bluuebunny/crossref_metadata_2025 huggingface dataset:
Coexistent pulmonary and portal hypertension: Yin and yang
Authors: Wanless I. R.
Published: March 2007

Nodular regenerative hyperplasia (NRH), a rare hyperplastic condition of the liver, is reported in two patients with primary pulmonary hypertension (PPH). The first patient was a 26-year-old man who died of PPH and showed multiple NRH without cirrhosis of the liver. The second patient was a 25-year-old man who had a PPH with pulmonary arterial thrombi and NRH of the liver. NRH has been described in association with immune disease, hematopoietic disorder, and diabetes mellitus, so that NRH with PPH is considered to be very rare. Histologic findings of the lungs show typically plexogenic pulmonary arteriopathy in both cases, and the livers of these patients are composed of multiple nodules that are histologically represented by slightly larger hepatocytes arranged in a cobblestone-like fashion, and are ultramicroscopically characterized by massive proliferation of mitochondria. The pathogenetic association of nodular regenerative hyperplasia with primary pulmonary hypertension will be discussed.
Congestive gastropathy in portal hypertension: Variations in prevalence
Authors: Hosking S. W.
Published: March 2007

Mosaic pattern of gastric mucosa has been reported to be a sensitive and specific criterion for the diagnosis of portal hypertension and an important marker of nonvariceal upper gastrointestinal bleeding. So that the validity of this endoscopic sign could be assessed, 136 patients with portal hypertension, 25 chronic alcoholics without portal hypertension, and 366 controls were carefully endoscoped. Mosaic pattern was significantly (p < 0.01) more common in portal hypertension patients (7.4%) than in controls (1.4%). It was not seen in chronic alcoholics. The incidence of mosaic pattern was 10.9% in cirrhotics, 2.9% in noncirrhotic portal fibrosis, and 5.4% in extrahepatic portal obstruction patients; the differences were not significant. Mosaic pattern was significantly (p < 0.01) more often seen in postsclerotherapy (13.8%) than in presclerotherapy patients (2.6%). Bleeding from nonvariceal causes was uncommon, and was seen in only one patient (0.8%) showing mosaic pattern. Endoscopic gastric biopsies from areas showing mosaic pattern did not reveal any vascular abnormalities. In conclusion, gastric mucosal lesions are not very common in Indian patients with portal hypertension. In our experience, “mosaic pattern” is not a useful diagnostic feature in portal hypertension patients.
Hemodynamic and metabolic responses to leukotriene C4 in isolated perfused rat liver
Authors: Krell Herbert , Dietze Eberhard
Published: March 2007

Responses of isolated perfused rat liver to leukotriene C4 were studied in order to assess the mechanisms involved in leukotriene-mediated liver injury. Infusion of leukotriene C4 (11 and 44 pmoles per min per gm liver weight) into the portal vein resulted in a rise in portal pressure, a decrease in oxygen consumption, an increase in hepatic glucose and lactate efflux and lactate/pyruvate ratio in the perfusate and a small decrease in bile flow. Isoproterenol (1 μM) counteracted the effects of leukotriene C4 on respiration and portal pressure, whereas bile flow and glucose efflux were reversibly stimulated. The same changes were observed upon with-drawal of leukotriene C4. The release of glucose was correlated with the increase in oxygen consumption upon both isoproterenol addition and withdrawal of leukotriene C4. These results are indicative of leukotriene C4-induced microcirculatory redistribution of perfusate flow. Since, in the presence of nitroprusside (50 μM), both the effects of leukotriene C4 and their reversal by isoproterenol were diminished, a vascular site of action can be assumed. Accordingly, the accompanying metabolic responses can be explained by gradual changes in oxygen supply to parts of the liver. Reversibility of the leukotriene C4 effects and lack of short-term impairment of viability of the isolated liver suggest that leukotriene-mediated liver injury is a long-term effect related to events subsequent to microcirculatory changes.
A simple animal model of hyperammonemia
Authors: Azorín Inmaculada , Miñana María-Dolores , Felipo Vicente , Grisolía Santiago
Published: March 2007

Rats were fed a standard diet or the standard diet supplemented with ammonium acetate (20% w/w) for up to 100 days. The effect of the ingestion of the high-ammonium diet on some aspects of nitrogen metabolism in rats was studied. Ammonia levels in blood increased ≈3-fold; in brain, liver and muscle the increases were 36, 34 and 50%, respectively. Urea levels in blood and urea excretion increased ≈2-fold. There was no increase of carbamyl phosphate synthase. Liver glutamine synthase activity increased by 58% and glutamate dehydrogenase by 40%, whereas glutaminase was not affected. Glutamine content in brain was twice that of controls. This new animal model to study hyperammonemia offers several advantages over others: it is simpler, is bloodless, requires no animal manipulation and permits long-term studies.
Is increased ammonia liberation after bleeding in the digestive tract the consequence of complete absence of isoleucine in hemoglobin? A study in pigs
Authors: van Berlo Charles L. H. , van de Bogaard Anton E. J. M. , van der Heijden Marion A. H. , van Eijk Hans M. H. , Janssen Mieke A. , Bost May C. F. , Soeters Peter B.
Published: March 2007

