bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibodies to polymerized human serum albumin in acute and chronic liver disease
Authors: Lee William M. , McLeod Lizabeth , Martin Kylie , Emerson David L. , Galbraith Robert M.
Published: March 2007

Since antibodies to polyalbumin have been noted to occur in patients with hepatitis or cirrhosis, we investigated sera from 219 patients with a variety of acute and chronic liver diseases with and without HBsAg using an ELISA. The prevalence of circulating polyalbumin antibodies was shown to be significantly increased over that of healthy controls (6.7%) in patients with autoimmune chronic active hepatitis (67%), acute viral hepatitis (41%) and fulminant hepatic necrosis (38%), but such antibodies were absent in chronic hepatitis B patients and other liver diseases. Serial studies in acute hepatitis showed evidence of antibodies early in the course of illness with disappearance prior to full recovery. In acute hepatitis B, the presence of polyalbumin antibodies was significantly associated with female sex (p < 0.01), 3-fold higher transaminase levels and shorter duration of clinical illness (<4 weeks in all cases). Polyalbumin antibodies appear to be associated with diseases characterized by active hepatocyte necrosis. Since they are evident early in acute hepatitis B when complexes of polyalbumin and virus are likely, these antibodies may play an adjunctive role to other hepatitis B-related antibodies in the clearance of hepatitis B virus infection.
Pityriasis rotunda: A new cutaneous marker of hepatocellular carcinoma?
Authors: Conn Harold O. , Van Voorhees Abby , Klaus Sidney N.
Published: March 2007

Although paraneoplastic phenomena occur frequently in patients with hepatocellular carcinoma, cutaneous changes have rarely been reported. During the past two years, ten South African blacks with hepatocellular carcinoma and pityriasis rotunda have been seen in a single hospital. The rash affected the trunk, especially the lower back and buttocks. The lesions ranged in size from 1.5 to 25 cm and were always multiple. They had a characteristic circular or arcuate configuration with scaling and varying degrees of hyperpigmentation. Pityriasis rotunda may prove to be a useful cutaneous marker of hepatocellular carcinoma in South African blacks.
Procollagen III peptide (PIIIP): Can it reflect hepatic fibrosis?
Authors: Alcorn Joseph , Chojkier Mario
Published: March 2007

Immunolocalization of type III collagen and procollagen in cirrhotic human liver was studied using monoclonal antibody specific for the helical determinant of type III collagen extracted from human placenta. Deparaffinized, trypsin-treated cirrhotic liver sections from 8 autopsy cases were examined by the unlabeled peroxidase-antiperoxidase and immunofluorescence techniques. These techniques revealed the localization of this epitope shared by type III collagen and procollagen not only in the extracellular matrix of hepatocytes and sinusoidal cells but also in the cytoplasm. In hepatocellular carcinoma concurrent with cirrhosis, neoplastic cells were shown to react with this antibody as well.

These results are consistent with data obtained using antiserum specific for bovine type III procollagen aminopeptide which appeared in our previous report.
Correlation between the biliary excretion of ouabain and the lateral mobility of hepatocyte plasma membrane proteins in the rat—the effects of age and spironolactone pretreatment
Authors: Kitani Kenichi , Zsolnai-Nagy Imre , Kanai Setsuko , Sato Yuko , Ohta Minoru
Published: March 2007

The biliary excretion of intravenously injected ouabain and the diffusion constant of the lateral mobility of hepatocyte plasma membrane proteins were examined in control (saline-treated) and spironolactone-treated Wistar male rats of different ages (4, 14 to 15 and 24 months old). The biliary excretion of ouabain progressively decreased with age in control rats, the first 10-min biliary recovery in 24-month-old animals being one-third that of the youngest rats (4-month-old). The oral administration of spironolactone for 4 days (10 mg per 100 gm body weight on the first day and 20 mg per 100 gm body weight for the successive 3 days) caused a marked increase in the biliary recovery of ouabain in all age groups. Similarly, the average lateral diffusion constant of hepatocyte plasma membrane proteins as measured by fluorescence recovery after photobleaching showed a linear decrease with age, as was previously observed with F-344 rats of both sexes. Markedly and significantly (30 to 40%) higher diffusion constants were observed in rats pretreated with spironolactone for all three age groups, compared with the respective control values of corresponding ages. The parallelism between ouabain excretion and protein diffusion (i.e., a decrease with age and an increase with spironolactone pretreatment) suggests that the lateral mobility of proteins in the hepatocyte plasma membrane is a candidate mechanism for regulating ouabain excretion through the liver into the bile, most probably by regulating the hepatic uptake process for ouabain.
Effect of vasodilators on hepatic microcirculation: A study of the inhibition of norepinephrine-induced vasoconstriction in the isolated perfused rat liver
Authors: Marteau Philippe , Ballet François , Chrétien Yves , Rey Colette , Jaillon Patrice , Poupon Raoul
Published: March 2007

