bluuebunny/crossref_metadata_2025 huggingface dataset:
Globular hepatic amyloid--an unusual morphologic presentation
Authors: Kanel Gary C. , Uchida Toshikazu , Peters Robert L.
Published: March 2007

Hepatic amyloid, when identified, is usually located in the sinusoids, portal tracts, and arterioles. We report 14 cases of hepatic amyloidosis where eosinophilic globules having the histochemical and electron microscopic features of classic amyloid were found. The globules were round to oval, 5 to 40 μm in diameter, and were found within the space of Disse as well as aggregated within the portal tracts. There were no distinctive clinical or laboratory features distinguishing this type of amyloidosis from classic hepatic amyloidosis. However, there were no cases of multiple myeloma and only one of benign monoclonal gammopathy. All seven patients who were studied at postmortem examination had systemic (nonglobular) amyloidosis. This form of hepatic amyloidosis is probably not an early form of the disease but is an original but rare presentation of hepatic amyloid deposition.
Pigment Gallstone Formation in the Cholesterol–Fed Guinea Pig
Authors: Lamorte Wayne W. , Brotschi Erica A. , Scott Thayer E. , Williams Lester F.
Published: March 2007

Female Hartley guinea pigs fed a 0.5% cholesterol–supplemented diet were found to form pigmented gallstones after 6 weeks (17/23) and 12 weeks (11/11), while only 2 of 44 animals fed a trace cholesterol diet formed gallstones over a comparable period. The light brown stones consisted primarily of aggregates of fine granular crystals, morphologically similar to calcium bilirubinate crystals. The stones were soluble in 0.1 N sodium hydroxide and were found to contain a substance which co–migrated with unconjugated bilirubin during thin–layer chromatography.

Despite hypercholesterolemia (202 ± 34 vs. 59 ± 22 mg per dl in controls, p < 0.05) and fatty infiltration of the liver, cholesterol–fed animals had a lithogenic index of only 0.22 ± 0.04 in gallbladder bile as compared to a lithogenic index of 0.02 ± 0.01 in animals fed the trace cholesterol diet. Accordingly, no cholesterol monohydrate crystals were found in any animals. Hematocrits among cholesterol–fed animals (47.6 ± 1.2%) were lower than those of controls (54.8 ± 1.3%, p < 0.05) probably as a result of the cholesterol–induced hemolytic anemia which has been reported by others in this species.

Fasting gallbladder volume was greater in cholesterol–fed animals (2.4 ± 0.18 ml) than in controls (1.7 ± 0.11, p < 0.0025), and a comparable increase in gallbladder dry tissue mass was found. There was no evidence of biliary obstruction, however, and the gallbladder contractile response to octapeptide cholecystokinin was comparable in both groups. The increase in gallbladder volume appeared to result from: (a) an increase in hepatic bile salt secretion with an associated increase in bile flow and (b) a decrease in the capacity of the gallbladder to absorb fluid from hepatic bile (6.0 ± 1.4 mg fluid per hr per mg tissue with cholesterol diet vs. 12.9 ± 0.9 in controls, p < 0.0005). Total bile salt concentration was also decreased in gallbladder bile of cholesterol–fed animals (13.79 ± 0.51 vs. 18.56 ± 2.19 mmoles per liter in controls, p < 0.05), probably as a result of increased hepatic bile flow and decreased gallbladder absorption. The absence of cholesterol gallstones in this model is consistent with the failure to supersaturate bile with cholesterol. The reasons for pigment gallstone formation are less clear but their occurrence may be the result of a cholesterol–induced hemolytic anemia.
Significance of Serum and Hepatic Markers of Hepatitis B Viral Infection in Hbsag–Positive and Hbsag–Negative Chronic Active Hepatitis
Authors: Freiman John , Eckstein Robert , McCaughan Geoffrey , Parsons Carolyn , Davies Stuart J. , Diegutis Peter , Burnett Leslie , Gallagher Neil
Published: March 2007