A variable protein-induced toxicity has been reported in liver disease. The aim of this study was to establish the cause of increased ammonia liberation in the gut after intraluminal bleeding. Therefore, blood was sampled from catheterized piglets [20 ± 0.8 kg (means ± S.E.); n = 10] to determine ammonia, urea and amino acid levels before and 1, 2, 3 and 6 hr after a standard pig meal (750 gm, 12% protein). After 1 week, this procedure was repeated after ingestion of an isonitro-genous amount of bovine whole blood (400 ml). In a second series of experiments, the same procedures were performed after ingestion of plasma, whole blood, eryth-rocytes and feed. Electromagnetically measured total intestinal, small and large bowel flow was not significantly influenced by the type of meal ingested. Portal ammonia release was significantly increased 2-fold after a blood meal, whereas intestinal glutamine utilization did not increase. Plasma urea levels were increased 200 to 300% after whole blood and erythro-cytes, whereas after ingestion of plasma, urea levels were similar to values in controls. Glutamine utilization was not different among the various groups and occurred predominantly in the small bowel. In the fasted state, small bowel glutamine utilization paralleled ammonia production. In the fed state, this equimolar relationship could not be assessed because luminal glutamine utilization could not be determined. Isoleucine levels decreased to 25% of fasting levels. Analysis of blood constituents revealed a complete lack of isoleucine in the hemoglobin molecule. Net total α-amino-nitrogen absorption was doubled after a blood meal. The highest absorption was found in the small bowel. These findings lead us to hypothesize that, due to complete lack of isoleucine in hemoglobin, ingestion of blood into the gut presents the organism with protein of low biological value, leading to decreased protein synthesis and to net protein degradation, which in turn may result in increased ammonia- and ureagenesis.
Detection of antibodies against hepatitis B virus polymerase antigen in hepatitis B virus-infected patients
Authors: Chang Lung-Ji , Dienstag Jules , Ganem Don , Varmus Harold
Published: March 2007

By the use of a truncated recombinant hepatitis B virus polymerase antigen, we have characterized a series of patient sera for anti-hepatitis B virus polymerase antibodies. Seven of 54 (13%) had antipolymerase antibodies detectable by Western blot analysis, and no close correlation was apparent between the disease status and patient’s immune response against hepatitis B virus polymerase antigen. Our results indicate that serologic responses to the viral polymerase are demonstrable but suggest that such antibodies are not likely to be clinically useful as diagnostic or prognostic markers of infection.
Spiders and capillaries
Authors: Sherlock Sheila
Published: March 2007

Nailfold capillary microscopical and hormonal investigations were carried out in 25 patients with cirrhosis of the liver and in 20 age- and sex-matched controls. Several structural and functional capillary microscopical parameters were significantly different between the group of cirrhotics as a whole and the controls; no capillaroscopic feature helped to distinguish cirrhotics with spiders from those without. Serum estradiol and total testosterone were comparable in cirrhotics and controls; free serum testosterone was reduced in male cirrhotics, particularly in cirrhotics with spider nevi. The estradiol/free testosterone ratio was highest in male cirrhotics with spiders. Cirrhosis, thus, leads to both structural and functional effects on the cutaneous capillary system whether or not spider nevi are present. The presence of spider nevi is accompanied by an increased serum estradiol/free testosterone ratio in male cirrhotics. It remains to be determined whether the hormonal alterations described do indeed play a role in spider nevi formation.
Balloon tamponade vs. endoscopic sclerotherapy in the management of active variceal hemorrhage
Authors: Terés Josep
Published: March 2007

Sengstaken-Blakemore tamponade is used for the initial control of bleeding esophageal varices (BEV), although it is known to be potentially dangerous. Sclerotherapy has been shown to be effective in the treatment of BEV. This trial has been designed to evaluate comparatively the effectiveness of both procedures in the initial control of the hemorrhage.

Forty-three patients with BEV were included in the trial. Twenty patients (group SB) were treated by tamponade. Twenty-three patients (group ST) were treated by sclerotherapy by means of a simple technique.

During the first 24 hours, hemostasis was obtained in 16 of the SB patients and in all 23 of the ST patients (p < 0.05). At seven days, nine SB patients and 19 ST patients were free of hemorrhagic relapse (p < 0.05). By stratifying in relation to hepatic failure, the difference was greater (p < 0.005) if patients with Child’s A classification were excluded. It is concluded that sclerotherapy should be undertaken in almost every instance at the same moment that diagnosis is made, bypassing the intermediate step of tamponade.
Bile acids inhibit endotoxin-induced release of tumor necrosis factor by monocytes: An in Vitro study
Authors: Greve Jan Willem , Gouma Dirk J. , Buurman Wim A.
Published: March 2007

Endotoxins play an important role in the pathogenesis of complications of surgery in obstructive jaundice. Preoperative treatment with orally administered deoxycholic acid prevented endotoxin-related complications, such as renal malfunction. Other bile acids, however, were less effective, and the mechanism of action is not known.

Endotoxin toxicity is considered to be largely mediated by tumor necrosis factor/cachectin, a cytokine release by mononucler phagocytes. Therefore, we studied the influence of different bile acids on endotoxin-induced tumor necrosis factor production by monocytes in vitro.

Bile acids inhibit tumor necrosis factor production through a direct inhibitory effect on the monocytes. Deoxycholic acid was the most effective, chenodeoxy-cholic acid was less effective and ursodeoxycholic acid was ineffective in the concentrations used. Bile acids did not inactivate endotoxin as measured in a chromogenic Limulus amebocyte lysate assay.