We studied the effects of a series of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in the isolated perfused rat liver. The vasodilators were nonselective α-adrenergic antagonists (phentolamine, ifenprofil, isoxsuprine and buflomedil), a nonselective β-adrenergic antagonist (propranolol) and an agonist (isoproterenol), an α2-adrenergic agonist (clonidine), calcium channel blockers (verapamil and diltiazem), nitrovasodilators (nitroglycerin, sodium nitroprusside), papaverine and other unclassified vasodilators, some of them with rheological properties (diazoxide, vincamine, cinepazide, naftidofuryl and pentoxifylline). The most potent drugs were ifenprofil, phentolamine, isoxsuprine, clonidine, sodium nitroprusside and buflomedil. Diazoxide, papaverine, pentoxifylline and trinitrine were less powerful. Verapamil, diltiazem, propranolol, isoproterenol, vincamine, cinepazide and naftidofuryl were ineffective. We conclude that different classes of pharmacological agents have significant vasodilatory properties on the hepatic microvasculature. This offers interesting perspectives in the treatment of cirrhosis and stressful states where high levels of circulating norepinephrine may contribute to the altered liver perfusion.
Effect of side chain length on bile acid conjugation: Glucuronidation, sulfation and coenzyme a formation of nor-bile acids and their natural C24 homologs by human and rat liver fractions
Authors: Kirkpatrick Robert B. , Green Mitchell D. , Hagey Lee R. , Hofmann Alan F. , Tephly Thomas R.
Published: March 2007

The effect of side chain length on bile acid conjugation by human and rat liver fractions was examined. The rate of conjugation with glucuronic acid, sulfate and coenzyme A of several natural (C24) bile acids was compared with that of their corresponding nor-bile acids. The rate of coenzyme A ester formation by nor-bile acids was much lower than that of the natural bile acids. In human liver microsomes, the rate of coenzyme A formation was <8% of the rate for the corresponding C24 bile acid. Rat liver microsomes formed the coenzyme A ester of nor-bile acids <20% of the rate of their corresponding C24 homologs. Glucuronidation rates were greater than sulfation rates in both species. With human liver microsomes, nor-bile acids were glucuronidated more rapidly than their corresponding C24 homologs, whereas with rat liver microsomes the reverse was true. Purified 3α-OH androgen UDP-glucuronyltransferase catalyzed the glucuronidation of both nor-bile acids and bile acids. Human liver cytosol sulfated nor-bile acids more slowly than the corresponding bile acids. Rat liver cytosol, however, sulfated nor-bile acids more rapidly than the corresponding bile acids. The highest rate was seen with lithocholylglycine. The results indicate that the novel biotransformation of nor-bile acids seen in vivo—sulfation and glucuronidation rather than amidation—is most likely explained as a consequent of defective amidation, to which the rate of coenzyme A formation contributes. Thus, side chain and nuclear structures as well as species differences in conjugating enzyme activity are determinants of the pattern of bile acid biotransformation by the mammalian liver.
Electropermeabilization: Getting inside the cell to study autophagy
Authors: Yamazaki Kiyoshi , Larusso Nicholas F.
Published: March 2007

Electropermeabilisation—i.e. subjecting cells to a short series of high-voltage pulses—has been used to make isolated rat hepatocytes transiently permeable to small molecules. The permeabilised cells can be loaded with [14C]sucrose at 0°C and resealed by a brief incubation at 37°C. The electrical treatment does not impair cellular function, since autophagic sequestration of sucrose occurs at the same rate as in untreated cells. The latter are permeable to sucrose immediately after isolation, due to the presence of hyperpermeable surface blebs similar to those formed in response to electrical treatment.

In order to separate [14C]sucrose-sequestering organelles from cytosol, the cells are broken up by electrodisruption—i.e. a single high-voltage pulse given in a non-ionic medium (isotonic sucrose)— and the resulting cell corpses are sedimented through a dense metrizamide/sucrose cushion to form a cytosol-free pellet containing intact lyso-somes. Since mitochondria also take up sucrose, the radioactivity in autophagosomes/lysosomes must be selectively extracted with a low concentration of digitonin.

The resulting procedure provides a specific bioassay of autophagic sequestration. The sequestration is virtually completely inhibited by the autophagy inhibitor 3-methyladenine, and at temperatures below 20°C. The sequestration step is energy-dependent, and can probably account for the known energy requirement of autophagic-lysosomal protein degradation.
Hepatic manifestations of total parenteral nutrition: Need for prospective investigation
Authors: Jeejeebhoy K. N.
Published: March 2007

Total parenteral nutrition is now widely used in the treatment of nutritional depletion. Among problems that persist in the use of this technique, the development of hepatic abnormalities has received increasing attention. In this review, the current understanding of the pathogenesis and management of liver injury during short-term total parenteral nutrition is summarized. These complications include fatty liver, cholestasis, and nonspecific triaditis. The experience with hepatic complications during long-term total parenteral nutrition is also reviewed. Evidence that progressive liver injury develops in some patients requiring lifelong total parenteral nutrition raises a serious dilemma for both patients and physicians. Better understanding of the pathogenesis is required before appropriate treatment can be prescribed.
Emergency liver transplantation in fulminant hepatitis
Authors: Lorber Marc I.
Published: March 2007

Seven patients with hepatitis delta virus (HDV) cirrhosis underwent liver transplantation. In every case the HDV infection was florid but accompanied by an inactive hepatitis B virus (HBV) infection. The patients were given anti-HB surface antigen (HBsAg) serum globulins and HBV vaccine. Two patients cleared the HBsAg and the HDV, and are alive and well 14 and 15 months, respectively, after transplantation. HDV infection recurred in the other five patients: hepatitis developed in three, another died, and the fifth was re-transplanted for causes unrelated to viral hepatitis (reinfection was shown by the presence of HD antigen in the graft). Liver transplantation is feasible in patients with HDV disease but involves a high risk of HDV reinfection that cannot be predicted by the virological pattern of the native HBV infection or prevented by conventional HBV prophylaxis.

