bluuebunny/crossref_metadata_2025 huggingface dataset:
The Liver in the Acquired Immunodeficiency Syndrome: A Clinical and Histologic Study
Authors: Lebovics Edward , Thung Swan N. , Schaffner Fenton , Radensky Paul W.
Published: March 2007

We reviewed the clinical data and hepatic histologic findings of 25 patients with the acquired immunodeficiency syndrome who underwent 29 liver biopsies. Our experience indicates that the only hepatic feature characteristic of acquired immunodeficiency syndrome is serologic evidence of exposure to the hepatitis B virus. The most common histologic finding was macrovesicular steatosis. Granulomas appeared in seven patients and were due to mycobacterial disease (3 patients), histoplasmosis (1 patient), adverse reaction to sulfonamide (2 patients) and unknown causes (1 patient). The clinical indication for liver biopsy was not significantly different in the patients without or with granulomas or with granulomas secondary to mycobacteria or fungi. Mycobacteria were cultured from all histologically positive specimens and one histologically negative specimen. Liver biopsy should be performed in any patient with acquired immunodeficiency syndrome who has unexplained fever, hepatomegaly or abnormal results of serum biochemical liver tests, and all specimens should be stained and cultured for mycobacteria and fungi.
Effects of Phenobarbital on Bilirubin Metabolism and Its Response to Phototherapy in the Jaundiced Gunn Rat
Authors: Cohen Arnold N. , Kapitulnik Jaime , Ostrow Donald J. , Zenone Eugene A. , Cochrane Cecile , Celic Lillian , Cheney Heidemarie
Published: March 2007

Jaundiced Gunn rats, treated with phenobarbital (60 mg per kg i.p. for 7 to 10 days) showed 25 and 36% decreases in mean plasma bilirubin levels in two experiments (p < 0.01). Kinetic studies with tracer 14C–bilirubin revealed that there was no change in bilirubin turnover or total pool size due to phenobarbital, but a 49% increase in the hepatic pool and a 27% decrease in the cutaneous pool of bilirubin. The increase in the hepatic pool accounted for over 90% of the bilirubin lost from the plasma. Such pretreatment with phenobarbital did not alter the decline in plasma bilirubin or total bilirubin pool due to subsequent phototherapy. Phenobarbital followed by phototherapy produced a significantly greater reduction in plasma bilirubin levels than either treatment alone. These studies demonstrate that phenobarbital does decrease plasma bilirubin in Gunn rats primarily by shifting the pigment to the liver, and suggests that combined treatment with phenobarbital and phototherapy might be of value in patients with congenital hyperbilirubinemia due to glucuronyl transferase deficiency.
Plasma Clearance of Intravenously Injected Aspartate Aminotransferase Isozymes: Evidence for Preferential Uptake by Sinusoidal Liver Cells
Authors: Kamimoto Yukio , Horiuchi Seikoh , Tanase Sumio , Morino Yoshimasa
Published: March 2007

Both cytosolic (c–AAT) and mitochondrial (m–AAT) isozymes of aspartate aminotransferase (EC 2.6.1.1) appear in serum in some diseases including hepatobiliary dysfunction. The present study aimed at elucidation of the mechanism by which AAT isozymes are cleared from blood. Intravenous injection into rats of m–AAT and c–AAT purified from rat liver exhibited a biphasic clearance curve with an overall half–life of 42 min and 4.7 hr, respectively. The tissue distribution of the radioactivity following intravenous administration of 125I–labeled isozymes revealed that the liver is a major organ involved in plasma clearance of these isozymes. This conclusion was also supported by the significant retardation in plasma clearance of m–AAT in hepatectomized as well as CCI4–intoxicated rats. Furthermore, clearance rate of each AAT isozyme in an isolated perfused liver exhibited a single exponential process with the uptake rate for m–AAT being much faster than that for c–AAT.

Separation of hepatocytes and sinusoidal liver cells from the rat intravenously injected with 125I–labeled AAT isozymes revealed that sinusoidal cells were responsible for the plasma clearances. In vitro uptake study showed that both isozymes were exclusively taken up by sinusoidal liver cells. The uptake rate for m–AAT was considerably greater than that for c–AAT. Endocytotic index for uptake by sinusoidal cells was 16 times with c–AAT and 34 times with m–AAT as compared with that for inulin or dextran which are taken up by fluid–phase endocytosis, suggesting involvement of adsorptive endocytosis in the uptake of the isozymes.
Evidence for A Channel for the Electrogenic Transport of Chloride Ion in the Rat Hepatocyte
Authors: Bear Christine E. , Petrunka Connie N. , Strasberg Steven M.
Published: March 2007