The therapeutic effect of bile acids in obstructive jaundice can be explained by an inhibition of endotoxin-induced tumor necrosis factor release by mononuclear phagocytes.
Mechanisms of a clonidine-induced decrease in portal pressure in normal and cirrhotic conscious rats
Authors: Roulot Dominique , Braillon Alain , Gaudin Christophe , Ozier Yves , Girod Catherine , Lebrec Didier
Published: March 2007

The effects of clonidine on portal pressure and splanchnic blood flow were studied in conscious rats with sinusoidal portal hypertension due to cirrhosis induced by bile duct ligation. In cirrhotic and sham-operated rats, clonidine (20 μg per kg body weight, intravenously) significantly reduced portal, pressure from 19.0 ± 0.6 to 14.5 ± 1.0 mmHg and from 9.8 ± 0.9 to 7.3 ± 0.5 mmHg, respectively. No significant change in systemic hemodynamics was observed. In cirrhotic rats, clonidine reduced portal pressure, probably by producing a significant increase in portal tributary vascular resistance leading to a 25% decrease in portal tributary blood flow (radioactive microsphere method). In shamoperated rats, clonidine reduced portal pressure presumably by decreasing hepatic portal vascular resistance, since no significant change in portal tributary blood flow was observed. In both groups, clonidine administration significantly decreased plasma noradrenaline concentration. Placebo administration produced neither significant hemodynamic nor significant plasma noradrenaline concentration change. These findings indicate that the sympathetic regulation of the splanchnic circulation is impaired in cirrhotic rats.
Cellular analysis of c-Ha- ras gene expression in rat liver after CCl4 administration
Authors: Sasaki Yutaka , Hayashi Norio , Morita Yasuhiro , Ito Toshifumi , Kasahara Akinori , Fusamoto Hideyuki , Sato Nobuhiro , Tohyama Masaya , Kamada Takenobu
Published: March 2007

Expression of the c-Ha-ras proto-oncogene is specifically enhanced during liver regeneration, in parallel with increased DNA replication, which suggests that c-Ha-ras may play a role in the control of regeneration. In this study, an in situ hybridization technique was applied for analysis of expression of the c-Ha-ras gene at the cellular level during liver regeneration induced by CCl4 administration. The in situ hybridization was compared with the observation for the p21c-Ha-ras protein, the corresponding protein of the c-Ha-ras gene, by immunohistochemistry. In normal rat liver, a few hepatocytes expressed the mRNAs and the corresponding proteins without any preferential localization. Zonal heterogeneity of c-Ha-ras gene expression first became evident at 12 hr after CCl4 administration, a higher number of gene products being detected in the pericentral zone than in the periportal zone. This heterogeneity became maximal at 24 hr after CCl4 administration. Zonal heterogeneity in the level of the p21c-Ha-ras protein paralleled that in the level of gene expression. Furthermore, both hepatocytes and nonparenchymal cells participated in expression of the c-Ha-ras gene during liver regeneration.
Reovirus 3 and neonatal biliary disease: Discussion of divergent results
Authors: Morecki Rachel , Glaser Joy
Published: March 2007

Infection with reovirus 3 (Reo-3) has been suggested as the cause of extrahepatic biliary atresia and idiopathic neonatal hepatitis but confirmation has been lacking. Therefore we have searched for a specific anti-Reo-3 antibody response in the sera of patients with biliary atresia or neonatal hepatitis and for Reo-3 antigens in their hepatobiliary tissues. Sera from 23 infants with extrahepatic biliary atresia, 12 with neonatal hepatitis, 30 age-matched control patients with other liver diseases, and 55 control patients without liver disease were tested by an enzyme-linked immunosorbent assay for total (IgA, IgG, and IgM) anti-Reo-antibodies; sera of infants younger than 6 months of age were tested also for IgM anti-Reo-3 antibodies alone. There was no difference between either total or IgM anti-Reo-3 antibody levels in infants with extrahepatic biliary atresia or neonatal hepatitis and levels in control infants. Reo-3 antigens were not detected in the hepatobiliary tissues of 19 infants (18 with biliary atresia, one with neonatal hepatitis) by an immunoperoxidase method that readily demonstrated Reo-3 in control in fected HEp-G2 cells. Our data do not support a relationship between neonatal liver diseases and infection with Reo-3.
Cytoplasmic Antigen in Hepatocytes of Chimpanzees Infected With Non–A, Non–B Hepatitis Virus or Hepatitis Delta Virus: Relationship to Interferon
Authors: Shimizu Yohko K. , Purcell Robert H.
Published: March 2007

We previously described a cytoplasmic antigen, detected by monoclonal antibodies, in hepatocytes of chimpanzees experimentally infected with the parenterally transmitted form of non–A, non–B hepatitis virus or with the hepatitis delta virus. The expression of this antigen appears to be a host–specified response to infection with these two hepatitis viruses but not with hepatitis A virus, hepatitis B virus or enterically transmitted non–A, non–B hepatitis virus. To determine whether this antigen, found in parallel with the hepatocyte cytoplasmic structures described previously, is associated with interferon, as suggested by others, we studied by immunofluorescence liver biopsies from chimpanzees treated with an interferon inducer or exogenous interferon for the presence of the antigen. In two hepatitis B virus carrier chimpanzees and one normal chimpanzee treated with the interferon inducer polyinosinic–poly–ribocytidylic acid–poly–l–lysine carboxymethylcellulose, the antigen became detectable in hepatocytes within 2 weeks of initiation of the treatment, remained detectable throughout the treatment and disappeared within 4 weeks after treatment was terminated. Electron microscopy revealed that the biopsies positive for the antigen exhibited the hepatocyte cytoplasmic changes; convoluted membranes and microtubular aggregates, identical to those described originally for chimpanzees infected with non–A, non–B hepatitis virus. The antigen was not detected in any of the biopsies from a control chimpanzee that received only the carboxymethylcellulose used to stabilize the interferon inducer. In addition, liver biopsies obtained from a hepatitis B virus carrier chimpanzee during treatment with exogenous human leukocyte interferon were found to be positive for the antigen as well. It is likely that expression of this antigen and induction of the hepatocyte cytoplasmic structures are a host response to interferon induced by non–A, non–B hepatitis virus and hepatitis delta virus infections.
Tumor Necrosis Factor α Production by Peripheral Blood Mononuclear Cells of Patients With Chronic Liver Disease
Authors: Yoshioka Kentaro , Kakumu Shinichi , Arao Motohiro , Tsutsumi Yasuhiko , Inoue Masaki
Published: March 2007

