bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis D virus RNA in acute delta infection: Serological profile and correlation with other markers of hepatitis D virus infection
Authors: Buti Maria , Esteban Rafael , Roggendorf Michael , Fernandez Juan , Jardi Rosendo , Rashofer Rudolf , Allende Helena , Genesca Juan , Esteban Juan Ignacio , Guardia Jaime
Published: March 2007

To evaluate the profile of hepatitis D virus replication and the corresponding immunoresponse after acute hepatitis D virus infection, sera from 50 patients with acute hepatitis D (36 with acute hepatitis B virus-hepatitis D virus coinfection and 14 HBsAg carriers with hepatitis D virus superinfection) were investigated for the presence of hepatitis D virus RNA and other serological hepatitis D virus markers. During the first week after onset of symptoms, hepatitis D virus RNA was detected by spot hybridization with a similar frequency among patients with coinfection (64%) and those with super-infection (71%). The presence of hepatitis D virus RNA in the first serum sample correlated with that of circulating hepatitis D antigen in both groups of patients. The presence of hepatitis D virus RNA was transient and its clearance paralleled that of serum hepatitis D antigen among patients with coinfection, so that 1 month after the onset of symptoms serum hepatitis D virus RNA was no longer detectable in any of these patients. Conversely, serum hepatitis D virus RNA was still present in 78% of those with superinfection, all of whom developed chronic liver disease, thus suggesting that the persistence of hepatitis D virus RNA in the serum for more than 4 weeks might indicate progression to chronicity. In nine of the 14 patients (64%) with hepatitis D virus superinfection progressing to chronicity, hepatitis D virus RNA was persistently detected throughout the follow-up, whereas in five patients it was detected occasionally. In four superinfected patients hepatitis D virus RNA and hepatitis B virus DNA were detected simultaneously in serial samples, thus suggesting that, at least during early stages of chronic hepatitis D virus infection, both viruses may replicate at the same time.
A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive chinese children
Authors: Lok Anna S. F. , Lai Ching-Lung
Published: March 2007

Fifty-one asymptomatic Chinese hepatitis B surface antigen (HBsAg) carrier children (34 boys, 17 girls), age 1 to 15 years (median: 10 years), were prospectively followed for up to 4 years (median: 30 months) to determine the natural evolution of clinical, biochemical and virological features during the early phase of chronic hepatitis B virus infection.

Hepatomegaly was the only abnormal finding on examination, being present in five children initially and four at follow-up. Serum ALT levels were normal in 80% of the children at presentation and remained within the normal range during the study in 60%. Fluctuations in ALT levels were mild. In four of 12 instances, transient elevations in ALT levels were associated with a fall in serum hepatitis B virus DNA levels.

At presentation, 43 (84%) children were hepatitis B e antigen (HBeAg) positive; only two (7%) cleared HBeAg on follow-up. None of the eight children who were initially positive for the antibody to HBeAg reverted back to HBeAg positivity. All the children remained HBsAg positive.

In this study, we demonstrated that chronic hepatitis B virus infection in asymptomatic Chinese children is usually associated with a mild and stable liver disease despite high levels of hepatitis B virus replication. This may reflect an immunological tolerance to the hepatitis B virus induced by early exposure to the virus and accounts for the persistently high levels of hepatitis B virus replication on follow-up.
Extent of measles hepatitis in various ages
Authors: Shalev-Zimels Hanna , Weizman Zvi , Lotan Chaim , Gavish Dov , Ackerman Zvi , Morag Abraham
Published: March 2007

To assess extent of hepatic involvement in measles, we evaluated prospectively 144 patients (ages 0.2 to 43 years) during an outbreak. Liver function parameters (AST, ALT, serum γ-glutamyl transpeptidase and bilirubin) were determined on presentation and at 2 and 4 weeks.

The study comprised 52 pediatric (≤14 years) and 92 adult patients. Liver dysfunction was evident quite often (56 to 66%) in adult patients. However, in the pediatric age group, these abnormalities were less frequent and less extensive. Moreover, a significant correlation was noted between age and each of the following parameters: AST (r = 0.61), ALT (r = 0.56) and serum γ-glutamyl transpeptidase (r = 0.39). In all subjects all parameters normalized after 2 to 4 weeks.

The data presented suggest that hepatic dysfunction in measles is probably not rare and is more frequent and more extensive in adults. However, these abnormalities seem to be subclinical, self-limited and probably with no long-term sequelae.
Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis
Authors: Schrier Robert W. , Arroyo Vicente , Bernardi Mauro , Epstein Murray , Henriksen Jens H. , Rodés Joan
Published: March 2007

Renal sodium and water retention and plasma volume expansion have been shown to precede ascites formation in experimental cirrhosis. The classical “underfilling” theory, in which ascites formation causes hypovolemia and initiates secondary renal sodium and water retention, thus seems unlikely. While the occurrence of primary renal sodium and water retention and plasma volume expansion prior to ascites formation favors the “overflow” hypothesis, the stimulation of the renin-angiotensin-aldosterone system, vasopressin release and sympathetic nervous system associated with cirrhosis is not consonant with primary volume expansion.

