bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of increase in heterozygous α1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma
Authors: Rabinovitz Mordechai , Gavaler Judith S. , Kelly Robert H. , Prieto Martin , Van Thiel David H.
Published: March 2007

Homozygous α1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous α1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous α1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers.

We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. α1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and X2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous α1-antitrypsin deficiency.

Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations. Heterozygosity of α1-antitrypsin Pi types (non-PiMM) does not mark an increased estimated risk for hepatocellular carcinoma (odds ratio = 0.78; 95% confidence index = 0.28, 2.16; p = not significant), or bile duct carcinoma (odds ratio = 2.27; 95% confidence index = 0.77, 6.70; p = not significant). Based on these results, we conclude that heterozygous α1-antitrypsin deficiency is not associated with hepatocellular carcinoma or bile duct carcinoma. (Hepatology 1992;15:407-410).
Ultrastructural and immunohistochemical studies of the intrahepatic peribiliary capillary plexus in normal livers and extrahepatic biliary obstruction in human beings
Authors: Kono Naoko , Nakanuma Yasuni
Published: March 2007

Ultrastructural and immunohistochemical study was conducted on the intrahepatic peribiliary capillary plexus in normal livers and in those with extrahepatic biliary obstruction. In both conditions, capillaries positive for Ulex europaeus agglutinin I and type IV collagen were always present in the vicinity of the bile ducts. Immunoelectron microscopy showed the presence of type IV collagen on the basal lamina of these capillaries; Ulex europaeus agglutinin I was also positive on their cytoplasms. Under electron microscope, a considerable number of these capillaries were seen as being composed of fenestrated endothelium with a diaphragm and with extreme cytoplasmic attenuations that were dense at the sides facing the bile duct in comparison with the opposite sides in normal livers. In extrahepatic biliary obstruction, plasmalemmal pinocytic vesicles, multivesicular bodies and other cellular organellae such as rough endoplasmic reticulum and Weibel-Palade bodies increased in number in these capillaries, relative to normal livers, probably reflecting increased permeability and functional activities. These characteristic ultrastructural features of the peribiliary capillary plexus might be arranged to transport substances effectively by way of intrahepatic biliary epithelial cells in normal livers and also might be altered to meet the increased functional demands of extrahepatic biliary obstruction. (Hepatology 1992;15:411-418).
Immunohistochemical study of extracellular matrix in acute galactosamine hepatitis in rats
Authors: Jonker Mieke A. , Dijkhuis Freke W. J. , Boes Adriana , Hardonk Machiel J. , Grond Joris
Published: March 2007

A single injection of D-galactosamine hydrochloride induces acute self-limiting liver disease in rats that morphologically resembles drug-induced hepatitis in human beings. In this immunohistochemical study we examined the localization and expression of the hepatic extracellular matrix components fibronectin, laminin, collagen type I, collagen type III and collagen type IV and of the cell surface receptors (integrins) for fibronectin and laminin. Sections of liver tissue obtained at intervals of 6, 12, 18, 24, 30, 36, 48 and 72 hr and 7 and 21 days after galactosamine administration were immunostained with a panel of polyclonal monospecific antibodies and studied independently by two of us. Fibronectin was the first extracellular matrix component found to be increased, 12 hr after galactosamine injection, followed by collagen type III, and, in a later phase, collagen type IV, type I and laminin. Increased deposition of extracellular matrix was found in areas with liver cell necrosis and along sinusoids. Extracellular matrix immunoreactivity reached a maximum at 36 to 48 hr and decreased thereafter to preinjury levels 3 wk after galactosamine. Immunostaining for the fibronectin and laminin receptors revealed tissue localization identical to that of their ligands. However, the intensity of staining was opposite of that for the extracellular matrix, with a decrease of immunoreactivity after 24 to 48 hr.

The observed sequence of changes in hepatic extracellular matrix proteins after galactosamine injection resembles the repair reaction in other tissues and may reflect the particular function that each carries out during the process of liver healing after toxic injury. (Hepatology 1992;15:423-431).
Evaluation of the iron chelation potential of hydrazones of pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde using the hepatocyte in culture
Authors: Baker Erica , Richardson Des , Gross Sharon , Ponka Prem
Published: March 2007

A range of new analogues of the promising iron chelator pyridoxal isonicotinoyl hydrazone was prepared and assessed for activity in reducing hepatocyte iron, mechanism of action and potential in iron-chelation therapy. A total of 45 compounds were synthesized by condensation of aromatic aldehydes (pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde) with various acid hydrazides prepared by systematic substitutions on the benzene ring or by the replacement of the ring with an acetyl, pyridyl, furoyl or thiophene moiety. The effects of these compounds on 59Fe uptake and intracellular distribution in hepatocytes in culture and on 59Fe mobilization from prelabeled hepatocytes were assessed. Toxicity, lipophilicity and the ability to chelate plasma transferrin-bound 59Fe were also evaluated. Several compounds were much more active than pyridoxal isonicotinoyl hydrazone and may have clinical potential. These included pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone, pyridoxal m-fluorobenzoyl hydrazone and pyridoxal 2-pyridyl hydrazone. All were more effective at reducing iron uptake than mobilizing hepatocyte iron; they also may act primarily on the transit iron pool rather than on storage iron. Other compounds (e.g., salicylaldehyde p-t-butyl-benzoyl hydrazone) redistributed ferritin-59Fe to different intracellular sites but had little net effect on hepatocyte iron levels. (Hepatology 1992;15:492-501).
Liver plasma membrane-associated fibroblast growth: Stimulatory and inhibitory activities during experimental cirrhosis
Authors: Belyaev Nickolay D. , Budker Vladimir G. , Deriy Ludmila V. , Smolenskaya Irina A. , Subbotin Vladimir M.
Published: March 2007

