concentrations. Propranolol, prazosin, verapamil, diltiazem, nifedipine and diazoxide were ineffective. Prazosin, papaverine and pentoxifylline reduced norepinephrine-induced vasoconstriction, whereas isoproterenol, clonidine and propranolol were ineffective. We conclude that several vasodilators can reduce resistance in the cirrhotic rat liver, but their potency is low and few are effective at therapeutic concentrations. Furthermore, their activity may be blunted when resistance is increased by norepinephrine.
Protective effect of vasodilators on liver function after long hypothermic preservation: A study in the isolated perfused rat liver
Authors: Chazouillères Olivier , Ballet François , Chrétien Yves , Marteau Philippe , Rey Colette , Maillard Dominique , Poupon Raoul
Published: March 2007

The effects of two vasodilators, papaverine and pentoxifylline (a methylxanthine derivative), on liver function after 19 hr hypothermic preservation were investigated. Hypothermic preservation was performed according to the standard technique, and liver hemodynamics and function were studied during 70 min immediately after reperfusion in an isolated perfused rat liver system. No significant changes occurred after hypothermic storage for 5 hr. However, when the storage was prolonged to 19 hr, bile flow and taurocholate intrinsic clearance were significantly reduced; transaminase release was markedly increased and histological studies demonstrated centrilobular necrosis. Concomitantly, liver blood flow was significantly reduced and intrahepatic vascular resistance was increased. Papaverine and pentoxifylline administered during preservation and at the time of reperfusion significantly improved all parameters. The improvement was more pronounced after pentoxifylline, and this group showed no significant difference in any of the studied parameters from the control livers. The results show that two vasodilators significantly protect the liver during long hypothermic preservation. The data suggest that abnormalities of liver microcirculation are of major importance in the pathogenesis of liver injury after hypothermic storage.
Histochemical and biochemical studies on the effect of the prostacyclin derivative iloprost on CCI4-induced lipid peroxidation in rat liver and its significance for hepatoprotection
Authors: Bursch Wilfried , Taper Hendryk S. , Somer Marie P. , Meyer Stefan , Putz Barbara , Schulte-Hermann Rolf
Published: March 2007

In the present study, it was investigated whether the prostacyclin derivative Iloprost would protect hepatocytes against CCl4-induced liver injury and which mechanism(s) of hepatocellular pathogenesis might be affected by it. Rats were treated with a single oral dose of CC14 (2 ml per kg); Iloprost was infused continuously from 2 to 4 hr before intoxication until killing. The following results were obtained.

The CCl4-induced release of AST, lactate dehydrogenase and alkaline phosphatase into the serum was reduced by 50 to 70% in rats treated with doses of 0.1 and 0.5 μg Iloprost per kg per min. Infusion of 0.02 and 0.004 μg Iloprost per kg per min did not affect the CCl4-induced enzyme release into the blood.

CCl4 induced the occurrence of aldehydes (products of lipid peroxidation), which were detected by histochemical and biochemical means. At 12, 48 and 72 hr after CCI4, the aldehyde-positive liver section area was about 58, 69 and 16% in rats treated with CCl4 alone, but only about 18, 13 and <1% in rats treated additionally with Iloprost. The aldehyde-positive hepatocytes were located predominantly in the centrilobular zone of the liver. At 24 hr the extent of the aldehyde-positive section area was the same in rats with or -without Iloprost treatment (about 90%). Biochemical determination, however, revealed that at this time point the malondialdehyde content after Iloprost in rats was about 70% lower than without Iloprost treatment.

Other histochemical and histological signs of cell damage were also reduced by Iloprost treatment, predominantly in the periportal zone: loss of granular pyroninophilia indicating destruction of ribosomal RNA, fatty degeneration and hepatocellular necrosis visible in hematoxylin and eosin-stained sections.

At 48 and 72 hr after CCI4, the mitotic activity in the liver of rats treated with Iloprost was about one-half and one-quarter of that without Iloprost treatment.