The correlation between serum and hepatic markers of hepatitis B virus (HBV) has been studied in 70 subjects with chronic active hepatitis of whom 18 were HBsAg+ and 52 were HBsAg-. In HBsAg+ subjects, sera were tested for HBeAg/anti–HBe status and for HBV DNA sequences using a DNA dot hybridization technique. Anti–HBs and anti–HBc were measured in serum in the HBsAg- group. Immunoperoxidase staining was used to detect HBsAg, HBcAg and delta antigen in liver tissue. Of the 18 HBsAg+ patients, 13 were HBeAg+ and 5 were anti–HBe+. A good correlation was shown between HBeAg and HBV DNA in serum and HBcAg expression in liver tissue. Neither HBV DNA in serum nor HBcAg in liver tissue was detected in any of the anti–HBe+ patients. HBsAg and/or HBcAg were detected in liver tissue in 17 of 18 HBsAg+ subjects (95%). However, neither HBsAg nor HBcAg were detected in liver tissue in 52 HBsAg- patients. This group included 11 patients with antibody markers in serum of past HBV infection. Thus, in contrast to previous studies, a good correlation was demonstrated between the serum and hepatic markers of viral replication, and no evidence was obtained to implicate the HBV as an etiological agent in HBsAg- chronic active hepatitis.
The Diagnostic Value of Fasting Individual Serum Bile Acids in Anicteric Alcoholic Liver Disease: Relation to Liver Morphology
Authors: Einarsson Kurt , Angelin Bo , Björkhem Ingemar , Glaumann Hans
Published: March 2007

The aim of the present study was to evaluate the diagnostic value of measuring individual serum bile acids in patients with suspected alcoholic liver disease. A highly accurate and specific massfragmentographic technique with high sensitivity was used. Anicteric patients with fatty liver (n = 10) and liver cirrhosis (n = 9) were compared with healthy controls (n = 27). The measurement of serum bile acids did not discriminate patients with fatty liver from controls. In general, an increased serum level of cholic acid indicated more serious liver disease. Determination of chenodeoxycholic acid and deoxycholic acid did not add any further diagnostic information.
T Lymphocyte Sensitization to Hbcag and T Cell–Mediated Unresponsiveness to Hbsag in Hepatitis B Virus–Related Chronic Liver Disease
Authors: Vento Sandro , Hegarty John E. , Alberti Alfredo , O'brien Charles J. , Alexander Graeme J.M. , Eddleston Adrian L.W.F. , Williams Roger
Published: March 2007

Using a newly developed indirect T lymphocyte migration inhibition test, cell–mediated immunity to HBsAg and HBcAg was directly and simultaneously examined in a total of 21 patients with HBsAg–positive chronic liver disease (CLD), and in seven subjects whose sera contained anti–HBs (2 previous acute hepatitis B; 4 hepatitis B vaccine recipients and 1 chronic active hepatitis). T cell sensitization to HBcAg was invariably detected in the HBsAg–positive CLD patients tested (12/12), whereas T cell sensitization to HBsAg was not present in any of the patients (0/21). In contrast, T cell sensitization to HBsAg was present in all anti–HBs–positive subjects.

These results support the hypothesis that the cellular immune response to HBcAg, rather than to HBsAg, is implicated in the pathogenesis of HBsAg–positive CLD. Moreover, the observation that the addition of T cells from patients with HBsAg–positive CLD to T cells from anti–HBs positive subjects in a ratio of 1 to 9 reversed their sensitization to HBsAg, suggests that a hyperactivity of HBsAg–specific suppressor T cell population may be responsible for persistent HBs antigenemia.
Endocytosis and Binding of Asialoorosomucoid by Hepatocytes From Rats With Jejunoileal Bypass
Authors: Serbource-Goguel/Seta Nathalie , Borel Béatrice , Dodeur Michèle , Scarmato Pierre , Bourel Benoit , Feger Jeanne , Durand Geneviève
Published: March 2007

Rats with Jejunoileal bypass were used to study the biological activity of the hepatic binding protein. Hepatocytes were prepared 11 weeks after surgical procedure, and presence of asialoo–rosomucoid in serum has been determined.

