bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult liver transplantation: An analysis of the early causes of death in 40 consecutive cases
Authors: Cuervas-Mons Valentin , Martinez Julio A. , Dekker Andrew , Starzl Thomas E. , Van Thiel David H.
Published: March 2007

One hundred twenty-nine adult patients who received an orthotopic liver transplantation and survived at least 24 hr after surgery were evaluated. During the period of follow-up, 48 of the 129 patients (37%) died. Only 40 of these 48 patients died at our institution and were included in this study. Seventeen of the 40 deaths (42.5%) occurred during the first month after orthotopic liver transplantation and 30 of the 40 deaths (75%) occurred during the first 60 days post-orthotopic liver transplantation. Death was related to infection in 21 cases (52.5%), to multiorgan failure in 8 (20%) and to uncontrollable rejection in 3 (7.6%). The remaining eight deaths (20%) were attributed to a variety of other causes. Eleven of the 21 deaths related to infection (52%) occurred during the first month after orthotopic liver transplantation. Bacterial sepsis was the leading cause of death and accounted for 17 of the 21 deaths (81%) in which infection was present at the time of death. The most frequently isolated bacteria were Pseudomonas and other enteric Gram-negative bacilli. Three patients had complete occlusion of the hepatic artery of the grafted liver. Six patients developed massive infarction of the liver despite patent vascular anastomoses. Histological signs of rejection were seen in 9 of the 31 patients autopsied (29%), but in only 3 of these (9.6%) was rejection the principal cause of death. The biliary anastomoses were patent in all 31 cases examined at autopsy.
ARA-AMP in chronic HBV hepatitis: Follow-up too short or too long?
Authors: Czaja Albert J.
Published: March 2007

A randomised controlled trial was conducted in 29 HBV carriers who had been HBs and HBe antigen positive for more than six months. Fifteen patients were treated with ARA-AMP 10 mg/kg/ day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days. The 14 controls received no treatment. Serum HBV-DNA polymerase, and HBV-DNA decreased in all patients during therapy. Six treated patients lost serum HBV-DNA polymerase, HBV-DNA and HBeAg, HBsAg concentrations decreased, and five developed anti-HBe. One of these six patients lost HBsAg and developed anti-HBs. No such changes were observed in the control group over a similar 18 month period of observation. A four week course of ARA-AMP inhibits HBV replication and in a significant minority of patients this is long lasting and is associated with a reduced level of inflammatory activity in the liver.
Hepatic granulomata in AIDS
Authors: Stenger Richard J.
Published: March 2007

During a one month period liver biopsy was carried out on eight patients with established acquired immune deficiency syndrome (AIDS) and two suspected of having AIDS to evaluate raised liver enzymes or unexplained fever and weight loss. Each of the 10 patients was found to have hepatic granulomas. Appropriate staining techniques showed acid-fast bacilli in seven of the liver specimens. One specimen contained numerous Cryptococcal organisms. Two biopsies showed granulomas but no organisms. Liver biopsy was found to be a high yield and rapid diagnostic procedure in patients with AIDS. Our results suggest that hepatic mycobacterial infection may be more common in the syndrome than previously recognized and that liver biopsy specimens should be examined routinely for the presence of acid-fast bacilli.
Strain-related patterns of biliary excretion and hepatic distribution of copper in the rat
Authors: Nederbragt Hubertus , Lagerwerf Aart J.
Published: March 2007

Biliary copper excretion was studied in male, bilecannulated rats of the inbred strains Fischer, Brown Norway, WAG/Rij and Lewis. After intravenous injection of 10, 30 and 50 μg copper per 100 gm body weight, two patterns of copper excretion were observed; their profiles varied with the copper dose and the strain of the rats used. The lowest amounts of copper were excreted by Fischer rats, the highest by WAG/Rij rats; this was related to the effect of the copper dose on both patterns. The subcellular distribution of copper in the liver was studied in Fischer and Brown Norway rats after doses of 50, 100, and 200 μg per 100 gm body weight. Brown Norway rats accumulated more copper in the liver, although the copper concentration was the same in both strains 1 hr after injection of all doses. Fischer rats accumulated proportionally more copper in lysosomal and nuclear mitochondrial fractions whereas Brown Norway rats accumulated proportionally more copper in the cytosol.

Gel filtration of liver supernatants revealed that the amount of copper accumulating in the protein presumed to be metallothionein was 2 to 3 times higher in Brown Norway rats, whereas in the Fischer rats more copper eluted in the void volume fraction. We conclude that both biliary copper excretion and copper distribution in the liver are under genetic control. Because of its low copper excretion and reduced binding of copper to metallothionein the Fischer rat, compared to other strains, may be a suitable model for studying the involvement of the liver in copper intoxication.
Serum mitochondrial aspartate aminotransferase as a marker of chronic alcoholism: Diagnostic value and interpretation in a liver unit
Authors: Nalpas Bertrand , Vassault Anne , Charpin Serge , Lacour Bernard , Berthelot Pierre
Published: March 2007

Serum mitochondrial aspartate aminotransferase activity was measured using an immunochemical method in 251 subjects, of whom 140 were chronic alcoholics. The alcoholic patients included 37 with normal liver routine tests (Group I), 61 with noncirrhotic alcoholic liver disease (Group II) and 42 with cirrhosis (Group III), of whom 21 had been abstainers for at least 2 months. All of the remaining 111 subjects were nonalcoholic: 61 had various types of liver disease (Group IV) and 50 were healthy controls. A second assay of serum mitochondrial aspartate aminotransferase activity was performed in 76 alcoholics after a period of abstinence of about 7 days. In addition, serial mitochondrial aspartate aminotransferase determinations were performed in four nonalcoholic volunteers prior to, during and following an alcohol bout.