In conclusion, Iloprost partially protects hepatocytes against CCI4-induced cell damage and death; periportal hepatocytes appear to be protected more effectively than centrilobular hepatocytes. The reduced content of lipid peroxidation products indicates that reduction of lipid peroxidation and/or stimulation of aldehyde elimination (repair) is involved in the hepatoprotective action of Iloprost.
Localization of adrenergic and neuropeptide tyrosine-containing nerves in the mammalian liver
Authors: Burt Alastair D. , Tiniakos Dina , MacSween Roderick N. M. , Griffiths Maureen R. , Wisse Eddie , Polak Julia M.
Published: March 2007

The distribution of adrenergic nerves in guinea pig and rat liver was studied by the immunolocalization of fibers containing tyrosine hydroxylase and dopamine β-hydroxylase, enzymes involved in the synthesis of catecholamines. In both species, adrenergic fibers were identified within portal tracts, often in close proximity hepatic artery branches. In guinea pig liver, but not liver, abundant intraacinar fibers were identified; fibers were also seen within the walls of terminal hepatic vein radicles and larger hepatic veins. The presence of peptidergic nerves containing the regulatory peptide neuropeptide tyrosine and the C-flanking peptide CPON was investigated by indirect immunofluorescence. The distribution of these nerves was similar to that of tyrosine hydroxylase- and dopamine β-hydroxylase-positive nerves and showed the same species difference. The effector sympathetic nature of tyrosine hydroxylase- and neuropeptide tyrosine-positive fibers rat liver was confirmed by chemical denervation studies using 6-hydroxydopamine.
Bile acid metabolism in human hyperthyroidism
Authors: Pauletzki Jürgen , Stellaard Frans , Paumgartner Gustav
Published: March 2007

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 < 0.01). Thyroid hormone excess caused a 34% reduction in cholic acid synthesis (5.8 ± 2.8 vs. 7.9 ± 4.2 μmoles per kg per day, p < 0.02), which was associated with a 47% decrease in cholic acid pool size (11.7 ± 3.4 vs. 22.0 ± 5.2 μmoles per kg, p < 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 chenodeoxycholic acid synthesis found in hyperthyroid subjects is compatible with an inhibition of hepatic 12α-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.
Effect of molecular charge on para- and transcellular access of horseradish peroxidase into rat bile
Authors: Hardison William G. M. , Lowe Philip J. , Shanahan Miya
Published: March 2007

The permeability pathway into the biliary tree for small inert molecules exhibits a charge selectivity. Using a method which distinguishes trans- from paracellular access, we have examined the charge selectivity of biliary access pathways for the 40-kD protein horseradish peroxidase (pI 7.5), which was derivatized to strongly anionic (pI < 3.5) and strongly cationic (pI > 9.5) isoenzymes. Each isoenzyme was injected as a bolus into the perfusate of an isolated rat liver perfused in situ with a nonrecirculating Krebs-Ringer buffer. Bile was collected at intervals and horseradish peroxidase activity was measured. Its appearance allowed differentiation of paracellular from transcellular access, and the amount entering via each pathway was quantified. The species of enzyme entering bile was the same as that injected as determined by cation-exchange high-performance liquid chromatography of biliary horseradish peroxidase. Paracellular biliary access of anionic horseradish peroxidase was less than 50% that of neutral and cationic horseradish peroxidase both in the control state and when paracellular entry was augmented with 10−10
M vasopressin. Transcellular access of anionic horseradish peroxidase was similarly restricted. To determine whether this restriction of anionic transcellular access was brought about by diminished hepatocellular uptake or augmented catabolism, we studied these parameters in 4-hr primary hepatocyte cultures. The uptake rates of all species were similar. Little or no degradation or efflux of any horseradish peroxidase species occurred over 30 min in the cultured cells. We conclude that access is charge selective for macromolecules and that this selectivity holds for trans- as well as for paracellular pathways. The selectivity of transcellular access may occur at the stage of intracellular sorting for biliary excretion.
Pharmacokinetics of tin-mesoporphyrin in man and the effects of tin-chelated porphyrins on hyperexcretion of heme pathway precursors in patients with acute inducible porphyria
Authors: Galbraith Richard A. , Kappas Attallah
Published: March 2007