Compared to control rat hepatocytes, endocytosis of [3H]asialoorosomucoid by bypassed rat hepatocytes was decreased by about 60%. This was due to a decreased number of total and surface receptors. In most sera, an accumulation of asialoorosomucoid was found. A reduction of protein synthesis or turnover could be considered.
Respective Roles of Hypoxia and Halothane Metabolism in Halothane–Induced Liver Injury in Rats
Authors: Hatano Hitoshi , Nomura Fumio , Ohnishi Kunihiko , Iijima Toshihiko , Hayasaka Akira , Iida Shinji , Koen Hirofumi , Okuda Kunio
Published: March 2007

To evaluate the respective roles of halothane metabolism and hypoxia in rats with halothane hepatotoxicity, experiments were designed with special reference to blood gas. After pretreatment with phenobarbital (80 mg per kg., i.p.) for four consecutive days, rats were exposed to 1.0% halothane under a mildly hypoxic condition (FiO2= 14%) for 2 hr. Since halothane anesthesia caused significant decrease in PaO2levels, rats exposed to a highly hypoxic atmosphere (FiO2= 10%) in which PaO2levels were comparable to those in the halothane group, served as the control. In the halothane group, marked centrilobular necrosis and elevation of SGPT activity were observed; neither significant histological lesions nor elevation of transaminase activity occurred in the highly hypoxic group. Although phenobarbital treatment did not decrease PaO2levels during halothane anesthesia, the serum fluoride level, which appears to reflect quantitatively the reductive pathway of halothane metabolism, increased. These results strongly indicate that halothane metabolism rather than hypoxia,per se, plays a major role in development of halothane–induced liver injury in rats.
The Effect of Cimetidine on Hepatic Drug Elimination in Cirrhosis
Authors: Nelson Donald C. , Avant George R. , Speeg Vincent K. , Hoyumpa Anastacio M. , Schenker Steven
Published: March 2007

Both cimetidine therapy and cirrhosis individually interfere with normal elimination of various drugs. Cimetidine is often prescribed in patients with cirrhosis but there is incomplete data on its effect on drug elimination in cirrhotics. The purpose of this study was to address this issue. Eight stable cirrhotics were studied prior to and following 7 days of cimetidine administration, (300 mg orally q.i.d.). Chlordiazepoxide (Librium®), which is eliminated by the liver after demethylation, and indocyanine green, which is removed by the liver without biotransformation, were used as probes. Consistent with the concept that cimetidine interferes with drug metabolism by inhibiting microsomal oxidation, chlordiazepoxide clearance in the cirrhotics was inhibited by cimetidine (p < 0.05), but indocyanine green clearance was unaffected. As shown by us previously (Roberts, R. K. et al., Gastroenterology 1978; 75:479-485), untreated cirrhotics had substantially lower chlordiazepoxide clearance than did controls. The inhibitory effect of cimetidine on chlordiazepoxide clearance was less in cirrhotics than in controls (p < 0.05). In all subjects, there was excellent correlation between initial clearance and magnitude of depression in clearance after cimetidine, i.e., the larger the initial clearance, the larger the change (r = 0.97, p < 0.0001). Forty–eight hours after stopping cimetidine, chlordiazepoxide clearance returned to baseline in cirrhotics and controls. Our data demonstrate that cimetidine and cirrhosis may act additively to impair drug metabolism. This effect of cimetidine on chlordiazepoxide clearance is smaller in cirrhotics than in controls, but, because of impaired initial drug elimination in cirrhosis, it may result in adverse clinical effects.
Synthesis of Heat Shock Proteins in Rat Liver After Ischemia and Hyperthermia
Authors: Cairo Gaetano , Bardella Lidia , Schiaffonati Luisa , Bernelli-Zazzera Aldo
Published: March 2007

Ischemia of rat liver is followed by recovery or cell death. Since heat shock proteins may be essential to cell survival under stress, we determined levels of heat shock proteins in liver after different periods of blood deprivation and correlated the results with cellular recovery. Cell–free synthesis by poly (A+)–mRNA and polysomes revealed 70 and 89 kd proteins which appear similar to proteins produced by the liver of rats with amphetamine–induced hyperthermia. The 70 and 89 kd proteins increased in the liver of rats which recovered from ischemia.
The Effect of Large Volume Paracentesis on Plasma Volume—A Cause of Hypovolemia?
Authors: Kao Henry W. , Rakov Neal E. , Savage Evelyn , Reynolds Telfer B.
Published: March 2007

