bluuebunny/crossref_metadata_2025 huggingface dataset:
Purified Rat Liver Fat-Storing Cells in Culture Divide and Contain Collagen
Authors: De Margreet Leeuw A. , Mccarthy Séan P. , Geerts Albert , Knook Dick L.
Published: August 2008

Primary cultures and cell lines were established from suspensions of purified fat-storing cells isolated from the rat liver. When seeded at a suitable density, fat-storing cells in primary culture reached confluency in 3 to 4 days and could be transferred and established as cell lines for at least two passages. The typical morphological characteristics of fat-storing cells in vivo were retained in the cells during primary culture. Vitamin A fluorescence was still associated with lipid droplets of cells in culture up to and including the second passage. Investigation of the cytoskeletal structure by indirect immunofluorescence showed the presence of vimentin, actin and tubulin in the cells; no a-prekeratin was present. The presence of vimentin suggested a fibroblastic or possible myogenic origin for fat-storing cells. The presence of connective tissue components in fat-storing cells in culture was demonstrated by indirect immunofluorescence. Collagen Types I and IV and laminin were present intracellular in small granules in fat-storing cells in primary culture and in the first passage. Cells in the fourth passage contained only collagen Type 1. Fibronectin was only aligned extracellularly along the cell membrane, which did not exclude an extracellular source. Rat liver fat-storing cells in culture show a high proliferating capacity. Cell multiplication during prolonged culture was associated with phenotypic transition to a more fibroblastic appearance and gradual disappearance of vitamin A. These results indicate that fat-storing cells may be among the cell types involved in pathological changes observed during development of liver fibrosis.
Early Hepatic Histologic Alterations Among Chemical (Vinyl Monomer) Workers†
Authors: Tamburro Carlo H. , Mark Laszlo , Popper Hans
Published: August 2008

Focal hepatocellular hyperplasia and focal mixed (hepatocytes and sinusoidal cells) hyperplasia are early histological alterations indicative of vinyl monomer exposure. To evaluate their uses in screening chemical workers, 93 liver biopsy specimens from 78 persons were examined in double-blind duplicative fashion. Forty-eight specimens were from exposed chemical workers, 35 of them having liver biopsy(ies) for hepatic test abnormalities and 13 for nonliver-related reasons. A comparison group consisted of 30 nonchemical workers who had undergone liver biopsy for nonliver related reasons. Twenty-three of the exposed workers (48%) had hepatic lesions consistent with exposure: 17 (35%) of these had focal hepatocytic hyperplasia, while 6 (13%) had focal mixed hyperplasia or more advanced lesions. Only five of the comparison group had like findings: four (13%) had focal hepatocytic hyperplasia; one had focal mixed hyperplasia and sinusoidal dilatation. This individual had persistent hepatic test abnormalities with the focal mixed hyperplasia and a sinusoidal dilatation, and on subsequent biopsy, angiosarcoma (and a history of using hair spray containing vinyl chloride propellant). Ten individuals had 25 multiple biopsies also read double-blindly; 10 had two or more readings of the same biopsy. Duplicate 21 of 23 (91%) and multiple 27 of 28 (96%) biopsy interpretations in the same individual were identical. Only 6% of either duplicate and/or multiple readings disagreed. Both focal hepatocellular and mixed hyperplasia were always associated with abnormalities in hepatic test results of which indocyanine green clearance was the most sensitive and γ-glutamyl transpeptidase the least specific. Focal hepatocellular hyperplasia is a more common finding and occurs earlier than the focal mixed hyperplasia among vinyl monomer exposed workers. Follow-up for 5 to 7 years yielded no biochemical or histological evidence of spontaneous progression of this lesion in a work environment where vinyl chloride levels were 10 ppm with time-weighted averages of 1 to 2 ppm. Focal mixed hyperplasia is, as noted, a later and less frequent finding among vinyl monomer-exposed workers. Some individuals with this lesion develop hepatic angiosarcoma independent of subsequent vinyl monomer exposure. In screening for chemical liver injury, indocyanine green clearance supplementary to routine tests is recommended with confirmation by liver biopsy.
Measurement of Azygos Venous Blood Flow by a Continuous Thermal Dilution Technique: An Index of Blood Flow Through Gastroesophageal Collaterals in Cirrhosis†
Authors: Bosch Jaime , Groszmann Roberto J.
Published: August 2008

A method to quantitate blood flow through the gastroesophageal collaterals in portal hypertensive patients was developed. Since gastroesophageal collaterals drain into the azygos system, it is postulated that measurement of blood flow in the azygos vein should provide a quantitative measurement of gastroesophageal collateral blood flow changes in portal hypertensive patients. Azygos blood flow was measured using a double thermodilution catheter directed under fluoroscopy to the azygos vein. Ten patients with alcoholic cirrhosis were studied. Five of these patients had a history of repeated bleeding from gastroesophageal varices (Group I). The azygos blood flow in these patients was 596 ± 78 ml per min. The other five patients all had decompressive surgery of the portal system (Group II). In these patients the azygos venous blood flow was 305 ± 29 ml per min (p < 0.01). The coefficient of variation of repeated baseline measurements was of 4.4 ± 0.6%. The azygos venous blood flow measurement is a rapid, simple and sensitive method to evaluate blood flow changes in the vessels involved in gastroesophageal bleeding due to portal hypertension.
Hepatic Peptidyl Prolyl Hydroxylase Activity and Liver Fibrosis-A Prospective Study of 94 Infants and Children with Hepatobiliary Disorders
Authors: Trivedi Premila , Tanner Stuart M. , Portmann Bernard , Mcclement Janet , Mowat Alex P.
Published: August 2008