Orthotopic liver transplantation was done in 17 patients with fulminant hepatitis. The cause of the liver disease was infection with hepatitis B virus, or co-infection with hepatitis B virus and hepatitis D virus, or infection with hepatitis A virus in 6 patients; drug hepatotoxicity in 5; and indeterminate in 6. Grafts from incompatible blood groups, steatotic grafts, or reduced-size grafts were used in 5, 4, and 4 patients, respectively. Of the 17 patients, 5 died: 2 of early liver failure due to the poor quality of the graft, 1 presumably of accidentally transmitted acute infection with the human immunodeficiency virus, and 2 of decerebration occurring during or immediately after surgery. The 12 other patients were alive 2 to 15 months after transplantation.
The ischemic liver—do not resuscitate too much
Authors: Isaacson Yisrael , Van Thiel David H.
Published: March 2007

The interest in liver transplantation has focused more attention on the mechanisms of injury during hepatic ischemia, preservation, and reperfusion. Although the human liver has been successfully maintained under hypothermic conditions for up to 10 hours, organ preservation remains the major obstacle to liver transplantation.

With tissue ischemia, cell respiration and oxidative phosphorylation cease, with a decline in high-energy phosphates including adenosine triphosphate (ATP). If oxygen and substrate are made available within a certain period of time, energy stores are regenerated and cells live. However, with irreversible ischemia, ATP stores cannot be regenerated despite the restoration of blood flow, and the cells consequently die. When ATP-MgCl2 has been given by intravenous infusion, animal survival has been improved in shock, and renal function and histology have been maintained after renal ischemia. The mechanism responsible for this beneficial effect of ATP-MgCl2 has not been defined, but it is generally presumed that ATP preserves sublethally injured cells by enhancing their repair and recovery after ischemic injury.

Although reperfusion is necessary to prevent cell death, it is not without hazard. During the period of ischemia, ATP is broken down to adenosine monophosphate, adenosine, inosine, and finally to hypoxanthine, which can be irreversibly converted by xanthine oxidase to xanthine. The introduction of oxygen into this reaction by reperfusion results in the production of the free radicals superoxide (02 ) and hydrogen peroxide (H2O2), which are mediators of tissue injury, probably by lipid peroxidation. Protection from these oxidative effects can be achieved by dismutation of superoxide to H2O2 by the enzyme superoxide dismutase (SOD) and reduction of H2O2 by catalase.
The effect of dexamethasone and glucagon on the expression of hepatocyte plasma membrane proteins during development
Authors: Bujanover Yoram , Amarri Sergio , Lebenthal Emanuel , Petell James K.
Published: March 2007

The regulation of different maturational processes in the liver is believed to be influenced by the hormonal system. The aim of this study was to investigate the effect of two hormones, glucagon and dexamethasone, on levels of plasma membrane proteins in rat liver cells during late fetal and early postnatal stages of development. For this purpose, 18-day-old rat fetuses and 1-day-old newborns were treated with glucagon or dexamethasone and killed at 22 days of gestation and 3, 5 and 7 days of age, respectively. Postnuclei liver membranes were isolated using a sucrose gradient method and assessed for levels of specific membrane proteins. Asialoglycoprotein receptor and 110,000 Mr glycoprotein, denoted GP 110, representing the sinusoidal and bile canalicular domains, respectively, were quantitated using the immunoblot method. Membrane enzymes alkaline phosphatase, leucine aminopeptidase and γ-glutamyl transferase were evaluated using enzymatic methods. The data showed that glucagon and dexamethasone have a differential effect on membrane constituents according to the stage of development. Glucagon increased the levels of membrane enzymes during the late fetal stage but had no effect on liver membrane proteins in the newborn animal. In contrast, although dexamethasone elevated GP 110 in fetal rat livers, none of the other marker proteins was significantly affected. On the other hand, in newborns dexamethasone reduced the amount of asialoglycoprotein receptor and alkaline phosphatase and leucine aminopeptidase enzyme activities but greatly augmented the level of γ-glutamyl transferase. Thus, glucagon primarily affects plasma membrane proteins in late gestation while dexamethasone does so during the early postnatal period. The roles that these two hormones may play during ontogeny is discussed with respect to liver development.
Thallium-201 per rectum for the diagnosis of cirrhosis in patients with asymptomatic chronic hepatitis
Authors: D’Arienzo Agesilao , Celentano Luigi , Scuotto Alessandro , Di Siervi Pasqualina , Lombardi Vinicio , Squame Giovanni , Mazzacca Gabriele
Published: March 2007

In normal subjects, thallium-201, administered per rectum, is taken up mainly by the liver (heart/liver ratio in normal subjects: 0.04 to 0.12). It has been claimed that an increased heart/liver ratio is suggestive of portal-caval shunting and portal hypertension. To evaluate the possibility of using thallium-201 as a test to diagnose cirrhosis, we administered this substance per rectum to 33 patients with biochemical evidence, but no clinical symptoms, of liver disease. Laparoscopy and liver biopsy revealed chronic active hepatitis without cirrhosis in 18 patients, and chronic active hepatitis with cirrhosis in the others. The results of conventional liver function tests were similar in both groups. A significant difference, however, was found between the means of fasting serum bile acid concentrations (9.8 ± 3.2 and 18.3 ± 4.2 μM per liter) in chronic active hepatitis without cirrhosis and cirrhotic patients, and between the means of the heart/liver ratios 20 min after thallium-201 administration (heart/liver: 0.09 ± 0.03 and 0.54 ± 0.13, respectively). Unlike the serum bile acid concentration which gave some overlapping values, the thallium-201 test clearly distinguished the chronic active hepatitis without cirrhosis group from the cirrhotics.