Tin-mesoporphyrin shares many of the properties of its parent compound, tin-protoporphyrin. These include competitive inhibition of heme oxygenase, amelioration of jaundice and suppression of chemically induced hepatic porphyria. Tin-mesoporphyrin is cleared from the plasma of normal subjects with dose-dependent pharmacokinetics (T1/2 = 3.8 hr following i.v. administration of 1 μmole per kg body weight), and small amounts (<1% of administered dose) are excreted into the urine and feces. Intramuscular administration of tin-mesoporphyrin resulted, within 2 hr, in plasma concentrations identical to those obtained following i.v. administration, but the compound was not absorbed orally. The only dose-limiting side effect was transient cutaneous photosensitivity. High doses (1 μmole per kg body weight) of tin-mesoporphyrin resulted in significant decreases in plasma bilirubin concentrations at 24 and 48 h after treatment of normal subjects. Administration of both tin-protoporphyrin and tin-mesoporphyrin resulted in decreases in the urinary excretion of heme pathway intermediates in stable hyperexcreters with acute hepatic porphyria.
Animal models for alcoholic liver disease
Authors: Mezey Esteban
Published: March 2007

The baboon is the only animal in which alcoholic fibrosis and cirrhosis of the liver has been produced with a nutritionally adequate diet. Zinc deficiency is associated with alcoholic liver disease and may contribute to liver damage. We have therefore investigated whether zinc supplementation would reduce liver damage in ten baboons receiving ethanol and an adequate diet. Eight received ethanol at up to 25 g/kg/day (70% of calories) for up to 60 months (four were supplemented with 50 mg zinc/day). All animals gained weight, and blood concentrations of ethanol were 63-342 mg/dl. Changes in liver blood tests were slight. Liver histology only showed fatty change in six animals, severe in two, and minor inflammatory changes but no significant fibrosis or cirrhosis. In one of the animals with severe fatty change there were also degenerative changes in parenchymal cells. There was thus no significant hepatic fibrosis or cirrhosis in baboons given large amounts of ethanol and an adequate diet for up to 5 years.
Characterization of the incorporation of woodchuck hepatitis virus surface antigen into hepatocyte plasma membrane in woodchuck hepatitis and in the virus-induced hepatocellular carcinoma
Authors: Michalak Tomasz I. , Snyder Robert L. , Churchill Norma D.
Published: March 2007

Interaction between woodchuck hepatitis virus surface antigen and proteins of hepatocyte plasma membranes were examined in the course of woodchuck hepatitis virus infection. Membranes purified from animals with histologically confirmed acute hepatitis, active or persistent chronic hepatitis and the virus-related hepatocellular carcinoma were evaluated for the virus surface antigen contents, treated with agents eluting plasma membrane-bound antigen to test the extent of the antigen-membrane associations and incubated with purified, particulate woodchuck hepatitis virus surface antigen to determine membrane potential for the antigen adsorption.

Hepatocyte plasma membranes originating from woodchucks chronically infected with the virus showed the highest quantities of the incorporated virus surface antigen among membranes studied, the behavior of bound antigen as an integral and a peripheral membrane protein and the resistance to bind an exogenous antigen. Similar properties were expressed by plasma membranes prepared from hepatocytes of nontumor parenchyma displaying chronic active hepatitis of a woodchuck hepatitis virus carrier with hepatoma. Furthermore, plasma membranes originating from animals with active or persistent chronic hepatitis demonstrated identical properties, implicating that histologic activity of the chronic liver inflammatory process is not dependent on the quantity of the virus surface antigen insertion into the membrane. In contrast, hepatocyte plasma membranes from animals with acute hepatitis showed significantly lower antigen quantities, presence of the antigen specificity exclusively behaving as an integral membrane protein and noticeable ability to bind an exogenous surface antigen of the virus. Comparable, but not identical, features were observed for hepatocyte membranes purified from nodules of hepatocellular carcinoma, suggesting that neoplastic transformation of infected hepatocytes is associated with loss of the membrane-bound antigen and with simultaneous, partial recovery of the membrane potential for the antigen binding.