To assess whether hepatic peptidyl prolyl hydroxylase (PPH) activity could serve as a practical quantitative indicator of hepatic fibrosis or aid in the categorization, diagnosis or prognosis of hepatobiliary disorders in infancy and childhood, the activity of this enzyme has been determined prospectively by a tritium release method in 97 biopsies from 94 infants and children with the following conditions: acute hepatitis of infancy, 10 patients; extrahepatic biliary atresia, 13; previous hepatitis of infancy, 8; α-1-antitrypsin deficiency, 6; chronic active hepatitis, 17; chronic persistent hepatitis, 5; glycogen storage disease, 5; and 25 patients with a miscellanea of other liver disorders. PPH activity was considered in relation to diagnosis, biochemical and histological abnormality and subsequent prognosis over a 4-year period. Five liver biopsies which showed no histological abnormality were considered as “controls” having PPH values of 0.72 ± 0.47 (mean ± S.D.). PPH activity was significantly elevated in acute hepatitis of infancy, 9 of the 10 infants having PPH >1.66 units (i.e., mean ± 2 S.D. of the “control” value). Nine infants (70%) with extrahepatic biliary atresia also had PPH activity above this value, as did two with a-1-antitrypsin deficiency and 12 patients all in different diagnostic categories. PPH activity did not correlate with hepatic fibrosis as indicated by hepatic hydroxyproline concentration or by histological assessment, or with biochemical tests of liver function within any diagnostic group or in the series as a whole.

PPH activity was similar in biopsies with and without histological features of cirrhosis. Of the 32 patients with significantly elevated PPH activity, deterioration of their hepatic state in the subsequent 4 years occurred in only 10: 5 with extrahepatic biliary atresia and individual children with acute hepatitis of infancy, α-1-antitrypsin deficiency, biliary hypoplasia, cystic fibrosis and biliary cirrhosis associated with hypogammaglobulinemia.

Thus, although elevated PPH activity may indicate an increase in hepatic collagen biosynthesis at the time of biopsy, it does not appear to be a prognostic indicator of progressive liver damage. We conclude that the determination of hepatic PPH activity is of no diagnostic or prognostic value in hepatobiliary disorders in childhood, and the need for a practical method of monitoring persisting or continuing accumulation of fibrous tissue within the liver remains.
Ascitic Fluid Analysis in the Differentiation of Spontaneous Bacterial Peritonitis from Gastrointestinal Tract Perforation into Ascitic Fluid
Authors: Runyon Bruce A. , Hoefs John C.
Published: August 2008

A review of patients with bacterial peritonitis and ascites revealed six patients with gastrointestinal tract perforation into their ascitic fluid and 33 episodes of spontaneous bacterial peritonitis in 32 patients. Signs and symptoms were not helpful in differentiating the two groups; however, ascitic fluid analysis was found to be useful. All patients with perforation peritonitis fulfilled at least two of the following criteria: ascitic fluid total protein ± 1 gm per dl, glucose < 50 mg per dl and lactate dehydrogenase ± 225 mU per ml. In only two episodes of spontaneous bacterial peritonitis were two of the criteria fulfilled.
Assessment of βrenergic Blockade with Propranolol in Patients with Cirrhosis
Authors: Bercoff Eric , Bataille Christian , Pariente Alexandre E. , Valla Dominique , Delhotal Brigitte , Lebrec Didier
Published: August 2008

Fourteen patients with cirrhosis and bleeding esophageal varices were treated with propranolol. The dose of propranolol was determined by decreasing the resting heart rate by 25% 12 hr after an oral dose of propranolol which was given twice a day. Significant decreases in the hepatic venous pressure gradient and cardiac output after 1 month of propranolol administration was observed. To assess β-adrenergic blockade, the isoproterenol test and plasma propranolol levels were evaluated. Increasing doses of isoproterenol were injected to increase the resting heart rate 25 beats per minute (chronotropic dose 25 or CD25). Plasma propranolol concentrations were measured in blood samples drawn 4 hr after the last oral dose. The mean CD25 was 5 ± 2 μg before and 146 ± 84 μg after 1 month of propranolol administration. The plasma propranolol level after 1 month of drug administration was 0.69 ± 0.47 μM per liter i.e. 2.33 ± 1.59 /ig per ml. A significant correlation was found between the CD25 measured after continuous propranolol administration and plasma propranolol level. In conclusion, the efficacy of β-adrenergic blockade was estimated by the isoproterenol test which correlates with the plasma propranolol level in patients with cirrhosis. This study suggests that the isoproterenol test is useful in assessing β-adrenergic blockade with propranolol in patients with cirrhosis.
Effects of Nutrition on Unconjugated Plasma Bilirubin Concentrations in Squirrel Monkeys†
Authors: Portman Oscar W. , Alexander Manfred , Cornelius Charles E. , Chowdhury Jayanta Roy , Chowdhury Namita Roy , Arias Irwin M.
Published: August 2008

Bolivian squirrel monkeys (Saimiri sciureus) have fasting unconjugated hyperbilirubinemia (males: 2.0 ± 0.14; females: 3.0 ± 0.26 mg per dl) which resembles that of humans with Gilbert's syndrome. Closely related Brazilian squirrel monkeys have fasting levels (males: 0.29 ± 0.045; females: 0.36 ± 0.073 mg per dl) similar to normal people. The purpose of this study was to identify the underlying mechanisms and the nutritional factors involved. Both Bolivian and Brazilian squirrel monkeys had higher plasma bilirubin concentrations after an 18 hr fast than 4 hr after feeding. The development of fasting hyperbilirubinemia was progressive for at least 24 hr. Both populations that received a semipurified diet containing 5% fat had lower fasting and postprandial plasma bilirubin concentrations than did animals receiving 0.3% fat but much lower than those receiving 20% fat. The emulsified complete meal, or glucose, sucrose, casein, or lactalbumin alone when given by intragastric tube lowered the plasma bilirubin levels of Bolivian monkeys to less than one-half of fasting values within 1 to 4 hr. Water or butter did not have a significant effect. Glucose or fructose, when given intravenously, lowered the plasma bilirubin levels to less than half of fasting values; the fat emulsion, Intralipid, did not have a statistically significant effect. Subcutaneous epinephrine increased plasma glucose concentrations and reduced plasma bilirubin concentrations. When glucose or glucose plus butter were given by stomach tube to Bolivian squirrel monkeys for 48 hr, a very low plasma bilirubin concentration resulted whereas butter given alone resulted in high values.