In the cirrhotic group, there was a significant correlation between the heart/liver ratio and signs of portal hypertension such as esophageal varices, increased diameter of the vena porta and hypersplenism.

The thallium-201 test is therefore useful in discriminating between chronic active hepatitis with and without cirrhosis in clinically asymptomatic subjects with biochemical evidence of moderate liver function impairment. A heart/liver uptake ratio much higher than normal (above 0.30) strongly suggests the development of hepatic cirrhosis.
Lipocytes and transitional cells in alcoholic liver disease: A morphometric study
Authors: Mak Ki M. , Lieber Charles S.
Published: March 2007

Lipocytes and transitional cells in alcoholic liver disease were analyzed by quantitative morphometry in liver biopsy specimens of 17 alcoholic patients. In fatty livers, 93% of the perisinusoidal cells were lipocytes with a volume of lipid droplets occupying more than 20% of the individual cell volume. In fatty livers with perivenular fibrosis, 83% of the cells were lipocytes and 17% were transitional cells with lipid droplets of less than 20% of the cell volume. In cirrhosis, 45% of the cells were lipocytes and 55% of the cells were transitional cells. Thus, the process of hepatic fibrosis was associated with a shift from lipocytes to transitional cells. The percentage of transitional cells (expressed as total perisinusoidal cells) was 5.1% in fatty livers, 16.5% in fatty livers with perivenular fibrosis (not significantly different when compared to fatty livers) and 59.7% in cirrhotic livers (p < 0.025) when compared to fatty livers or fatty livers with perivenular fibrosis). The number of transitional cells per 100 hepatocytes was estimated to be 0.5 in fatty livers, 1.3 in fatty livers with perivenular fibrosis and 2.1 in cirrhotic livers. The appearance of transitional cells was associated with a corresponding decrease in the number of lipocytes, supporting the hypothesis that transitional cells were derived from lipocytes. In comparison to lipocytes, the surface area of transitional cells (as measured by digitized morphometry) was 30 to 46% smaller (p < 0.01). When expressed as the percentage of the total cell area, the lipid droplet compartment in transitional cells was 34% smaller (p < 0.001) than that in lipocytes, whereas the nonlipid cytoplasmic and nuclear compartments in transitional cells were 18 to 20% (p < 0.01) and 15% (p < 0.05) larger than those in lipocytes, respectively. The rough endoplasmic reticulum in transitional cells became better developed than that in lipocytes, but only at the cirrhotic stage, confirmed by quantitative morphometry. We found a significantly higher collagen score in the Disse space surrounding transitional cells in fatty livers with perivenular fibrosis or cirrhosis compared to that of lipocytes. In two cases of alcoholic hepatitis with cirrhosis, virtually all perisinusoidal cells exhibited structural features and morphometric values comparable to those of transitional cells in the livers without hepatitis. In the liver of one nonalcoholic subject, perisinusoidal cells exhibited structural features and morphometric values comparable to those of lipocytes in the livers of alcoholics.
Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease
Authors: Guigui Bernard , Perrot Sylvain , Berry Jean Pierre , Fleury-Feith Jocelyne , Martin Nadine , Métreau Jean Michel , Dhumeaux Daniel , Zafrani Elie Serge
Published: March 2007

In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steaaosis and fibrosis, two cases; chronic venous congestion, one case; acute hepatitis, one case) that could be explained by another cause than amiodarone in seven cases and normal liver in two cases. In all cases, electron microscopy showed intralysosomal myelin figures suggestive of phospholipidosis. These myelin figures were associated with intralysosomal electron-dense deposits. In the four cases in which analysis by electron microprobe was performed, it demonstrated large amounts of iodine in the electron-dense deposit-containing lysosomes, indicating the accumulation of amiodarone. These results show that hepatic phospholipidosis is constantly observed in amiodarone-treated patients, whether or not pseudoalcoholic liver lesions are present. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug.
Specific loss of the high-molecular-weight form of S -adenosyl-l-methionine synthetase in human liver cirrhosis
Authors: Cabrero Carmen , Duce Antonio Martin , Ortiz Pablo , Alemany Susana , Mato Jose M.
Published: March 2007