Comparative analysis of the properties on the woodchuck hepatitis virus surface antigen incorporation into hepatocyte plasma membranes in studied cases indicated that sustained infection with woodchuck hepatitis virus leads to an increase in the quantity of the membrane-incorporated antigen and to the appearance of the virus surface antigen specificity behaving as a peripheral membrane protein. In conclusion, this study demonstrated that the extent and the character of the antigen interaction with hepatocyte plasma membranes undergoes significant variations in the natural course of hepadna viral infection in woodchucks and that histologically distinct forms of the virus-induced liver disease express specific properties on the association.
The effects of monensin on the transport of horseradish peroxidase into intracellular lumina in cultured rat hepatocytes
Authors: Hashieh Imad Abou , Rémy Lionel , Mathieu Sylvie , Gérolami André
Published: March 2007

A kinetic study of horseradish peroxidase transport was carried out on short-term cultured adult rat hepatocytes. After 4 hr of plating, cells were preincubated with monensin (1 μM) for 1 hr before their incubation with horseradish peroxidase for different times. Monensin treatment resulted in the dilatation of the Golgi apparatus and caused the appearance of numerous intracellular lumina lined with microvilli in associated as well as isolated hepatocytes but did not modify newly formed bile canaliculi.

The frequency of their appearance increased to 28% in cells pretreated with monensin compared to 2% in controls. Intracellular lumina membranes had the morphological features of apical membranes and were stained with horseradish peroxidase more frequently than those of newly formed bile canaliculi. This work therefore provides a model for studying bile secretion in cultured hepatocytes. Our results also suggest that the biliary transport of horseradish peroxidase does not involve the Golgi apparatus, since horseradish peroxidase was never observed in the Golgi stacks even after monensin treatment.
The role of nonparenchymal and parenchymal liver cells in the catabolism of extracellular purines
Authors: Leser Hans-Georg , Holstege Axel , Gerok Wolfgang
Published: March 2007

Adenosine-degrading enzymes within the liver lobule can modulate both vascular and metabolic effects of circulating adenosine in the liver. Since it has not been fully established whether nonparenchymal cells participate in the elimination of sinusoidal purines, isolated Kupffer cells and endothelial cells were tested for their capacity to degrade extracellular purines. After perfusion and digestion of rat livers by collagenase, the resulting mixed cell population was separated by centrifugal elutriation. The isolated parenchymal and nonparenchymal cells were incubated for up to 2 hr in the presence of [8-14C]adenosine, [8-14C]guanosine and [8-14C]hypoxanthine (50 μmoles per liter). In the deproteinized medium, adenosine, guanosine, inosine, adenine, guanine, xanthine, hypoxanthine, uric acid and allantoin were separated by reversed-phase high-performance liquid chromatography. Radioactive peaks were collected and counted. Nonparenchymal cells catalyzed the degradation of adenosine into inosine and hypoxanthine. However, the formation of xanthine, uric acid or allantoin from adenosine could only be detected in hepatocyte suspensions. Within 15 min, adenosine was completely eliminated from the medium by Kupffer cells, whereas endothelial cells catabolized only less than half of the initial amount of the adenine nucleoside during this time period. Accordingly, incubation of nonparenchymal cells in the presence of hypoxanthine did not result in the formation of further breakdown products of the purine, whereas its catabolites slowly accumulated in the medium of hepatocytes. Guanosine conversion into guanine and xanthine was much slower in endothelial cells as compared to Kupffer cells and hepatocytes. Further degradation of xanthine occurred only in the presence of hepatocytes. The results of our study indicate a rapid breakdown of extracellular purine nucleosides by Kupffer cells and a much slower catabolism by endothelial cells. Further degradation of hypoxanthine or xanthine was exclusively catalyzed by hepatocytes, indicating metabolic cooperation between parenchymal and nonparenchymal liver cells.
In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: Evidence for predominant expression in nonparenchymal liver cells
Authors: Milani Stefano , Herbst Hermann , Schuppan Detlef , Hahn Eckhart G. , Stein Harald
Published: March 2007