Fasting Bolivian squirrel monkeys had impaired plasma clearance of [3H]bilirubin; intravenous glucose normalized the pattern. Glucose administration markedly increased excretion of bilirubin into bile. Glucose or bilirubin given intravenously or sucrose administered by gastric tube lowered plasma bile acid concentrations. The complete ration or fat given alone by gastric tube raised plasma bile acid concentrations.

Thus carbohydrate, but not fat, lowered fasting hyperbilirubinemia and increased bilirubin excretion in Bolivian squirrel monkeys. Exogenous glucose may increase the availability of UDP-glucuronate for hepatic conjugation of bilirubin in the fasting subject.
Hepatocytes of Zones 1 and 3 Conjugate Sulfobromophthalein with Glutathione
Authors: Chen Elinor H. , Gumucio Jorge J. , Ho Norman H. , Gumucio Deborah L.
Published: August 2008

The capacity of hepatocytes of Zones 1 and 3 of the liver acinus to conjugate sulfobromophthalein (BSP) with glutathione and to secrete the conjugate into bile was studied. BSP was infused into the insituperfused rat liver in concentrations of 0.01 and 0.05 mM. Perfusions were performed either in the portal to hepatic vein direction (forward perfusion) or in the hepatic vein to portal vein direction (retrograde perfusion). Hepatocytes contributing to the uptake, metabolism and biliary secretion of BSP were directly assessed qualitatively by light microscopy, and also semi-quantitatively by microspectrophotometry. BSP was taken up predominantly by hepatocytes of Zone 1 during forward perfusion and by those of Zone 3 during the retrograde perfusion of BSP. The biliary products of BSP metabolism by each acinar zone were subsequently assessed. Hepatocytes of both Zones 1 and 3 of the acinus secreted BSP into bile in the form of BSP-glutathione, and BSP-glutathione conjugate represented about 78% of the total BSP secreted into bile by each zone. The rate of BSP biliary secretion by both zones was similar at a concentration of 0.01 mM BSP, while a slight decrease (15%) in BSP secretory rate by hepatocytes of zone 3 was observed at concentrations of BSP near biliary Tm. Liver perfusion with exogenous BSP-glutathione provided results similar to those obtained with BSP. In contrast, the perfusion of 3,6-dibromosul-phthalein, a compound which is not conjugated by hepatocytes, resulted in similar biliary secretory rates regardless of the direction of perfusion. These results indicate that: (a) the capacity for glutathione conjugation of BSP is distributed among hepatocytes of all acinar zones; (b) near biliary Tm, the biliary secretory rate of BSP by hepatocytes of Zone 3 is slower than that of hepatocytes of zone 1, and (c) in vivo, all hepatocytes likely contribute to the uptake, metabolism and biliary secretion of BSP.
Hepatic Transport of Sulfated and Non-Sulfated Bile Acids in the Rat Following Relief of Bile Duct Obstruction
Authors: Cleland Paul D. , Bartholomew Carl T. , Billing Barbara H.
Published: August 2008

The effect of bile duct ligation for 5 days on the hepatic transport of sulfated and nonsulfated bile acids was studied. Tracer doses of radioactive bile acids [3H]taurochenodeoxycholate-3-sulfate [3H]chenodeoxycholate-3-sulfate, [3H]taurochenodeoxycholic acid and [14C]taurocholic acid were injected 90 min after relief of obstruction when the plasma total bile acid concentration had reverted to normal. Plasma clearance and biliary excretion of sulfated bile acids were lower than those of nonsulfated bile acids, particularly in the cholestatic rats (p < 0.02). For each bile acid, hepatic transport in the cholestatic rats was significantly reduced compared with the control rats. [3H]Chenodeoxycholate-3-sulfate and [3H]taurochenodeoxycholic acid were partially metabolized to [3H]taurochenodeoxycholate-3-sulfate prior to biliary excretion. This data suggests that the hepatic transport system for sulfated bile acids is less efficient and more easily impaired by cholestasis than that for nonsulfated bile acids.
δ Agent Infection in Patients with Chronic Liver Diseases and Hepatocellular Carcinoma-An Infrequent Finding in Taiwan
Authors: Chen Ding-Shinn , Lai Ming-Yang , Sung Juei-Low
Published: August 2008

Taiwanese have a high prevalence of HBsAg carrier rate and chronic liver diseases. To evaluate the role of delta (δ) agent infection in our patients, 45 HBsAg-positive patients with chronic active hepatitis, 4 with chronic persistent hepatitis and 11 with HBsAg-positive hepatocellular carcinoma were studied for δ antibody by radioimmunoassay of serum; liver was studied for δ antigen by immunofluorescence in 23 patients. δ Antibody was only found in three patients with chronic active hepatitis (6.7%); the prevalence was 5% in HBsAg-positive chronic liver diseases and hepatocellular carcinoma. None of the liver specimens studied had δ antigen. The study indicates that δ agent infection does not seem to play an important role in chronic liver diseases and hepatocarcinoma in Chinese who live in Taiwan, despite a high prevalence of chronic hepatitis B virus infection.
Nuclear Particles of Non-A, Non-B Type in Healthy Volunteers and Patients with Hepatitis B
Authors: Spichtin Hanspeter , Gudat Fred , Berthold Hans , Krey Gunthild , Schmid Martin , Pirovino Mauro , Altorfer Josef , Stalder Georg , Eder Gerald , Bianchi Leonardo
Published: August 2008