We have measured the activity of S-adenosyl-L-methionine synthetase, the ratio between the high- and low-molecular-weight forms of this enzyme and the concentration of S-adenosyl-L-methionine in liver biopsies from a group of controls (n = 6) and in six cirrhotics (five posthepatitic and one alcoholic). The total activity of S-adenosyl-L-methionine synthetase was markedly reduced in cirrhosis (37.5% of that found in the control group). This was due to a specific reduction in the high-molecular-weight S-adenosyl-L-methionine synthetase in the group of cirrhotics (73.9 pmoles per min per mg protein) when compared with that observed in controls (460.3 pmoles per min per mg protein). Despite this reduction in the rate of synthesis of S-adenosyl-L-methionine (the high-molecular-weight form of the enzyme is 15 times more active than the low-molecular-weight form at physiological concentration of substrates), the concentration of this metabolite was the same in the control group (17.3 ± 2.6 μM) and in the group of cirrhotics (17.8 ± 3.1 μM). To explain these findings, it is postulated that in human liver, where the concentration of S-adenosyl-L-methionine is lower than the Km values of a variety of enzymes that use this metabolite (around 50 to 100 μM), a reduction in the synthesis of S-adenosyl-L-methionine is compensated by a reduction in the rate of utilization of this molecule without affecting the intrahepatic concentration of S-adenosyl-L-methionine. This postulate was tested by decreasing the activity of the high-molecular-weight S-adenosyl-L-methionine synthetase in rat liver by treatment with galac-tosamine. In the rat liver, the concentration of S-adenosyl-L-methionine is about 100 μM. Galactosamine treatment reduced the high-molecular-weight S-adenosyl-L-methionine synthetase from 66.5 pmoles per min per mg protein in the control group (n = 9) to 31.4 pmoles per min per mg protein (n = 8). This reduction of the activity of the high-molecular weight S-adenosyl-L-methionine synthetase was accompanied by a reduction of the concentration of S-adenosyl-L-methionine from 111.3 ± 5.7 μM in the control group to 56.9 ± 3.2 μM in the group of animals treated with galactosamine. Our results support the hypothesis that in human cirrhotic liver there is a marked reduction in the rate of synthesis and utilization of S-adenosyl-L-methionine.
Regulation of the hepatic transferrin receptor in hereditary hemochromatosis†
Authors: Lombard Martin , Bomford Adrian , Hynes Miriam , Naoumov Nikolai V. , Roberts Stephanie , Crowe John , Williams Roger
Published: March 2007

The liver is the main site of iron accumulation and pathologic sequelae in hereditary hemochromatosis. Whether this is a result solely of inappropriately increased absorption of iron by the gastrointestinal tract or a more generalized regulatory failure of iron balance is unknown. Using immunohistochemical techniques, we have examined the effects of therapeutic changes in liver iron stores on the expression of the hepatic trans-ferrin receptor in hereditary hemochromatosis. Ten patients with untreated hereditary hemochromatosis had no detectable staining for transferrin receptor in their liver biopsies. All had increased hepatic ferritin (mean = 19.9 μg per mg protein, range = 1 to 31.7 μg per mg protein) and hepatic iron levels (mean = 36.2 μg per mg protein, range = 3.6 to 69.9 μg per mg protein). In contrast, hepatocyte transferrin receptor was detected in seven patients in whom hepatic iron stores were markedly depleted by venesection (hepatic ferritin mean = 0.32 μg per mg protein, range = 0.16 to 0.53 μg per mg protein; hepatic iron mean = 0.98 μg per mg protein, range = 0.3 to 2.1 μg per mg protein). Sequential data from one patient confirmed the reexpression of receptor in response to therapeutic iron depletion, whereas data from another patient studied during treatment illustrated a reciprocal relationship between liver tissue distribution of iron and expression of transferrin receptor.

The finding that appropriate physiologic regulation of the hepatic transferrin receptor operates in hereditary hemochromatosis does not support the concept of a generalized defect in receptor-mediated uptake of trans-ferrin-bound iron.
The role of membranous obstruction of the inferior vena cava in the etiology of hepatocellular carcinoma in southern African Blacks
Authors: Kew Michael C. , McKnight Ann , Hodkinson John , Bukofzer Stanley , Esser Jan D.
Published: March 2007

Membranous obstruction of the inferior vena cava has been incriminated as a risk factor for hepatocellular carcinoma in South African Blacks and in Japanese. However, the frequency with which this anomaly is found in patients with hepatocellular carcinoma, and hence its numerical importance as an etiological association of the tumor, has not been ascertained. Using radionuclide and contrast venography as well as necropsy and laparotomy examination, we investigated 162 unselected southern African Blacks with hepatocellular carcinoma together with appropriate controls for the presence of membranous obstruction of the inferior vena cava. Membranous obstruction of the inferior vena cava was detected in six of 162 (3.7%) hepatocellular carcinoma patients, compared with one of 279 subjects (0.36% p = 0.011) dying a violent death, none of 55 patients (p = 0.169) with malignant disease other than hepatocellular carcinoma and eight of 150 patients (5.3%; p = 0.336) being investigated for conditions which might have been associated with membranous obstruction of the inferior vena cava. Six of the 15 individuals (40%) found to have membranous obstruction of the inferior vena cava had concomitant hepatocellular carcinoma, confirming that membranous obstruction of the inferior vena cava constitutes a risk factor for the development of the tumor. However, only a very small proportion of hepatocellular carcinoma patients have this abnormality, so that it is a minor causal association of the tumor only. All of the patients found to have membranous obstruction of the inferior vena cava and hepatocellular carcinoma, but only a minority of those with membranous obstruction of the inferior vena cava alone, were born and had grown up in the Transvaal province. This suggests that membranous obstruction of the inferior vena cava per se does not cause hepatocellular carcinoma, but rather that its presence renders the individual susceptible to one or more environmental hepatocarcinogens. The nature of these putative carcinogens is not known, but there is no evidence that chronic hepatitis B virus infection, alcohol ingestion or cigarette smoking is implicated.
Metoprolol-induced hepatitis: Is the rate of oxidation related to drug-induced hepatotoxicity?
Authors: Lennard M. S.
Published: March 2007