Mean mitochondrial aspartate aminotransferase and mitochondrial aspartate aminotransferase/total aspartate aminotransferase ratio were significantly increased in the alcoholics whatever their liver status, with a sensitivity of the ratio of 81, 85 and 66% for Group I, Group II and the 21 drinkers of Group III, respectively. Only 1 of the 21 cirrhotic abstainers had an increased ratio. Among the 61 nonalcoholic patients with liver disease, 11 had an increased mitochondrial aspartate aminotransferase/total aspartate aminotransferase ratio, specificity of which was 82%. After drinking had been stopped for about 1 week, mitochondrial aspartate aminotransferase decreased by more than 50% and therefore appears as a reliable tool to assess abstinence. In the four cases of alcohol bouts, no significant modifications in mitochondrial aspartate aminotransferase serum values were observed, thus suggesting that mitochondrial aspartate aminotransferase is indeed a marker of chronic, but not of acute, alcohol intake.
Immunoglobulin a antibody against hepatitis B core antigen of polymeric and monomeric forms, as well as of IgA1 and IgA2 subclasses, in acute and chronic infection with hepatitis B virus
Authors: Hikata Mikio , Tachibana Katsumi , Imai Mitsunobu , Naito Shigeko , Oinuma Akira , Tsuda Fumio , Miyakawa Yuzo , Mayumi Makoto
Published: March 2007

Solid-phase radioimmunoassays using monoclonal antibodies were used to assay antibody to hepatitis B core antigen of immunoglobulin A class in terms of polymeric and monomeric forms, as well as of IgA1 and IgA2 subclasses, in the serum of persons infected with hepatitis B virus. The level of secretory immunoglobulin A antibody was significantly higher in patients with acute hepatitis (mean ± S.E., sample per normal ratio = 29.2 ± 1.9) than that in asymptomatic carriers (2.1 ± 0.1), patients with chronic persistent hepatitis (3.5 ± 0.5), patients with chronic active hepatitis (6.9 ± 1.3) or patients with cirrhosis (5.8 ± 1.1). In acute type B hepatitis, only polymeric immunoglobulin A antibody of either IgA1 or IgA2 subclass was detected. In contrast, in chronic infection, antibody to hepatitis B core antigen of IgA2 subclass was found in the polymeric form, but antibody of IgA1 subclass was detected in both polymeric and monomeric forms.
Calcitonin gene-related peptide in the hepatic and splanchnic vascular systems of the rat
Authors: Sasaki Yutaka , Hayashi Norio , Kasahara Akinori , Matsuda Hiroyuki , Fusamoto Hideyuki , Sato Nobuhiro , Hillyard Carmel J. , Girgis Samia , Macintyre Iain , Emson Piers C. , Shiosaka Sadao , Tohyama Masaya , Shiotani Yahe , Kamada Takenobu
Published: March 2007

The distribution and origin of calcitonin gene-related peptide immunoreactive structures in hepatic and splanchnic vasculature of the rat were investigated by the immunofluorescent technique. Calcitonin gene-related peptide immunoreactive fibers were dissociated from compact thick calcitonin gene-related peptide immunoreactive fiber bundles located around the hepatic and splanchnic vasculature, and reached the tunica adventitia of the vasculature. Some fibers penetrated further into the tunica media of the vasculature. In the tunica adventitia of the vasculature, calcitonin generelated peptide immunoreactive fibers formed a fine meshwork which could be traced to the branches and arterioles. In the liver, calcitonin gene-related peptide immunoreactive innervation extended from porta hepatis to portal triads, running with branches of the hepatic artery and portal vein. Some calcitonin generelated peptide immunoreactive fibers separated from thinner calcitonin gene-related peptide immunoreactive fiber bundles in portal triads and coursed into the immediately adjacent parenchyma. In the doral spinal ganglia (T8-10, L1), calcitonin gene-related peptide immunoreactive cells accounted for about 60% of the total number of ganglion cells. Bilateral vagotomy just below the diaphragm or bilateral transection of the greater splanchnic nerve resulted in a marked decrease of the number of calcitonin gene-related peptide immunoreactive fibers in the vasculature, whereas a combined operation was followed by the complete depletion of calcitonin gene-related peptide immunoreactive fibers. These results indicate that calcitonin gene-related peptide immunoreactive innervation in hepatic and splanchnic vasculature may have a dual origin.

In conclusion, the widespread distribution of calcitonin gene-related peptide immunoreactive fibers in the hepatic and splanchnic vasculature suggest that calcitonin gene-related peptide innervation may be involved in sensory transmission.
Renal function in ascites: Position is everything in life
Authors: Rastegar Asghar
Published: March 2007