Chloride is the major inorganic anion in bile but its mechanism of passage from blood to bile is uncertain. Specific membrane channels account for most net inorganic anion flux in other cell types such as the proximal tubular cell and red blood cell; disulfonic stilbenes inhibit anion movement through these channels. Therefore, we have sought the presence of similar channels in the hepatocyte. Net inorganic anion flux or conductance was initiated in isolated rat hepatocytes by valinomycin in the presence of an outward potassium gradient. Potassium concentration in the extracellular medium increased from 2.75 ± 0.02 in control cell suspensions to 3.15 ± 0.04 in valinomycin–treated cell suspensions. Membrane potential difference (Em) (mV), determined as the distribution of [14C]tetraphenyl phosphonium ion was -28 mV in control cells and -42 mV in valinomycin–treated cells (p < 0.05). Intracellular chloride concentration (36Cl-) (mEq per liter of cell water) decreased significantly from 38.6 in control cells to 32.0 in valinomycin–treated cells. The observed intracellular concentration (36Cl-) in both control and valinomycin–treated cell suspensions closely approximates values predicted on the basis of the Nernst equation: 41 and 29 (mEq per liter of cell water), respectively, suggesting that the chloride ion is passively distributed on the basis of the membrane potential difference. Furthermore, net rate–limited cell water loss of approximately 15% of control values was associated with the above valinomycin–stimulated changes in ion distribution, as assessed using three methods of cell water volume determination. 4,4′–Diisothiocyanostilbene–2,2′–disulfonate (DIDS), a specific inorganic anion channel blocker, inhibited the valinomycin–induced changes in chloride ion distribution; DIDS (0.8 mM–treated cells contained 45.2 ± 4.4 mEq per liter (36Cl-) following hyperpolarization with valinomycin whereas untreated cells contained 33.3 ± 4.8 mEq per liter of cell water after valinomycin treatment (p < 0.05). Preincubation with DIDS (0.8 mM) also significantly suppressed valinomycin–induced changes in external K+ concentration and cell water volume. These observations are consistent with the hypothesis that a channel exists for the electrogenic transport of chloride ion in isolated rat hepatocytes.
The Immunologic Diagnosis of Chronic Active “Autoimmune” Hepatitis: Distinction From Systemic Lupus Erythematosus
Authors: Gurian Lawrence E. , Rogoff Thomas M. , Ware Athol J. , Jordan Robert E. , Combes Burton , Gilliam James N.
Published: March 2007

We have evaluated the immunologic characteristics often associated with systemic lupus erythematosus in a series of patients with a variety of different liver diseases. Antibody to doublestranded DNA as measured by the Farr assay was detected frequently in patients with various forms of liver disease. No patient with liver disease, including those with a presumed immunologic etiology, was found to have antibody to double–stranded DNA using more specific assays. Other immunologic phenomena such as the presence of immunofluorescent staining at the dermalepidermal junction in the lupus band test, circulating immune complexes and the presence of antinuclear antibody were present in a number of patients with different forms of liver disease. The absence of antibody to double–stranded DNA in patients with liver disease suggests that there may be a true immunologic distinction between systemic lupus erythematosus and chronic active (“lupoid”) hepatitis.
Presinusoidal Portal Hypertension in Non–Alcoholic Cirrhosis
Authors: Pomier-Layrargues Gilles , Kusielewicz Daniel , Willems Bernard , Villeneuve Jean-Pierre , Marleau Denis , Côté Jean , Huet P.-Michel
Published: March 2007

The simultaneous measurement of wedged hepatic vein pressure (WHVP) and portal vein pressure (PVP) was performed in 156 cirrhotic patients. In the 110 alcoholic cirrhotic patients (97 micronodular and 13 macronodular cirrhosis), WHVP and PVP were closely related (25.8 ± 6.3 vs. 25.9 ± 6.3 mm Hg; p = not statistically significant). The difference between the two parameters was greater than 4 mm Hg in only six patients. In the 46 patients with nonalcoholic cirrhosis (41 macronodular and 1 micronodular cirrhosis; 4 primary biliary cirrhosis), PVP was significantly higher than was WHVP (25.8 ± 6.2 vs. 21.7 ± 6.8 mm Hg; p < 0.001); in 20 patients, PVP exceeded WHVP by more than 4 mm Hg, and the mean difference was 7.5 mm Hg. There was no correlation between the porto–hepatic gradient and total hepatic blood flow measured by the indocyanine green single injection method or the portal fraction of total hepatic blood flow measured by indicator dilution curves. It is concluded that: (i) measurement of WHVP in alcoholic cirrhosis provides a reliable estimate of the severity of the portal hypertension, and (ii) hemodynamic evaluation of nonalcoholic cirrhosis should include PVP measurement in order to avoid underestimation of the porto–hepatic gradient.
Transmission of Ground Squirrel Hepatitis Virus to Homologous and Heterologous Hosts
Authors: Trueba Daniel , Phelan Michael , Nelson John , Beck Fred , Pecha Brian S. , Brown James R. , Varmus Harold E. , Ganem Don
Published: March 2007

The infectivity and host range of ground squirrel hepatitis virus (GSHV) have been further examined by animal inoculation experiments. Although carrier squirrel sera usually harbor 109 to 1010 virions per ml as determined by physical measurements, titration of one such serum revealed that squirrel infectivity was lost following dilution of the sample over 106–fold. Infectivity is markedly reduced by NP40 pretreatment of infected serum. GSHV infection cannot be readily transmitted to several related ground squirrel species, but chipmunks can be experimentally infected by GSHV virions or by cloned GSHV DNA, and the resulting infection closely resembles that seen in the normal host.
Serum Type Iii Procollagen Peptide in Alcoholic Liver Disease and Idiopathic Hemochromatosis: Its Relationship to Hepatic Fibrosis, Activity of the Disease and Iron Overload
Authors: Colombo Massimo , Annoni Giorgio , Donato Maria Francesca , Conte Dario , Martines Dino , Zaramella Maria Grazia , Bianchi Paolo A. , Piperno Alberto , Tiribelli Claudio
Published: March 2007

To assess the value of type III procollagen peptide (sPIIIP) as a marker of hepatic fibrosis, sera from 73 patients with alcohol–related liver disease and 30 patients with idiopathic hemochromatosis (IHC) were studied by a specific radioimmunoassay. sPIIIP was increased in 87% of 30 patients with cirrhosis, in 16% of 32 with steatofibrosis but in none of 11 with steatosis.

There was a significant correlation with histologic hepatocellular necroinflammation (r = 0.42, p < 0.01), but not with hepatic fibrosis.

sPIIP was increased in 33% of 30 patients with IHC, whether or not they had cirrhosis or fibrosis, and whatever the level of iron overload or the extent of the hepatic deterioration. IHC patients with increased levels of sPIIIP had a higher prevalence of superimposed hepatic damage than did those with normal procollagen levels (p < 0.05).