We investigated the production of tumor necrosis factor α by peripheral blood mononuclear cells of patients with chronic liver disease and its association with hepatitis activity. Tumor necrosis factor α production was measured with an enzyme–linked immunosorbent assay. Tumor necrosis factor α production by peripheral blood mononuclear cells stimulated with recombinant γ–interferon of patients with chronic active hepatitis (5.8 ± 4.0 units per ml, p < 0.05) and patients with cirrhosis (4.1 ± 2.1 units per ml, p < 0.05) was significantly increased when compared with controls (2.5 ± 1.6 units per ml). Tumor necrosis factor α production by peripheral blood mononuclear cells stimulated with a combination of recombinant γ–interferon and recombinant interleukin 2 of patients with chronic persistent hepatitis (5.8 ± 3.8 units per ml, p < 0.05), patients with chronic active hepatitis (8.9 ± 3.0 units per ml, p < 0.001) and patients with cirrhosis (6.7 ± 3.2 units per ml, p < 0.05) was significantly increased in comparison with controls (3.3 ± 1.8 units per ml). Tumor necrosis factor α production of patients with chronic active hepatitis was significantly higher than that of patients with chronic persistent hepatitis ( p < 0.05). There was a significant correlation (r = 0.5699, p < 0.005) between tumor necrosis factor α production and histologic activity index in patients with chronic persistent hepatitis or chronic active hepatitis. These findings show that tumor necrosis factor α production is increased in chronic liver disease and that the increased tumor necrosis factor α production is related to hepatitis activity.
The Integrated Value of Serum Procollagen Iii Peptide Over Time Predicts Hepatic Hydroxyproline Content and Stainable Collagen in A Model of Dietary Cirrhosis in the Rat
Authors: Ruwart Mary J. , Wilkinson Karen F. , Rush Bob D. , Vidmar Thomas J. , Peters Kenneth M. , Henley Keith S. , Appelman Henry D. , Kim Kiyoung Y. , Schuppan Detlef , Hahn Eckert G.
Published: March 2007

To determine whether a serum parameter of collagen metabolism, serum procollagen type III peptide, correlated with hepatic collagen in a model of diet–induced fibrosis, rats were fed a control or cirrhogenic diet for 6 months and treated with either subcutaneous vehicle or the hepatoprotective prostaglandin 16,16–dimethyl prostaglandin E2 (100 μg per kg) twice daily. Pair–fed rats from each group were killed after 2, 4 or 6 months. The value of serum procollagen type III peptide to body weight integrated over time (Kt) correlated linearly with hepatic hydroxyproline content (r = 0.97) at killing time t. Good correlations were also seen between Kt and histopathological assessment of aniline blue–stainable collagen (r = 0.93) and between the histopathology and hydroxyproline content (r = 0.97). Rats receiving 16,16–dimethyl prostaglandin E2 had lower values of all three parameters compared to rats receiving vehicle, confirming the previously demonstrated hepatoprotective effect of 16,16–dimethyl prostaglandin E2. The excellent correlation between Kt and the two other traditional parameters of hepatic collagen suggest that sequential measurements of serum procollagen type III peptide can be used to predict alterations in liver collagen deposition in rats.
Further Studies on the 37 Kd Liver Protein–Acetaldehyde Adduct That Forms In Vivo During Chronic Alcohol Ingestion
Authors: Lin Renee C. , Lumeng Lawrence
Published: March 2007

We have previously reported the detection of a 37 kD liver protein–acetaldehyde adduct in rats fed alcohol chronically with the AIN'76 diet. It was surprising that only one liver protein–acetaldehyde adduct was found. In this report, we have tried to detect additional protein–acetaldehyde adducts by electroimmunotransblot with rabbit anti–hemocyanin–acetaldehyde adduct IgG and to further characterize the 37 kD liver protein–acetaldehyde adduct. Sensitivity of electroimmunotransblot increased 10–to 20–fold when alkaline phosphatase–linked antibody was used in place of horseradish peroxidase, but only one protein–acetaldehyde adduct band was detected in liver. Feeding rats the Lieber–DeCarli alcohol diet also did not produce more protein–acetaldehyde adduct bands in electroimmunotransblot. Addition of cyanamide, an aldehyde dehydrogenase inhibitor, to the AIN'76 alcohol diet greatly increased the intensity of the 37–kD protein–acetaldehyde adduct band on electroimmunotransblot but did not produce other bands. The 37 kD protein–acetaldehyde adduct decayed in vivo with a half–life of 4 days when alcohol was removed from the diet. The 37 kD protein–acetaldehyde adduct in liver is cytosolic. Its interaction with anti–hemocyanin–acetaldehyde adduct IgG was blocked by polylysine–acetaldehyde adduct and polytyrosine–acetaldehyde adduct. It could be removed by immunosorption with anti–hemocyanin–acetaldehyde adduct IgG–bound immunoresin. When immunoblotted with anti–alcohol dehydrogenase and anti–aldehyde dehydrogenase antibodies, the alcohol dehydrogenase and aldehyde dehydrogenase bands in liver of alcoholfed rats showed identical intensities before and after immunosorption. These data indicate that: (i) the 37 kD protein–acetaldehyde adduct is neither alcohol dehydrogenase nor aldehyde dehydrogenase; (ii) its interaction with anti–hemocyanin–acetaldehyde adduct IgG is by way of acetaldehyde adducts of ε– and/or α–amino groups; (iii) its formation and decay in liver in vivo are likely to depend on acetaldehyde concentration.
Extramural Cross–Validation of the Mayo Primary Biliary Cirrhosis Survival Model Establishes Its Generalizability
Authors: Grambsch Patricia M. , Dickson Rolland E. , Kaplan Marshall , Lesage Gene , Fleming Thomas R. , Langworthy Alice L.
Published: March 2007