The assumption of upright posture by patients with liver cirrhosis leads to striking activation of adrenergic and renin-angiotensin systems. The tilting-induced modifications in renal function of eight healthy controls and 14 untreated patients with liver cirrhosis and ascites were related to plasma concentrations of noradrenaline, renin activity and aldosterone. All patients had preserved renal blood perfusion. All parameters were evaluated during bed rest for two hours and in the sitting posture for one hour. Basal plasma renin activity (0.1 < p < 0.05), aldosterone and noradrenaline concentrations (p ± 0.01) were raised in cirrhotics. The renal function tests (creatinine clearance, filtered sodium, tubular rejection fraction, urinary sodium excretion) were significantly reduced in cirrhosis. Under basal conditions, in cirrhotic patients tubular rejection fraction and urinary sodium excretion were inversely related to both noradrenaline and aldosterone concentrations. After tilting, the noradrenaline and aldosterone integrated outputs (ΣΔ) were significantly greater in cirrhosis. All renal function tests significantly decreased in cirrhotics, whereas creatinine clearance only significantly decreased in controls. Patient's tubular rejection fraction of sodium and sodium excretion were related to ΣΔ aldosteronaemia (r = −0.72; p < 0.01), but no longer to ΣΔ plasma noradrenaline.
Phagocytosis, an unrecognized property of murine endothelial liver cells†
Authors: Steffan Anne-Marie , Gendrault Jean-Louis , McCuskey Robert S. , McCuskey Patricia A. , Kirn André
Published: March 2007

Impairment of the phagocytic capacities of Kupffer cells, as is found in Frog Virus 3 hepatitis of mice, allows the endothelial liver cells to take up intravenously inoculated latex particles of 1.0 μm diameter. In vitro experiments with cultivated endothelial cells isolated by collagenase perfusion of the liver and purified by centrifugal elutriation demonstrate that uptake occurs via a typical mechanism of phagocytosis involving pseudopodia. Ingestion of latex is inhibited by incubation of the cells at 4°C and by treatment with cytochalasin B, whereas colchicine has no effect. These results demonstrate that: (i) the Kupffer cells are not the only cells of the hepatic sinusoid capable of phagocytosis; and (ii) under conditions where the phagocytosis in Kupffer cells is impaired, the endothelial cells may participate in the clearance of large particles from the blood.
The mechanisms of iron uptake by fetal rat hepatocytes in culture
Authors: Trinder Deborah , Morgan Evan , Baker Erica
Published: March 2007

The mechanisms of iron accumulation by cultured hepatocytes isolated from fetal rat liver (19 days gestation) were investigated using rat transferrin labeled with 125I and 59Fe. The rates of iron and transferrin internalization by the cells were measured by incubating the hepatocytes with the labeled transferrin at 37°C followed by treatment with pronase at 4°C to remove surface-bound transferrin and iron. Iron internalization increased linearly with time. Approximately 65% of the internalized iron was incorporated into ferritin. In contrast to iron, the rate of transferrin internalization was biphasic, with a rapid phase during the first 10 to 15 min and a second slower phase which becomes more apparent after that time. Iron and transferrin internalization were temperature-dependent. Chase experiments showed that the internalized transferrin donated all of its iron to the cell and was then released in a biphasic manner which was dependent on the time of preincubation with radiolabeled transferrin.

These experiments showed that iron uptake occurs by at least three processes. The first mechanism involves the specific receptor-mediated endocytosis of transferrin. Each cell has an average of 7.8 ± 1.0×105 (mean ± SE, n = 5) transferrin binding sites with an apparent association constant of 2.0 ± 0.4×106
M
−1. The second process is nonsaturable up to a transferrin concentration of at least 6 μM but like the specific process, also leads to accumulation of iron in excess of transferrin. It involves the endocytosis of transferrin mediated by 4.2×106 transferrin binding sites which have a K′a value of 2.6×105
M
−1. Third, fluid-phase endocytosis of transferrin occurs at a rate of 0.13×104 molecules per cell per min at 1.25 μM transferrin concentration. This rate is not sufficient to account for the additional iron accumulated by the cells by the second process.
Gallstone prevention in prairie dogs: Comparison of chow vs. semisynthetic diets
Authors: Cohen Bertram I. , Mosbach Erwin H. , McSherry Charles K. , Stenger Richard J. , Kuroki Syoji , Rzigalinski Beverly
Published: March 2007

The effects of a standard rodent chow were compared with those of a semisynthetic diet of known composition (with and without added cholesterol) in the prairie dog model of cholesterol cholelithiasis. Gallstone incidence was 40% higher in animals fed a semisynthetic diet plus cholesterol compared to chow plus cholesterol. The semisynthetic diet plus cholesterol caused significant increases in tissue cholesterol levels (serum, liver and bile) and lithogenic index, but significant decreases in the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and cholesterol 7α-hydroxylase compared to chow plus cholesterol. Histologic study of liver sections revealed that the semisynthetic diet plus cholesterol resulted in moderate to marked portal tract changes characterized by bile duct proliferation, inflammatory infiltration and fibrosis, whereas the cholesterol-supplemented chow diet caused only slight bile duct proliferation with minimal inflammation and fibrosis in the portal areas. Dietary hyodeoxycholic acid prevented cholesterol gallstones and biliary cholesterol crystals when added to either chow plus cholesterol or semisynthetic plus cholesterol diets. The hyodeoxycholic acid supplements also prevented the development of severe histopathologic alterations along the portal tracts. Biliary cholesterol levels were elevated in prairie dogs fed cholesterol plus hyodeoxycholic acid; these animals had liquid crystals in the bile, and hyodeoxycholic acid and its 6β-isomer became the major biliary bile acids. A semisynthetic diet plus cholesterol is superior to a high cholesterol chow diet for gallstone formation and prevention studies, but in prolonged feeding experiments, the potential hepatotoxicity of this diet in the prairie dog must be appreciated.
In vivo studies of GABAergic effects in experimental hepatic encephalopathy
Authors: Rzepczynski David , Zieve Leslie , Lindblad Sandra , Lafontaine Darlene
Published: March 2007