Our findings, therefore, weaken the diagnostic value of sPIIIP as an index of connective tissue deposition in the liver, and suggest that, at least in alcohol–related liver disease and IHC, hepatocellular necroinflammation influences the results.
Increased Serum Antibody Levels Against Cow's Milk Proteins in Children With Chronic Liver Disease
Authors: Lerner Aaron , Park Byung H. , Rossi Thomas M. , Lebenthal Emanual
Published: March 2007

We measured IgG, IgM and IgA antibodies to cow's milk proteins: α–casein, α–lactalbumin, bovine serum albumin, β–lactoglobulin–a and β–lactoglobulin–b in the sera of 29 pediatric patients with liver disease. IgG antibodies to bovine serum albumin, β–lactoglobulin–a and β–lactoglobulin–b and IgA antibodies to α–casein were elevated in most of the patients compared to age–matched controls. We postulate that, in patients with liver disease either increased intestinal uptake resulting in increased humoral response, or decreased hepatic clearance of food antigens intensifying a humoral response to these foreign antigens, may occur.
Histopathological Lesions of the Liver in Hairy Cell Leukemia: A Report of 14 Cases
Authors: Roquet Marie-Laurence , Zafrani Elie-Serge , Farcet Jean-Pierre , Reyes Félix , Pinaudeau Yvon
Published: March 2007

Pathological lesions of the liver were studied in 14 cases of hairy cell leukemia, a rare hematologic neoplasm involving numerous organs. Tumor infiltration of hepatic parenchyma was observed in all cases. Tumor cells were easily recognized by their cytological features, namely their “halo” appearance consisting of a clear rim of abundant cytoplasm surrounding uniform round or slightly indented nuclei. Portal infiltration was observed in all cases, associated with sinusoidal infiltration in 12 cases. A peculiar change of the sinusoids, i.e., the angiomatous lesions, was noted in 9 of 14 patients. Angiomatous lesions consisted of intralobular cavities without zonal predominance which were lined by tumor cells which replaced the normal sinusoidal wall and were filled with red blood cells and tumor cells. This pattern of involvement is different from hepatic localization of other blood malignancies and is highly suggestive of hairy, cell leukemia. It might reflect the unique phenotype of the tumor cells, which express lymphocytic and monocytic features. The angiomatous lesion strongly mimics peliosis hepatis and could be, as well as in peliosis, the consequence of modification of the sinusoidal barrier. In hairy cell leukemia, sinusoidal wall abnormalities might be secondary to infiltration of the sinusoids by tumor cells.
Cellular Theories of Aging As Related to the Liver
Authors: Dice Fred J.
Published: March 2007

The age–associated decjline in function of several organs, including the liver, may be caused by mechanisms operating on the cellular level. Fibroblasts and several other cell types derived from normal individuals have limited lifespans in culture, and several abnormalities described for senescent cultured fibroblasts also apply to hepatocytes and other cell types obtained from aged organisms.

Cellular theories of aging can be divided into two broad and overlapping categories: (a) those that view cell death as an actively programmed developmental process, and (b) those that consider cellular aging to result from a passive accumulation of errors in macromolecules. These theories are not necessarily mutually exclusive, and many of the phenotypic changes in senescent hepatocytes, fibroblasts and other cells are compatible with several different theories. The challenge for the future is to distinguish primary causes from secondary consequences of cellular aging so that rational attempts to intervene in the aging process are possible.
Time Course and Mechanism of Alterations in Proton Relaxation During Liver Regeneration in the Rat
Authors: Sostman Dirk H. , Gore John C. , Flye Wayne M. , Johnson Allan G. , Herfkens Robert J.
Published: March 2007

We studied the proton T1 and T2, water and lipid content of regenerating rat liver from 1 to 7 days after 70% hepatectomy. Liver from normal and sham–operated animals and splenic tissue from all animals were studied as controls. In vivo proton spectroscopy and imaging of liver was performed in a separate group of control and posthepatectomy rats. The T2 of regenerating liver, but not of sham or normal control liver, was prolonged. Changes in T1, relative to normal tissue, were found in liver and spleen of both operated groups. Lipid content, assessed both by extraction of tissue samples and by in vivo spectroscopy, was increased in regenerating tissue but not in controls. Water content was similarly increased in regenerating liver tissue. Changes in water and lipid content appeared to contribute to the alterations in proton relaxation which we observed.
Choline Fails to Prevent Liver Fibrosis in Ethanol–Fed Baboons But Causes Toxicity
Authors: Lieber Charles S. , Leo Maria A. , Mak Ki M. , Decarli Leonore M. , Sato Shinkichi
Published: March 2007

To determine how choline supplementation affects the liver and whether it can protect against ethanol–induced liver injury, baboons were fed either normal or choline–supplemented diets, each with or without ethanol. Eighteen baboons were pair–fed for 3 to 4 years liquid diets with 50% of total energy as ethanol or isocaloric carbohydrate; ten animals were given our regular diets, whereas in eight the choline content was increased 5–fold. Six additional animals were fed individually with the control diets (with or without additional choline). With both ethanol–containing diets, ethanol intake was comparable and resulted in hepatic steatosis and striking mitochon–drial lesions, with increases in serum biliburin and SGOT, SGPT and glutamate dehydrogenase activities. In addition, of the five animals fed alcohol with the regular diet, one progressed to incomplete cirrhosis and two others developed perivenular and associated perisinusoidal fibrosis. Similarly, in the four baboons fed alcohol with choline supplementation, incomplete cirrhosis developed in one and perivenular fibrosis in two. Collagen deposition was demonstrated by immunoperoxidase with a specific antibody against procollagen Type III. These animals also displayed proliferation of myofibroblasts in the perivenular area and transformation of fat–storing cells to transitional cells in the perisinusoidal space, with associated enhanced collagen fiber deposition. Thus, in baboons, choline supplementation failed to prevent alcohol–induced steatosis and fibrosis. All parameters remained normal in the eight baboons fed the regular control diet. However, in the choline–supplemented controls, serum bilirubin, SGOT and glutamate dehydrogenase activities increased moderately and serum albumin decreased. Occasional fat droplets appeared in hepatocytes with mitochondrial changes (enlargement and alterations of the cristae) and an abundance of “myelin” figures in the cytoplasm, indicating that choline supplementation exerts moderate hepatotoxicity.
Hereditary Chronic Conjugated Hyperbilirubinemia in Mutant Rats Caused by Defective Hepatic Anion Transport
Authors: Jansen Peter L.M. , Peters Wilbert H. , Lamers Wouter H.
Published: March 2007