Large volume paracentesis, while effectively relieving symptoms in patients with tense ascites, has been generally avoided due to reports of complications attributed to an acute reduction in intravascular volume. Measurements of plasma volume in these subjects have been by indirect methods and have not uniformly confirmed hypovolemia. We have prospectively evaluated 18 patients (20 paracenteses) with tense ascites and peripheral edema due to chronic liver disease undergoing 5 liter paracentesis for relief of symptoms. Plasma volume pre– and postparacentesis was assessed by a 125I–labeled human serum albumin dilution technique as well as by the change in hematocrit and postural blood pressure difference. No significant change in serum sodium, urea nitrogen, hematocrit or postural systolic blood pressure difference was noted at 24 or 48 hr after paracentesis. Serum creatinine at 24 hr after paracentesis was unchanged but a small but statistically significant increase in serum creatinine (+0.1 ± 0.3 mg per dl, p < 0.01) was noted at 48 hr postparacentesis. Plasma volume changed -2.7% (n = 6, not statistically significant) during the first 24 hr and -2.8% (n = 12, not statistically significant) during the 0- to 48–hr period. No complications from paracentesis were noted. These results suggest that 5 liter paracentesis for relief of symptoms is safe in patients with tense ascites and peripheral edema from chronic liver disease.
Natural History of Chronic Hepatitis B Virus Infection in Taiwan: Studies of Hepatitis B Virus Dna in Serum
Authors: Chu Chia-Ming , Karayiannis Peter , Fowler Martin J.F. , Monjardino Jon , Liaw Yun-Fan , Thomas Howard C.
Published: March 2007

Hepatitis B virus DNA (HBV DNA) in serum was measured by a Spot hybridization technique in a consecutive series of 79 cases with chronic HBV infection from Taiwan. HBV DNA was found in 96.3% (52/54) of HBeAg–positive, 66% (2/3) with neither HBeAg or anti–HBe and in 63.6% (14/22) of anti–HBe positive patients. The levels of HBV DNA in the HBe–Ag–positive patients were significantly higher than in the anti–HBe positive patients (median, 944 vs. 58 pg per ml, p < 0.001). The mean ages increased from 28.7 years for the cases with high levels of HBV DNA, to 34.7 years for those with low levels (p < 0.01) and to 41.0 years in those without HBV DNA in serum (p < 0.05 when compared with those with low level of HBV DNA). Ninety per cent of patients (27/30) with high levels of HBV DNA showed only minor hepatic inflammatory activity, as did 91% (10/11) of those without HBV DNA. In contrast, histologic signs of chronic active hepatitis or chronic lobular hepatitis were demonstrated in 76% of cases (29/38) with low levels of HBV DNA. These data are consistent with the hypothesis that liver damage occurs during the period of clearance of hepatocytes supporting HBV replication, and are inconsistent with the view that HBV may be directly cytopathic. Thus, the natural history of chronic HBV infection may be divided into three phases. The high replicative phase, characterized by HBeAg reactivity in serum and only minor histological activity, the low replicative (immune clearance) phase, during which the serum is positive for HBeAg or anti–HBe and histologic signs of chronic active liver disease are usually prominent, and finally, the nonreplicative phase, when the patient is anti–HBe positive and there is no evidence of inflammatory liver disease.
Cefotaxime Is More Effective Than Is Ampicillin–Tobramycin in Cirrhotics With Severe Infections
Authors: Felisart Josefina , Rimola Antoni , Arroyo Vicente , Perez-Ayuso Rosa M. , Quintero Enrique , Gines Pere , Rodes Joan
Published: March 2007

We compared the effectiveness and incidence of nephrotoxicity of ampicillin–tobramycin and cefotaxime in 73 cirrhotics who had severe bacterial infection. Most of these patients had spontaneous peritonitis and/or bacteremia. Patients were randomly allocated into two groups. Group I included 36 patients treated with ampicillin–tobramycin and Group II comprised 37 patients treated with cefotaxime. Patients from both groups were similar with respect to clinical data, standard liver and renal function tests, types of infection and isolated organisms. Ninety–two per cent of bacteria isolated in Group I and 98% of those isolated in Group II were susceptiblein vitroto ampicillin–tobramycin and to cefotaxime, respectively. Ampicillin–tobramycin cured the infection in 56% of Group I patients, and cefotaxime in 85% of Group II patients (p < 0.02). Five patients treated with ampicillin–tobramycin, and none treated with cefotaxime developed superinfections (p = 0.024). Nephrotoxicity (impairment of renal function associated with an increase of urinary β2–microglobulin to over 2,000 μg per liter) occurred in two patients in Group I and none in Group II. These results suggest that broad–spectrum cephalosporins should be considered as first choice antibiotics in cirrhotic patients with severe infections.
Immunologic Analysis of Mononuclear Cells in Liver Tissues and Blood of Patients With Primary Sclerosing Cholangitis
Authors: Whiteside Theresa L. , Lasky Steven , Si Lusheng , van Thiel David H.
Published: March 2007