The GABAergic agonist, muscimol, and antagonists, picrotoxin and bicuculline, have been studied in rats with chronic portacaval shunts and in rats developing hepatic encephalopathy after massive ischemic necrosis due to hepatic artery ligation within 48 hr of a portacaval shunt. After the chronic portacaval shunt and to a lesser extent in normal rats intraventricular muscimol resulted in chewing and eating behavior, ataxia and loss of balance that lasted 2 to 3 hr. Lethargy, stupor and coma did not occur. Intraventricular saline had no effect. Bicuculline i.p. lessened the effects of the muscimol. In rats developing hepatic encephalopathy, intraventricular muscimol shortened the time to precoma and coma by approximately 40%. Bicuculline i.p. counteracted this effect of muscimol significantly. However, neither bicuculline nor picrotoxin given alone altered the times to precoma (Stage III), coma (Stage IV) or death. While hepatic encephalopathy in this experimental model is susceptible to GABAergic effects, its natural progression does not appear to be due to GABA.
Release of prostanoids into the portal and hepatic vein in patients with chronic liver disease
Authors: Wernze Heinrich , Tittor Wolfgang , Goerig Matthias
Published: March 2007

Arterial and hepatovenous concentrations of circulating prostaglandin E2 and prostaglandin F2α, the stable metabolites of prostacyclin and thromboxane A2 were measured in patients with chronic liver disease and compared with those in control patients with coronary artery disease but without hepatic dysfunction. Specific radioimmunoassays were used after extraction on octadecyl C 18-silica gel columns and thin-layer chromatography. While low levels of all cyclooxygenase products were found in hepatic arterial blood in patients with proven cirrhosis (n = 10) and fibrosis (n = 8), significantly higher concentrations were detected in the hepatic vein. A similar concentration profile was observed in controls (n = 4). Thus, there is a marked but comparable release of prostanoids from the normal as well as the diseased liver. Hepatovenous prostaglandin E2 was 11.6-fold, prostaglandin F2α was 7.5-fold, prostacyclin was 12.2.-fold and thromboxane B2 was 3.9-fold above the level in the artery in both groups of patients. The hepatovenous concentrations of all arachinodate metabolites were unrelated to changes of liver morphology, biochemical abnormalities or the presence of ascites. No correlation could be demonstrated between hepatic venous pressure gradient and the concentration of prostanoids in the hepatic vein with the exception of thromboxane B2 (r = 0.55, p < 0.05). The occurrence of esophageal varices was not associated with a specific pattern of circulating prostanoids in the posthepatic vasculature. Moreover, the portal-venous concentrations of all prostanoids (five patients: two with fibrosis, three with cirrhosis) exceeded the level in the hepatic vein substantially.

While the functional significance of high levels of arachinodate metabolites in the hepatic and portal vein remains questionable, excessive release of prostanoids from the prehepatic splanchnic area occurs in advanced stages of chronic liver disease as well as in patients with minor morphological changes and apparently in healthy subjects, too. We suggest that the high content of prostanoids in the portal vein primarily reflects its predominant role in regulating gastrointestinal motility as well as in regulating splanchnic microcirculation.
Prognostic value of preoperatively obtained clinical and laboratory data in predicting survival following orthotopic liver transplantation
Authors: Cuervas-Mons Valentin , Millan Isabel , Gavaler Judith S. , Starzl Thomas E. , van Thiel David H.
Published: March 2007

Twenty-seven clinical and laboratory data and the subsequent clinical course of 93 consecutive adult patients who underwent orthotopic liver transplantation for various chronic advanced liver diseases were analyzed retrospectively to assess the risk factors of early major bacterial infection and death after the procedure. Forty-one patients (44%) had early major bacterial infection during hospitalization for orthotopic liver transplantation. The mortality rate was 70.7% in patients with early major bacterial infection and was 7.7% in patients without early major bacterial infection (p < 0.001). Total serum bilirubin, total white blood cell count and polymorphonuclear cell count, IgG (all p < 0.05) and plasma creatinine level (p < 0.001) were higher in patients that developed early major bacterial infection than in those who did not. By step-wise discriminant analysis, the strongest risk factor for early major bacterial infection was the serum creatinine level, which achieved an accuracy of 69% for a creatinine level greater than 1.58 mg per dl.

Seven variables (ascites, hepatic encephalopathy, elevated white blood and polymorphonuclear cell count, decreased helper to suppressor T cell ratio and elevated plasma creatinine and bilirubin levels) were associated with a significant increased risk for death. A step-wise discriminant analysis of these seven factors resulted in the demonstration of serum creatinine as the greatest risk factor for mortality. A preoperative serum creatinine either less than or greater than 1.72 mg per dl accurately predicts survival or death, respectively, in 79% of cases. These data suggest that the baseline preoperative serum creatinine level provides the best indication of the short-term prognosis after liver transplantation than does any other preoperatively obtained index of the patient's status.
Heterogeneous expression of phenobarbital-inducible cytochrome P-450 genes within the hepatic acinus in the rat
Authors: Chianale Jose , Dvorak Caroline , May Maryann , Gumucio Jorge J.
Published: March 2007