In this present article, the “Peripheral Arterial Vasodilation Hypothesis” is proposed as the initiator of sodium and water retention in cirrhosis. Peripheral arterial vasodilation is one of the earliest observations in the cirrhotic patient and experimental animals with cirrhosis. Arterial vasodilators and arteriovenous fistula are other examples in which renal sodium and water retention occur secondary to a decreased filling of the arterial vascular tree. An increase in cardiac output and hormonal stimulation are common features of cirrhosis, arteriovenous fistula and drug-induced peripheral arterial vasodilation. However, a predilection for the retained sodium and water to transudate into the abdominal cavity occurs with cirrhosis because of the presence of portal hypertension. The Peripheral Arterial Vasodilation Hypothesis also explains the continuum from compensated to decompensated cirrhosis to the hepatorenal syndrome.
Technology transfer—from agnogenic portal vein thrombosis to agnogenic myeloid metaplasia
Authors: Witte Charles L. , Witte Marlys H.
Published: March 2007

In a prospective study of 33 adults with portal vein thrombosis unrelated to a liver tumor, we have assessed the prevalence of primary myeloproliferative disorders using conventional criteria and cultures of bone marrow progenitor cells. A primary myeloproliferative disorder was documented in 14 patients investigated at the time of recognition of portal vein thrombosis. Among these 14 patients, the main clue to the presence of the myeloproliferative disorder was (a) the observation of suggestive abnormalities of peripheral blood cell counts in 4 patients; (b) characteristic findings at bone marrow biopsy or determination of total red cell volume in 3 patients; and (c) formation of “spontaneous” erythroid colonies in cultures of bone marrow progenitor cells in erythropoietin-poor medium in 7 patients. In 2 other patients, agnogenic myeloid metaplasia with myelosclerosis of apparently recent onset developed 5 yr after recognition of portal vein thrombosis. In conclusion, primary myeloproliferative disorders—in a full-blown or latent form, or at an early stage—are a major cause of portal vein thrombosis.
Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portacaval shunt
Authors: Pomier-Layrargues Gilles , Huet Pierre-Michel , Infante-Rivard Claire , Villeneuve Jean-Pierre , Marleau Denis , Duguay Lester , Tanguay Serge , Lavoie Pierre
Published: March 2007

The objective of this study was to assess the prognostic value of spontaneous portosystemic shunting and liver function for survival and spontaneous hepatic encephalopathy after end-to-side portacaval shunt in cirrhotic patients. One hundred ninety-eight patients with variceal hemorrhage as shown by endoscopy were evaluated. Forty-five were excluded because of uncontrollable hemorrhage; 84 were rejected because they were poor operative risk, had portal vein thrombosis or had been previously treated with β-blockers, sclerotherapy or surgery. The remaining 69 patients were enrolled in this prospective study. There were 43 patients with alcoholic cirrhosis, 23 with cryptogenic cirrhosis and three with primary biliary cirrhosis. The severity of liver disease was assessed according to the Pugh classification: 37 patients (54%) had Pugh’s score 5 to 7, 26 (38%) had 8 to 10 and six (8%) had 11 to 12. Indocyanine green intrinsic clearance was used as a probe of preoperative liver function and lidocaine systemic availability as an index of spontaneous preoperative shunting. All the patients underwent an elective end-to-side portacaval shunt. The length of minimal follow-up was 40 months. One-year survival was 76% and 5-year survival was 46%. During follow-up, 25 patients died from their liver disease and 11 patients died from various causes unrelated to their liver disease. Spontaneous chronic encephalopathy occurred in 16 patients (23%). Age, Pugh’s score, active alcoholism, indocyanine green intrinsic clearance and lidocaine systemic availability were tested as prognostic factors in a multivariate analysis. A stepwise analysis using the Cox proportional hazard demonstrated that, in this population of cirrhotic patients, the Pugh score was the only variable significantly related to survival (β = 0.3; S.E. = 0.12, p < 0.05). A stepwise multiple logistic regression analysis showed that none of the studied parameters was significantly related to the onset of postoperative spontaneous encephalopathy. These findings suggest that in this population of cirrhotic patients the Pugh score remains the best predictive variable for survival and that pharmacokinetic parameters have no role in the prediction of postoperative outcome after end-to-side portacaval shunt.
Hepatic dopamine sulfotransferases in untreated rats and in rats subjected to endocrine or hypertension-related treatments
Authors: Singer Sanford S. , Palmert Mark R. , Redman Michael D. , Leahy Diane M. , Feeser Theresa C. , Lucarelli Mark J. , Volkwein Linda S. , Bruns Margie
Published: March 2007

Here we describe the dopamine sulfotransferase activity of rat liver cytosol. With cytosol, 3′-phosphoadeno-sine-5′-phosphosulfate and dopamine Km values were 17.2 ± 4.1 and 22.4 ± 3.5 μM. Females possessed 23 to 37% of dopamine sulfotransferase levels, per gm liver, in males. DEAE-Sephadex A-50 chromatography resolved dopamine sulfotransferase activity to dopamine sulfotransferase I and dopamine sulfotransferase II. Dopamine sulfotransferase II comprised 79 ± 10 or 61 ± 18% of dopamine sulfotransferase in males or females in routine assays. 4-Methoxytyramine gave 609 or 179% of mean dopamine sulfotransferase activity with dopamine sulfotransferase I or II. Dopamine and 3-methoxytyramine were comparable substrates. Epinephrine was less effective. Mn++, Cd++, Zn++, Na+ and K+ inhibited dopamine sulfotransferase II. Mg++ activated it. Dopamine sulfotransferase II from males was purified 184 ± 64-fold. Its Km values for 3′-phosphoad-enosine-5′-phosphosulfate and dopamine were 12.7 ± 1.5 and 47.5 ± 6.7 μM, respectively. Its dopamine sulfotransferase mechanism was sequential. The molecular weight of dopamine sulfotransferase II was 49,100 ± 4,000 by Sephadex G-100 chromatography. Dopamine sulfotransferase II preferred phenol to catecholamines. Dopamine and 3,4-dihydroxybenzylamine were its best catecholamine substrates. Adrenalectomy or castration of males led to 35 or 45% mean decreases of dopamine sulfotransferase levels, indicating adrenal and gonadal participation in control of dopamine sulfotransferase production. Testosterone had no effect in either sex, whereas estradiol led to 40% mean decreases of dopamine sulfotransferase levels in males. This suggested a role for ovaries in dopamine sulfotransferase production, supported by 55 to 102% increased dopamine sulfotransferase levels after ovariectomy. Okamoto-hypertensive males or males given hypertensogenic doses of cortisol exhibited 37 or 48% mean increases of dopamine sulfotransferase levels per gm liver. Antihypertensive spironolactone or hydralazine led to 30% mean decreases of dopamine sulfotransferase levels. Altered dopamine sulfotransferase levels after all experimental manipulations were due mostly to changed dopamine sulfotransferase II content. Dopamine sulfotransferase II is compared to other reported enzymes that sulfate catecholamines.
Electron microscopic and time lapse studies of mitosis in cultured rat hepatocytes
Authors: Sattler Carol A. , Sawada Norimasa , Sattler Gerald L. , Pitot Henry C.
Published: March 2007