Using monoclonal antibodies to surface antigens, we typed and quantitated the mononuclear cells (MNCs) infiltrating liver tissues from 23 patients with primary sclerosing cholangitis. The circulating T lymphocytes were also enumerated by flow cytometry in 12 of these patients. In blood, T lymphocytes and especially T8+ cells were decreasd. T cells were the major components of MNCs (78%) in portal tracts. Few of these cells were Tac+ or HLA–DR+. Total MNCs (929 ± 90 vs. 106 ± 18 in controls) included 11% M1+ and 8% B1+ cells. Aggregates of T4+ and T8+ cells were common in portal areas. The portal T4/T8 ratio of 1.27 ± 0.1 was significantly (p < 0.01) different than that around proliferating bile ductules (0.8 ± 0.1). The T8+ and M5+ cells localized in these areas of proliferation and infiltrated ductal epithelium. On the other hand, T4+ cells accumulated on the parenchymal side of fibrosed tissue and densely surrounded certain intralobular bile ducts. Even late in the disease, variability in the extent of MNCs infiltration, ductal proliferation and periductal fibrosis was seen in each biopsy.
Ranitidine–Acetaminophen Interaction: Effects on Acetaminophen–Induced Hepatotoxicity in Fischer 344 Rats
Authors: Leonard Thomas B. , Morgan Gwyn D. , Dent John G.
Published: March 2007

Cimetidine has been shown to protect against acetaminophen–mediated hepatotoxicity in both rats and mice. In contrast to cimetidine, ranitidine recently has been determined to potentiate the hepatotoxic action of acetaminophen in Fischer 344 rats. The present studies were designed to characterize this ranitidine–acetaminophen interaction. Acetaminophen administration (750 mg per kg, p.o.) to F344 rats produced maximal hepatic necrosis, 24 hr after treatment, as assessed by SGPT activity and histopathology. Ranitidine pretreatment 30 min prior to acetaminophen treatment increased the toxicity but did not alter its course. Ranitidine administration (50 mg per kg) enhanced acetaminophen hepatotoxicity throughout the toxic dose range of acetaminophen (600 to 1,000 mg per kg) and potentiation of acetaminophen hepatotoxicity by ranitidine was dose–dependent. Maximal increases were observed at 50 mg per kg ranitidine whereas, doses of ranitidine greater than 100 mg per kg inhibited acetaminophen toxicity. SGPT data were corroborated by histopathologic evaluation. Ranitidine was not intrinsically hepatotoxic when administered alone (500 mg per kg), or following glutathione depletion, or after induction of hepatic mixed–function oxidase activity. The results obtained in these studies support the suggestion that, at high doses (>100 mg per kg), ranitidine reduces acetaminophen hepatotoxicity by reducing metabolic activation, while at lower doses ranitidine potentiates acetaminophen hepatotoxicity. Inhibition by ranitidine of acetaminophen conjugation is proposed as a possible mechanism of this potentiation.
The Spectrum of Complement–Fixing Antinuclear Antibodies in Patients With Hepatocellular Carcinoma
Authors: Kiyosawa Kendo , Daemer Richard J. , He Li-Fang , Bonino Ferruccio , Prozesky O. W. , Purcell Robert H.
Published: March 2007