Within the hepatic acinus, the functional unit of liver parenchyma, the induction of cytochrome P-450 protein by phenobarbital is manifested primarily in hepatocytes located closer to the hepatic venule, i.e., distal hepatocytes. The objective of this study was to determine the levels of cytochromes P-450b and P-450e mRNAs in populations of hepatocytes originating in the proximal or distal half of the liver acinus in the rat, as an approach to the elucidation of the mechanisms responsible for the heterogeneous zonal expression of cytochrome P-450 protein. The development of a new method to isolate hepatocytes originating from the proximal or distal half of the liver acinus enabled the measurement of total cytochrome P-450 content and of cytochromes P-450b and P-450e mRNAs in these hepatocytes. Levels of cytochromes P-450b and P-450e mRNAs were assessed in proximal and distal hepatocytes by Northern blot hybridization of poly(A+)RNA with a cDNA recognizing sequences of these two cytochromes. The kinetics of induction were defined by measuring these parameters after a single phenobarbital injection. Cytochrome P-450 mRNA levels reached maximum induction at 16 hr, returning to basal values by 48 hr. In contrast, total cytochrome P-450 microsomal protein content reached maximum induction after 33 hr. Hepatocytes of the distal half of the hepatic acinus responded to phenobarbital with higher levels of cytochromes P-450b and P-450e mRNAs than proximal hepatocytes. These results indicated that there is modulation of the expression of the cytochromes P-450b and P-450e genes within the hepatic acinus.
Hepatic inclusions during interferon therapy in chronic viral hepatitis
Authors: Schaff Zsuzsa , Hoofnagle Jay H. , Grimley Philip M.
Published: March 2007

Two types of cytomembranous abnormalities were identified for the first time in liver biopsies from patients with chronic active type B hepatitis during treatment with recombinant α-interferon. Tubuloreticular inclusions were present in the hepatic endothelial cells, Kupffer cells and perisinusoidal cells of liver biopsies from both patients, and they were absent in liver biopsies obtained before treatment. Cylindrical confronting lamellae, having “test tube” or “ring-shape” forms were observed in the cytoplasm both of Kupffer cells and macrophages in the second liver biopsy of one of the patients. The findings suggest that interferon can be involved in the pathogenesis of both cytomembranous abnormalities, but that additional biological factors may play a role in formation of the cylindrical confronting lamellae.
Is shock-wave lithotripsy the solution for gallstones in this, the year of the boom?
Authors: Schoenfield Leslie J.
Published: March 2007

We treated nine patients with functioning gallbladders containing one to three symptomatic radiolucent stones not larger than 25 mm in diameter, as well as five patients with stones in the common bile duct that were not removable by endoscopic procedures, by means of extracorporeally generated shock waves during general anesthesia. The patients with gallbladder stones received adjuvant treatment with a combination of ursodeoxycholic acid and chenodeoxycholic acid. All gallbladder stones were disintegrated into sludge or fragments with diameters of no more than 8 mm. In six of the nine patients the fragments disappeared completely within 1 to 25 weeks. No adverse effects were detected during a follow-up period of 10 to 34 weeks, except transient biliary pain in two patients, with mild pancreatitis in one. In four of the five patients with common-bile-duct stones, shock-wave treatment permitted stone disintegration and successful endoscopic extraction or spontaneous passage of fragments. We conclude that gallstone disease may be treated successfully and without serious adverse effects by extracorporeally generated shock waves in selected patients.
Zinc therapy of Wilson's disease: Two views
Authors: Brewer George J. , Scheinberg Herbert I.
Published: March 2007

After initial promotion of copper excretion with D-penicillamine, the effect of oral zinc sulphate (3×150 mg/day, loading dose; 3×100 mg/day, maintenance dose) in two children with clinically stable Wilson's disease was evaluated after completion of three years' treatment. The course, judged by clinical, biochemical, and histological parameters was satisfactory in both. The urinary copper concentration reverted to less than 1.26 μmol/24 hours; and the serum copper concentration decreased further during zinc sulphate treatment. In one child the rise in 24 hour urinary copper excretion observed after a challenge dose of D-penicillamine (±20 mg/kg) remained constant throughout the period of observation while the liver copper content fell from 1460 μg/g dry weight to 890 μg/g dry weight. In the other patient, however, the liver copper content as well as the 24 hour urinary copper excretion increased after D-penicillamine challenge during the third year of treatment.

We conclude that zinc sulphate is a low toxic and well tolerated alternative for D-penicillamine. The dosage depends, however, on individual factors not yet well understood, and we recommend restriction of its use to patients who do not tolerate D-penicillamine well. We suggest monitoring of treatment with yearly D-penicillamine challenge and a liver biopsy if liver function deteriorates.
Membrane potential and hepatic uptake: Another rule of the game
Authors: Tiribelli Claudio
Published: March 2007

Since glucagon can hyperpolarize hepatic plasma membrane and stimulate biliary bile acid secretion in vitro, we studied the effect of glucagon on taurocholate uptake and its relationship to plasma membrane potential in isolated rat hepatocytes. [14C]Taurocholate uptake was linear through 1 min and contained a saturable sodium-dependent and a nonsaturable sodium-independent component, Km of taurocholate uptake by the sodium-dependent system was 18.4 μM. Hill coefficient for Na+ was 2.59 and for taurocholate was 1.1, suggesting that the stoichiometry is 2 Na+:1 bile acid. Stimulation of taurocholate uptake by glucagon was limited to the sodium-dependent component, detected within 5 min of hormone exposure, and was maximum at 30 min. Glucagon, from 10−8 to 10−5 M, stimulated taurocholate uptake and hyperpolarized concurrently the plasma membrane potential. Because valinomycin produced a dose-related depolarization of plasma membrane potential, this agent was used to counteract the effects of glucagon. With 10−6 M glucagon, valinomycin (10−10 M) depolarized membrane potential from -35.50 to -28.00 mV and inhibited taurocholate uptake from 60% above the control rate to 5% below. These data strongly suggest that taurocholate uptake by isolated hepatocytes is an electrogenic process, and its stimulation by glucagon may be mediated by changes in plasma membrane potential.
Emergency portacaval anastomosis (EPCA): The long-awaited trial
Authors: Conn Harold O.
Published: March 2007

A prospective randomized trial was conducted in all comers with cirrhosis and bleeding varices comparing 1) emergency portacaval shunt (EPCS) performed within 8 hr of admission, with 2) emergency medical therapy (EMT) followed in 2-6 wks by elective portacaval shunt in survivors. All patients received identical supportive therapy initially, and the EMT group received vasopressin in continuous infusion and, if necessary, esophageal balloon tamponade to control varix bleeding. No patients refused to participate in the trial, and there were no escape or cross-over provisions in the protocol. Randomization resulted in 21 patients receiving EPCS and 22 patients receiving EMT. All patients were followed up for at least 3 yrs.