Primary cultures of adult rat hepatocytes in a serum-free medium were observed by time lapse cinematography to proceed through mitotis and cytokinesis. An ultrastructural study of these cultures is presented with electron micrographs of each stage of mitosis and cytokinesis. The cultured hepatocytes begin to enter prophase about 48 hr after plating and proceed through mitosis in approximately 70 min not including cytokinesis. During this time, they remain somewhat flattened and joined to neighboring cells rather than rounding up. Both mononucleate and binucleate hepatocytes proceed through mitosis. Some mononucleate cells do not undergo cytokinesis, resulting in the formation of binucleate cells. In binucleate hepatocytes, both nuclei proceed through prophase simultaneously. Usually a single mitotic spindle with a large metaphase plate containing chromosomes from both nuclei is observed. Cytokinesis frequently occurs in binucleate hepatocytes which have a single mitotic spindle. Some binucleate cells form tripolar or 4-polar metaphase plates. In tripolar metaphases, some cells do not divide, resulting in multinucleate cells, whereas others undergo cytokinesis yielding three mononucleate cells or one binucleate and one mononucleate cell. Two mitotic spindles located perpendicularly to each other with microtubules intertwining have been observed in 4-polar metaphases. In this latter case, no cytokinesis has been observed.

This study shows that both mononucleate and binucleate adult rat hepatocytes cultured in a serum-free medium in the presence of epidermal growth factor not only synthesize DNA, but progress through mitosis and often cytokinesis.
Uptake and modification of 125I-lipopolysaccharide by isolated rat Kupffer cells
Authors: Fox Eben S. , Thomas Peter , Broitman Selwyn A.
Published: March 2007

While it is generally believed that hepatic clearance of lipopolysaccharide involves Kupffer cells, the mechanism involved has not been fully elucidated. This study assesses this phenomenon in terms of in vitro uptake and post-uptake modification experiments with an 125I-labeled Salmonella minnesota lipopolysaccharide. 125I-Lipopolysaccharide was added to Kupffer cells in suspension cultures under a variety of conditions. In vitro uptake of 125I-Lipopolysaccharide was not saturable up to concentrations of 33.33 μg per ml. Kinetics experiments performed at 16.67 μg per ml demonstrated that Kupffer cells were unsaturable after 60 min of incubation. The kinetics of uptake could be inhibited, however, by incubation in the presence of a 10-fold excess of unlabeled lipopolysaccharide, indicating that a component of the uptake process may be limited. Energy dependence in this process was demonstrated by incubation in the presence of 1 mM 2-deoxyglucose which inhibited 125I-lipopolysaccharide uptake by approximately 30%. Pretreatment with 7.5 × 10−5
M colchicine had no effect on kinetics, implying no role for the cell cytoskeleton in lipopolysaccharide uptake. These results are inconsistent with a receptor-mediated process as previously suggested. Modification of internalized label has been demonstrated by changes in buoyant density in CsCl isopyknic density gradients following overnight incubation with Kupffer cells. These results indicate that Kupffer cells clear bacterial endotoxin in vitro and post-uptake degradation occurs within 20 hr of incubation.
23-Methyl-3α, 7β-dihydroxy-5β-cholan-24-oic acid: Dose-response study of biliary secretion in rat
Authors: Roda Aldo , Aldini Rita , Grigolo Brunella , Simoni Patrizia , Roda Enrico , Pellicciari Roberto , Lenzi Pier Luigi , Natalini Benedetto
Published: March 2007

A side chain derivative of ursodeoxycholic acid, 23-methylursodeoxycholic acid, was synthesized and the effect of i.v. infusion of the acid at different doses (0.75, 1.5, 3.0 and 6.0 μmoles per min per kg body weight over 1 hr) on bile flow, on its hepatic biotransformations and on biliary lipid secretion has been studied in bile fistula rats. The results were compared with those of ursodeoxycholic and cholic acid administered under similar conditions. 23-Methylursodeoxycholic acid is poorly secreted into bile and poorly taurine and glycine conjugated, at all infusion doses.