In an electron microscopic study, nuclear aggregates of virus-like spherical and tubular particles measuring 20 to 29 nm in diameter were found in 5 of 7 clinically healthy volunteers with normal liver histology, 6 of 10 patients with hepatitis B and 17 of 18 patients with hepatitis non-A, non-B. The incidence of hepatocytes containing nuclear particles was approximately 0.5 to 2% in all three groups. We conclude that these nuclear particles are not specific ultrastructural markers of hepatitis non-A, non-B in man as originally claimed for experimental hepatitis non-A, non-B in chimpanzees.
Human aldolase B serum levels: A marker of liver injury
Authors: Asaka Masahiro , Miyazaki Tamotsu , Hollinger Blaine F. , Alpert Elliot
Published: August 2008

A solid-phase, noncompetitive radioimmunoassay has been developed for aldolase B in human serum and tissues. Aldolase B was purified from human liver, and specific antisera to purified aldolase B were obtained from chickens. Specific antihuman aldolase B IgG was purified by affinity chromatography. Disposable polypropylene plates were coated with affinity purified specific IgG antibody and used for radioimmunoassay with 125I-specific IgG antibody to aldolase B. The nonspecific binding was minimized by saturating the binding sites of the plates with 2% ovalbumin in 0.1% Tween 20. This radioimmunoassay is specific for the aldolase B subunit, with no cross-reactivity with human aldolase A or aldolase C subunits. Aldolase B is predominantly found in normal liver. Relatively high aldolase B levels are also observed in kidney. Serum levels of aldolase B in 21 normal subjects ranged from 21 to 39 ng per ml, with a mean of 28.7 ± 8.6 (2 S.D.) ng per ml. Forty of 42 (95%) patients with acute and chronic hepatitis without cirrhosis had serum aldolase B levels greater than 40 ng per ml. Serum aldolase B levels correlated well with total serum aldolase enzyme activities (r = 0.967) and SGPT (r = 0.951) in patients with liver diseases. In cancer patients, serum aldolase B was slightly elevated in 15 of 26 (58%) patients with cancer metastatic to the liver or primary liver cell carcinoma, whereas no elevation of serum aldolase B was observed in 16 cancer patients without liver metastasis. Measurements of aldolase B serum levels by radioimmunoassay appear to be a useful measure of liver cell necrosis from benign or malignant liver diseases.
Simultaneous Occurrence of Hepatic Adenoma and Focal Nodular Hyperplasia: Report of a Case and Review of the Literature
Authors: Friedman Lawrence S. , Gang David L. , Hedberg Stephen E. , Isselbacher Kurt J.
Published: August 2008

We report the case of a 28-year-old woman with a history of oral contraceptive use and the simultaneous occurrence of histologically proven hepatic adenoma and focal nodular hyperplasia. A review of the literature discloses that the simultaneous occurrence of these hepatic lesions is a rare event. Epidemiologic evidence suggests that hepatic adenomas are etiologically related to oral contraceptive use, whereas focal nodular hyperplasia does not seem to be caused by these agents. The finding of the two lesions in the same liver may represent the chance occurrence of two rare diseases.
Hepatic Glutathione Homeostasis in the Rat: Efflux Accounts for Glutathione Turnover
Authors: Lauterburg Bernhard H. , Adams James D. , Mitchell Jerry R.
Published: August 2008

Hepatic glutathione turnover and the efflux of glutathione from the liver into bile and blood were measured in male Sprague-Dawley ratsin vivo.In fed rats the efflux of glutathione into blood, calculated from the hepatic arteriovenous concentration gradient and hepatic blood flow, amounted to 12.4 ± 1.4 nmoles min.gm liver. Together with the excretion of glutathione into bile (3.4 ± 0.4 nmoles per min.gm liver) total efflux accounted for the hepatic turnover of glutathione of 15.2 ± 0.9 nmoles per min.gm liver. Fasting animals for 48 hr markedly increased hepatic glutathione turnover to 26.4 ±1.2 nmoles per min-gm liver. Increased efflux into blood rather than increased intrahepatic catabolism accounted for this increased turnover. The systemic clearance of glutathione was 3.22 ± 0.51 ml per min 100 gm body weight. The efflux of glutathione from liver therefore was calculated to contribute over 90% of total glutathione inflow into the circulation, as determined from the clearance and the arterial concentration of glutathione. Thus, the liver is the major source of plasma glutathione, and turnover of hepatic glutathione in the basal state is accounted for almost entirely by efflux of glutathione from the liver. During fasting, the plasma clearance of exogenous glutathione increased to 5.32 ± 0.35 ml per min-100 gm body weight, and the utilization of methionine for glutathione synthesis increased markedly. The increased extrahepatic catabolism during fasting results in a decrease in plasma glutathione, which in turn may account for the observed increase in sinusoidal glutathione efflux with concomitant stimulation of the rate of hepatic glutathione turnover and of synthesis. By utilizing methionine for glutathione synthesis, the liver thus is able to make more cysteine available to other organs when dietary sources of cysteine are deficient.
Sinusoidal Endothelial Cells from Normal Guinea Pig Liver: Isolation, Culture and Characterization†
Authors: Shaw Gideon R. , Johnson Alice R. , Schulz Werner W. , Zahlten Rainer N. , Combes Burton
Published: August 2008