The expression of α2(I), α1(III) and α1(IV) procollagen mRNA was analyzed in normal and CCl4-induced fibrotic rat liver by in situ hybridization using RNA probes. In normal liver, moderate amounts of α2(I) and α1(III) procollagen transcripts were found in sinusoidal cells, in stromal cells of the portal tracts and in the vicinity of central veins, whereas a1(IV) procollagen gene expression was below the threshold of detection. After 2 weeks of CCl4 treatment, increased transcription of α2(I) and α1(III) procollagen genes was observed in sinusoidal cells. At this stage, α1(IV) procollagen mRNA was detectable in the same cell types and localization as α2(I) and α1(III) procollagen transcripts, although with a weaker signal. After 4 weeks, newly formed fibrous septa showed many cells intensely labeled by α2(I), α1(III) and α1(IV) procollagen probes. Neither in normal liver nor at any stage of fibrosis was any hybridization signal above background observed in hepatocytes. These patterns suggest that in the liver Type I, Type III and Type IV procollagen expression takes place predominantly in nonparenchymal cells. Therefore, hepatocytes do not appear to be significantly involved in procollagen production in this experimental model of liver fibrosis.
The portocardiorenal axis and refractory ascites: The underfilled cup runneth over
Authors: Witte Charles L. , Witte Marlys H.
Published: March 2007

Plasma immunoreactive alpha-human atrial natriuretic peptide (ANP) was measured in six cirrhotic patients with massive refractory ascites, under strict metabolic conditions, while they were receiving a 20-meq sodium diet, both before and at two-hour intervals for eight hours following peritoneovenous shunting (PVS). The mean preoperative level of ANP was 75±18pg/ml, which was found to be significantly higher than the normal range for this laboratory *8 to 24pg/ml) (p<0.05). This value was also significantly higher than the value of 21±5pg/ml (p<0.05) obtained in six patients with cirrhosis but without ascites. Following shunt insertion, an immediate natriuresis and diuresis were observed in five of the six cirrhotic patients with refractory ascites. In these five, right atrial pressure and ANP rose immediately, followed by a rise in the level of urinary cyclic guanosine monophosphate. The sixth subject had a delayed rise in right atrial pressure, and correspondingly the rise in ANP, the diuresis, and natriuresis were with changes in right atrial pressure (p<0.05), urinary cyclic guanosine monophosphate (p<0.05), urinary sodium excretion (p<0.05), and urine volume (p<0.05). These results suggest that ANP may be important in mediating the acute response to PVS.

Human atrial natriuretic factor (ANF) levels were measured before and after peritoneovenous shunt implantation in 10 cirrhotic patients with ascites in whom sodium retention is a major clinical problem. The mean preoperative plasma level of ANF was 82ng/L (normal range, 5-80ng/L). Peritoneovenous shunting resulted in a significant rise in plasma ANF to 308ng/L (<0.0025) immediately after operation. This was followed by a constant fall until the seventh postoperative day, when mean plasma ANF was still significantly elevated (149ng/L) compared with the preoperative value (p<0.01). Three months after shunt implantation mean plasma ANF had returned to the preoperative level (75ng/L). Mean sodium excretion increased from 2.6mEq/h peoperatively to 10.2mEq/h at the second postoperative day (p<0.025). No direct relationship was noted between changes in plasma ANF level and changes in urinary sodium excretion after shunt implantation. These data demonstrate that intact ANF release response to intravascular volume expansion in cirrhotic patients with ascites, but exclude ANF as the diminished natriuretic factor as proposed by the overflow theory of ascites formation. Sodium excretion and fluid retention seem to be the result of vascular underfill and fluid maldistribution, and hormonal changes are likely to be secondary to them.
Assessment of portal vein patency: Pitfalls and problems in diagnostic comparative studies
Authors: Taylor Caroline R.
Published: March 2007

The accuracy of ultrasound assessment of portal vein patency has been defined by comparing it with the results of arterial portography in 115 cases. The accuracy of arterial portography was confirmed in 21 cases where orthotopic liver transplantation was performed and used as a “benchmark” against which to assess the ultrasound findings. Ultrasound correctly assessed portal vein patency in 87.5% of patients. It was more accurate in assessing patency (90%) than occlusion (68%). Ultrasound correctly assessed portal vein patency in 90% of cases of cirrhosis and hepatic malignancy. Difficulties occurred in children with biliary atresia particularly following the Kasai operation (37.5% accuracy). In the absence of previous surgery to the portal vein or biliary system, ultrasound is comparable to arterial portography and can be used as the sole means of assessment.
Acute massive necrosis of the liver induced by antibody/complement, not by T-cells
Authors: Okuda Kunio
Published: March 2007