The generalizability of the Mayo model for predicting survival in individual primary biliary cirrhosis patients without liver transplantation was tested and confirmed. The model was applied to a data base of patients from the New England Medical Center Hospitals (n = 141) and the Scott and White Clinic (n = 35) and found to predict their survival accurately. It was also shown to be accurate for Mayo primary biliary cirrhosis patients with very advanced disease (n = 30), those with less than a 33% chance of surviving 12 months. The analyses confirmed that the addition of histologic stage did not significantly improve the predictive power of the model (p > 0.10). We suggest that the Mayo model is a practical tool for clinical management and decision making.
Survey of Iron–Accumulative Macroregenerative Nodules in Cirrhotic Livers
Authors: Terada Tadashi , Nakanuma Yasuni
Published: March 2007

Recently, macroregenerative nodules in cirrhotic livers have been suspected to be among the putative precancerous lesions in human hepatocarcinogenesis. We examined the morphologies of 99 macroregenerative nodules in 44 cirrhotic livers with special emphasis on stainable iron. In 26 macroregenerative nodules (26%), stainable iron selectively accumulated within the macroregenerative nodules themselves, and little or no iron was found in the surrounding regenerative nodules. In nine macroregenerative nodules (9%), an appreciable amount of stainable iron was present in both the macroregenerative nodules and the surrounding regenerative nodules. In the remaining 64 macroregenerative nodules (65%), stainable iron was absent in both the macroregenerative nodules and the surrounding regenerative nodules. Hyperplastic hepatocellular foci were present within 19 (73%) of the 26 iron–accumulative macroregenerative nodules, one (11%) of the nine iron–positive macroregenerative nodules and 20 (31%) of the 64 iron–negative macroregenerative nodules. These findings suggest that iron–accumulative macroregenerative nodules are frequently associated with hyperplastic hepatocellular foci and should be included among the precancerous lesions in human hepatocellular carcinoma.
Reduced–Size Orthotopic Liver Transplantation: Use in the Management of Children With Chronic Liver Disease
Authors: Emond Jean C. , Whitington Peter F. , Thistlethwaite Richard J. , Alonso Estella M. , Broelsch Christoph E.
Published: March 2007

Reducing the size of a liver for use in a recipient smaller than the donor is one way to reduce mortality before orthotopic liver transplantation in children because of the scarcity of pediatric organ donors. In this report, we review the results of this approach over the past 2 years, during which we have used reduced–size orthotopic liver transplantation routinely in small children.

Forty–nine children underwent orthotopic liver transplantation between September, 1986, and October, 1988; orthotopic liver transplantation with a whole organ (full–size orthotopic liver transplantation) was performed in 36 children, whereas 13 patients received reduced–size orthotopic liver transplantation. In two pairs of patients, the reduced grafts were obtained from single donors, using a “split–liver” procedure. All grafts were implanted in the orthotopic position following total recipient hepatectomy.

The preoperative diagnostic categories were not significantly different between groups. Patients receiving reduced–size orthotopic liver transplantation were younger (1.6 ± 1.5 vs. 4.4 ± 4.6 years), and a higher percentage were in the intensive care unit prior to transplant (31 vs. 9%). Thirty of 36 (82%) patients receiving full–size orthotopic liver transplantation and 10 of 13 (77%) patients receiving reduced–size orthotopic liver transplantation are alive 3 to 27 months after transplantation. The rates of retransplantation were 24% for full–size orthotopic liver transplantation and 15% for reduced–size orthotopic liver transplantation.

Despite the greater complexity of reduced–size ortho–topic liver transplantation and the higher frequency of critically ill recipients selected for the procedure, the results of reduced–size orthotopic liver transplantation are comparable with full–size orthotopic liver transplantation. These results justify the continued use of reduced–size orthotopic liver transplantation in children with end–stage liver disease.
Intrahepatic Markers of Hepatitis Delta Virus Infection: A Study By In Situ Hybridization
Authors: Negro Francesco , Bonino Ferruccio , Bisceglie Adrian Di , Hoofnagle Jay H. , Gerin John L.
Published: March 2007

The intrahepatic distribution of hepatitis delta virus RNA was studied by in situ hybridization in 33 formalin–fixed, paraffin–embedded biopsies from 17 chronic hepatitis B virus carriers superinfected with hepatitis delta virus. The findings were correlated with the expression of the hepatitis delta antigen, the duration of the hepatitis delta virus infection and the eosinophilic degeneration of the hepatocytes. Intranuclear hepatitis delta virus RNA and antigen were found in 28 specimens, whereas the remaining five were negative for both markers. Hepatitis delta virus RNA and antigen were mostly found within the same cell. In 20 specimens, however, a variable number of hepatocytes showed the presence of hepatitis delta virus RNA alone. The percentage of these over the total number of infected cells was higher in the specimens taken within 1 year from the acute delta hepatitis, whereas their absence was invariably associated with a long–established hepatitis delta virus infection. Interestingly, the vast majority of hepatocytes undergoing eosinophilic degeneration, a change significantly associated with hepatitis delta virus infection, did not show the presence of either hepatitis delta virus RNA or the viral antigen, suggesting a lack of association, at the cellular level, between viral replication and cytopathological change. The specificity of the detection of hepatitis delta virus RNA was confirmed by negative findings in nine specimens from seven chronic hepatitis B virus carriers without evidence of past or current hepatitis delta virus infection. The loss in sensitivity due to the formalin fixation was estimated to be 50% of that obtained in frozen biopsies, as determined by counting autoradiographic grains over infected cells. Consistent results were obtained when sections from the same biopsies were hybridized in separate experiments. Detection of hepatitis delta virus RNA by in situ hybridization in formalin–fixed, paraffin–embedded sections is therefore a rapid, specific, sensitive and reproducible assay for monitoring intrahepatic hepatitis delta virus replication and might have diagnostic relevance.
Propranolol Decreases Portal Pressure Without Changing Portocollateral Resistance in Cirrhotic Rats
Authors: Pizcueta Pilar M. , de Lacy Antonio M. , Kravetz David , Bosch Jaime , Rodés Joan
Published: March 2007