Metoprolol is as widely used beta-adrenoreceptor antagonist. There is no report of hepatitis involving this drug as well as other beta-adrenoreceptor antagonists. Metoprolol is metabolized by three major oxidation pathways. Two of them, Odealkylation and alpha-hydroxylation, undergo genetically controlled polymorphisms correlated with that of debrisoquine oxidation. This finding strongly suggests that metoprolol oxidation depends at least partly on the same isozyme of cytochrome P-450 involved in the genetic polymorphism of oxidation of debrisoquine and other drugs such as sparteine, perhexiline, and other beta-adrenoreceptor antagonists. Poor metabolizers of debrisoquine and metoprolol exhibit abnormal pharmacokinetics of metoprolol, which can result in an overdose after administration of a standard dose. There is a clear association between impairment of debrisoquine oxidation and susceptibility to develop liver injury with perhexiline. Does such an association exist for metoprolol? We report the first case of hepatitis induced by metoprolol and the result of drug oxidation phenotyping.
Analysis of hepatitis B virus transcripts in infected human livers
Authors: Su Tsung-Sheng , Lui Wing-Yiu , Lin Ling-Huang , Han Shou-Hwa , P’eng Fang-Ku
Published: March 2007

The hepatitis B virus transcripts in human hepatoma and its adjacent nontumorous liver were examined with probes specific to hepatitis B virus surface antigen, core antigen, X region and pre-S region. The study shows that the patterns of hepatitis B virus transcripts for tumorous tissue and the counterpart in nontumorous liver differ. In most of the tissues examined, the surface antigen gene is transcribed. Most of these transcripts, besides having surface antigen sequences, also have an X region; some also include a pre-S region. The transcripts that hybridized to a core-specific probe were a pair of poly(A+) RNA, 3.5 and 2.2 kilobases in size, present in two of the nontumorous hepatocytes where the virus was actively replicating. The 3.5-kilobase transcript not only hybridized to the core probe, but was able to be hybridized to other hepatitis B virus subgenomic probes and might represent the RNA pregenome involving hepatitis B virus DNA replication. Whereas most of the transcripts hybridizable to hepatitis B virus probe are in the size range of 2.1 to 2.7 kilobases, some transcripts other than the pregenomic RNA appear to be greater than 3.2 kilobases in size and may represent the hybrid RNAs of viral and host sequences.
Immunization of newborns of HBsag- positive mothers: A successful first step in control of hepatitis B virus in Taiwan
Authors: McMahon Brian J.
Published: March 2007

To combat hepatitis B virus (HBV) infection in Taiwan, a mass immunoprophylaxis program was launched on July 1, 1984, aiming first at prevention of chronic HBV carriage from perinatal mother-to-infant infection. In the first 15-month period, 352721 (78%) of 450585 pregnant women were screened for hepatitis B surface antigen (HBsAg); HBsAg was present in 62359 (18%), with 50% of them categorized as highly infectious. Infants born to HBsAg-positive women were given 5 μg of a plasma-derived hepatitis B vaccine at ages 1, 5, and 9 weeks, with a booster at age 12 months. Infants of highly infectious carrier mothers recived an additional 0.5 mL of hepatitis B immune globulin within 24 hours after birth. The coverage rate of the hepatitis B immune globulin was 77% in 27375 infants born to highly infectious mothers, and that of the first, second, third, and the fourth doses of vaccine was 88%, 86%, 84%, and 71%, respectively, in infants of 55620 carrier mothers. The reported untoward reactions to immunization were negligible. We conclude that a mass hepatitis B vaccination program is feasible in hyperendemic areas such as Taiwan; this should be a significant step toward the effective control of HBV infection in these areas.

To evaluate the efficacy of the mass hepatitis B vaccination program in Taiwan in interrupting perinatal hepatitis B virus transmission, 3464 randomly selected 18-month-old infant vaccinees born to hepatitis B surface antigen-carrier mothers were recruited from 9697 eligible infants during a six-month period of the program. They were divided into ten groups according to maternal in-fectivity and compliance with the vaccination schedule. Serum samples were tested for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. In 786 infants who had highly infectious mothers and who received hepatitis B immune globulin and vaccine on schedule, the protective efficacy was about 85%. The efficacy seemed to be slightly lower in those immunized off schedule. Overall, 11% of infants still carried hepatitis B surface antigen, and 81% of the infants had antibody to hepatitis B surface antigen that exceeded 10 mlU/ mL in more than 90% of them. The geometric mean titers of antibody to hepatitis B surface antigen were more than 200 mlU/mL in every group of infants. We conclude that the mass vaccination program is efficacious in preventing perinatal hepatitis B virus transmission and the chronic carrier state; most infant vaccinees have adequate levels of protective antibody at 18 months of age. This program is extremely significant in the control of hepatitis B virus infection in Taiwan.
Correlation of IgM anti-hepatitis D virus (HDV) to HDV RNA in sera of chronic HDV
Authors: Govindarajan Sugantha , Gupta Sanjeev , Valinluck Boontar , Redeker Allan G.
Published: March 2007