Acute fulminant hepatic injury was induced in rats within 1 hour after a single intravenous injection of a monoclonal antibody to rat liver cell membrane (MoAb). The liver injury induced by MoAb was characterized by multiple focal hepa-tocellular necrosis which was associated with marked increase in serum AST, ALT, and LDH activity. Inflammatory cell infiltration was not observed in the necrotic foci. Immunohistological study showed marked deposition of complement in the necrotic area, suggesting that the membrane-damaging action of the complement system activated by the antigen-antibody reaction between the hepatocyte membrane and MoAb may play an important role in the pathogenesis of MoAb-in-duced hepatic injury in rats.
The effects of intraduodenal bile acid administration on biliary secretion of ionized calcium and carbonate in man
Authors: Knyrim Klaus , Vakil Nimish , Pfab Rudolf , Classen Meinhard
Published: March 2007

The importance of calcium in gallstone formation is increasingly recognized. Calcium carbonate is an important constituent of gallbladder stones and may be present in the nidus of cholesterol stones. Secondary deposition of calcium carbonate on the surface of cholesterol gallstones is an important reason for failure of oral bile acid dissolution therapy. We sought to determine the effects of bile acids on the crystallization conditions of calcium carbonate in bile.

We studied 18 patients with choledocholithiasis with a percutaneous or endoscopically placed catheter high in the biliary tree. Samples of bile in the basal state and following replacement of the bile acid pool with cholic acid, chenodeoxycholic acid and ursodeoxycholic acid were analyzed for total calcium, ionized calcium, bicarbonate and carbonate, and the saturation index for calcium carbonate was calculated.

Hepatic bile in the basal state was supersaturated with calcium carbonate. Total calcium concentrations rose linearly with rising bile acid concentrations but ionized calcium was maintained in a relatively narrow range. These data are consistent with an important role for bile acids in binding calcium. Extrapolation of the linear regressions between bile acid concentration and calcium concentrations suggested that in the absence of bile acids, biliary calcium concentrations are in passive equilibrium with plasma. Chenodeoxycholic acid and ursodeoxycholic acid caused a bicarbonate-rich choleresis and significantly augmented the saturation index for calcium carbonate, whereas cholic acid caused no change. In contrast with animal models, the apparent choleretic activity of cholic acid, chenodeoxycholic acid and ursodeoxycholic acid was similar, and no hypercholeresis was observed with ursodeoxycholic acid. Chenodeoxycholic acid and ursodeoxycholic acid therefore increase the thermodynamic possibility for calcium carbonate precipitation.
Blunted natriuretic response and low blood pressure after atrial natriuretic factor in early cirrhosis
Authors: Beutler Jaap J. , Koomans Hein A. , Rabelink Ton J. , Gaillard Carlo A. , van Hattum Jan , Boer Peter , Mees Evert J. Dorhout
Published: March 2007

We compared the natriuretic response to a standard dose of atrial natriuretic factor in nine patients with early cirrhosis (no ascites or edema) with the response in normal subjects displaying a range of baseline sodium excretions due to different sodium intakes (20 mmoles per day, n = 9; 100 mmoles per day, n = 9, and 200 mmoles per day, n = 9). In these normal subjects, sodium output rose, in the same order, from 49 ± 12 to 177 ± 26, from 116 ± 21 to 365 ± 106 and from 228 ± 29 to 901 ± 85 μmoles per min in the first 20 min after 100 μg atrial natriuretic factor (human atrial natriuretic factor 99-126). Thus, irrespective of basal excretion, natriuresis rose by at least 2-fold. In the cirrhotic patients, natriuresis rose from 173 ± 42 to 305 ± 77 μmoles per min, that is by hardly 1-fold, significantly less than in the normal subjects (p < 0.01). Renal function studies indicated that atrial natriuretic factor caused less rise in glomerular filtration rate and in fractional sodium excretion. Atrial natriuretic factor induced a fall in blood pressure only in the cirrhotic group, from 130 ± 4/81 ± 2 to 108 ± 4/68± 3 mmHg (p < 0.001). Plasma atrial natriuretic factor was not low in the cirrhotic patients. Although these data are compatible with a primary disturbance of sodium excretion in early cirrhosis without ascites, such an explanation is complicated by the concomitant drop in blood pressure after atrial natriuretic factor. Whether this hypotensive reaction reflects impending underfill, or rather an abnormality in the regulation of vascular tone specific for cirrhosis, is obscure.
Serial antipyrine clearance studies detect altered hepatic metabolic function during spontaneous and interferon-induced changes in chronic hepatitis B disease activity
Authors: Williams Stephen J. , Farrell Geoffrey C.
Published: March 2007