Propranolol decreases portal pressure by reducing portal blood inflow. Studies in rats with prehepatic portal hypertension due to portal vein stenosis (a model with extensive portosystemic shunting) have shown that propranolol increases the portocollateral resistance, which hinders the fall in portal pressure. The present study examined the effects of propranolol on splanchnic and systemic hemodynamics in rats with portal hypertension due to cirrhosis of the liver, a model which is characterized by mild portosystemic shunting. Two groups of rats with CCl4–induced cirrhosis were studied: the propranolol group (n = 8), which received a propranolol infusion of 2 mg per 15 min, and controls (n = 9), which received a placebo (saline) infusion. Hemodynamic measurements were done using radiolabeled microspheres. Propranolol–treated rats had signficantly lower cardiac output (-31%) and heart rate (-26%) than controls (p < 0.001). Hepatic artery flow was not modified by propranolol. Propranolol caused splanchnic vasoconstriction, manifested by increased splanchnic resistance (+57%) and by a significant fall in portal blood inflow (4.8 ± 0.4 vs. 6.3 ± 0.5 ml per min · 100 gm in controls, p < 0.05). In contrast with rats with prehepatic portal hypertension, propranolol did not increase portal resistance in cirrhotic rats [2.0 ± 0.2 vs. 2.0 ± 0.1 mmHg per ml per min · 100 gm body weight (not significant)]. Hence, the fall in portal pressure (-19%) was expected from the decrease in portal inflow (-24%). These results suggest that increased portal resistance in rats with prehepatic portal hypertension may represent an intrinsic effect of propranolol on the portocollateral an intrinsic effect of propranolol on the portocollateral vessels, since β–blockade does not modify portal vascular resistance in cirrhosis.
Association of Transdermal Nitroglycerin to Vasopressin Infusion in the Treatment of Variceal Hemorrhage: A Placebo–Controlled Clinical Trial
Authors: Bosch Jaime , Groszmann Roberto J. , García-Pagán Joan C. , Terés Josep , García-Tsao Guadalupe , Navasa Miquel , Mas Antoni , Rodés Joan
Published: March 2007

The aim of this study was to evaluate, using a doubleblind technique, the efficacy of the association of transdermal nitroglycerin to vasopressin infusion for the treatment of variceal bleeding. Sixty–nine cirrhotic patients with active variceal bleeding were randomly allocated to receive vasopressin (0.4 to 0.8 unit per min until variceal bleeding has been controlled for 12 hr) associated with nitroglycerin administered transdermically in a slow–release preparation (10 mg in 24 hr) or placebo. An initial control of variceal hemorrhage was achieved in 83% of the patients receiving vasopressin–nitroglycerin and in 74% in the vasopressin–placebo group. Owing to a lower frequency of recurrent bleeding during therapy (18 vs. 42%, p = 0.11), vasopressin–nitroglycerin achieved a definitive control of bleeding in a higher proportion of patients than vasopressinplacebo (73 vs. 54%, p = 0.13). The group treated with the drug combination showed favorable results in relation to transfusion requirements (2.9 ± 0.4 vs. 4.2 ± 0.5 units, p = 0.05), total dose of vasopressin required (453 ± 47 vs. 587 ± 50 units, p < 0.05), need of balloon tamponade (6 vs. 15, p < 0.05) and requirement for emergency surgery (0 vs. 4, p = 0.07). There were no significant differences in the undesirable effects associated with treatment, observed in 37 and 49% of cases, respectively. Hospital mortality was similar (33 vs. 25%). This study demonstrates that transdermal nitroglycerin improves the effectiveness of vasopressin for controlling variceal hemorrhage.
Monitoring of Sodium: Proton Exchange in Isolated Hepatocytes by Electronic Cell Sizing
Authors: Stewart David J.
Published: March 2007

To investigate volume–regulating processes in the hepatocyte, a rapid and precise method of measuring cell volume in isolated hepatocytes was devised which uses a Coulter Counter equipped with a Channelyzer. Isolated hepatocytes exhibit a volume–decreasing mechanism (potassium channel) which is triggered by cell volume increases as small as 10%. Cell volume increases in the hepatocyte may be mediated by activity of the Na:H exchanger. To examine Na:H exchange–mediated cell volume increases, without apparent interference by the volume–decreasing mechanism, acetate was substituted for chloride in the incubation medium. Hepatocytes placed in a medium containing sodium acetate at an acidic pH exhibit a continuous amiloride–sensitive swelling. A simple procedure was devised for estimating Na:H exchanger set–point by electronic cell sizing. In a sodium acetate medium, the internal pH equilibrates with the external pH. By placing cells in sodium acetate medium of various pH values and measuring the rate of amiloride–sensitive swelling, an estimate of Na:H exchanger set–point can be obtained. By this method, the exchanger was estimated to cease activity above an intracellular pH of 7.2. This method could be useful for identification of stimuli that might promote cell enlargement by raising the exchanger set–point. The phorbol ester 12–O–tetradecanoylphorbol–13–acetate tetraacetic acid raises the set–point of the exchanger in the isolated hepatocytes, resulting in exchanger activity at normal cellular pH, and at the same time promotes hepatocyte swelling. Exchanger activation via a kinase C–mediated mechanism is one possible way that hepatocyte enlargement may occur.
Angiographically Undetected Small Hepatocellular Carcinoma: Clinicopathological Characteristics, Follow–Up and Treatment
Authors: Sonoda Takashi , Shirabe Ken , Takenaka Kenji , Kanematsu Takashi , Yasumori Kotaro , Sugimachi Keizo
Published: March 2007