Guinea pig nonparenchymal hepatic cells were isolated by enzymatic digestion and subsequent separation on a 17.5% metrizamide gradient. Endothelial cell and Kupffer cell-enriched fractions were separated by centrifugal elutriation. Viability of both cell fractions was approximately 80%. Endothelial cells were cultured on a substratum of guinea pig liver collagen and 1% gelatin (1:1). Freshly isolated and cultured sinusoidal endothelial cells contained Factor VIII R:antigen, angiotensin I converting enzyme activity, and they synthesized prostaglandins characteristic of other endothelial cells. Sieve plates were identified in both freshly isolated and cultured cells. Fresh endothelial cells and Kupffer cells formed Fc receptor-mediated rosettes with IgG-opsonized sheep red blood cells, but cultured endothelial cells did not. Only Kupffer cells demonstrated Fc and C3 receptor-mediated phagocytosis. These methods for isolating and culturing sinusoidal endothelial cells should permit further functional assessment of endothelial cells and their interrelationship with other sinusoidal lining cells.
Transmission of Duck Hepatitis B Virus from Chinese Carrier Ducks to Japanese Ducklings: A Study of Viral DNA in Serum and Tissue
Authors: Omata Masao , Yokosuka Osamu , Imazeki Fumio , Matsuyama Yasuhisa , Uchiumi Katsuo , Ito Yoshimi , Mori Junko , Okuda Kunio
Published: August 2008

Human hepatitis B-like viruses have been found in several animal species, including Chinese ducks. Sera from Chinese carrier ducks which were positive for duck hepatitis B virus (DHBV) were inoculated in 33 Japanese one-day-old ducklings. The same sera were inoculated in four 3-week-old ducklings, and three 3-month-oId ducks. Ten uninoculated ducklings served as controls. Hepatitis B e-antigen positive human sera and DNA polymerase-positive woodchuck sera were also inoculated into ducklings. DHBV was demonstrated in serum of all ducklings inoculated at one day of age and persisted for more than 6 months in 17 of 20 ducks. In the three ducks in which viremia disappeared, viral DNA was found in liver tissue. Southern hybridization revealed only free viral DNA in infected ducks. Only 1 of 7 ducklings inoculated at 3 weeks or later developed persistent infection. No cross-infectivity by hepatitis B virus or by woodchuck hepatitis virus was demonstrated.

By inoculating DHBV-positive sera into 1-day-old ducklings of a virus-free Japanese flock, we were able to transmit DHBV in all of them and established a chronic carrier state in all ducks which were inoculated at 1 day of age.
Hepatitis B Vaccination in Down’s Syndrome and Other Mentally Retarded Patients
Authors: Heijtink Rudolf A. , Jong Pieter De , Schalm Solko W. , Masurel Nic
Published: August 2008

The immune response after vaccination with H-B-VAX (20 μg, Months 0, 1 and 6) was investigated in 23 Down’s syndrome patients and compared to that in 30 other mentally retarded patients and 32 staff members. About 90% of Down’s syndrome and other mentally retarded patients and 100% of staff members had anti-HBs at Month 9, but anti-HBs less than 10IU per liter were found in 6/23 (26.1%) of Down’s syndrome, 7/30 (23.3%) of other mentally retarded patients, in contrast to 2/32 (6.2%) of staff members. No differences in anti-HBs response with regard to sex and age were observed in staff members, but geometric mean titers of anti-HBs were lower in older Down’s syndrome and other mentally retarded patients, and in male Down’s syndrome patients. Supplementary vaccination is necessary in these individuals to obtain “protective levels” of anti-HBs.
The Window Period Between Hepatitis B e Antigen and Antibody in Chronic Type B Hepatitis
Authors: Liaw Yun-Fan , Huang Miau-Ju , Chu Chia-Ming , Sheen I-Shyan , Lin Deng-Yn
Published: August 2008

To examine the period between disappearance of hepatitis B e antigen (HBeAg) and appearance of anti-HBe, 48 patients with clinicopathologically verified chronic B hepatitis were followed every 1 to 3 months after HBeAg clearance. Sera were tested by radioimmunoassay for HBeAg and anti-HBe. Anti-HBe appeared in days to years, mostly (78.7%) within 1 year, after disappearance of HBeAg. Only 40.5% of patients had an “e-window” shorter than 1 month. Clinical and histological exacerbation preceding HBeAg clearance precipitated or accelerated appearance of anti-HBe. Since the patients in the “e-window” period were positive for DNA polymerase, it is suggested that the “e-window” reflects relative insensitivity of the radioimmunoassay rather than absence of HBeAg/anti-HBe. Therefore, HBeAg can reappear and clinical activity can relapse particularly during immunosuppressive therapy.
Complete Resolution of Inflammatory Activity Following Corticosteroid Treatment of HBsAg-Negative Chronic Active Hepatitis†
Authors: Czaja Albert J. , Davis Gary L. , Ludwig Jurgen , Taswell Howard F.
Published: August 2008

To assess the frequency and significance of complete resolution of inflammatory activity following corticosteroid therapy, 115 patients with severe HBsAg-negative chronic active hepatitis were followed regularly for 84 ± 5 months. Of 83 patients eligible to revert to normal liver tissue, 18 did so after 56 ± 8 months. Five of the 18 relapsed after treatment withdrawal. Only patients who improved spontaneously after cessation of treatment from histologic features of chronic persistent hepatitis to normal invariably sustained the improvement. Of 32 patients with cirrhosis at presentation, 17 reverted to inactive cirrhosis after 48 ± 10 months, but only 3 remained inactive after discontinuation of treatment. Mortality was similar in patients with and without reversion to normal tissue (0 vs. 14%, p ± 0.2), but the frequency of relapse was less after complete resolution (28 vs. 76%, p < 0.001). Reversion to inactive cirrhosis did not improve survival or reduce relapse frequency after remission and treatment withdrawal. Findings prior to therapy did not predict outcome. We conclude that complete resolution of inflammatory activity is possible, but that it occurs slowly, infrequently and unpredictably after therapy. In patients without cirrhosis, reversion to normal liver tissue decreases the likelihood of relapse and the requirement for retreatment. In patients with cirrhosis at presentation, elimination of inflammatory activity is rarely sustained and does not improve prognosis after remission and treatment withdrawal.
Electron Microscopic Evidence of Non-A, Non-B Hepatitis Markers and Virus-Like Particles in Immunocompromised Humans
Authors: Watanabe Seishiro , Reddy Rajender K. , Jeffers Lennox , Dickinson Gordon M. , O’Connell Mark , Schiff Eugene R.
Published: August 2008