Mean age was 48 yrs in each group. Cirrhosis was caused by alcoholism in 95% of each group. On admission, there were similar incidences in the 2 groups of ascites (EPCS-52%, EMT-50%), jaundice (EPCS-48%, EMT-50%), encephalopathy (EPCS-33%, EMT-14%), severe muscle wasting (EPCS-48%, EMT-59%), hyperdynamic state (82% in both groups), SGOT ≥ 100 u (EPCS-33%, EMT-36%), ICG retention ≥ 50% (EPCS-24%, EMT-23%), and ingestion of alcohol within 7 d of bleeding (EPCS-62%, EMT-59%). Child's risk classes in the EPCS group were A-10%, B-38%, and C-52%, while in the EMT group they were A-41%, B-32%, and C-27%, suggesting that the EPCS group had somewhat more severe liver disease.

There were highly significant differences (p < 0.01) in the results obtained by the 2 forms of treatment. Bleeding was permanently controlled in 100% of patients who underwent EPCS, but in 45% who received EMT. Mean requirement for blood transfusion was 5.8 u in the EPCS group and 15.5 u in the EMT group. 81% of the EPCS patients survived to leave the hospital compared to 45% of the EMT group. The 3-yr survival rate was 67% following EPCS compared to 27% following the combination of EMT and elective shunt. It is concluded that EPCS is significantly more effective than EMT followed by elective shunt in the treatment of bleeding varices in alcoholic cirrhosis.
Portal venous flow in response to acute β-blocker and vasodilatatory treatment in patients with liver cirrhosis
Authors: Zoli Marco , Marchesini Giulio , Brunori Alessandra , Cordiani Maria Rita , Pisi Emilio
Published: March 2007

The drugs currently under investigation in the prevention of recurrent gastrointestinal bleeding in cirrhosis are likely to decrease the portal pressure by means of a primary reduction of portal blood flow. The hemodynamic effects of β-blocking agents and vasodilatory drugs were noninvasively measured in eight patients with cirrhosis by means of pulsed echo-doppler equipment. Portal caliber, blood velocity and flow were recorded hourly after a single dose of propranolol (40 mg p.o.) or atenolol (100 mg p.o.), and every 5 min after treatment with isosorbide dinitrate (5 mg sublingually). The drugs were administered at random with an interval of 2 days or more. The portal caliber decreased after atenolol, but did not change after propranolol and isosorbide. The blood velocity decreased by 29 ± 2% 3 hr after propranolol, by 26 ± 2% 3 hr after atenolol and by 31 ± 3% 15 min after isosorbide. The portal blood flow decreased by 0.29 ± 0.03 liters per min after propranolol, by 0.34 ± 0.06 after atenolol and by 0.26 ± 0.03 after isosorbide, without any difference among the various treatments. β-blockers and vasodilatory drugs have comparable effects on portal blood flow. β1-selective and nonselective β-blockers are similarly effective in keeping with the hypothesis that changes in portal blood flow are mainly due to the block of β1-receptors.
Regulation of low density lipoprotein receptor activity in primary cultures of human hepatocytes by serum lipoproteins
Authors: Havekes Louis M. , Verboom Hans , de Wit Elly , Yap Sing Hiem , Princen Hans M. G.
Published: March 2007

The low density lipoprotein receptor activity was measured in primary cultures of human hepatocytes. The receptor-mediated association and degradation of low density lipoprotein increased gradually up to 140 and 190%, respectively, upon incubation of the cells with increasing amounts of whole serum (up to 100%). Preincubation of the cells with low density lipoprotein resulted in a weak downregulation of the receptor-mediated association of low density lipoprotein (only 35% reduction at 100 μg low density lipoprotein per ml). However, preincubation with high density lipoproteins with density between 1.16 and 1.20 gm per ml (heavy high density lipoprotein) resulted in a more than 2-fold stimulation of the receptor-mediated association of low density lipoprotein. This heavy high density lipoprotein-mediated stimulation could not be antagonized by a simultaneous addition of low density lipoprotein during that preincubation.