One hundred forty-four serum samples from 52 patients with chronic hepatitis D virus infection were analyzed for hepatitis D virus RNA by dot-blot hybridization using hepatitis D virus cDNA probe labeled with 32p. The results were correlated with the presence of serum IgM anti-hepatitis D virus and hepatitis D antigen in liver biopsy specimens when available. Although there was a trend of positive correlation between serum hepatitis D virus RNA and IgM anti-hepatitis D virus, no statistical significance could be found. In the serum samples with hepatitis D virus RNA, 32% were found to be negative for IgM anti-hepatitis D virus. Therefore, in chronic hepatitis D virus, absence of IgM anti-hepatitis D virus does not rule out active viral infection, as suggested by previous studies. There was a strong correlation between serum hepatitis D virus RNA and hepatic hepatitis D virus antigen. These data indicate that detection of hepatitis D virus RNA in serum samples is a reliable noninvasive marker of active viral infection.
Extrahepatic malignancy following long-term immunosuppressive therapy of severe hepatitis B surface antigen-negative chronic active hepatitis
Authors: Wang Kenneth K. , Czaja Albert J. , Beaver Sandra J. , Go Vay L. W.
Published: March 2007

To determine the frequency, predisposing factors and consequences of extrahepatic malignancy following long-term immunosuppressive therapy of severe HBsAg-negative chronic active hepatitis, 149 patients who had received prednisone (20 mg daily) or prednisone (10 mg daily) in combination with azathioprine (50 mg daily) for at least 6 months were evaluated systematically for 109 ± 5 months (range: 7 to 223 months). Seven neoplasms involving cervix (2), lymphatic tissue (1), breast (1), bladder (1), soft tissue (1) and unknown site (1) developed in seven patients after 116 ± 23 months (range: 18 to 164 months). The incidence of extrahepatic neoplasm was 1 per 194 patient-years of surveillance, and the probability of tumor occurrence was 3% after 10 years. Tumor frequency was similar in men and women and the risk was 1.4-fold greater than that in an age-and sex-matched normal population (95% confidence interval, 0.6- to 2.9-fold normal). Patients with extrahepatic malignancy were not distinguished by age, sex, treatment regimen, cumulative duration of treatment (42 ± 9 vs. 60 ± 4 months, p = 0.7) or individual features of the liver disease. Five of the seven patients survived during 48 ± 25 months of follow-up, including two patients who have lived for at least 5 years after the diagnosis of malignancy. We conclude that extrahepatic malignancy develops infrequently during long-term immunosuppressive therapy. Its occurrence is not related to the type or duration of treatment, and long-term survival after tumor detection is possible. The low but probably increased risk of extrahepatic neoplasm does not militate against the use of immunosuppressive therapy in these patients.
Effect of ursodeoxycholic acid on bile acid metabolism in primary biliary cirrhosis
Authors: Batta Ashok K. , Salen Gerald , Arora Renu , Shefer Sarah , Tint Stephen G. , Abroon John , Eskreis David , Katz Seymour
Published: March 2007

We have compared the effect of ursodeoxycholic acid with placebo on the clinical state, blood liver chemistries and serum and urinary bile acids in four patients with primary biliary cirrhosis. All parameters were evaluated monthly, and bile acid composition was measured by capillary gas-liquid chromatography. At the time of admission, all patients showed intense pruritus, and their serum alkaline phosphatase, AST and ALT levels were elevated 4.3, 2.7 and 2.3 times over control values. Serum bile acids were elevated almost 38-fold with 2.5 times more cholic acid than chenodeoxycholic acid. Urinary bile acid output was elevated 28 times the control values, and 36% were 1β-hydroxycholic acid, 1β-hydroxydeoxycholic acid and hyocholic acid (3α,6α,7α-trihydroxy-5β-cholanoic acid). Three months of placebo administration did not significantly affect the clinical or biochemical presentations, and the serum and urinary bile acid composition did not change. In contrast, ursodeoxycholic acid feeding (12 to 15 mg per kg per day) for 6 months abolished pruritus in two and lessened itching in two subjects and reduced serum alkaline phosphatase, AST and ALT levels by 21, 35 and 47%, respectively. The mean values for the total serum bile acid concentrations in these patients declined 26% from the pretreatment value, but the proportion of ursodeoxycholic acid increased from 3 to 40% of the total bile acids; thus, total fasting serum endogenous bile acid levels decreased almost 50%. Similar changes were noted in the urinary bile acids, in which ursodeoxycholic acid became the major bile acid, and approximately 18% were hydroxylated at C-1, C-6 and C-21. These results demonstrate that, compared with placebo, ursodeoxycholic acid significantly lowers serum and urinary bile acids in primary biliary cirrhosis and produces considerable clinical and biochemical improvement.
Primary sclerosing cholangitis: Natural history, prognostic factors and survival analysis
Authors: Wiesner Russell H. , Grambsch Patricia M. , Dickson Rolland E. , Ludwig Jurgen , Maccarty Robert L. , Hunter Ellen B. , Fleming Thomas R. , Fisher Lloyd D. , Beaver Sandra J. , Larusso Nicholas F.
Published: March 2007

The natural history of primary sclerosing cholangitis was assessed in 174 patients; 37 were asymptomatic and 137 had symptoms related to underlying liver disease. At the time of diagnosis, the mean age was 39.9 years, 66% of the primary sclerosing cholangitis patients were male and 71% had associated inflammatory bowel disease, most commonly chronic ulcerative colitis. Longterm follow-up (mean: 6.0 years; range: 2.7 to 15.5 years) was available in all patients. During follow-up, 59 (34%) of the patients died: 55 in the symptomatic group and four in the asymptomatic group. Median survival from the time of diagnosis of primary sclerosing cholangitis at the Mayo Clinic was 11.9 years. Survival in the asymptomatic group was significantly decreased compared with that in a control population matched for age, race and sex. Multivariate analysis (Cox proportional hazards regression modeling) revealed that age, serum bilirubin concentration, blood hemoglobin concentration, presence or absence of inflammatory bowel disease and histologic stage on liver biopsy were independent predictors of high risk of dying.