A mutant rat strain is described with autosomal recessive conjugated hyperbilirubinemia. Transport of conjugated bilirubin and tetrabromosulfophthalein from liver to bile is severely impaired whereas uptake of organic anions from plasma to liver is normal. During the first 10 days of life, serum bilirubin levels are 147 ± 11 μmoles per liter with 68.7% diconjugates and 27.9% monoconjugates. In adult rats, serum bilirubin is 33 ± 8 μmoles per liter with 81.8% diconjugates and 12.1% monoconjugates vs. 0.3 ± 0.1 μmole per liter unconjugated bilirubin in normal adult rats. Bile acid metabolism is only mildly affected. In young rats, serum bile acid levels are normal. In adult rats, bile acid levels are elevated to 49 ± 11 μmoles per liter vs. 10 ± 6 μmoles per liter in normal rats. The bile flow in mutant rats is reduced to about 50%. This might be caused by a reduction of the bile acid–independent bile fraction.

Liver marker enzyme activities in mutant rat serum are normal. Liver morphology is also normal. Total urinary coproporphyrin excretion is not elevated but urinary coproporphyrin isomer I excretion is increased, a pattern like that in Dubin–Johnson syndrome in humans. However, unlike Dubin–Johnson syndrome, the mutant rats do not have the characteristic black hepatic pigment. These rats provide a unique model to study mechanisms of bile formation and cholestasis.
Endoscopic Sclerosis and Esophageal Balloon Tamponade in Acute Hemorrhage From Esophagogastric Varices: A Prospective Controlled Randomized Trial
Authors: Paquet Karl-Joseph , Feussner Hubertus
Published: March 2007

A prospective randomized controlled clinical trial was performed in 43 consecutive histologically proved cirrhotic patients with endoscopically proved actively bleeding esophageal varices. Twenty–two were randomly selected to have esophageal tamponade with the Sengstaken–Blakemore tube, and 21 were selected to have endoscopic sclerosis of the esophageal wall.

The two groups were similar in demographic, clinical and laboratory data. Bleeding was controlled by the Sengstaken–Blakemore tube in 16 of 22 patients (73%) and by endoscopic sclerosis in 20 of 21 (95%). Among those controlled by the Sengstaken–Blakemore tube, seven (44%) rebled and three (43%) were again controlled by the Sengstaken–Blakemore tube; in the endoscopic sclerosis group, four (20%) rebled and three (75%) were controlled. Thus, hemorrhage was definitively controlled in 52% of patients and 66% of bleeding episodes in the Sengstaken–Blakemore tube group and in 90% of patients and 92% of bleeding episodes in the endoscopic sclerosis group. The definite control of hemorrhage was significantly better in the endoscopic sclerosis group (p < 0.01). The Sengstaken–Blakemore tube patients received no definitive therapy after bleeding had been controlled.

Within 30 days, six patients (27%) in the Sengstaken–Blakemore tube group had died compared to 2 (10%) in the endoscopic sclerosis group which is statistically significant (p < 0.01) in favor of endoscopic sclerosis. The frequency of complications was similar in the two groups. Endoscopic sclerosis patients received serial endoscopic sclerosis after bleeding had been stopped during the whole period of follow–up. After 6 months, 11 patients in the Sengstaken–Blakemore tube group had died (55%) compared to three patients (16%) in the endoscopic sclerosis group. Cumulative survival was statistically better in the endoscopic sclerosis group after 6 months (p < 0.01) and after 3 years of follow–up (p < 0.001). Survival was related to Child classification on admission. This investigation shows that endoscopic sclerosis is effective and superior to the Sengstaken–Blakemore tube in stopping active hemorrhage from esophageal varices and highly superior to the Sengstaken–Blakemore tube in reducing short– and long–term mortality.
A Prospective, Randomized Controlled Trial of Chronic Esophageal Variceal Sclerotherapy
Authors: Korula Jacob , Balart Luis A. , Radvan George , Zweiban Bruce E. , Larson Alan W. , Kao Henry W. , Yamada Suyenori
Published: March 2007