We studied 36 cases (38 nodules) of small hepatocellular carcinoma with special attention directed to detectability using angiography and histology. Among the 38 nodules, 31 nodules (81.6%) were evident. The remaining seven (18.4%) were not evident angiographically but were detected using ultrasonography and/or computed tomography, prior to angiography. An elevated level of serum α–fetoprotein also suggested a diagnosis of hepatocellular carcinoma. When comparisons were made between angiographically detected and undetected nodules, there was no statistically significant difference in parameters, including sex of the patient, tumor size, location of the tumor, positive rate for hepatitis B surface antigen, history of liver disease and values of α–fetoprotein.

The small hepatocellular carcinomas not detected angiographically and evidenced only histologically had the following characteristics: (i) no fibrous capsule surrounding the nodules; (ii) well–differentiated tumors; (iii) replacing growth pattern of cancer cells, and (iv) remains of portal tracts within the tumor. The replacing growth pattern and the presence of portal tracts may correlate with the low detectability in angiography.

When a definite diagnosis of angiographically undetectable tumors cannot be made using close surveillance with ultrasonography or α–fetoprotein and/or needle biopsy under ultrasonic guide, surgical intervention should be considered, particularly for patients at high risk for hepatocellular carcinoma.
Alcohol Infusion to Measure Hepatic Blood Flow: Vanquishing the Běte Noire?
Authors: Lee Samuel S.
Published: March 2007

Experiments were carried out to determine the accuracy and validity of estimations of hepatic blood flow from systemic clearances of ethanol during very low dose (8 μmol. min.-1· kg-1) infusions of ethanol in anesthetized cats. Systemic clearances were compared with directly measured hepatic blood flow using a hepatic venous longcircuit technique. This technique allowed direct measurement and alteration of hepatic blood flow and collection of arterial, portal, and hepatic venous blood samples without depletion of the animal's blood volume. In 18 cats, Vmax for ethanol was 93 ± 7 μmol·min-1 per 100 g liver or 21 ± 2 μmol·min-1 · kg body weight-1 and Km was 144 ± 19 μM in terms of logarithmic mean sinusoidal concentration. At the dose of 8 μmol·min-1· kg body weight-1 used for estimation of hepatic blood flow, extraction was 0.95 ± 0.07 (mean ± SD). Systemic clearance of ethanol overestimated directly measured hepatic blood flow by 15 ± 16%. Hepatic blood flow changes expressed as percentages of the control level were accurately estimated from systemic ethanol clearance (100 ± 10%). Since 73 ± 12% of the infused ethanol was eliminated by the liver and 83 ± 11% was eliminated by the splanchnic bed, an extraslanchnic uptake of 17% accounted for the overestimation of hepatic blood flow. Estimation of hepatic blood flow from systemic clearances of ethanol during very low dose infusions may have advantages over other clearance methods. Its use in cats was illustrated in a separate series of experiments and it was shown that surgery significantly reduced hepatic blood flow. The method may merit trial for estimation of hepatic blood flow in humans.
Isolation of Tryptic Fragment of Antigen From Mitochondrial Inner Membrane Proteins Reacting With Antimitochondrial Antibody in Sera of Patients With Primary Biliary Cirrhosis
Authors: Muno Daisaku , Kominami Eiki , Ishii Hideo , Usui Koh , Saifuku Koji , Sakakibara Yuji , Namihisa Toshihiko
Published: March 2007

Most of the sera from patients with primary biliary cirrhosis contains antimitochondrial antibodies, which react with four proteins of the mitochondrial inner membrane. We reported in a previous paper that when beef heart mitochondrial inner membrane proteins were digested by trypsin, a new reactive 36 kDa fragment with antimitochondrial antibody was obtained. This 36 kDa fragment derives from original 70 kDa protein because the monoclonal antibody specific to 70 kDa protein reacts with the 36 kDa band equivalent to 70 kDa band. The 36 kDa fragment was purified using an affinity column conjugated with an immunoglobulinrich fraction of primary biliary cirrhosis serum containing antimitochondrial antibody, preparative electrophoresis and high–performance liquid chromatography using a reverse phase column. The final preparation showed a single band in sodium dodecyl sulfate polyacrylamide gel electrophoresis. Its amino acid composition is in good agreement with that of the subunit binding domain of the pyruvate dehydrogenase complex E2 from bovine heart.
Prospective Study of Bacterial Infection in Acute Liver Failure: An Analysis of Fifty Patients
Authors: Rolando Nancy , Harvey Felicity , Brahm Javier , Philpott-Howard John , Alexander Graeme , Gimson Alexander , Casewell Mark , Fagan Elizabeth , Williams Roger
Published: March 2007

Fifty consecutive patients admitted with acute liver failure, minimal grade II encephalopathy, were studied prospectively to determine to incidence, timing and cause of bacterial infection, the relationship to clinical criterial for infection; and the influence of early microbiological diagnosis on clinical outcome. There were 53 proven bacterial infections in 40 patients, whereas in 5 of the remaining 10 patients infection was suspected on clinical grounds in the absence of significant cultures. Seven patients (14%) had more than one bacterial infection, and four patients had simultaneous infections caused by different organism at each site. Fourteen infections (26.4%) were associated with backteremia, and in six of these no source was found. Twenty–five infections (47.1%) arose from the respiratoory tract, 12 (22.6%) from the urinary tract and 2 (3.7%) from central venous due to gram–positive bacteria; Staphylococcus aureus accounted for 19 (35.8%) of all the infections.