Ursodeoxycholic acid is quantitatively recovered at low doses and recovered less at high infusion rates. Cholic acid is almost entirely recovered at all infusion doses. Ursodeoxycholic acid conjugation pattern is dependent on the dose, and glucuronidation and sulfation operate at high doses. Cholic acid is taurine conjugated at low doses; at high doses, large amounts of unconjugated bile acids are observed. Methylursodeoxycholic acid presents a delayed secretion and hypercholeresis. Ursodeoxycholic acid presents similar results at high infusion rates, possibly by reaching a high intrahepatic concentration of free form. The octanol/water partition coefficients of ursodeoxycholic acid and 23-methylur-sodeoxycholic acid are similar and higher than that of cholic acid. A chole-hepatic shunting of 23-methylursodeoxycholic acid may explain both the low recovery in bile and hypercholeresis and is consistent with its hydrophobicity. The high water solubility and hydrophilicity of cholic acid, on the contrary, makes possible its high recovery in bile. The effect on biliary lipid secretion is unpredictable and affected by the dose and, in consequence, by the conjugation pattern of the bile acid. The detergency of the intrahepatic pool of the secreted bile acid and the physicochemical state of the native bile may be the driving force determinant for cholesterol and phospholipid biliary secretion.
Severe cholestasis leads to vitamin D depletion without perturbing its C-25 hydroxylation in the dog
Authors: Plourde Victor , Gascon-Barré Marielle , Willems Bernard , Huet P.-Michel
Published: March 2007

The role of the liver as a contributory factor in the vitamin D deficiency of cholestatic liver disease has been studied in vivo in dogs with chronic bile duct ligation, whereas controls underwent diversion of the bile flow through the urinary bladder via a choledococystostomy anastomosis. The hepatic extraction of vitamin D3 was evaluated by the multiple indicator dilution technique, and the formation of 25-hydroxyvitamin D3 was assessed by directly sampling the hepatic effluent for up to 150 min after vitamin D3 administration. The serum and hemodynamic data indicate that dogs with chronic bile duct ligation had severe cholestasis and hepatocel-lular injury; histologically, macronodular cirrhosis was present. Dogs with choledococystostomy anastomosis had normal livers and normal liver function. The data indicate that the absence of normal bile flow into the intestinal lumen led to a progressive depletion of vitamin D reserve in both animals with choledococystostomy anastomosis and those with chronic bile duct ligation. However, neither the hepatic fractional extraction of vitamin D3, its hepatic clearance nor its transformation into 25-hydroxyvitamin D3 was significantly changed by chronic bile duct ligation. The results of the present studies indicate that the hepatic handling of vitamin D3 including its C-25 hydroxylation, is well preserved in the presence of severe cholestasis. They also suggest that the state of vitamin D depletion which often accompanies chronic cholestatic liver disease can largely be accounted for by factors such as secondary malabsorption of the vitamin due to the absence of adequate amounts of bile salts in the intestinal lumen, or by other factors which seem independent of the hepatic metabolism of vitamin D.
Evoked potential abnormalities in children with chronic cholestasis
Authors: Cynamon Harry A. , Norcross Karyl , Isenberg Nevin J.
Published: March 2007

To assess the effect of chronic cholestasis and vitamin E deficiency on nervous system function, we did multimodality evoked potential testing of 17 children (mean age = 47 months) who had chronic liver disease. Evoked potential testing was repeated periodically in 11 patients 1 to 33 months after the initial study.

Eight children had abnormal delays of the P100 peak of the visual evoked potential, and these children each had significantly higher total serum bile acid levels than did children who had normal visual evoked potentials (p = 0.002). Bilateral brainstem auditory evoked potential abnormalities consistent with conductive hearing losses were initially present in six patients. However, persistent conductive losses were found in four patients, all of whom had arteriohepatic dysplasia. Four children had mildly abnormal somatosensory evoked potentials that were due solely to a mild peripheral neuropathy. Biochemical measures of vitamin E status were not consistently associated with either normal or abnormal visual, brainstem auditory or somatosensory evoked potentials or a combination of evoked potential abnormalities, and an abnormality of one evoked potential type was not associated with an abnormality of any other. A similar lack of relationship between evoked potential results and plasma vitamin A measurement was noted. Following marked improvement in or resolution of cholestasis in four patients, the visual evoked potential became normal, but other evoked potentials did not change. Visual evoked potential improvement was greatest in two patients who underwent orthotopic liver transplantation.

This is the first report that demonstrates frequent, potentially reversible visual system abnormalities that are associated with cholestasis and cannot be attributed solely to vitamin E and/or A deficiency. Bilateral brainstem auditory evoked potential abnormalities consistent with conductive hearing losses were repeatedly present only in patients with arteriohepatic dysplasia and may represent another extrahepatic feature of this syndrome; we are not aware of any previous report of this association. Evoked potential studies provide a sensitive means with which to monitor neurological function and give objective, quantitative assessments necessary for comparing patients, and they may prove useful in understanding the pathophysiology of nervous system disorders associated with chronic cholestasis.
Status of hepatitis B virus DNA in alcoholic liver disease: A study of a large urban population in the United States
Authors: Fong Tse-Ling , Govindarajan Sugantha , Valinluck Boontar , Redeker Allan G.
Published: March 2007