Sera from 230 hepatocellular carcinoma patients were tested for antinuclear antibodies by anticomplement immunofluorescence in 16 types of transformed, diploid or primary cells of human, monkey, chimpanzee or rat origin. As controls, we tested 85 sera from patients with chronic liver diseases, 48 sera from patients with nonhepatic cancers and 164 sera of normal controls. Exactly 11.2% of all cancer patients but only 3.6% of noncancer patients had complement–fixing antinuclear antibody that reacted with all substrates. Only sera from hepatocellular carcinoma reacted with subsets of the tumor cell substrates. These sera reacted with hepatocellular carcinoma cells and nonhepatic cancer cells (antitumor) or only with one or more of the human hepatocellular carcinoma cell lines, PLC/PRF/5, Hep3B and Mahlavu, that were derived from HBsAg–positive patients (antihepatocellular carcinoma). Three of these reacted only with hepatitis B virus DNA–positive cells (PLC/PRF/5 and Hep3B) that contained “hepatitis B–associated nuclear antigen,” 1 reacted only with hepatitis B virus DNA–negative Mahlavu cells, 1 reacted with PLC/PRF/5 and Mahlavu and 3 reacted with all 3 cells. The nuclear antigen in Mahlavu was expressed as a homogeneous fluorescence that spared the nucleoli, was present in a lower percentage of cells than hepatitis B–associated nuclear antigen and was more thermostable than hepatitis B–associated nuclear antigen. However, it resembled hepatitis B–associated nuclear antigen in kinetics of expression and susceptibility to digestion with DNase, RNase and proteinase K. The nature of the nuclear antigens in the hepatocellular carcinoma cells is poorly understood but one possibility is that they may represent the expression of viral or tumor–related genes. We found also tumor cell–specific nuclear antigens in tumor cell lines. These antigens might represent the expression of cellular transforming genes.
Effect of Systemic Ph, Pco2 and Bicarbonate Concentration on Biliary Bicarbonate Secretion in the Rat
Authors: Corbic Michèle , Muñoz Cristina , Dumont Micheline , De Couët Ghislaine , Erlinger Serge
Published: March 2007

The effect of acute metabolic or respiratory acid–base disturbances on biliary bicarbonate secretion was examined in bile fistula rats. Animals were infused with ursodeoxycholate at a rate that stimulates bicarbonate secretion (1 μmole · min-1 · 100 gm-1), in control conditions and during acute acid–base disturbances. Metabolic acidosis or alkalosis were induced by HCl or NaHCO3 infusions, and respiratory acidosis or alkalosis were created respectively by adding CO2 to the inspired gas or by hyperventilation in artificially ventilated animals. Biliary bicarbonate concentration was always higher than plasma bicarbonate concentration. During metabolic disturbances, changing the plasma bicarbonate concentration from 9.2 to 30.2 mM stimulated biliary bicarbonate secretion by 113%. During respiratory disturbances, changing the plasma PCO2 from 25.5 to 59.8 mm Hg also increased biliary bicarbonate secretion by 89%. Biliary bicarbonate output was thus independent of plasma pH. When all animals were considered, bile flow was positively correlated with biliary bicarbonate concentration (r = 0.71, p < 0.001). Acetazolamide significantly decreased ursodeoxycholate–induced bile flow and bicarbonate secretion by 20 and 22%, respectively. These results support the hypothesis that there is a relationship between ursodeoxycholate–induced bicarbonate secretion and bile flow. They are also consistent with the view that ursodeoxycholate–stimulated biliary bicarbonate secretion in the rat is strongly affected by plasma bicarbonate and PCO2, but not by plasma pH, and involves carbonic anhydrase.
Cimetidine Inhibits the Formation of the Reactive, Toxic Metabolite of Isoniazid in Rats But Not in Man
Authors: Lauterburg Bernhard H. , Todd Elizabeth L. , Smith Charles V. , Mitchell Jerry R.
Published: March 2007

The hepatotoxicity of isoniazid in rats results from the metabolic activation of acetylhydrazine, a metabolite of isoniazid, by the cytochrome P450 monooxygenase system. Inhibition of the drugmetabolizing enzyme system with a compound suitable for clinical use such as cimetidine might therefore prevent liver injury in experimental animals and in patients on isoniazid without interfering with the antituberculous activity of the drug. To test this hypothesis, we studied the effect of cimetidine on acetylhydrazine–induced hepatocellular necrosis in rats and the formation of 14CO2 from [14C]acetylisoniazid, which provides an indirect assessment of the fraction of a dose of isoniazid metabolized via the toxifying pathway. Pretreatment of rats with 150 mg per kg of cimetidine significantly decreased the extent of hepatocellular necrosis produced by 100 mg per kg of aeetylhydrazine and the formation of 14CO2 from [14C]acetylisoniazid. In man, however, 300 mg of cimetidine administered every 6 hr did not decrease the formation of 14CO2 from [14C] acetylisoniazid administered concomitantly with 300 mg of isoniazid; similarly, cimetidine did not affect the urinary excretion of isoniazid, acetylisoniazid, acetylhydrazine and diacetylhydrazine. These data demonstrate that the mechanistic information obtained in animal models cannot be applied readily in clinical practice and that measurable inhibition of acetylhydrazine metabolism to prevent isoniazid liver injury does not occur after administration of therapeutic doses of cimetidine to patients.
Effects of Anesthetic Agents on Bile Pigment Excretion in the Rat
Authors: Gourley Glenn R. , Mogilevsky William , Arend Richard A. , Siegel Frank L. , Odell Gerard B.
Published: March 2007