The present study was performed to establish whether sequential determinations of antipyrine clearance, using a simplified two-point test, are sensitive and specific indicators of changes in chronic hepatitis B disease activity. Sixteen patients were studied on four or more occasions during 18 to 30 months. Eleven patients were treated with recombinant human α-interferon (2.5, 5.0 or 10 × 106 per m2, intramuscularly, three times per week, for 24 weeks), and five patients were untreated controls. Among seven patients, (six interferon-treated and one control) who lost hepatitis B e antigen from serum, antipyrine clearance improved by 46% (range: 20 to 160%) from 0.37 ± 0.14 ml per kg per min (mean ± S.D.) to 0.54 ± 0.13 ml per kg per min, p < 0.005. This change paralleled the loss of symptoms and reduction of serum ALT levels (from 206 ± 189 IU per liter (mean ± S.D.) to 38 ± 12 IU per liter, p < 0.005). Conversely, antipyrine clearance declined to previous levels when reactivation of chronic hepatitis B with reappearance of HBeAg in serum occurred. Regardless of changes in hepatitis B serology, when serum ALT values fluctuated by more than 20% (presumed to reflect fluctuations in necroinflammatory activity of the liver disease), antipyrine clearance also changed whereas serum albumin and bilirubin concentrations and prothrombin time did not. It is concluded that antipyrine clearance is a more sensitive and specific parameter than conventional indices for assessing hepatic metabolic function during changes in chronic hepatitis B disease activity. Remission in disease with loss of HBeAg from serum is associated with improved hepatic metabolic function as determined by the antipyrine clearance test.
Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen
Authors: Brunetto Maurizia Rossana , Oliveri Filippo , Rocca Giuseppe , Criscuolo Domenico , Chiaberge Elisabetta , Capalbo Maria , David Ezio , Verme Giorgio , Bonino Ferruccio
Published: March 2007

The course of chronic hepatitis B was studied in 30 patients who had antibody to hepatitis e antigen and hepatitis B virus DNA in the serum and hepatitis B core antigen in the liver. Over a 2-year period, no patient experienced a sustained spontaneous remission of disease, and follow-up liver histology revealed worsening of the disease in four patients. After 2 years of observation, 24 patients were allocated randomly to one of two groups: 12 patients served as untreated controls and 12 received recombinant human α-interferon-2a in a dose of 9 million units intramuscularly three times weekly for 16 weeks. Patients who remained viremic after 16 weeks received 3 million units three times weekly for an additional 8 weeks. Abnormal aminotransferases and serum hepatitis B virus DNA persisted without appreciable changes in all untreated patients. Hepatitis B virus DNA rapidly became undetectable and serum aminotransferases fell to normal in eight treated patients. After the end of treatment, hepatitis B virus DNA became detectable once again in seven patients, in six of whom a peak of aminotransferases (range: 256 to 850 units per liter) ensued; subsequently, hepatitis B virus DNA disappeared, and serum aminotransferases again fell to normal in two of the seven. Overall, hepatitis B virus DNA was no longer detectable in serum and liver histology improved in three treated patients. These results suggest that chronic hepatitis B with anti-HBe in serum differs from chronic hepatitis with HBeAg in both natural history and response to interferon. Peculiar features are the frequency of spontaneous remissions and a high frequency of reactivation after a response to interferon. New and more effective schedules of antiviral treatment are needed for this subset of patients with chronic hepatitis B.
Lymphokine-activated killer cell activity in patients with primary and metastatic malignant liver tumors
Authors: Schwarz Roderich E. , Iwatsuki Shunzaburo , Herberman Ronald B. , Whiteside Theresa L.
Published: March 2007