We conclude that, in primary cultures of human hepatocytes, the downregulation of the low density lipoprotein receptor activity by low density lipoprotein is weak and completely overruled by heavy high density lipoprotein. If these results for human hepatocytes in vitro hold true for hepatocytes in vivo, our results might explain why in vivo liver cells still display low density lipoprotein receptor activity notwithstanding the exposure of these cells to physiological concentrations of low density lipoprotein.
Induction of cystine transport activity in isolated rat hepatocytes by sulfobromophthalein and other electrophilic agents
Authors: Bannai Shiro , Takada Akira , Kasuga Hitomi , Tateishi Noriko
Published: March 2007

The uptake of cystine in isolated rat hepatocytes was enhanced after incubation of the cells with sulfobromophthalein. The enhancement was time- and dose-dependent, with a lag of about 6 hr, and an approximately 4-fold increase in the activity occurred after 24 hr with 0.2 mM sulfobromophthalein. Actinomycin D or cycloheximide completely blocked the time-related increase in the uptake. The enhanced activity of cystine uptake was almost entirely Na+-independent and inhibited by some anionic amino acids, such as glutamate. The uptake of glutamate was also enhanced by sulfobromophthalein. It is concluded that sulfobromophthalein induces the activity of the Na+-independent, anionic amino acid transport system (System x−
c) which mediates the transport of cystine. Some other electrophilic agents also enhanced the cystine uptake. The glutathione level of hepatocytes was rapidly reduced by sulfobromophthalein to about 10% of the control level at 6 hr, but at 12 hr it began to rise. It seems likely that this restoration resulted from the induced activity of the cystine uptake because inhibitors of the cystine uptake blocked the restoration and because the uptake of other sulfur amino acids was not enhanced significantly by sulfobromophthalein. System x−
c may thus participate in the detoxication of electrophilic agents in hepatocytes.
Permeability characteristics of the guinea pig biliary apparatus†
Authors: Tavoloni Nicola , Wyssbrod Herman R. , Jones Mary Jane T.
Published: March 2007

To determine the mechanism and pathway of entry of polar nonelectrolytes into bile, we studied first the permeation of [3H]H2O, [14C]urea, [14C]erythritol, [14C]mannitol, [3H]sucrose, [3H]inulin and [3H]dextran across an isolated, in situ perfused segment of the guinea pig's extrahepatic bile duct. All of these molecules, except [3H]dextran, permeated the bile duct. The diffusive permeability coefficients (cm per sec per 106) ranged from 248 for [3H]H2O to 1.2 for [3H]inulin. On the basis of these results, we formulated two models of solute biliary excretion. In Model I, permeation across both the canaliculus and ductule/duct was assumed to be by simple diffusion. In Model II, solute was assumed to enter the canaliculus by convection and diffusion, and the ductule/duct by diffusion. Reflection coefficients and/or permeability coefficients for the canalicular membrane were then determined by fitting the equations describing these processes to the bile-to-plasma ratios of [14C] erythritol, [14C]mannitol, [3H]sucrose and [3H]inulin observed at different rates of bile flow produced by partially clamping the bile duct cannula and subsequently infusing taurodehydrocholate. Only when convection was included as a mechanism of canalicular permeation (Model II) was excellent fitting observed. In such a case, the reflection coefficients and permeability coefficients for the carbohydrates in question were similar to those reported for other transporting epithelia. Cholestasis produced by taurolithocholate (10 to 40 μmoles per kg, i.v.) was associated with an irreversible increase in both the sieving coefficient and permeability coefficient for [3H]sucrose and [3H]inulin, even when the inhibition of bile flow was fully reversible. The permeability to [14C] erythritol and [14C]mannitol was either not affected or minimally increased. These findings suggest that, in the guinea pig: (i) solutes as large as [3H]inulin enter the biliary tree both at the canaliculus and bile ductule/duct; (ii) [14C]erythritol and [14C]mannitol gain access into the canalicular lumen primarily by convection, whereas [3H]sucrose and [3H]inulin permeate mainly by diffusion; (iii) distal permeation of these carbohydrates is small, and accounts for 1 to 11% of their total biliary entry; (iv) the canalicular membrane permeability to [3H]sucrose and [3H]inulin is not functionally important in bile secretion, and (v) a fraction of canalicular bile flows through the transjunctional shunt pathway.
Apolipoprotein AI and alcoholic liver disease
Authors: Poynard Thierry , Abella Annie , Pignon Jean-Pierre , Naveau Sylvie , Leluc Robert , Chaput Jean-Claude
Published: March 2007

A prospective study of apolipoprotein AI has been undertaken in 581 alcoholic patients and in 100 controls in order to describe the changes of apolipoprotein AI according to the different stages of the alcoholic liver disease, to correlate the changes to serum liver tests and to estimate its diagnosis and prognostic value. Results showed that apolipoprotein AI concentration is highly related to the degree of liver injury, reaching a maximum in patients with steatosis (229 ± 90 mg per dl), beginning to decrease in patients with fibrosis (188 ± 88 mg per dl) and reaching a minimum in patients with severe cirrhosis (91 ± 46 mg per dl). Apolipoprotein AI had an independent and discriminative value for the diagnosis of fibrosis (p < 0.001) vs. steatosis and for the diagnosis of cirrhotic vs. noncirrhotic fibrosis (p < 0.001) or vs. acute alcoholic hepatitis without cirrhosis (p < 0.001). Cirrhotic patients with apolipoprotein AI less than 100 mg per dl had a lower survival rate at 1 year (62 ± 7%) than patients with greater value (80 ± 6%; p < 0.05), but this prognostic value disappeared in multivariate analysis when other known prognostic factors were taken into account.
Somatostatin analogues: Treatment for portal hypertension?
Authors: Blei Andres T.
Published: March 2007