During experimental CCl4 cirrhosis, an increase of membrane-associated factor stimulating 3T3 cell proliferation in vitro was observed. This stimulator is a 150-kD protein similar to one previously described. In situ perfusion released growth stimulatory activity, suggesting a peripheral plasma membrane protein localizing on basolateral surfaces. The activity increased with increasing number of CCl4 treatments, reaching a maximum at the 14th intoxication. It was faster than the proliferation of connective tissues determined histologically. Cessation of treatment caused a decrease in activity to that of the level of untreated liver, although the number of fibroblastlike cells remained large. This data, taken with the results of experiments with enriched hepatocyte fraction, may serve as an evidence in favor of hepatocyte origin of the factor.

A factor inhibiting fibroblast proliferation was measured in detergent extracts from membranes, suggesting an integral membrane protein. The activity of the inhibitory factor increased in acute liver lesions, but at the stage of maximal fibrogenesis this factor is reduced to levels comparable to those of the intact liver. Therefore it is unlikely that this factor is involved in CCl4-induced fibrogenesis at the final stages.

These factors may be common controls for various hepatic lesions causing fibrosis, both in clinical and experimental modeling. (Hepatology 1992;15:525-531).
Acetylcysteine and fulminant hepatic failure
Authors: Sheiner Patricia , de Majo Wilfred , Levy Gary A.
Published: March 2007

Background.

When administered early after an overdose of acetaminophen, intravenous acetylcysteine prevents hepatic necrosis by replenishing reduced stores of glutathione. How acetylcysteine improves the survival of patients with established liver damage induced by acetaminophen, however, is unknown. This study was undertaken to determine whether the beneficial effect of acetylcysteine under such circumstances could be due to enhancement of oxygen delivery and consumption.

Methods.

We studied the effect of acetylcysteine on systemic hemodynamics and oxygen transport in 12 patients with acetaminophen-induced fulminant hepatic failure and 8 patients with acute liver failure from other causes. The acetylcysteine was given in a dose of 150 mg per kilogram of body weight in 250 ml of 5 percent dextrose over a period of 15 minutes and then in a dose of 50 mg per kilogram in 500 ml of 5 percent dextrose over a period of 4 hours; measurements were made before treatment began and after 30 minutes of the regimen.

Results.

In the patients with acetaminophen-induced liver failure, the infusion of acetylcysteine resulted in an increase in mean oxygen delivery from 856 to 975 ml per minute per square meter of body-surface area (P = 0.0036), due to an increase in the cardiac index from 5.6 to 6.7 liters per minute per square meter (P = 0.0021). Mean arterial pressure rose from 88 to 95 mm Hg (P = 0.0054) despite a decrease in systemic vascular resistance from 1296 to 1113 dyn · sec · cm−6 per square meter (P = 0.027). There was an increase in oxygen consumption from 127 to 184 ml per minute per square meter (P = 0.0007) associated with an increase in the oxygen-extraction ratio from 16 to 21 percent (P = 0.022). The effects in the patients with acute liver failure from other causes were similar.

Conclusions.

The increase in oxygen delivery and consumption in response to acetylcysteine may account for its beneficial effect on survival in patients with fulminant hepatic failure induced by acetaminophen.
Propranolol for portal hypertensive gastropathy: Another virtue of β-blockade?
Authors: Muñoz Santiago J.
Published: March 2007

The two main causes of gastrointestinal bleeding in cirrhosis are oesophageal varices and portal hypertensive gastropathy (PHG). Rebleeding from varices can be prevented by beta-blockers, but it is not clear whether these drugs effectively reduce rebleeding from PHG. 54 cirrhotic patients with acute or chronic bleeding from severe PHG took part in a randomised, controlled trial to investigate the efficacy of propranolol in prevention of rebleeding from PHG. 26 patients were randomised to receive propranolol daily at a dose that reduced the resting heart rate by 25% or to 55 bpm (20-160 mg twice daily), throughout mean follow-up of 21 (SD 11) months. 28 untreated controls were followed-up, with the same examinations, for 18 (13) months. The actuarial percentages of patients free of rebleeding from PHG were significantly higher in the propranolol-treated patients than in the untreated controls at 12 months (65% vs 38%; p < 0.05) and at 30 months of follow-up (52% vs 7%; p < 0.05). Propranololtreated patients had fewer episodes of acute bleeding than controls (0 · 010 [0 · 004] vs 0 · 120 [0 · 040] per patient per month). Multivariate analysis showed that absence of propranolol treatment was the only predictive variable for rebleeding. Actuarial survival was slightly higher in the propranolol group than in the controls, but the difference was not significant. Thus, long-term propranolol treatment significantly reduces the frequency of rebleeding from severe PHG, and may improve the prognosis of cirrhotic patients with this disorder.
Portosystemic shunt without surgery
Authors: Elta Grace H. , Eckhauser Frederic E.
Published: March 2007

Objective.

- To determine the effectiveness of the Palmaz balloon expandable stent for the creation of a transjugular intrahepatic portosystemic shunt. The device is designed to achieve portal decompression in patients with variceal hemorrhage secondary to portal hypertension.