The results of a prospective, randomized controlled trial of chronic esophageal variceal sclero–therapy conducted over a 38–month period are presented. One–hundred twenty patients were randomized following variceal bleeding, 63 to esophageal variceal sclerotherapy and 57 to control. Mean follow–up was similar in both groups (esophageal variceal sclerotherapy, 12.5 ± 8.8 months; control, 14.9 ± 6.6 months). Twenty–one percent of the patients in each group were lost to follow–up. Esophageal variceal sclerotherapy decreased rebleeding as evidenced by a decrease in the mean bleeding risk factor, transfusion requirement and by an increase in bleeding free interval; differences between the treated and control groups in these parameters were especially significant after variceal obliteration. A high incidence of asymptomatic ulceration and low frequency of strictures were notable effects of esophageal variceal sclerotherapy. Cumulative life table analysis revealed no differences in survival between esophageal variceal sclerotherapy and control groups. However, when patients who received portal–systemic shunt surgery (esophageal variceal sclerotherapy, 6%; control, 28%) were removed from the analysis at the time the shunt surgery was performed (defining the shunt as an endpoint, a significant difference in survival (p < 0.05, F ratios) in favor of esophageal variceal sclerotherapy was observed.
A Carrier–Protein Receptor Is Not A Prerequisite for Avid Hepatic Elimination of Highly Bound Compounds: A Study of Propranolol Elimination by the Isolated Perfused Rat Liver
Authors: Jones Brian D. , Ching Michael S. , Smallwood Richard A. , Morgan Denis J.
Published: March 2007

The highly efficient hepatic extraction of propranolol by the isolated perfused rat liver does not diminish when albumin binding is increased from 30 to 75%. One possible explanation of this insensitivity of propranolol uptake to changes in albumin binding is the mediation of uptake of bound ligand by an albumin receptor on the hepatocyte as postulated for oleate, taurocholic acid and rose bengal. To test this hypothesis, the hepatic extraction of propranolol was studied in the isolated perfused rat liver using α1–acid glycoprotein, which lacks a hepatocyte receptor, as the carrier protein in the perfusate rather than albumin. Livers were perfused with a medium containing propranolol (4 μM) and varying concentrations of α1–acid glycoprotein (0 to 25 μM). Hepatic extraction of propranolol was very high (0.990 ± 0.006; mean ± S.D.) and did not alter significantly despite an increase in bound fraction from 0.2 to 0.8, thus closely paralleling the findings when albumin is the carrier protein. This result indicates that bound propranolol is efficiently cleared by the liver, presumably by a “free intermediate” mechanism, in the absence of a specific carrier–protein receptor on the hepatocyte. This study does not, therefore, support the albumin receptor hypothesis.
Increased Serum Levels of Hyaluronate in Liver Disease
Authors: Engström-Laurent Anna , Lööf Lars , Nyberg Anders , Schröder Torbjörn
Published: March 2007

Recent animal studies show that endothelial cells in liver sinusoids are the main site for removal of sodium hyaluronate from the circulation. Few data with respect to hyaluronate metabolism are available in man. Serum hyaluronate levels were measured in 119 patients with liver disease by a sensitive assay. The hyaluronate level was significantly increased in liver cirrhosis, in comparison with healthy controls and with patients with noncirrhotic liver disease. The results suggest a role for the human liver in elimination of hyaluronate from circulation. Quantification of serum hyaluronate may be a useful test of liver endothelial cell function.
The Intrahepatic Biliary Epithelium in the Guinea Pig: Is Hepatic Artery Blood Flow Essential in Maintaining Its Function and Structure?
Authors: Tavoloni Nicola , Schaffner Fenton
Published: March 2007

To determine whether hepatic artery blood flow is essential in maintaining the function and structure of bile ductules/ducts, the acute effects of hepatic artery ligation on bile secretion and hepatic ultrastructure were examined in anesthetized, bile duct–cannulated guinea pigs. Sixty minutes after hepatic artery ligation, spontaneous bile flow (5.08 + 0.4 μl per min per gm liver) was virtually the same as that before hepatic artery ligation (5.31 + 0.3 μl per min per gm), as were the choleretic effects of 10 CU per kg per 30 min secretin (7.14 + 0.9 vs. 7.21 + 0.9 μl per min per gm), 300 μg per kg per 30 min glucagon (6.72 + 0.9 vs. 6.59 + 0.8 μl per min per gm) and 60 μmoles per kg per 30 min glycochenodeoxycholate (6.43 + 0.6 vs. 6.45 + 0.6 μl per min per gm). The failure of hepatic artery ligation to affect bile secretory function could not be attributed to the existence of collateral arterial blood flow to the liver. First of all, hepatic artery ligation resulted in diminishing significantly hepatic venous, but not portal, oxygen content. More importantly, in isolated guinea pig livers, perfused through the portal vein alone, secretin, glucagon and glycochenodeoxycholate produced changes in bile flow and composition similar to those seen in vivo. Electron microscopy showed no major ultrastructural changes of hepatic parenchyma and biliary epithelium 2 hr after hepatic artery ligation, or 2 hr after perfusing the liver through the portal vein alone save for some portal edema in the latter instance. Failure to perfuse the hepatic artery resulted in dilatation of periportal bile canaliculi, but no evidence of anoxia was observed. These studies indicate that, in the guinea pig, the intrahepatic biliary epithelium receives oxygen in absence of hepatic artery perfusion. Thus, manipulation of hepatic vascular anatomy is not useful for separating canalicular from ductular function.
Changes of Hepatitis B Virus Dna in Liver and Serum Caused by Recombinant Leukocyte Interferon Treatment: Analysis of Intrahepatic Replicative Hepatitis B Virus Dna
Authors: Yokosuka Osamu , Omata Masao , Imazeki Fumio , Okuda Kunio , Summers Jesse
Published: March 2007

Twenty patients with HBeAg–positive chronic liver disease were given large doses of recombinant leukocyte interferon for 4 weeks. Changes of hepatitis B virus DNA in livers and sera were analyzed by the molecular hybridization technique in paired biopsies obtained before and 2 weeks after treatment. Serum hepatitis B virus DNA was examined before, during and after the treatment until 4 weeks post–interferon.