Characteristic pathological alterations of the liver in chimpanzees inoculated with non-A, non-B hepatitis sera have been described, but no corresponding findings have been reported in humans. Electron microscopic studies of the liver biopsy specimens of two homosexual patients with acquired immune deficiency syndrome, one without hepatitis (Patient 1) and one with chronic active hepatitis in remission (Patient 2), revealed the cytoplasmic tubular structures which are characteristic of chimpanzee non-A, non-B hepatitis. A cluster of 23 nm double-shelled particles was also seen in the cytoplasm of a hepatocyte in patient 1 who had received a blood transfusion 8 days before the biopsy. These particles were smaller than the Dane particles, Epstein-Barr virus, cytomegalovirus or herpes simplex virus, and different from hepatitis A virus particles; the antibodies to all of which are found in high concentration in acquired immune deficiency syndrome patients. These observations may reflect the morphologic findings for non-A, non-B hepatitis infection in humans.
Bioluminescence Assays for Bile Acids in the Detection and Follow-Up of Experimental Liver Injury
Authors: SchÖLmerich Jürgen , Deluca Marlene , Chojkier Mario
Published: August 2008

We evaluated the usefulness of recently developed bioluminescence assays for serum bile acids (BA) in the detection and follow-up of experimental liver injury. Liver damage was induced in rats by either D-galactosamine or CC14, and BA were compared to SGPT and aminopyrine breath test (ABT). In severe liver injury, following D-galactosamine administration, all three methods revealed a significant difference from control values. The degree of abnormality was, however, far greater with SGPT and BA than with ABT. In moderate liver injury, induced by CC14, the increase in BA was not significant. Values of SGPT and BA showed a very good correlation (3α1-OH: r = 0.88; 7α1-OH: r = 0.90; 12α1-OH: r = 0.83; p < 0.001 for all correlations). Application of different assays for 3α1-OH, 7α1-OH and 12α1-OH BA allowed us to assess changes in individual BA. A 96-hr follow-up study in D-galactosamine-treated animals showed an increase in BA up to 48 hr and a decrease thereafter. The bioluminescence assays for BA are simple, rapid and require only 10 μl of serum. Thus, these assays may be the method of choice in detecting and monitoring liver injury in small laboratory animals.
The Effects of Prostacyclin on Canine Hepatic Bile Flow
Authors: Kaminski Donald L. , Deshpande Yashwant G.
Published: August 2008

The effect of prostacyclin on canine hepatic bile flow was evaluated. Utilizing chronic, unanesthetized bile fistula dogs, prostacyclin was found to significantly increase bile flow rates and bile bicarbonate and cyclic AMP concentration and output when compared to control values. The choleretic response was not due to the effect of the principal metabolic endproduct of prostacyclin, 6-keto-PGF1α, as this substance increased bile flow but did not increase bicarbonate or cyclic AMP concentrations in bile. Prostacyclin did not increase [14C]erythritol clearance in bile suggesting that it stimulates bile duct secretion rather than the bile salt-independent fraction of canalicular bile. To ascertain if a relationship exists between the bicarbonate-rich choleresis produced by prostacyclin and that produced by secretin, the effects of prostacyclin and indomethacin on the choleresis produced by endogenous secretin stimulation were evaluated. During intraduodenal acid infusion, prostacyclin significantly increased bile flow. The increase was not secondary to increased secretin release as plasma secretin levels were not significantly changed from control levels. Prostaglandin synthetase inhibition by indomethacin administration did not alter the choleresis produced by intraduodenal acid. The prostacyclin-induced changes in bile flow were further evaluated in acute experiments in anesthetized dogs during which the effects of prostacyclin on systemic blood pressure, hepatic blood flow and cyclic AMP metabolism could be simultaneously determined. The choleresis produced by prostacyclin occurred in the presence of decreased systemic arterial blood pressure and hepatic blood flow. The increased bile cyclic AMP secretion produced by prostacyclin was not associated with increases in systemic or hepatogenous cyclic AMP. Prostacyclin increases canine bile flow and bicarbonate secretion, a process which may be mediated by cyclic AMP. The choleresis is not secondary to changes in hepatic blood flow or secretin release.
16,16-Dimethyl-PGE2 Protection Against α — Napthy lisothiocy anate - Induced Experimental Cholangitis in the Rat
Authors: Ruwart Mary J. , Rush Bob D. , Friedle Nanette M. , Stachura Jerzy , Tarnawski Andrzej
Published: August 2008