Design.

- Transjugular intrahepatic portosystemic shunting was performed in eight patients during a 9-month period. Mean follow-up was 5 months.

Patients.

- All patients had cirrhosis with portal hypertension and varices. Bleeding occurred in seven patients from esophageal varices and in one patient from hemorrhoids.

Main Outcome Measures.

- Shunt patency and recurrent variceal hemorrhage.

Results.

- Shunts created from a transjugular approach between a hepatic and a portal vein (diameters of 8 to 12 mm) lowered the average portosystemic pressure gradient from 36 to 11 mm Hg. Mean postoperative hospital stay was 7.7 days. Complete variceal decompression after transjugular intrahepatic portosystemic shunt placement was identified endoscopically in all eight patients. The patient treated for hemorrhoids rebled and was treated successfully by transfemoral balloon expansion of the shunt diameter from 8 to 12 mm. All shunts were patent at 1 to 9 months (mean, 5 months) of follow-up.

Conclusion.

- Initial results suggest that transjugular intrahepatic portosystemic shunt is a safe and effective method of portal decompression for the treatment of variceal hemorrhage.
Effects of Amiloride on Renal Lithium Handling in Nonazotemic Ascitic Cirrhotic Patients With Avid Sodium Retention
Authors: Angeli Paolo , De Bei Erica , Pria Manuela Dalla , Caregaro Lorenza , Ceolotto Giulio , Albino Grazia , Gatta Angelo
Published: March 2007

The reliability of lithium clearance as an index of distal fluid delivery in cirrhosis with ascites and in other clinical conditions characterized by low fractional sodium excretion has not yet been proven. In particular, lithium reabsorption in the amiloridesensitive segment of the distal tubule, as evidenced in experimental studies, has not been excluded in such clinical conditions. Thus the acute effect of amiloride on renal lithium handling in 15 nonazotemic ascitic cirrhotic patients with avid sodium retention was evaluated after at least 5 days of controlled sodium intake. Renal plasma flow, glomerular filtration rate, fractional sodium excretion, fractional lithium excretion, fractional potassium excretion, fractional excretion of uric acid, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide were evaluated before and for 6 hr after the administration of amiloride (20 mg/os).

After amiloride administration a volume replacement scheme was enacted with intravenous amounts of saline solution, determined by the diuretic and natriuretic effect of the drug, to avoid volume depletion. Amiloride induced a prompt and sustained increase in fractional sodium excretion (from 0.28% ± 0.09% to 1.0% ± 0.41%, p < 0.001) and a decrease in fractional potassium excretion (from 9.38% ± 5.98% to 3.28% ± 2.24%, p < 0.0025), whereas it did not affect fractional lithium excretion and fractional excretion of uric acid. No change was observed in renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide.

It was concluded that lithium is not reabsorbed in the amiloride–sensitive segment of the distal tubule in nonazotemic ascitic cirrhotic patients with avid sodium retention. (Hepatology 1992;15:651-654).
A Chromosome 17:7 Translocation Is Associated With A Hepatitis B Virus Dna Integration in Human Hepatocellular Carcinoma Dna
Authors: Meyer Markus , Wiedorn Klaus Hermann , Hofschneider Peter Hans , Koshy Rajen , Caselmann Wolfgang Helmut
Published: March 2007

Chronic hepatitis B virus infection is often associated with major structural rearrangements of both the integrated viral DNA and the associated cellular sequences. We present here the structure of a single–copy hepatitis B virus insert cloned from human hepatocellular carcinoma DNA recently reported to encode a novel transcriptional trans–activator function. The hepatitis B virus portion of the clone consists of two colinear fragments covering the X gene with its promoter and enhancer (nucleotides 717 to 1796) and a 3′ truncated pre–S/S gene (nucleotides 2703 to 423). The lack of the entire pre–C/C gene caused a fusion of the 3′ end of the X gene with sequences upstream from the pre–S gene. The structure of the integrated viral DNA fragments suggests insertion of hepatitis B virus replication intermediates into cellular DNA and subsequent recombination between these primary integrations to generate the final structure of the clone. The 5′ and 3′ cellular flanking sequences mapped to the centromeric α–satellite DNA of chromosome 17 and to the short arm of chromosome 7 (p 14–pter), respectively, indicating that chromosomal translocation was associated with the hepatitis B virus DNA integration. Because this is the fourth case reported in which hepatitis B virus–associated rearrangements have affected chromosome 17, it is conceivable that a loss of important cellular genes (such as the p53 antioncogene on chromosome 17) may be a crucial step in hepatitis B virus–related hepatocarcinogenesis. (Hepatology 1992;15:665-671).
Abnormal Surface Distribution of the Human Asialoglycoprotein Receptor in Cirrhosis
Authors: Burgess James B. , Baenziger Jacques U. , Brown William R.
Published: March 2007