Two reports have shown hepatitis B virus DNA in serum and liver tissue in alcoholic liver disease with negative serum HBsAg, suggesting a pathogenetic role for hepatitis B virus. We studied hepatitis B virus DNA in serum and liver from three groups of alcoholic patients; (Group 1) 50 patients without liver disease, (Group 2) 108 patients with alcoholic liver disease and (Group 3) five patients with alcoholic liver disease and hepatocellular carcinoma. Serum was tested for HBsAg, anti-hepatitis B core and anti-hepatitis B surface by radioimmunoassay and hepatitis B virus DNA by direct spot hybridization. Liver tissue from Groups 2 and 3 (113 patients) was examined by Southern blot analysis using 32P-labeled hepatitis B virus DNA clone from pBR322. Controls were 21 patients with chronic hepatitis B virus (14 patients with chronic active hepatitis, seven patients with cirrhosis and hepatocellular carcinoma). Serum and tissue were analyzed for hepatitis B virus DNA. Hepatitis B virus DNA was not detected in either serum or liver tissue in any of the 163 patients (Groups 1 to 3). In contrast, among the controls, hepatitis B virus DNA was present in the serum of 15 of the 21. Tissue DNA in those with chronic active hepatitis revealed 10/14 with free hepatitis B virus DNA, two with integrated sequences and two with no viral sequences. All seven patients with hepatocellular carcinoma had integrated viral DNA sequences in the tumor tissues. From these results, it appears that hepatitis B virus does not play a role in the pathogenesis of alcoholic liver disease.
Ethanol-induced increase in cytosolic estrogen receptors in human male liver: A possible explanation for biochemical feminization in chronic liver disease due to alcohol
Authors: Villa Erica , Baldini Grazia M. , Rossini Gian Paolo , Pasquinelli Claudio , Melegari Margherita , Cariani Elisabetta , Tata Cristina , Bellentani Stefano , Ferrari Alberto , Manenti Federico
Published: March 2007

The hepatic cytosolic estrogen receptor content was measured in liver samples from patients with normal livers and from patients with nonalcoholic cirrhosis, alcoholic cirrhosis and alcoholic hepatitis. The estrogen receptor content of normal liver was 5.2 ± 3.5 fmoles per mg of cytosolic protein. Levels which were not significantly different from this were found in the samples from patients with nonalcoholic cirrhosis (2.1 ± 2.0 fmoles per mg of cytosolic protein).

The cytosolic estrogen receptor content in the livers of patients with alcoholic cirrhosis who were abstaining was 4.2 ± 3.6 fmoles per mg of cytosolic protein, but it increased to 10.4 ± 4.9 fmoles per mg of protein in the livers of patients with alcoholic cirrhosis who were drinking, to 17.3 ± 8.7 fmoles per mg of protein in the livers of patients with alcoholic hepatitis with cirrhosis and to 22.7 ± 15.7 fmoles per mg of protein in the livers of patients with alcoholic hepatitis without cirrhosis.

Alcohol abuse appeared, therefore, to induce an increase in the estrogen receptor content of human liver, especially in patients who were drinking and had histological evidence of acute liver damage (alcoholic hepatitis).

The increase in hepatic estrogen receptor which we have observed may be involved in the molecular mechanisms underlying the feminization of the liver in alcoholic males.
Large regenerative nodules and dysplastic nodules in cirrhotic livers: A histopathologic study
Authors: Wada Katsunori , Kondo Fukuo , Kondo Yoichiro
Published: March 2007

In order to reveal the precursor lesion of hepatocellular carcinoma, a histopathologic study was performed on 141 cases of liver cirrhosis with or without hepatocellular carcinoma. Exclusive of primary or metastatic hepatocellular carcinoma nodules, 94 nodular lesions (>5 mm) were detected in 53 cirrhotic livers. They consisted of 83 large regenerative nodules and 11 dysplastic nodules. Besides some common features with those observed in the former type, the dysplastic nodules presented increased cytoplasmic basophilia, nuclear and nucleolar enlargement, nuclear crowding, occasional microacinar formation and proliferation of the hepatocytes within fibrous septa. These changes were not substantial enough to allow the diagnosis of hepatocellular carcinoma. In one case, however, malignant transformation of hepatocytes was suspected because of their pattern of extranodular outgrowth. It is important to recognize these subtle abnormalities in order to define premalignant hepatic lesions. A possible connection between benign large regenerative nodules and dysplastic nodules is also discussed.
Acyclovir in chronic hepatitis B virus infection
Authors: Dusheiko Geoffrey M.
Published: March 2007

In a previous study a partial inhibition of viral replication was observed in HBeAg-positive patients after acyclovir (ACV) treatment.

To assess those results and to evaluate different treatment regimens, a randomized controlled trial with ACV given at 45 mg/kg/day by continuous infusion (in 5 patients) or by intermittent 8-hourly infusion (in 6 patients) for 28 days versus placebo has been performed in 20 patients affected by chronic hepatitis positive for both HBsAg and HBeAg for at least 6 months.

Patients were stratified for sex, presence of cirrhosis and homosexual activity.

Modest inhibition of serum DNA polymerase activity was observed after intermittent ACV treatment but not with the continuous infusion. After a 8-12 months follow-up, 2 of 10 of the ACV-treated patients and 3 of the controls had become HBe-Ag-negative, with 1 and 2 seroconversions to anti-HBe in the treated and placebo group respectively. No adverse effects were observed in ACV-treated patients after continuous infusion, but 2 of 6 patients who received intermittent therapy had to stop treatment, because of abdominal colics and elevation of the serum creatinine.

Our data confirm that ACV partially inhibits viral replication in HBeAg-positive patients but without significantly affecting the rate of seroconversion to anti-HBe.

Histological remission is recognized to follow loss of viral replication in chronic hepatitis B virus infection. The aim of antiviral therapies has been to accelerate seroconversion from HBeAg to anti-HBe, but so far none has been shown to be of significant advantage in adequate, controlled trials and toxicity has been common.