Male rats were treated with subcutaneous vehicle or 16, 16-dimethyl-PGE2(dmPGE2, 100 μg per kg), 24,18 and 0.5 hr prior to and 6, 24 and 30 hr after challenge with oral α1-napthylisothio-cyanate (ANIT, 30 mg per kg). Forty-eight hours after challenge, rats were sacrificed by decapitation; serum and liver samples were taken for biochemical and histological analysis, respectively. Rats treated with vehicle (2% ethanol in saline) and ANIT exhibited elevations in alkaline phosphatase, SGPT and bilirubin as well as cholangitis and mild parenchymal necrosis. Rats treated with dmPGE2 and ANIT had normal serum biochemical findings, no necrosis and only mild proliferation of bile duct epithelium. Thus, dmPGE2may be able to protect the rat liver against the deleterious effects of orally administered ANIT.
Influence of Hydroxylation and Conjugation of Bile Salts on Their Membrane-Damaging Properties-Studies on Isolated Hepatocytes and Lipid Membrane Vesicles†
Authors: SchÖLmerich Jürgen , Becher Maria-Sybille , Schmidt Karlheinz , Schubert Rolf , Kremer Bernd , Feldhaus Susanne , Gerok Wolfgang
Published: August 2008

To characterize the relative toxicity of different bile salts, isolated hepatocytes were incubated with different concentrations of one bile salt or with identical concentrations of different bile salts and their conjugates. Incubation lasted for 1 hr; samples were taken at different intervals and studied for enzyme release, urea synthesis and stimulation by glucagon, and by electron microscopy. While the trihydroxylated bile salt, taurocholate, did not produce alterations at concentrations up to 1,500 μM, the dihydroxylated salts, chenodeoxy- and deoxycholate, caused enzyme release and membrane lysis, and inhibited urea synthesis at concentrations above 500 μM. In contrast, urso-deoxycholate was ineffective at concentrations up to 1,500 μM. Conjugation of these bile salts did not result in significant differences with the exception of deoxycholate conjugates which induced enzyme leakage more rapidly. Studies of lipid membrane vesicles revealed corresponding alterations. The monohydroxylated salt, taurolithocholate, caused cellular damage as indicated by enzyme loss and impairment of hormonal sensitivity of cells at low concentrations (30 to 100 μM). Dihydroxylated salts produced a different time course of membrane leakage, ultrastructural changes and release of volume marker and lipid in liposomes, suggesting a possible different mechanism of damage induced by this bile salt. Both systems can readily be used to study bile salt membrane interactions.
Does Primary Biliary Cirrhosis in Men Differ from Primary Biliary Cirrhosis in Women?† ‡ §
Authors: Rubel Lawrence R. , Rabin Lionel , Seeff Leonard B. , Licht Harvey , Cuccherini Brenda A.
Published: August 2008

Primary biliary cirrhosis is infrequently diagnosed in men, so that the clinical, biochemical and histopathological spectrum of this disease in men has not been evaluated. Therefore, we studied 30 men who had a histological diagnosis of primary biliary cirrhosis and had positive tests for antimitochondrial antibodies. Five patients had no hepatobiliary symptoms, and two of these patients had neither biochemical nor histological evidence of cholestasis. These 30 male patients’ findings were compared with the findings in 30 age-matched women who also had primary biliary cirrhosis and antimitochondrial antibodies. Six of these patients were asymptomatic. Clinical findings and symptomatic status, in addition to biochemical and histopathological features, were generally similar in both male and female patients. The possible significance of higher serum alkaline phosphatase activities and lower frequency of occurrence of piecemeal necrosis in men with primary biliary cirrhosis, as compared with women, requires further study.
Pigment Gallstones of the Common Bile Duct in Infancy
Authors: Descos Bruno , Bernard Olivier , Brunelle Francis , Valayer Jacques , Feldmann Delphine , Hadchouel Michelle , Alagille Daniel
Published: August 2008

Ten infants of less than 6 months of age presented with cholestatic jaundice and gallstones. Jaundice occurred after a lag period, and sepsis was present in three children. Ultrasound examination showed dilatation of intrahepatic and extrahepatic bile ducts in eight patients and detected cholelithiasis in three. Percutaneous transhepatic cholangiography and/or surgery allowed separation of the patients into two groups: (i) six children with lithiasis in the distal common bile duct, and (ii) four children with lithiasis associated with bile duct perforation at the junction between the cystic and common bile ducts with gallstones probably secondary to bile stasis and infection. Surgical treatment was confined to removal of calculi and drainage in eight children; biliary reconstructive surgery was necessary in the other two who had serious biliary duct lesions. No recurrence was observed after 1 to 7 years. The pigmentary nature of cholelithiasis was established by stone morphology in all cases, and by bile and stone analysis in several cases.
A Comparison of Liver Ultrastructure in Salicylate Intoxication and Reye’s Syndrome
Authors: Partin Jacqueline S. , Daugherty Cynthia C. , Mcadams James A. , Partin John C. , Schubert William K.
Published: August 2008

All childhood liver biopsy specimens from The Cincinnati Children’s Hospital Research Foundation which had been prepared for light and electron microscopy were reviewed to identify biopsies from children with salicylate intoxication. Only two cases of primary salicylate intoxication were identified. The histopathology and ultrastructural pathology were compared to that in two cases of Reye’s syndrome which were selected because they had been treated with salicylates and had comparable serum salicylate concentrations at the time of liver biopsy.

Liver biopsy specimens from the cases of salicylate intoxication were nearly normal by light microscopy. Lipid accumulation was minimal, and the content of glycogen and succinic acid dehydrogenase activity was normal. Mitochondria and peroxisomes appeared normal. Light and electron microscopy of liver specimens from the two cases of Reye’s syndrome revealed swollen hepatocytes with microvesicular fat and central nuclei. Glycogen content and succinic acid dehydrogenase activity were diminished. All hepatocyte mitochondria were enlarged, pleomorphic, and had an expanded matrix and no mitochondrial dense bodies. The histopathology and ultrastructural pathology of liver biopsy specimens in salicylate intoxication were different from those in Reye’s syndrome. In children in whom the diagnosis of Reye’s syndrome is obscure, liver biopsy with electron microscopic examination is necessary for definitive diagnosis.
Possible Defect in the Bile Secretory Apparatus in Arteriohepatic Dysplasia (Alagille’s Syndrome): A Review with Observations on the Ultrastructure of Liver†
Authors: Valencia-Mayoral Pedro , Weber James , Cutz Ernest , Edwards Vernon D. , Phillips James M.
Published: August 2008