Serum concentrations of asialoglycoproteins are increased in cirrhosis. We hypothesized that this increase results from abnormalities in the asialoglycoprotein receptor, which is located on the sinusoidal and lateral membrane of hepatocytes. Therefore we searched for morphological alterations in the distribution of the asialoglycoprotein receptor in human liver, using a light microscopic immunoperoxidase method in autopsy livers. In 24 of 25 (96%) of patients without liver disease, the asialoglycoprotein receptor was located on the sinusoidal and, less prominently, the lateral surface of hepatocytes but not the canalicular surface. In contrast, in 12 of 18 (67%) patients with cirrhosis of various causes, the receptor also was localized strikingly along the canalicular surface, with a corresponding decrease on the sinusoidal and lateral surfaces. We conclude that an abnormal cell–surface distribution of the asialoglycoprotein receptor commonly occurs in cirrhosis. This abnormality might result in impaired clearance of desialylated glycoproteins from plasma. (Hepatology 1992;15:702-706).
Hepatocyte Regeneration in Acute Fulminant and Nonfulminant Hepatitis: A Study of Proliferating Cell Nuclear Antigen Expression
Authors: Wolf Helmut K. , Michalopoulos George K.
Published: March 2007

It has been suggested that in fulminant hepatitis it is the lack of hepatocyte regeneration that in the presence of an ongoing loss of hepatocytes leads to hepatic failure and ultimately determines the grim prognosis of this disease. However, little data are available concerning hepatocyte regeneration in human acute hepatitis. We compared the nuclear expression of proliferating cell nuclear antigen with the incorporation of bromodeoxyuridine in formalinfixed, paraffin–embedded liver tissues of rats at different stages of regeneration after two–thirds partial hepatectomy. Immunohistochemical staining for proliferating cell nuclear antigen was performed using the monoclonal antibody 19F4. A good correlation was seen between nuclear labeling for bromodeoxyuridine and proliferating cell nuclear antigen, which indicates that the immunoreactivity for proliferating cell nuclear antigen accurately reflects hepatocyte prolifeation. Subsequently, we determined the nuclear expression of proliferating cell nuclear antigen on archival paraffin–embedded samples of the normal human liver (8 cases), acute nonfulminant hepatitis (10 cases) and fulminant hepatitis (4 cases). The mean proliferating cell nuclear antigen labeling indices were the following: normal liver = 0.4%; acute nonfulminant hepatitis = 43.0%; and fulminant hepatitis = 45.9%. The indices for proliferating cell nuclear antigen were significantly greater in acute hepatitis than in the normal liver, reflecting the high cell turnover in hepatitis. However, no significant difference was seen between the expression of prolifernting cell nuclear antigen in nonfulminant and fulminant acute hepatitis. These data suggest that the net loss of hepatocytes in fulminant hepatitis may not be caused by a lack of hepatocyte regeneration but rather results from overwhelming hepatocyte injury with subsequent cell death. (Hepatology 1992;15:707-713).
Erythrocyte Membrane Transport of Glutathione Conjugates and Oxidized Glutathione in the Dubin–Johnson Syndrome and in Rats With Hereditary Hyperbilirubinemia
Authors: Board Philip , Nishida Toshirou , Gatmaitan Zenaida , Che Mingxin , Arias Irwin M.
Published: March 2007

The Dubin–Johnson syndrome is manifested by conjugated hyperbilirubinemia and pigment accumulation in hepatocellular lysosomes. The TR– rat model is a phenotypic model of the Dubin–Johnson syndrome and is characterized by defective ATP–dependent transport of a group of nonbile acid organic anions, including glutathione–S–conjugates and oxidized glutathione, across the bile canaliculus. Similar ATP–dependent transport mechanisms have been described in erythrocytes. Intact erythrocytes and inverted erythrocyte membrane vesicles from Dubin–Johnson patients, TR–rats and appropriate controls were studied with regard to ATP–dependent transport of dinitrophenyl glutathione and oxidized glutathione. No significant differences were observed, indicating that the erythrocyte and canalicular ATP–dependent transporters for these substrates are functionally and potentially genetically distinct. (Hepatology 1992;15:722-725).
Cholescintigraphy in Acalculous Biliary Pain: If Abnormal, Should Cholecystectomy Follow?
Authors: Shaffer Eldon A.
Published: March 2007

A 45–minute infusion of an octapeptide of cholecystokinin (Kinevac; Squibb Diagnostics, New Brunswick, NJ) was used to measure the gallbladder ejection fraction during cholescintigraphy in 40 normal volunteers. Cholecystokinin cholescintigraphy was shown to be a reproducible test. The maximum mean gallbladder ejection fraction occurred 15 minutes after cholecystokinin infusion and was 74.5% ± 1.9% (mean ± SEM). A gallbladder ejection fraction >40% (mean - 3SD) was arbitrarily defined to be normal. The gallbladder ejection fraction test was then used to identify patients with acalculous biliary symptoms who may respond to cholecystectomy. A total of 103 patients was tested; 21 had abnormal gallbladder ejection fractions and were randomized into two groups, cholecystectomy or no operation. These patients were followed up symptomatically at 3–month intervals for 13-54 months (mean, 34 months). Of the 11 patients who underwent cholecystectomy, 10 (91%) lost their symptoms and 1 improved. Of the 10 patients in the group that did not undergo surgery, all continued to be symptomatic, 2 of whom requested cholecystectomy after 13 and 24 months, respectively. Of the 13 gallbladders obtained from surgery, 12 showed evidence of chronic cholecystitis, muscle hypertrophy, and/or narrowed cystic duct. A normal gallbladder ejection fraction was recorded in 82 patients, and further treatment was left to the discretion of their referring clinician. On follow–up, 50 patients were asymptomatic and 10 were symptomatic without specific treatment of the biliary tract; 14 underwent cholecystectomy, 8 of whom were asymptomatic. Pathological abnormalities were recorded in 6 of the removed gallbladders. It is concluded that the gallbladder ejection fraction obtained after a 45–minute infusion of cholecystokinin during cholescintigraphy is a reproducible measure of gallbladder emptying, and that cholecystectomy alleviates the biliary–type pain of patients with a reduced gallbladder ejection fraction.
Effects of Ethanol on Intercellular Communications and Polarization of Hepatocytes in Short–Term Culture
Authors: Hashieh Imad Abou , Mathieu Sylvie , Gerolami André
Published: March 2007

ABSTRPlCT

The formation of intracellular lumina with apical differentiation is observed in several cancerous epithelial cell lines including human hepatocarcinoma. This disorder of cell polarization can be induced by the inhibition of cell–cell communication, a known factor of carcinogenesis.