Analysis of hepatic hepatitis B virus DNA revealed species that appeared to represent various forms of replicative hepatitis B virus DNA, i.e., relaxed circular, linear, supercoiled and single–stranded hepatitis B virus DNA, respectively. No evidence of integration of hepatitis B virus DNA in genomic DNA was obtained. Of 15 cases which were positive for hepatic hepatitis B virus DNA before treatment and in which paired biopsies were obtained, hepatic hepatitis B virus DNA became negative in 4, decreased in 5 and unchanged in 6. Among several types of replicative viral DNA in liver tissue, supercoiled hepatitis B virus DNA tended to remain after other forms were reduced.

A close correlation between hepatic and serum hepatitis B virus DNA was found in 37 liver biopsy samples and corresponding sera.

These results indicate that interferon treatment reduces serum hepatitis B virus levels by inhibiting viral replication in the liver and that persistence or reappearance of hepatitis B virus in serum after interferon is associated with replication.
Regulation of the Human Immune Response to Hbsag: Effects of Antibodies and Antigen Conformation in the Stimulation of Helper T Cells by Hbsag
Authors: Celis Esteban , Kato Ikunoshin , Miller Richard W. , Chang Tse Wen
Published: March 2007

The role of accessory cells (antigen–presenting cells) in binding HBsAg in the response of human T cells to this antigen was studied. Antibodies to HBsAg of IgG class increased significantly the amount of HBsAg that was captured and internalized by accessory cells in vitro. On the other hand, antibodies to HBsAg of IgM class or the F(ab–)2 and Fab fragments of antibodies to HBsAg of IgG class did not modify the amount of HBsAg associated to these cells. HBsAg that was subjected to various denaturing treatments (acid, organic solvents, urea and heat) was compared for its capacity to react with antibody to HBsAg and stimulate the response of helper T lymphocytes. Results presented here indicate that HBsAg denatured by treatment with formic acid was captured by accessory cells and presented to the T cells much more efficiently than the native HBsAg. These results suggest that the response of helper T lymphocytes to some antigens such as HBsAg can be affected greatly by the presence of antibodies or the antigens– conformation.
Naturally Occurring Serum Antiidiotypic Antibody Against Antiliver–Specific Membrane Lipoprotein in Patients With Hepatitis
Authors: Tsubouchi Akinori , Yoshioka Kentaro , Kakumu Shinichi
Published: March 2007

Studies were undertaken to evaluate whether antiidiotypic antibody against antiliver–specific membrane lipoprotein is related to the disease activity of patients with hepatitis. Sera from normal individuals, patients with viral hepatitis and medical staffs were depleted of antiliver–specific membrane lipoprotein antibody by absorbing with liver–specific membrane lipoprotein–bearing cell line SK–Hep–1. Anti–antiliver–specific membrane lipoprotein was detected by binding activity to antihuman liver–specific membrane lipoprotein monoclonal antibody using solid–phase radioimmunoassay and by inhibitory activity for binding of antiliver–specific membrane lipoprotein monoclonal antibody to SK–Hep–1 using competitive radioimmunoassay. The results obtained by the two assays were equivalent for detecting anti–antiliver–specific membrane lipoprotein. Sera from patients with acute viral hepatitis during recovery phase (n = 6) and chronic persistent hepatitis (n = 12), respectively, showed significantly increased anti–antiliver–specific membrane lipoprotein activity (p < 0.01) when compared to those from normal individuals (n = 10), whereas sera from patients with chronic active liver disease (n = 12) did not reveal significantly different values from controls. Sera from the medical staff (n = 11) who had contact with hepatitis patients also demonstrated increased anti–antiliver–specific membrane lipoprotein activity (p < 0.05). Inhibitory activity of anti–antiliver–specific membrane lipoprotein in the serum appeared localized within the F(ab–)2 fragments of immunoglobulin G fraction by competitive radioimmunoassay. The specificity of the inhibitory activity of the serum was confirmed by its inability to block unrelated antigen–antibody reactions. These findings suggest that the presence of antibody against antiliver–specific membrane lipoproteins is related to the disease activity in certain patients with hepatitis.
Cell–Mediated Cytotoxicity of Sensitized Spleen Cells Against Target Liver Cells— In Vivo And In Vitro Study With A Mouse Model of Experimental Autoimmune Hepatitis
Authors: Mori Teruo , Mori Yoshio , Yoshida Hiromichi , Ueda Shiro , Ogawa Makoto , Iesato Kenji , Wakashin Yoko , Wakashin Masafumi , Okuda Kunio
Published: March 2007

Spleen cells obtained from C57BL/6 (B6) mice with an experimental autoimmune hepatitis were transferred to normal C57BL/6 recipient mice. Most prominent liver damages occurred in the recipient mice injected with sensitized nylon wool column–adherent spleen cells from the donor mice. Production of such liver damage was blocked by treatment of the sensitized adherent spleen cells with anti–Thy 1,2 monoclonal antibody and complement before injection. Based on these in vivo results, a microcytotoxicity assay was performed using isolated C57BL/6 hepatocytes as target cells and sensitized spleen cells obtained from hepatitis donor mice as effector cells. The fraction of sensitized nylon wool–adherent spleen cells demonstrated a high cytotoxic activity against isolated syngeneic hepatocytes, although the other fractions and spleen cells of control animals showed no such effect. The cytotoxic activity of sensitized–adherent spleen cells against target hepatocytes was significantly reduced after treatment with anti–Thy 1,2 antibody and complement, but it increased after depletion of B cells and Fc receptor–bearing T–cells. Although these sensitized nylon wool–adherent spleen cells showed high cytotoxic activities against syngeneic hepatocytes, their cytotoxicity against allogeneic hepatocytes was lower. They exerted no cytotoxic activity against syngeneic renal glomerular cells and EL–4 thymoma cells. These results suggest that sensitized T–cells in the nylon wool column–adherent fraction play the role of cytotoxic killer cells against target liver cells in vitro.
Analysis of Dna Polymerase Reaction Products for Detecting Hepatitis B Virus in Serum—Comparison With Spot Hybridization Technique
Authors: Imazeki Fumio , Omata Masao , Yokosuka Osamu , Matsuyama Yasuhisa , Ito Yoshimi , Okuda Kunio
Published: March 2007

An assay for DNA polymerase reaction products using slab gel electrophoresis and autoradiography was compared with the spot hybridization technique for the detection of hepatitis B virus DNA in 317 blood samples. The former could identify the nature and size of DNA on electrophoresis, and reduce potentially false–positive results due to artifacts.