Ultrastructural observations on 12 liver biopsies from 10 patients with arteriohepatic dysplasia syndrome (Alagille’s syndrome) are reported. The electron microscopic changes in the liver in this condition are different from those seen in other forms of chronic intra- and extrahepatic cholestasis. In particular, the bile canalicular and pericanalicular changes classically observed in cholestasis are infrequently seen. When compared with other forms of intrahepatic cholestasis including syndromes associated with paucity of intrahepatic bile ducts, the ultrastructural changes in Alagille’s syndrome appear to be distinctive. Bile pigment retention is found in the cytoplasm especially in lysosomes and in vesicles of the outer convex face of the Golgi apparatus (cis-Golgi), but rarely in bile canaliculi or the immediate pericanalicular region. These results suggest a block in the Golgi apparatus or in the pericanalicular cytoplasm.
Correlation Between Liver Morphology and Portal Pressure in Alcoholic Liver Disease
Authors: Krogsgaard Kim , Gluud Christian , Henriksen Jens H. , Christoffersen Per
Published: August 2008

In 14 alcoholic patients, the degree of hepatic architectural destruction was graded (preserved architecture; nodules alternating with preserved architecture; totally destroyed architecture) and related to portal pressure. A positive correlation was found between the degree of architectural destruction and both wedged hepatic vein pressure (r = 0.72, p < 0.01) and wedged-to-free hepatic vein presure (r = 0.67, p < 0.02). Degree of fatty change, fibrosis, inflammation, necrosis and occurrence of Mallory bodies showed no correlation with portal pressure. After morphometrical evaluation of liver biopsies, no significant correlation was found between mean hepatocyte volume or relative sinusoidal vascular volume and portal pressure. To test whether an increase in hepatocyte volume compresses the vascular structures and causes portal hypertension, the ratio of relative sinusoidal vascular volume to mean hepatocyte volume, which expresses the compression of the vascular structures exerted by enlargement of hepatocytes, was related to portal pressure. No significant correlation was found. Further, mean hepatocyte volume was not significantly correlated to relative sinusoidal vascular volume. The present findings are in accordance with the hypothesis that elevated hepatic vascular resistance and portal pressure in alcoholic liver disease are in part detemined by the severity of the hepatic architectural destruction and subsequent distorsion and compression of the efferent vein system. Parenchymal changes, including changes in hepatocyte volume, seem to be of minor importance.
Disposition and Metabolism of Metronidazole in Patients with Liver Failure
Authors: Farrell Geoffrey , Baird-Lambert Judith , Cvejic Mara , Buchanan Neil
Published: August 2008

A pharmacokinetic study of metronidazole disposition was performed in 10 patients with severe liver disease, the majority of whom also had impaired renal function. Following a single intravenous dose, systemic clearance of metronidazole was decreased by 66% in patients compared with healthy controls (p < 0.001). The apparent volume of distribution for metronidazole was also decreased in patients (by 21%), but the greater effect on clearance resulted in the elimination half-life being prolonged 152%. Total urinary excretion of unaltered metronidazole was not reduced in patients compared with controls, and systemic clearance of metronidazole did not correlate with creatinine clearance.

Hepatic production of hydroxymetronidazole [l-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroim-idazole], the major oxidative metabolite of metronidazole, was significantly lowered in patients with liver failure. Peak plasma levels of this metabolite were lower, the time taken to achieve peak levels was longer and the area under the plasma concentration ± time curve (AUC0-25h) was reduced in patients compared to controls (p < 0.05). Similarly, urinary recovery of hydroxymetronidazole was lower in patients with liver disease while excretion of the other major oxy-metabolite, 1-acetic acid-2-methyl-5-nitroimidazole, appeared reduced to an even greater extent. Thus, while the presence of renal function impairment in a patient with cirrhosis indicates that metronidazole elimination is likely to be abnormal, the principal mechanism for delayed elimination is impaired hepatic drug metabolism rather than reduced renal clearance of metronidazole and its major metabolites.
Woodchuck Hepatitis Virus: Experimental Infection and Natural Occurrence
Authors: Millman Irving , Southam Lenore , Halbherr Theresa , Simmons Heidi , Kang Chong Myung
Published: August 2008

Sera from 588 woodchucks were assayed for woodchuck hepatitis virus (WHV) markers using hepatitis B virus (HBV) reagents which have cross-reactivity with WHV markers. Twenty per cent of these woodchucks, trapped in Delaware, Maryland and Pennsylvania, had WHsAg; 50% of these had DNA polymerase. There are areas of high and low endemicity within these states. Female woodchucks may have a higher incidence of WHV markers than do males. Woodchuck hepatitis surface antigen (WHsAg) and anti-WHc often occur together but less commonly than HBsAg and anti-HBc do in human HBV infection. Experimental infection of woodchucks with WHV produced a prolonged infection (up to 40 weeks). WHsAg and DNA polymerase appeared to be more reliable indicators of infectivity than anti-WHc, woodchuck hepatitis e antigen (WHeAg) or anti-WHe. WHeAg was not detected throughout this period of infection, while anti-WHe appeared late in two of three experimentally infected animals. Four male and four female woodchucks which developed primary hepatocellular carcinoma in captivity were analyzed for WHV markers throughout their period of confinement. Seven were WHsAg and anti-WHc positive when captured. The animal that was free of WHV markers on capture converted to the WHsAg and anti-WHc positive state prior to the development of primary hepatocellular carcinoma. One primary hepatocellular carcinoma animal produced WHeAg and none anti-WHs or anti-WHe.