The development of a multivariate statistical survival model is a major step in identifying individual primary sclerosing cholangitis patients at low, moderate and high risk of dying. Such models will be useful for stratifying patients in therapeutic trials, in patient counseling and in patient selection and timing of liver transplantation.
Hepatic denervation alters hemodynamic response to hemorrhage in conscious rats
Authors: Ozier Yves , Braillon Alain , Gaudin Christophe , Roulot Dominique , Hadengue Antoine , Lebrec Didier
Published: March 2007

We investigated the effect of liver denervation on cardiovascular homeostasis. Three days after surgical denervation of the liver, hemodynamic studies (radioactive microsphere method) were conducted in conscious rats. The efficacity of the liver denervation procedure was confirmed by a significant decrease in norepinephrine content in various lobes of the liver. Liver denervation did not affect either systemic or splanchnic resting hemodynamics. However, hemorrhage (2 ml per 100 gm body weight) induced a decrease in cardiac index which was significantly more marked in rats with liver denervation (-62 ± 3%) than in sham-operated rats (-47 ± 5%; p < 0.05). This more severe response to hemorrhage may be due to a lack of portal territory vasoconstriction since the fraction of cardiac output reaching portal territory did not decrease during hemorrhage in rats with liver denervation (16 ± 1 % to 14 ± 1%) but significantly decreased in sham-operated rats (from 15 ± 1 % to 11 ± 1 %, p < 0.05), this value being significantly lower, after hemorrhage, in sham-operated rats than in denervated rats. The results confirm the lack of tonic neural influence on hepatic circulation during physiological experimental conditions and indicate that hepatic nerve function has a significant contribution to the overall cardiovascular homeostasis.
Diverticular Bile Duct Lesion in Chronic Active Hepatitis
Authors: Vyberg Mogens
Published: March 2007

Liver needle biopsies from patients with non–A, non–B chronic active hepatitis and so–called abnormal bile duct epithelium were studied with a three–dimensional method. Photographs of bile duct structures in serial sections were transferred to acrylic plates. Five bile duct lesions of a not previously described diverticular type were revealed. The diverticuli were of varying shape with a diameter of 30 to 110 μ and a length of 75 to 150μm budding from small (12 to 25μm), slightly ectatic bile ducts. The diverticular epithelium was disordered. Some cells appeared as bile duct cells, but most were larger, with rounded nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, sometimes with periodic acid–Schiff–positive, diastase–resistant granules. The lesions were only partly surrounded by a basement membrane. They were all embedded in a tight mononuclear inflammatory infiltrate associated with pronounced periportal piecemeal necrosis. In two cases, a germinal center was adjacent to the epithelium.

The pathogenesis of the diverticular bile duct lesion is unknown, but the diverticuli probably represent Hering ducts and groups of periportal liver cells which have escaped the piecemeal necrosis.
Orthotopic Liver Transplantation and the Cytosolic Estrogen–Androgen Receptor Status of the Liver: the Influence of the Sex of the Donor
Authors: Kahn Delawir , Zeng Qihua , Makowka Leonard , Murase Noriko , Nakajima Yasuaki , Eagon Patricia K. , Francavilla Antonio , Starzl Thomas E. , van Thiel David H.
Published: March 2007

Mammalian liver is known to contain cytosolic receptors for both estrogens and androgens. Furthermore, certain mammalian hepatic functions are known to display a sexual dimorphism. However, in clinical liver transplantation, the sex of the donor is not taken into consideration in selection of the donor. In this study, the effect of liver transplantation on the estrogen and androgen receptor content of the liver was determined.

Adult male and female rats were subjected to orthotopic liver transplantation, using donors form both the same and the opposite sex as the recipient. The animals were killed on the tenth postoperative day, and the livers were assayed to determine their cytosolic estrogen and androgen receptor content.

Transplantation of a liver from a male donor into a male recipient, from a male donor into female recipient and from a female donor into a male recipient produced similar changes in the number of cytosolic estrogen and androgen receptors in hepatic cytosol. In all three situations, the estrogen receptor content in the cytosol of the transplanted liver was the same as that found in an unoperated male liver, and the cytosolic content of the androgen receptor was the same as that of an unoperated female liver. After transplantation of the liver from a female donor into a female recipient, the estrogen and androgen receptor content in the cytosol of the transplanted liver was the same as that of an unoperated female. A consistent finding in this study was a reduction in the cytosolic androgen receptor activity of the transplanted liver when a male was either the recipient or donor. This reduction was maximal at 10 days posttransplantation. At 40 days following transplantation, a partial recovery in the androgen receptor acitivy of hepatic cytosol had occurred. These studies demonstrate that orthotopic liver transplantation changes the cytosolic content of both the estrogen and androgen receptors of the liver, and their ratios may have important effects during the immediate postoperative period and profound long–term consequences relative to gender differences in hepatic function.