A randomized controlled trial of acyclovir, 45 mg/kg/day by continuous intravenous infusion for 28 days versus no therapy has been completed in 30 patients positive for HBsAg and HBeAg for a minimum of 6 months. Patients were stratified for sex, histology and homosexual activity.

Twenty-eight days therapy was associated with only a modest reduction in serum markers of viral replication. At 12-months DNAp was lost in 5/15 treated and 2/11 of the untreated group, while of the latter, 2 patients initially negative became positive. Seroconversion from HBeAg to anti-HBe had occurred in 4 of 15 treated and 1 of 15 untreated patients (95% confidence limits 12% and 51%) and was associated with histological improvement.

Acyclovir had only a weak effect on viral replication and did not significantly accelerate the rate of seroconversion to anti-HBe.
Selection of portal-systemic shunts with an eye to subsequent liver transplantation
Authors: Flye Wayne M.
Published: March 2007

Patent distal splenorenal shunts (Warren shunt) have been reported to cause decreases in the portal perfusion pressure and the total hepatic blood flow. Such hemodynamic alterations could have adverse effects on the transplanted liver. The experience with hepatic replacement in four patients with patent Warren shunts is reported. Operative findings were phlebosclerotic portal veins of small size and diminished portal blood flows. Hepatofugal collateral channels created by the construction of the Warren shunt were eliminated by division of the shunt and splenectomy in three patients and splenectomy alone in the other. All patients recovered. A Warren shunt is not a contraindication for transplantation.
Do branched chain keto amino acids regulate their own metabolism?
Authors: Schauder Peter
Published: March 2007

The effects of branched-chain α-ketoacids on flux through and activity state of the branched-chain α-ketoacid dehydrogenase complex were studied in hepatocytes prepared from chow-fed, starved, and low-protein-diet-fed rats. Very low concentrations of α-ketoisocaproate caused a dramatic stimulation (50% activation at 20 μM) of α-ketoisovalerate decarboxylation in hepatocytes from low-protein-fed rats. α-Keto-β-methylvalerate was also effective, but less so than α-ketoisocaproate. α-Ketoisocaproate did not stimulate α-ketoisovalerate decarboxylation by hepatocytes from chow-fed or starved rats. To a smaller degree, α-keto-β-methylvalerate and α-ketoisovalerate stimulated α-ketoisocaproate decarboxylation by hepatocytes from low-protein-fed rats. The implied order of potency of stimulation of flux through branched-chain α-ketoacid dehydrogenase was α-ketoisocaproate > α-keto-β-methylvalerate > α-ketosiovalerate, i.e., the same order of potency of these compounds as branched-chain α-ketoacid dehydrogenase kinase inhibitors. Fluoride, known to inhibit branched-chain α-ketoacid dehydrogenase phosphatase, largely prevented α-ketoisocaproate and α-chloroisocaproate activation of flux through the branched-chain α-ketoacid dehydrogenase. Assay of the branched-chain α-ketoacid complex in cell-free extracts of hepatocytes isolated from low-protein-diet-fed rats confirmed that α-ketoacids affected the activity state of the complex. Branched-chain α-ketoacids failed to activate flux in hepatocytes prepared from chow-fed and starved rats because essentially all of the complex was already in the dephosphorylated, active state. These findings indicate that inhibition of branched-chain α-ketoacid dehydrogenase kinase activity by branched-chain α-ketoacids is important for regulation of the activity state of hepatic branched-chain α-ketoacid dehydrogenase.
Hepatic innervation in hepatic regeneration
Authors: Cruise Jennifer L.
Published: March 2007

The autonomic nervous system in rats has been assessed by means of indirect immunofluorescence using monospecific antibodies to neuron-specific enolase, neurofilaments, glial fibrillary acidic protein and S-100 protein [10 days after partial (70%) hepatectomy]. Different groups of rats were studied:

All rats of groups A and D showed normal liver/body weight ratios after 10 days in contrast to groups B and C where liver weights were 50-60% of the preresection weight. In group A the regeneration process was histologically normal and associated with a remarkable increase of autonomic innervation patterns in the portal triad. In contrast, livers of animals in groups B and C showed under the light microscope features of hepatocyte degeneration associated with a decreased autonomic innervation compared to the controls. The changes are identical in groups B and C, and are therefore irrespective of the type of blood deprivation (arterial or portal).

These results support the importance of dual blood supply for an optimal regenerative response in liver remnants after liver resection. We suggest that the autonomic nerve supply of the portal triad plays at least an important permissive role in liver regeneration.
Acinar heterogeneity of fatty acid binding protein expression in the livers of male, female and clofibrate-treated rats†
Authors: Bass Nathan M. , Barker Mary E. , Manning Joan A. , Jones Albert L. , Ockner Robert K.
Published: March 2007