The effects of a somatostatin analogue, SMS 201-995 on hepatic haemodynamics were studied in rats with dimethylnitrosamine-induced cirrhosis. An intravenous infusion of 1, 2 or 4 μg kg−1 body wt h−1 SMS 201-995 produced a rapid and sustained decrease in portal pressure, portal venous flow and liver blood flow without significantly altering arterial blood pressure or pulse. The reductions in portal pressure, portal venous flow and liver blood were accompanied by an increase in splanchnic vascular resistance. Portal venous resistance was not affected. Subcutaneous injection of 2 μg kg−1 body wt SMS 201-995 produced a gradual decrease in portal pressure, the maximum reduction occurring 18 min after administration. This reduction in portal pressure was sustained for a further 20 min. The results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, the prolonged duration of action of SMS 201-995 following its subcutaneous administration suggests that the analogue may be useful in the long-term management of portal hypertension in patients with cirrhosis.
HLA antigens in patients with various courses after hepatitis B virus infection
Authors: Van Hattum Jan , Th. Schreuder Geziena M. , Schalm Solko W.
Published: March 2007

The course after hepatitis B virus infection seems to be determined by the host's immune response, which in turn may be regulated by the major histocompatibility complex. In order to find a possible relationship between the course of disease and the phenotype frequency of HLA determinants, we studied 396 Dutch subjects of northern European local race. Six groups of individuals with various courses after hepatitis B virus infection were compared to healthy controls. The hepatitis B patients were grouped according to standard criteria: (i) 47 had recovered from acute symptomatic hepatitis B virus infection; (ii) 60 had recovered from asymptomatic hepatitis B virus infection; (iii) 26 were asymptomatic hepatitis B surface antigen carriers; (iv) 16 had chronic persistent hepatitis B; (v) 37 had chronic active hepatitis B, and (vi) 10 had chronic active hepatitis after elimination of hepatitis B antigens. Twenty-nine Class I and 13 Class II HLA antigens were assayed by standard microlymphocytotoxicity tests.

The phenotype frequency of the Class II antigen DQw1 appeared to be significantly lower in patients with chronic active hepatitis B virus infection. Some other HLA specificities showed deviations from control values, but they were not statistically significant after correction for the number of antigens tested.

In conclusion, we have found no evidence that the elimination of hepatitis B virus is related to HLA phenotype. DQw1, however, may affect the morphologic type of chronic hepatitis B infection, since its presence may protect against chronic active hepatitis.
Acute exacerbation in chronic type B hepatitis: Comparison between HBeAg and antibody-positive patients
Authors: Liaw Yun-Fan , Tai Dar-In , Chu Chia-Ming , Pao Chia C. , Chen Tong-Jong
Published: March 2007

The incidence, clinicopathological features and etiology of acute exacerbation occurring in patients with chronic type B hepatitis were assessed prospectively among 385 patients who had HBeAg and 279 who had anti-HBe in serum. During an average follow-up of 23.5 months, acute exacerbations occurred in 197 HBeAg-positive patients and in 56 anti-HBe positive patients, with a calculated annual incidence of 28.6 and 10.3%, respectively (p < 0.001). The clinical and laboratory findings of acute exacerbations were similar in the HBeAg-positive and anti-HBe positive patients. The mean serum bilirubin and α-fetoprotein levels were higher in anti-HBe positive patients (p < 0.01), but actual differences were small. The histologic features of acute exacerbations were also similar in the HBeAg-positive patients and anti-HBe positive patients. Lobular alterations were the main histologic findings; in addition, one-fourth of patients had bridging necrosis and one-fourth had piecemeal necrosis. Spontaneous reactivation of hepatitis B was the major cause of these exacerbations in both HBeAg-positive patients (91.5%) as well as anti-HBe positive patients (62.5%). Hepatitis delta virus superinfection accounted for a higher percentage of exacerbations in anti-HBe positive patients (14.3%) than in HBeAg-positive cases (6.5%). Hepatitis A and possibly non-A, non-B virus superinfections also contributed to some episodes of exacerbation. Thus, acute exacerbations of disease occurred more frequently in HBeAg-positive patients than in anti-HBe positive patients with chronic type B hepatitis, but the clinicopathological features and etiologies were similar.
The effect of changes in the fluid state of rat liver plasma membrane on the transport of taurocholate
Authors: Mills Peter R. , Meier Peter J. , Smith Daniel J. , Ballatori Nazzareno , Boyer James L. , Gordon Ellen R.
Published: March 2007

The fluidity of basolateral and canalicular rat liver plasma membranes was compared with respect to their response to the membrane perturbants ethanol and calcium. The relation between membrane fluidity and taurocholate transport, a liver plasma membrane function mediated by carrier proteins, was also examined. Membrane fluidity was measured by fluorescence polarization using 1,6-diphenyl-1,3,5-hexatriene as a probe. Uptake of [3H]taurocholate into basolateral rat liver plasma membrane and canalicular rat liver plasma membrane vesicles was measured by a rapid Millipore filtration technique. Anisotropy values were found to be significantly lower for the basolateral rat liver plasma membrane (0.2287 ± 0.0014) than for the canalicular rat liver plasma membrane (0.2612 ± 0.0012), indicating that basolateral rat liver plasma membranes are more fluid than canalicular rat liver plasma membranes. Ethanol produced a concentration-dependent effect on lipid fluidity and inhibition of taurocholate uptake, in both membrane preparations. Pretreatment of the membrane with calcium increased the rigidity of both membrane preparations. However, the change in the anisotropy with calcium was only slight in the more rigid canalicular rat liver plasma membrane, while the change in anisotropy was greater and associated with a decrease in taurocholate uptake in the basolateral rat liver plasma membrane. Both the effects of ethanol and calcium were more pronounced in basolateral rat liver plasma membrane than in canalicular rat liver plasma membrane. These results indicate that the fluid state of the hydrophobic bilayer of liver plasma membrane lipids play an important role in regulating bile acid transport in both sinusoidal and canalicular domains.