This work was designed to study the effects of ethanol on the differentiation of hepatocytes in short–term culture. Isolated hepatocytes were plated on plastic culture dishes that were 35 mm in diameter (106 cells/dish). Three hours after plating, the hepatocytes were incubated in the presence of 20 mmol/L ethanol for 1 hr. Treated cells were compared with controls using morphometric methods after conventional treatment for ultramicroscopy and by measuring cellular dye coupling by the fluorescent Lucifer Yellow CH transfer method.

Bile canaliculi formation decreased in alcoholtreated cells (6.5% vs. 9.9%, 2p < 0.05), whereas intracellular lumina incidence increased (3.1% vs. 0.5%, 2p < 0.01). In parallel, the dye–coupling capacity decreased significantly when hepatocytes were treated with alcohol (2p < 0.01).

This work shows that short–term ethanol treatment induces significant disturbances of cell polarization and inhibits the reestablishment of cell–cell communication in cultured hepatocytes. These disorders could, at least in part, explain the carcinogenic effects of ethanol. (Hepatology 1992;15:751-756).
Genetic Alterations in the Gene Encoding the Major Hbsag: Dna and Immunological Analysis of Recurrent Hbsag Derived From Monoclonal Antibody—Treated Liver Transplant Patients
Authors: McMahon Gerald , Ehrlich Paul H. , Moustafa Zeinab A. , McCarthy Linda A. , Dottavio Diane , Tolpin Mark D. , Nadler Paul I. , Östberg Lars
Published: March 2007

ABSTRPlCT

A gene region encoding a segment of the major surface protein, HBsAg, of hepatitis B virus was analyzed from serum samples after orthotopic liver transplantation of three hepatitis B virus chronic carrier patients treated with a human anti—hepatitis B virus monoclonal antibody (SDZ OST 577). Each of these three patients became HBsAg negative after transplantation and therapy with the human anti—hepatitis B virus monoclonal antibody but returned to HBsAg positivity (first detected 143,251 and 252 days after the transplantation). Polymerase chain reaction DNA amplification was performed on DNA from serum samples showing low levels of recurrent HBsAg and reduced antigen reactivity with SDZ OST 577 antibody. Polymerase chain reaction DNA included a 230–bp highly conserved, major S gene region that was cloned into M13 bacteriophage; analysis of this DNA segment provided a consensus of DNA sequences for the serum samples exhibiting altered reactivity with the therapeutic monoclonal. Analysis of independent DNA clones from serum samples of patients exhibiting low but detectable recurrent serum levels of posttherapy HBsAg revealed the presence of S protein variant sequences when compared with polymerase chain reaction DNA derived from the original infected liver or pretherapy serum HBsAg. Genetic variation was predominant in a highly conserved peptide domain that has previously been implicated in antibody binding and neutralizing antibody epitopes. In independent patients infected with eitheradworaywhepatitis B virus subtypes, single nucleotide changes resulted in one to two amino acid differences for each variant allele (residues 124, 129, 131, 137, 140 and/or 145) when compared with pretherapy viral DNA. Administration of serum containing one of these variant viruses to a single hepatitis B—naive chimpanzee resulted in subclinical hepatitis and detectable levels of circulating anti–HBs and anti–HBc antibodies 49 and 70 days after virus administration, respectively. Hepatitis B virus DNA was recovered on liver biopsy between 6 and 8 wk after inoculation, although the animal remained persistently seronegative for HBsAg. DNA sequence analysis of both primate and patient liver hepatitis B virus confirmed the presence of the DNA encoding the S protein variant and associates this DNA with the predominant hepatotropic virus in liver infection. (Hepatology 1992;15:757-766).
Interferon–α in Acute Posttransfusion Hepatitis C:. A Randomized, Controlled Trial
Authors: Viladomiu Lluis , Genescà Joan , Esteban Juan I. , Allende Helena , González Antonio , López-Talavera Juan Carlos , Esteban Rafael , Guardia Jaime
Published: March 2007