Discordant results between the two methods occurred in 36 of 317 samples; 22 were positive by the spot technique alone, and 14 were positive by the analysis of DNA polymerase reaction products alone. However, the samples positive with the spot test alone showed weak radioactive signals on electrophoresis/autoradiography that were often interpreted as “inconclusive” by blind observations.

Correlation of hepatitis B e antigen/antibody with hepatitis B virus DNA was studied in 91 patients with various chronic liver diseases. Discordant results, i.e., presence of the DNA in antibody positive sera, or its absence in the antigen positive sera, were obtained in 15 (19%) cases. Such patients tended to have advanced liver disease with fluctuating serum aminotransferase levels.

Analysis of DNA polymerase reaction products by slab gel electrophoresis and autoradiography is not only sensitive, but is also as specific as the Southern blot technique in the detection of hepatitis B virus DNA in serum, and may prove useful in selected samples, especially where no cloned hepatitis B virus DNA is available, or in search of new hepatitis B virus–like viruses.
Reduced Transport of Bilirubin and Asialoorosomucoid in Regenerating Rat Liver Is A Microtubule–Independent Event
Authors: Stollman Yacov R. , Theilmann Lorenz , Stockert Richard J. , Wolkoff Allan W.
Published: March 2007

In previous studies, we found that uptake of bilirubin and asialoorosomucoid is depressed in regenerating rat liver. To determine what role the hepatic cytoskeleton plays in this modulation of uptake, animals were treated with colchicine, an inhibitor of microtubular polymerization. Normal unoperated rats or rats following two–thirds hepatectomy or sham surgery were injected with colchicine, lumicolchicine (50 μg per 100 gm of body weight, i.p.) or normal saline. Lumicolchicine, an analog of colchicine, has no effect on microtubules and was used as a control. At 12 hr after surgery, sham–operated and unoperated animals received a second equal dose. Partially hepatectomized animals received one–third the initial dose. At 24 hr after surgery, livers were perfused in situ and single–pass multiple indicator dilution studies were performed. Colchicine as compared to lumicolchicine pretreatment reduced apparent influx of bilirubin and asialoorosomucoid in regenerating liver by 50% but had no effect in liver from normal or sham–operated rats. Analysis of indicator dilution curves revealed that reduced influx in colchicine–treated liver was attributable to an increased vascular volume of distribution. These results suggest that microtubules may play a role in maintenance of normal hepatic vascular architecture during regeneration. Lack of effect of colchicine on modulation of bilirubin and asialoorosomucoid uptake during regeneration suggests that other, as yet unknown, factors result in down–regulation of the specific hepatocellular transport systems for these two ligands.
Sequestered Tracer Outflow Recovery in Multiple Indicator Dilution Experiments
Authors: Goresky Carl A. , Bach Glen G. , Wolkoff Allan W. , Rose Colin P. , Cousineau Daniel
Published: March 2007

The rapid, single injection, multiple indicator dilution technique has been, with suitable modeling of hepatic venous outflow curves, the standard approach for quantitative kinetic assessment of tracer cell entry and intracellular sequestration in the steady state, both in the in situ and the isolated perfused liver. Analysis of the underlying system yields, for a substance sequestered within liver cells, identical theoretical expressions for expected cumulative tracer fractional recovery and the steady–state fractional outflow recovery of the bulk substance whose behavior is being traced. Luxon and Forker (Am. J. Physiol. 1982; 243:G76-G89) pointed out that experimental cumulative tracer fractional recovery must match the value predicted by use of fitted model parameters in the theoretical recovery expression, and that this agreement must be regarded as the hallmark of successful fitting and modeling. Their attempts to demonstrate this agreement, by use of previously published data, were unsuccessful; this led them to question whether previous model analyses were valid. To reexamine the question we, therefore, analyzed three sets of data, on bilirubin, free fatty acid and galactose uptake, including those they had previously analyzed. We found excellent agreement between experimentally determined cumulative tracer recovery and theoretically predicted recovery. The theoretical recovery expression, now validated experimentally, provides a direct way of using fitted parameters for the rapid calculation of outflow recovery, which should prove generally useful in this area of kinetics. Demonstration of the expected agreement, moreover, restores confidence in the self–consistency of procedures used in the past to analyze multiple indicator dilution data.
Hepatocellular Carcinoma in Young, Mentally Retarded Hbsag Carriers Without Cirrhosis
Authors: Lohiya Ghanshyam , Pirkle Hubert , Hoefs John , Lohiya Sunita , Ngo Vinh Trong
Published: March 2007

In a Californian institution for the mentally retarded, surveillance by autopsy of all deaths (n = 138) identified three cases of hepatocellular carcinoma. Hepatocellular carcinoma cases occurred in young (mean age = 26 years) male carriers of HBsAg and were not associated with cirrhosis. They were of the nonfibrolamellar oncocytic type and were rapidly fatal. Hepatocellular carcinoma incidence in HBsAg carriers was estimated to be 246 times greater than United States males.
Transferrin and Its Receptor: Their Roles in Cell Function
Authors: Bomford Adrian B. , Munro Hamish N.
Published: March 2007