Lymphokine-activated killer cells were generated from peripheral blood mononuclear cells of 33 patients with liver tumors (benign, 6; primary malignant, 10; metastatic, 17) and 10 healthy individuals. Although peripheral blood mononuclear cell yield was significantly lower (p < 0.01) in patients with hepatocellular carcinoma or with metastatic colorectal cancer, natural killer activity in the peripheral blood mononuclear cell fraction was comparable in all groups tested. Optimal lymphokine-activated killer activity was demonstrated after 9 to 12 days of culture in recombinant interleukin 2. Lymphokine-activated killer activity, interleukin 2-induced lymphocyte proliferation and total lytic activity generated per culture in all patient groups studied were similar to those of normal control cells cultured under the same conditions. These in vitro data demonstrate the feasibility of obtaining lymphokine-activated killer cells from the blood of patients with liver tumors and provide a rationale for the future use of lymphokine-activated killer cells in adoptive immunotherapy of patients with primary and metastatic hepatic neoplasms.
Acute viral hepatitis in chronic carriers of hepatitis B virus: Different patterns in different places
Authors: Lok Anna
Published: March 2007

The aetiology of sporadic acute hepatitis in Taiwan was studied in a consecutive series of 273 patients, 209 males and 64 females, aged from < 1 to 73 years. Only eight patients (2.9%) had acute hepatitis A, 36 (13.2%) acute hepatitis B and 57 (20.9%) had acute non-A, non-B hepatitis (NANB). The remaining 172 patients (63.0%) were HBsAg positive but antiHBc IgM negative and were classified as acute hepatitis in chronic HBsAg carriers. Age-specific analysis revealed that acute hepatitis types A and B accounted for 35% and 47%, respectively of acute hepatitis in patients below age 10, but their prevalence decreased dramatically with increasing age and remained quite low in patients over age 40. In contrast, acute hepatitis NANB occurred predominantly in the older patients. The prevalence of acute hepatitis NANB was 11 to 15% in patients below age 40, but increased gradually with increasing age thereafter. Of the patients over age 60, 58% had acute hepatitis NANB. Acute hepatitis in chronic HBsAg carriers accounted for 59 to 76% of acute hepatitis episodes in patients over age 10 and below age 60. Sex-specific analysis revealed that the prevalence of acute hepatitis A or B showed no significant sex difference, whereas acute hepatitis in chronic HBsAg carriers occurred predominantly in males and acute hepatitis NANB occurred predominantly in females. Of the acute hepatitis episodes in chronic HBsAg carriers about one-third was due to hepatitis Delta virus superinfection, while the remaining two-thirds were most likely acute exacerbations of the underlying hepatitis B virus infection and a few were due to non-A, non-B hepatitis superinfection.
Carbohydrate metabolism in hepatocellular carcinoma: Where does the glucose go?
Authors: Marchesini Giulio , Bianchi Gianpaolo
Published: March 2007

Fourteen normal controls, eleven patients with non-alcoholic cirrhosis, twenty-nine with hepatocellular carcinoma (HCC) and six with HCC and hypoglycemia were studied. The tests performed include iv glucose tolerance test (25 g) and glucagon challenge test (2 mg). In cirrhosis, glucose intolerance and insulin resistance were demonstrated. The fasting hyperinsulinemia in cirrhosis is the result of decreased degradation as shown by the normal fasting C-peptide. The increased insulin responses to glucose, despite a normal C-peptide response, further supports the importance of impaired degradation in the pathogenesis of hyperinsulinemia after challenge. Despite a strong etiological association between cirrhosis and HCC, patients with HCC do not have significant hyperinsulinemia or glucose intolerance. This provides metabolic evidence to support the clinico-pathological observation that HCC patients with clinically overt hypoglycemia, the fasting glucose, insulin and C-peptide were very low. the C-peptide responses to glucose and glucagon challenges were suppressed despite pharmacologic stimulation. this can be explained by the suppression of insulin secretion by a circulating substance secreted by heptoma. the results support the pathogenetic importance of insulinlike activities recently detected in HCC patients with hypoglycemia.