ABSTRPlCT

To assess the efficacy of interferon–α in acute hepatitis C, 28 patients with acute posttransfusion hepatitis were randomized to receive 3 million units of recombinant interferon–α three times weekly for 12 wk or no treatment. Biochemical, histological and serological parameters were monitored during 1 yr of follow–up. Serum ALT levels were normal at the end of therapy in 73% of treated patients and only in 38% of control patients (p = 0.06); these differences disappeared at 6 and 12 mo of follow–up. Anti-hepatitis C virus seroconversion occurred later and at a lower rate in the group of patients who received interferon–α. Treated patients had a trend toward less severe hepatic lesions with lower histological activity as compared with the control group, but no statistical differences were observed. No severe side effects of interferon–α were detected during the study. In summary, a 3–mo course of interferon–α in acute hepatitis C is safe and might have some effect in diminishing disease activity only during the treatment period; however, and probably because of a small sample size, no benefit of interferon–α in the long–term outcome of this disease was demonstrated. (Hepatology 1992;15:767-769).
Cellular Immune Response to Hbcag in Mother–To–Infant Transmission of Hepatitis B Virus
Authors: Hsu Hong-Yuan , Chang Mei-Hwei , Hsieh Kue-Hsiung , Lee Chin-Yun , Lin Ho-Hsiung , Hwang Lih-Hwa , Chen Pei-Jer , Chen Ding-Shinn
Published: March 2007

ABSTRPlCT

Cellular immunity to HBcAg was studied in hepatitis B virus carrier children and neonates born to hepatitis B virus carrier mothers. A significant proliferative response of peripheral blood mononuclear cells to HBcAg was found in 5 of 10 children with elevated ALT levels but in none of the nine HBeAg–positive children with normal ALT levels. HBeAg but not HBsAg was detected in cord blood of 9 of 10 neonates born to HBeAg–positive carrier mothers, suggesting exposure of these neonates to HBeAg in utero. However, cord mononuclear cells from neonates born to HBeAg–positive carrier mothers did not show a significant change in the proportion of suppressor and helper T–cell subsets or proliferative response to HBcAg. Nor did they produce interleukin–2 receptor after being cocultured with HBcAg. The unresponsiveness of peripheral–blood mononuclear cells or cord mononuclear cells to HBeAg was not reversed by CD8+ cell depletion. Although cord blood mononuclear cells from neonates born to carrier mothers positive for antibody to HBeAg also did not respond to HBcAg, we encountered an infant, born to a carrier mother positive for antibody to HBeAg, who contracted acute hepatitis B at 2.5 mo of age. The baby's peripheral–blood mononuclear cells showed a significant proliferative response to HBcAg. These results support the view that transplacental maternal HBeAg probably induces a specific unresponsiveness of helper T cells to HBcAg and HBeAg in the neonates born to HBeAg–positive carrier mothers. This specific helper T cell tolerance could be maintained throughout the early replicative phase of carrier state but might break someday with the appearance of raised ALT level. (Hepatology 1992;15:770-776).
Non–A, Non–B Chronic Hepatitis Is Chronic Hepatitis C: A Sensitive Assay for Detection of Hepatitis C Virus Rna in the Liver
Authors: Hosoda Kazuhiko , Omata Masao , Yokosuka Osamu , Kato Naoya , Ohto Masao
Published: March 2007

ABSTRPlCT

To study the role of hepatitis C virus in non–A, non–B chronic hepatitis, 49 liver biopsy samples from 40 patients with non–A, non–B chronic hepatitis and 9 control patients were analyzed by complementary DNA/polymerase chain reaction. Two segments of the HCV genome, one in the nonstructural region and the other in the noncoding region, were amplified by two sets of primer pairs. With use of the nonstructural region primers, hepatitis C virus RNA was detected in 24 (60%) of 40 patients with non–A, non–B chronic hepatitis. Of these 40 patients, RNA was detected in 19 (70%) of 27 patients positive for antibody to hepatitis C virus and in 5 (38%) of 13 patients negative for antibody to hepatitis C virus. However, with the noncoding region primers, hepatitis C virus RNA was detected in 38 (95%) of 40 patients with non–A, non–B chronic hepatitis. Of these patients, the RNA was detected in 26 (96%) of 27 patients positive for antibody to hepatitis C virus and also in 12 (92%) of 13 patients positive for antibody to hepatitis C virus. Hepatitis C virus RNA was not detected in any of the control patients. Sequence analysis showed homology between our samples and the prototype to be only 66% to 77% in the nonstructural region but 99% to 100% in the noncoding region.

We conclude that almost all patients with non–A, non–B chronic hepatitis in Japan are currently infected with hepatitis C virus, regardless of the presence or absence of antibody to hepatitis C virus. This assay appears useful for the diagnosis, treatment and prevention of hepatitis C virus infection. (Hepatology 1992;15:777-781).
Energy Expenditure and Substrate Oxidation in Patients With Cirrhosis: the Impact of Cause, Clinical Staging and Nutritional State
Authors: Müller Manfred J. , Lautz Hans U. , Plogmann Birgit , Bürger Mechthild , Körber Jürgen , Schmidt Friedrich W.
Published: March 2007

ABSTRPlCT

Many clinicians subjectively feel that cirrhotic patients frequently have clinical signs of hypermetabolism. However, it is unknown whether hypermetabolism is a constant feature of chronic liver disease, corresponds to liver destruction and repair or is of prognostic value. This article is about resting energy expenditure and substrate oxidation rates in 123 patients with biopsy–proven cirrhosis differing with respect to cause, duration of the disease, biochemical parameters of parenchymal cell damage, cholestasis, liver function, number of complications, clinical staging and nutritional state.