Liver fatty acid binding protein may play a role in the intracellular transport and compartmentation of long-chain fatty acid metabolism. The distribution of liver fatty acid binding protein in the hepatic acinus was determined by means of immunocytochemistry as well as by measurement of liver fatty acid binding protein in cellular protein selectively released from zone 1 and zone 3 cells by means of anterograde and retrograde liver perfusion with digitonin. In untreated male rats, specific immunocytochemical staining for liver fatty acid binding protein showed a declining portal-to-central hepatocellular gradient in intensity, consistent with the portal-to-central ratio of liver fatty acid binding protein abundance measured in effluents from digitonin-perfused livers of 1.6:1. Female and clofibratetreated male rats, in both of which hepatic synthesis and abundance of liver fatty acid binding protein are greater than in untreated males, differed as well in the pattern of acinar expression of this protein. In females, periportal concentrations of liver fatty acid binding protein determined from the effluent of livers perfused anterograde with digitonin were similar to male values, whereas liver fatty acid binding protein concentration in pericentral hepatocytes determined from the effluent of retrograde perfused livers was increased, resulting in a marked attenuation of the portal-to-central gradient of this protein; this was also apparent on immunocytochemistry. Clofibrate-treated rats, in contrast, displayed a panacinar increase in liver fatty acid binding protein with maintenance of the portal-to-central ratio observed in untreated males. We conclude that there exists a declining portal-to-central gradient in liver fatty acid binding protein cellular abundance in the hepatic acinus of untreated male rats. Furthermore, the increased synthesis and abundance of liver fatty acid binding protein in female and clofibrate-treated male rats results in two different alterations in the acinar expression of this protein, i.e. a pericentral increase (female) or a panlobular increase (clofibrate). Elucidation of the relationship between the zonation of hepatic fatty acid metabolism and the acinar expression of liver fatty acid binding protein should provide a more detailed understanding of the function of this protein.
Dynamics of hepatic connective tissue matrix constituents during murine schistosoma mansoni infection
Authors: Meneza Safaa El , Olds Richard G. , Kresina Thomas F. , Mahmoud Adel A. F.
Published: March 2007

Hepatic fibrosis is the major clinical sequela of infection with the helminth Schistosoma mansoni. However, little is known regarding its dynamics and regulation in schistosomiasis. The present study presents the dynamics of deposition and resorption of two major extracellular matrix components of fibrosis, glycosaminoglycans and collagens, during the course of experimental S. mansoni infection. Early in infection (6 weeks), glycosaminoglycan biosynthesis was markedly elevated, as was collagen biosynthesis. This led to significant accumulations of these two molecules at a glycosaminoglycan/collagen ratio similar to that observed in livers of un-infected mice (uronic acid/hydroxyproline ratio of 1.10 at 6 weeks compared to normal value of 1.25). During maximal hepatic fibrosis (12 to 18 weeks), both collagen and glycosaminoglycan biosynthesis continued to increase but the extracellular matrix shifted to a lower glycosaminoglycan/collagen ratio of 0.42, suggesting enhanced glycosaminoglycan breakdown. In addition, during this acute stage of infection, Type I collagen was the predominant isotype synthesized, whereas total collagenolytic activity degrading Type I collagen was maximal.

During chronic infection, a decrease in the content of both hepatic glycosaminoglycans and collagens were noted, with a glycosaminoglycan/collagen ratio of 0.63. Decreased glycosaminoglycan content paralleled diminished biosynthetic rates. On the other hand, an over 50% reduction in collagen content (from 18 to 24 weeks) appeared not to result from diminished biosynthesis but from a switch in the predominant collagen isotype synthesized (from Type I to Type III), matched by an enhanced constitutive collagenolytic activity directed toward this type of collagen. These differences in the extracellular matrix separate schistosomal-induced hepatic fibrosis from most other types of fibrotic liver disease and may explain differences in the clinical manifestations observed during different stages of infection.
Preferential covalent binding of acetaldehyde to the α-chain of purified rat liver tubulin†
Authors: Jennett Richard B. , Sorrell Michael F. , Saffari-fard Abbas , Ockner James L. , Tuma Dean J.
Published: March 2007

Hepatic ethanol oxidation generates the reactive intermediate acetaldehyde, which binds to proteins. Previous work, using bovine brain tubulin as a model protein, has shown that acetaldehyde preferentially formed stable adducts on the α-chain of the heterodimeric molecule. This binding resulted in functional impairment of the tubulin/microtubule system as evidenced by a decreased ability of adducted tubulin to form microtubules. Since tubulin/microtubules are believed to be very important cytoskeletal components of the hepatocyte and results with brain tubulin were interesting, our goal was to extend these studies to liver tubulin. We purified tubulin from rat liver by a polymerization-based cycle method followed by phosphocellulose chromatography. We then characterized the covalent binding of [14C]acetaldehyde to liver tubulin. Naturally forming and cyanoborohydride-stimulated stable adducts formed linearly with liver tubulin in a manner almost identical to that with brain tubulin. We also found that the α-chain of the native heterodimeric liver tubulin molecule was the preferred site of adduct formation at low acetaldehyde to protein ratios. These results confirm and extend our previous findings with the brain tubulin model and further suggest that the α-chain of tubulin may be a preferential site for acetaldehyde-adduct formation during ethanol oxidation in the liver.
A quantitative study of fluorescein isothiocyanate-dextran transport in the microcirculation of the isolated perfused rat liver†
Authors: Stock Richard J. , Cilento Eugene V. , McCuskey Robert S.
Published: March 2007