Thirty patients died (60%), 28 of whom had bacterial infection at some time; in 24 of these the infection was diagnosed less than 24 hr before death. All nine deaths that occurred more than 7 days after admission were directly attributable to microbial infection.

Clinical features such as elevated temperature and elevated peripheral white blood cell count were poor indicators of bacterial infection because these were absent in 30.2% of cases.

These data show that there is a high incidence of bacterial infection early in the course of acute liver failure and suggest that porphylactic antimicrobial therapy, although unproven, might be justified. (HEPATOLOGY 1990; 11: 49-53.
Amiodarone– and Desethylamiodarone–Induced Myelinoid Inclusion Bodies and Toxicity Cultured Rat Hepatocytes
Authors: Somani Pitambar , Bandyopadhyay Subhankar , Klaunig James E. , Gross Susan A.
Published: March 2007

Hepatocytes isolated from Sprague–Dawley rats were incubated with various concentrations of either amiodarone or desethylamiodarone fro 0 to 69 hr. Both drugs produced a concentration–dependent increase of lactate dehydrogenase release in the culture medium, which correlated well with cell death as measured by trypan blue exclusion test. Desethylamiodarone was more toxic than amiodarone in the cultured hepatocytes. Incubation with subtoxic concentrations of either amiodarone (7.6 μ) or desethylamiodarone (8 μM) for 24 hr resulted in the development of myelinoid inclusion bodies in the hepatocytes without any excess release of lactate dehydrogenase. In experimental protocols where the hepatocytes were exposed to either amiodarone or desethylamiodarone for up to 96 hr, there was an increase in lactate dehydrogenase and the percent volumedensity of multilamellar inclusion bodies with cumulative drug exposure with time. A linear correlation between hepatocyte drug concentration and multilamellar inclusion bodies was found for both amiodarone and desthylamiodarone. These results demonstrate that both amiodarone and its major metabolite, desethylamiodarone, induce lysosomal inclusions, which, under appropriate conditions, can be dissociated from cell death,. Withdrawal of the drug after 24 hr exposure did not result in disappearance of the inclusion bodies from the hepatocytes for up to 96 hr of tissue culture. The concentrations at which amiodarone– or desethylamiodarone–induced electron microscopic changes and hepatotoxicity were only two to five times as high as the usual serum drug levels in patients given antiarrhythmic therapy with amiodarone. (HEPATOLOGY 1990; 11: 81-92.)
Hepatic Mitochondrial Malondialdehyde Metabolism in Rats With Chronic Iron Overload
Authors: Britton Robert S. , O'Neill Rosemary , Bacon Bruce R.
Published: March 2007

Peroxidative decomposition of mitochondrial membrane phospholipids with subsequent mitochondrial dysfunctin is a postulated mechanism of liver cell injury in parenchymal iron overload. Malondialdehyde is formed when polyunsaturated fatty acids of membrane phospholipids undergo peroxidative decomposition, and it is metabolized by aldehyde dehydrogenase. We studied mitochondrial metabolism of malondialdehyde in rats with chronic dietary iron overload. Hepatic malondialdehyde concentrations were significantly increased in iron–loaded livers, and mitochondrial respiratory control ratios using glutamate as a substrate were decreased by 47% largely owing to reductions in state 3 respiration. When exogenous malondialdehyde was added to mitochondrial fractions, there was significantly less metabolism of malondialdehyde in mitochondria of iron–loaded livers as compared with controls. In addition, there was a 28% decrease in mitochondrial aldehyde dehydrogenase in iron–loaded livers but no change in cytosolic aldehyde dehydrogenase. Increased hepatic malondialdehyde in chronic iron overload may result from a combination of increased production and decreased metabolism of malondialdehyde, both of which may be due to ironinduced mitochondrial lipid peroxidation.
Hemodynamic Mechanisms of Emerging Portal Hypertension Caused by Schistosomiasis in the Hamster
Authors: Morgan James S. , Groszmann Roberto J. , Rojkind Marcos , Enriquez Rosa
Published: March 2007

A hamster model of schistosomiasis has provided the first opportunity to sequentially examine the early phases of the development of portal hypertension in a natural model of chronic liver disease.

Groups of hamsters were infected with 50 cercariae of Schistosoma mansoni and underwent hemodynamic evaluation at intervals of 5, 8, 12 and 20 wk after infection. A progressive rise in intrahepatic resistance (from 4.0 ± 0.4 to 8.4 ± 1.0 mm Hg min. ml-1. gm liver weight [p <0.01]) appeared to play a major role in the initial stages of evolving portal hypertension. A gradual decline in portal blood flow (from 2.1 ± 0.3 to 1.3 ± 0.1 ml. min-1gm-1liver weight [p <0.01]) was only partially compensated for by an increase in hepatic arterial flow. Accordingly, by week 20, total hepatic blood flow decreased 23%. Liver weight that increased markedly between 5 and 12 wk after infection, as a result of the acute accumulation of obstructing granulomas, stabilized between wk 12 and 20, while a gradual but progressive rise in hepatic collagen content was seen. Portal pressure increased 75% during the study period.

Chronic examination of this natural model should help define the pathogenesis of the complications of portal hypertension and contribute to the basis for effective intervention in this disease process.