Transferrin, its receptor and the entry of iron into the cell have sprung into prominence because of recent evidence that proliferation of various cell types involves regulation of this sequence of events, as evidenced especially by changes in receptor number. A third component functionally linked to transferrin and its receptor is the intracellular iron–storage protein, ferritin, which ensures against toxic levels of free ferrous iron, which might otherwise cause peroxidative damage to cell membranes and other cell structures (1). In this article, we shall focus on interactions between these three proteins of iron exchange, their roles in homeostasis and especially their role in relation to the liver which is a major organ of iron storage.
Ultrastructural Immunocytochemical Demonstration of Hla Class I Antigens in Human Pathological Liver Tissue
Authors: De Vos Rita , De Wolf-Peeters Chris , Den Van Oord Joost J. , Desmet Valeer
Published: March 2007

Major histocompatibility complex products Class I (HLA Class I) antigens are not expressed on the surface of normal human hepatocytes but become so in pathological conditions. The purpose of this study was to specify the ultrastructural topography of HLA Class I antigens expression.

Nine human liver specimens, known from light microscopic investigation to display membranous positivity for HLA Class I antigens, were processed for immunoelectronmicroscopy using monoclonal anti–HLA Class I in an indirect immunoperoxidase procedure.

HLA Class I antigens were detected on the basolateral membrane of hepatocytes and bile duct cells; some cisternae of the endoplasmic reticulum were also positive. The membranes of normal bile canaliculi of hepatocytes and the apical border of bile duct cells were negative. In one case of presumably drug–induced cholestasis, abnormal cholestatic canaliculi displayed HLA Class I antigens.

These results indicate that HLA Class I antigens are synthesized by the hepatocytes and bile duct cells and incorporated into the plasma membrane; the basolateral expression follows the pattern as in other polarized cells. The expression in cholestatic canaliculi suggests a disturbed polarity of the hepatocyte.
Electron Microscopy of Rejected Human Liver Allografts
Authors: Fennell Robert H. , Vierling John M.
Published: March 2007

Recognition by biopsy of liver allograft rejection has been less successful than diagnosis of rejection of cardiac and kidney allografts. In a study of 138 failed liver allografts, we recognized damage to small interlobular bile ducts by lymphocytes as the most useful indicator of the presence of rejection. This is a report of the electron microscopic features of three patients with unequivocal allograft rejection. Lymphocytes and occasional granulocytes penetrated the epithelia of interlobular bile ducts. Ducts with diameters of 30 to 60 μM were preferentially affected but ducts up to 120 μM were also occasionally involved. Point contacts between infiltrating inflammatory cells and bile duct epithelial cells were observed occasionally. Degenerative changes of bile duct epithelial cells were conspicuous and involved nuclei and cellular organelles. Degeneration was often accompanied by aggregation of dense bundles of filaments in the cytoplasm. In severely affected ducts, epithelial cell disintegration was noted. In all involved bile ducts, the basement membrane was markedly thickened. Hepatocytes were well–preserved but contained lipid vacuoles, pigment granules, and blunted canalicular microvilli. The similarity between these observations and those seen in primary biliary cirrhosis and chronic graft–versus–host disease is striking.
Screening Methods for Early Detection of Hepatocellular Carcinoma
Authors: Kobayashi Kenichi , Sugimoto Tatsuho , Makino Hiroshi , Kumagai Mikio , Unoura Masashi , Tanaka Nobuyoshi , Kato Yasuhiro , Hattori Nobu
Published: March 2007

The value of various screening methods in the detection of early hepatocellular carcinoma was investigated in 95 patients with cirrhosis. Infusion hepatic angiography and computed tomography with angiography were performed yearly, ultrasound every 3 months, and determination of serum α–fetoprotein levels every 2 months. “Space–occupying lesions” suspicious for hepatocellular carcinoma were found in 13 of the 95 cases (13.7%). Detection rates of “space–occupying lesions” were 77% for infusion hepatic angiography, 77% for computed tomography with angiography and 54% for ultrasonography, respectively. In 8 of the 13 cases, “space–occupying lesions” were subsequently confirmed as hepatocellular carcinoma by operative findings or clinical course. Serum α–fetoprotein levels were negative in 3 of the 8 hepatocellular carcinoma–confirmed cases, and 3 of the remaining 5 cases demonstrated levels above 400 ng per ml at the time of diagnosis. A radical resection of hepatocellular carcinoma was successfully performed in two cases. Although it was difficult to differentiate hepatocellular carcinoma from other lesions in the case of “space–occupying lesions” smaller than 2 cm in diameter, the results suggest that regularly scheduled screening may be useful to detect early hepatocellular carcinoma.
Hepatocellular Carcinoma After Thorotrast Exposure: Establishment of A New Cell Line (Mz–Hep–1)
Authors: Dippold Wolfgang G. , Dienes Hans-Peter , Knuth Alexander , Sachsse Walter , Prellwitz Winfried , Bitter-Suermann Dieter , zum Büschenfelde Karl-Hermann Meyer
Published: March 2007

A human hepatoma cell line, associated with thorotrast exposure, from an hepatitis B markernegative patient was established as a permanent cell line (Mz–Hep–1) in tissue culture. Histology of the primary tumor, as well as phase contrast, transmission and scanning electron microscopy of the cultured cells showed typical characteristics of liver cells. Mz–Hep–1 cells secreted complement components (C2, C3, C4), carcinoembryonic antigen, lactate dehydrogenase, chymotrypsin, haptoglobin and retinol–binding protein and expressed HLA–, transferrin–, blood group B–related determinants and complement component C5 and carcinoembryonic antigen on their cell surface. Mz–Hep–1 cells represent the first human hepatoma cell line, which is strongly associated with a carcinogen.