Resting energy expenditure varied between 1,090 and 2,300 kcal/day and differed from the predicted values in 70% of the patients. Resting energy expenditure was closely related to fat–free mass, and 52% of the variability could be explained by fat–free mass, age and sex. Of all the patients, 18% were hypermetabolic and 31% were hypometabolic. Hypermetabolism showed no strict association with the cause of cirrhosis, the duration of the disease, liver function, cholestasis, cell damage, clinical staging, blood hemoglobin, plasma thyroid hormone levels or human leukocyte antigens. An increased resting energy expenditure was associated with significant losses of muscle, body cell mass and extracellular mass at unchanged body fat, whereas fat and fat–free mass were increased in hypometabolic patients when compared with normometabolic patients. Lipid oxidation was increased, but glucose oxidation was reduced in nearly all patients with cirrhosis. This was most pronounced at advanced stages of liver disease.

Although similar with respect to liver function and clinical staging, 76.2% of hypermetabolic patients had transplants within the observation period, compared with only 16.7% and 8.1% in the normometabolic group and hypometabolic group, respectively. Posttransplantation mortality was independent of pretransplantation resting energy expenditure, but it increased significantly in patients with losses in body cell mass.

In conclusion, hypermetabolism is not a constant feature of cirrhosis and results more from extrahepatic than from hepatic factors. It may cause malnutrition and contributes to the clinical outcome of patients with chronic liver disease. (Hepatology 1992;15:782-794).
The Prevalence and Prognostic Significance of Spontaneous Bacterial Peritonitis in Severe Acute Hepatitis With Ascites
Authors: Chu Chia-Ming , Chiu King-Wah , Liaw Yun-Fan
Published: March 2007

ABSTRPlCT

The prevalence and prognostic significance of spontaneous bacterial peritonitis were prospectively studied in a series of 82 acute hepatitis patients decompensated with ascites. The in–hospital prevalence of spontaneous bacterial peritonitis was 31.7% (26 of 82 patients). Twenty cases were culture positive, including one with multiple isolates, and six cases were culture negative. E. coli and Klebsiella pneumoniae were the most common pathogens, accounting for 71.4% (15 of 21) of the total isolates, whereas only 9.5% were gram–positive organisms. No significant difference in the age, sex, cause of acute hepatitis, liver biochemistry, prothrombin time and ascites fluid concentration of total protein was noted between patients with spontaneous bacterial peritonitis and those without spontaneous bacterial peritonitis, except that bacteremia was recognized significantly more frequently in the former (57.7% or 15 of 26 patients) than in the latter (25.0% or 14 of 56 patients, p < 0.005). In addition, patients with spontaneous bacterial peritonitis, when compared with those without spontaneous bacterial peritonitis, were more likely to have kidney failure (57.7% vs. 30.4%, p < 0.05) and gastrointestinal hemorrhage (53.8% vs. 30.4%, p < 0.05) and had a significantly higher mortality rate (73.1% vs. 39.3%, p > 0.01). Among patients without spontaneous bacterial peritonitis, the prevalence of kidney failure and gastrointestinal hemorrhage and the mortality rate in patients with bacteremia (57.1%, 64.3% and 71.4%, respectively) were significantly higher than in those without bacteremia (21.4%, 19.0% and 28.6%, respectively; p < 0.05, p < 0.01 and p < 0.01, respectively). In conclusion, 31.7% of severe acute hepatitis patients with ascites were recognized as having spontaneous bacterial peritonitis; the other 17.1% had bacteremia. Patients with spontaneous bacterial peritonitis, bacteremia or both had high morbidity and mortality rates. Whether prophylactic antimicrobial therapy might be justified in patients with severe acute hepatitis awaits further study. (Hepatology 1992;15:799-803).
Cholesterol Nucleation Time in Gallbladder Bile of Patients With Solitary or Multiple Cholesterol Gallstones
Authors: Jüngst Dieter , Lang Thomas , von Ritter Christoph , Pratschke Ekkehard , Paumgartner Gustav
Published: March 2007

ABSTRPlCT

Patients with multiple cholesterol gallbladder stones have been found to be at a higher risk for the recurrence of gallstones after successful nonsurgical treatment than those with a solitary stone. Cholesterol gallstone recurrence, like primary gallstone formation, probably involves a triple defect with supersaturation, abnormally rapid nucleation of cholesterol in bile and altered gallbladder motor function. We investigated whether the increased recurrence rate of patients with multiple stones might be caused by more rapid nucleation. Therefore the time required for cholesterol monohydrate crystals to appear in ultracentrifuged bile of patients with solitary (n = 71) or multiple (n = 42) cholesterol gallstones was determined.

The cholesterol nucleation time was significantly (p < 0.01) longer in the bile from patients with solitary stones (< 1 to 16 days, median = 2.0 days) than in the bile from patients with multiple stones (< 1 to 8 days, median = 1.0 days). Moreover, 15 of 71 (21.1%) patients with solitary cholesterol stones but only 1 of 42 (2.4%) patients with multiple cholesterol stones showed a normal (> 4 days) nucleation time.