Hepatic extraction of solutes depends on microvascular angioarchitecture, hemodynamics and solute concentrations. These factors may contribute to the heterogeneity observed in solute transport and uptake in the hepatic lobules. However, predictions of liver extraction based on black-box models require assumptions about these factors and the microvascular transport mechanisms involved. Consequently, the purpose of this study was to investigate solute transport and uptake by hepatocytes. Livers from male Sprague-Dawley rats were perfused at physiological flowrates and portal pressures on the stage of an in vivo microscope using a low-hematocrit Ringer solution. A bolus of fluorescein isothiocyanate-dextrans (17,900, 39,000, 65,600 or 156,900 MW), which are considered inert fluid-phase markers, was injected into the portal vein. Fluorescein isothiocyanate fluorescence, as a measure of solute concentration, was video recorded in periportal or centrivenular regions of the lobules. Spatial and temporal fluorescence data, measured in sinusoids and hepato-cytes, were fit to one-dimensional transport models to determine estimates for an intracellular effective diffusion coefficient and for hepatocyte permeability. The calculated effective diffusion coefficients were 2.5 times larger for dextrans less than 66,000 MW, but were not different between the periportal and centrivenular regions. Also, the values did not show the inverse log-log molecular weight dependency for dextrans seen in other microvascular tissues. Values of permeability were much larger than values for nonfenestrated capillaries and also did not exhibit any regional differences. Finally, comparison of the magnitudes of effective diffusion coefficients and permeability suggested that the controlling resistance to dextran uptake occurs intracellularly.
Long-term hemodynamic effects of ketanserin, a 5-hydroxytryptamine blocker, in portal hypertensive patients
Authors: Vorobioff Julio , Garcia-Tsao Guadalupe , Groszmann Roberto , Aceves Guillermo , Picabea Eduardo , Villavicencio Roberto , Hernandez-Ortiz Jorge
Published: March 2007

Ketanserin, a 5-hydroxytryptamine-2 receptor blocker, has been shown to decrease portal pressure in recent acute hemodynamic studies that have been performed both in experimental animals and portal hypertensive patients. The present study was designed to investigate the effects of chronic oral administration of ketanserin in portal hypertensive patients with cirrhosis. The mean baseline hepatic venous pressure gradient in the 13 patients with alcoholic cirrhosis who completed the study was 15.7 ± 2.7 mmHg. It decreased significantly to 13.3 ± 2.0 mmHg (p < 0.001) after ketanserin was administered at a mean dose of 51 mg per day for a mean period of 32 days. This 14.6% reduction in hepatic venous pressure gradient resulted mainly from a decrease in mean wedged hepatic venous pressure (from 22.2 ± 4.0 to 20.1 ± 3.6 mmHg) and was accompanied by significant decreases in cardiac index (18.8%) and in mean arterial pressure (8.1%). However, changes in cardiac index or in mean arterial pressure were not predictive of modifications in the hepatic venous pressure gradient. Eight of 16 patients entered in the study developed side effects, the most significant being a reversible portosystemic encephalopathy, which occurred in three patients who had poor liver function.

This study confirms evidence in favor of a role for 5-hydroxytryptamine in portal hypertension and adds a new group of agents for the chronic treatment of portal hypertensive patients.

Although the long-term oral administration of ketanserin reduces the mean portal pressure in patients with alcoholic cirrhosis and portal hypertension, the high incidence of side effects may limit its value, especially in patients who have a poor liver function.
HBsAg carrier infants with serum anti-HBc negativity
Authors: Lee Shou-Dong , Lo Kwang-Juei , Tsai Yang-Te , Wu Jaw-Ching , Wu Tzee-Chung
Published: March 2007

A total of 128 HBsAg carrier infants born to HBeAg-positive HBsAg carrier mothers were tested for serum HBsAg, HBeAg, hepatitis B virus DNA and anti-HBc. Ninety-three of them had received hepatitis B vaccination. Anti-HBc had been found to be negative in sera of 12 infants who were HBsAg, HBeAg and hepatitis B virus DNA positive during the follow-up period of 3 to 5 years. Liver damage, as measured by serum ALT levels, was found to be normal among the 12 HBsAg carrier infants with serum anti-HBc negativity, whereas 39.7% of the 116 anti-HBc-positive HBsAg carrier infants had abnormal ALT levels during the follow-up period. Anti-HBe and anti-HBs also were not detected in sera of these anti-HBc-negative HBsAg carrier infants. Thus, HBsAg carrier infants with anti-HBc negativity probably result from immune incompetency of the hepatitis B virus antigens.
The use of a monoclonal antibody against α-fetoprotein for the radioimmunodetection of hepatocellular carcinoma
Authors: Springolo Elsa , Kew Michael C. , Esser Jan , Beyers Margaretha , Conradie Jan D. , Levin Joseph
Published: March 2007

The purpose of this study was to investigate the use of a radiolabeled mouse monoclonal antibody (and its F(ab′)2 fragment) against α-fetoprotein in the scinti-graphic diagnosis of hepatocellular carcinoma. Twenty-six southern African Blacks and one Caucasian with hepatocellular carcinoma and four patients with other malignant tumors of the liver were studied. Although six hepatocellular carcinomas appeared to selectively concentrate α-fetoprotein antibody, one of these tumors was not producing α-fetoprotein. Moreover, in another 18 patients with α-fetoprotein-producing hepatocellular carcinomas, uptake of α-fetoprotein antibody was at best only equal to that in nontumorous hepatic tissue, and three hepatocellular carcinomas that were not producing α-fetoprotein concentrated the antibody to the same extent as did the α-fetoprotein-producing tumors and hepatic tissue. All four tumors other than hepatocellular carcinoma concentrated α-fetoprotein antibody as well as did hepatic tissue. These findings suggest that the penetration of hepatocellular carcinomas by α-fetoprotein antibody is a passive and nonselective process. This conclusion is supported by an in vitro study in which a non-α-fetoprotein-producing hepatic metastasis took up as much radiolabeled α-fetoprotein antibody as did three of four α-fetoprotein-producing hepatocellular carcinomas. A likely explanation for the failure of α-fetoprotein monoclonal antibody to be selectively concentrated by hepatocellular carcinomas is that α-fetoprotein is an export protein and is not expressed on the cell membranes of malignant hepatocytes.