However, no difference in the cholesterol saturation index was found between the bile samples from patients with solitary stones and the bile samples from patients with multiple stones (1.55 ± 0.65 vs. 1.54 ± 0.59, mean ± S.D., respectively). The more rapid cholesterol nucleation in gallbladder bile may, therefore, be the major risk factor causing the higher percentage of stone recurrence in patients with multiple cholesterol stones as compared with patients with solitary cholesterol stones. (Hepatology 1992;15:804–808).
Phenotypic and Functional Characteristics of Lymphocytes Isolated From Liver Biopsy Specimens From Patients With Active Liver Disease
Authors: Hata Kensaku , van Thiel David H. , Herberman Ronald B. , Whiteside Theresa L.
Published: March 2007

ABSTRPlCT

Liver–derived lymphocytes were isolated from 73 liver biopsy specimens obtained from patients with chronic active liver disease and from six samples of normal liver. Mean absolute numbers (±S.E.M) of liver–derived lymphocytes recovered from needle biopsy specimens by mild enzymatic digestion of the liver tissue varied from 0.7 ± 0.3 × 10/mm in allografts being rejected to 8.9 ± 0.9 × 10/mm in chronic non–A, non–B hepatitis. By two–color flow cytometry, T lymphocytes (CD3+) were the major liver–derived lymphocyte population in all biopsy specimens. The mean CD4/CD8 ratio (0.6 ± 0.2) was similar for liver–derived lymphocytes obtained from samples of normal or diseased liver. However, activated (human leukocyte antigen DR+) T cells were significantly (p < 0.05) increased in liver–derived lymphocytes obtained from liver disease specimens than they were in samples from normal livers. Natural killer cells were less numerous than T cells in specimens obtained from diseased livers, with the mean natural killer/T cell ratio ranging from a low of 0.1 in allograft rejection to a high of 0.8 ± 0.3 in primary sclerosing cholangitis. Liver–derived lymphocytes isolated from diseased liver contained significantly fewer (p < 0.05) CD3-CD56+ or CD56+CD16-natural killer cells than did those obtained from normal liver samples. Natural killer activity was consistently detectable in liver–derived lymphocytes obtained from specimens of normal or diseased livers. Moreover, natural killer activity in the liver did not differ significantly from that in either normal or patient peripheral blood. Spontaneous cytotoxic activity against natural killer–resistant targets, Daudi cells, was detectable but low in liver–derived lymphocytes obtained from specimens of both normal and diseased livers. In liver–derived lymphocytes obtained from livers with chronic active liver disease, the proportion of natural killer cells was reduced; T lymphocytes were more prominent and displayed human leukocyte antigen DR antigens more frequently than in end–stage liver disease. (Hepatology 1992;15:816-823).
Renal Effects in Cirrhotic Patients With Avid Sodium Retention of Atrial Natriuretic Factor Injection During Norepinephrine Infusion
Authors: Badalamenti Salvatore , Borroni Gianmario , Lorenzano Elettra , Incerti Pierluigi , Salerno Francesco
Published: March 2007

ABSTRPlCT

The administration of atrial natriuretic factor to patients with cirrhosis, and avid sodium retention causes marked hypotension and blunted kidney responses. To evaluate whether the unresponsiveness of the kidney is caused by a fall in mean blood pressure below a critical value for the renal blood perfusion pressure (80 mm Hg), we studied nine such patients and compared the effects of synthetic atrial natriuretic factor alone (1 μg/kg as a bolus) with those of an atrial natriuretic factor combination with infused norepinephrine titrated to raise baseline blood pressure by 15 to 20 mm Hg (182 to 625 ng/kg/min). The administration of atrial natriuretic factor during norepinephrine infusion caused a fall in mean blood pressure to values not less than 80 mm Hg in eight of nine patients, with a slight natriuresis (> 5 μmol/min) in five patients but no changes in the other four. The mean urinary sodium output was markedly lower than that previously observed after atrial natriuretic factor injection into normal subjects and into cirrhotic patients without avid sodium retention. Unlike sodium excretion, urine flow rate and free water clearance (which were not affected by atrial natriuretic factor alone) were markedly improved by the coadministration of norepinephrine and atrial natriuretic factor. In four additional patients we studied the urinary electrolyte excretion during a low–dose infusion of atrial natriuretic factor (20 ng/kg/min) to which an infusion of norepinephrine titrated to maintain blood pressure over 80 mm Hg was added. In only one of these four patients urinary sodium output consistently increased during atrial natriuretic factor infusion, and the output increased even more when norepinephrine was added. These data suggest that the blunted natriuretic activity of atrial natriuretic factor in patients with advanced cirrhosis cannot be offset by preventing the blood pressure from falling below a critical value of 80 mm Hg. Kidney responsiveness to atrial natriuretic factor activity, however, is partly restored by the ability of the peptide plus norepinephrine to stimulate diuresis and free water excretion. (Hepatology 1992;15:824-829).
Nonsyndromic Paucity of Intrahepatic Bile Ducts in Infancy and Idiopathic Ductopenia in Adulthood: the Same Syndrome?
Authors: Bruguera Miquel , Llach Josep , Rodés Joan
Published: March 2007

ABSTRPlCT

Eleven patients with chronic intrahepatic cholestasis in whom a liver biopsy specimen showed unexplained bile duct paucity were investigated. Cholestasis developed during the neonatal period in three, at infancy (before 14 yr) in four and after 14 yr in the remaining four patients. In all patients other conditions characterized by chronic cholestasis associated with ductopenia such as primary biliary cirrhosis, primary sclerosing cholangitis, drug–induced liver disease, sarcoidosis or graft–vs.–host disease were excluded. Cardiovascular abnormalities in the three patients who had neonatal cholestasis permitted diagnosis of Alagille's syndrome. Clinical, biochemical and histological features were similar in the remaining eight patients, independent of the age at which the disease appeared. Idiopathic adulthood ductopenia may be a late–onset form of the nonsyndromic paucity of interlobular bile ducts seen in children, or it may be due to a still–unidentified cause that strikes later in life. (Hepatology 1992;15:830-834).