Anesthesia–induced alterations in bilirubin conjugation were studied. Rats were fitted with bile duct and jugular vein catheters while anesthetized with diethyl ether, ketamine or pentobarbital. As anesthesia abated, bile was collected for the next 5 hr and analyzed for flow rate, total bilirubin excretion and bilirubin glucuronide composition. The high–performance liquid chromatography method used allowed direct analysis of bile without derivatization or extraction. Ether anesthesia was associated with a reversible suppression of diglucuronide formation and total bilirubin excretion, with reciprocal monoglucuronide changes. Bile flow and pigment excretion were variable with ketamine. Pentobarbital provided the most uniform excretion data, although the ratio of C–8:C–12 monoglucuronide varied with all drugs. These data are consistent with recently reported drug–induced alterations in hepatic uridine diphosphoglucuronic acid concentration and support the hypothesis that alterations in this substrate concentration are capable of influencing rates of hepatic glucuronide formation.
Maternal Transmission of Duck Hepatitis B Virus in Pedigree Pekin Ducks
Authors: Tsiquaye Kwesi N. , McCaul Thomas F. , Zuckerman Arie J.
Published: March 2007

A 14–month old female Pekin duck experimentally infected as an embryo with duck hepatitis B virus via the amniotic route has been a chronic carrier of duck hepatitis B virus with very high (P/N) values of DNA polymerase activity since hatching. All the progeny were, on evaluation for congenital infection, found to be duck hepatitis B virus positive by endogenous DNA polymerase reaction and electron microscopy. These offspring remained persistently viremic throughout the study. Maternal transmission therefore bred true to a total of 49 offspring—24 ducklings (<24 hr old) and 25 ducks—studied. Six of these 25 ducks matched for age and sex and bled weekly for 6 weeks exhibited fluctuating plasma levels of DNA polymerase activity. Higher DNA polymerase activity was detected in newly hatched ducklings than in older viremic ducks. This observation was corroborated with the results of electron microscopic examination of thin sections of liver. Duck hepatitis B virus particles, located within vesicles of rough endoplasmic reticulum in the cytoplasm of hepatocytes, were more abundant, and therefore more readily observed, in ducklings than in older ducks.
Opsonic Activity of Human Ascitic Fluid: A Potentially Important Protective Mechanism Against Spontaneous Bacterial Peritonitis
Authors: Runyon Bruce A. , Morrissey Richard L. , Hoefs John C. , Wyle Frederic A.
Published: March 2007

The opsonic activity of 60 ascitic fluids from 47 patients was measured using a standard opsonophagocytic assay. Curve analysis of the opsonic activity compared to the ascitic fluid concentration of total protein, total hemolytic complement, C3 and C4 yielded correlation coefficients of 0.84 (p < 0.001), 0.84 (p < 0.001), 0.94 (p < 0.001) and 0.92 (p < 0.001), respectively. There appeared to be a threshold of concentration for each protein below which there was no killing of bacteria. Cirrhotic ascites had significantly (all p < 0.001) lower concentrations of total protein and complement and less opsonic activity than noncirrhotic ascites (including malignant, cardiac and miscellaneous types). Perhaps it is the dilution of crucial antimicrobial proteins below a threshold which predisposes to spontaneous bacterial peritonitis.
Localization of Increased Hepatic Vascular Resistance in Liver Cirrhosis
Authors: Shibayama Yuro , Nakata Katsuji
Published: March 2007

To determine the localization of increased vascular resistance in cirrhotic liver, blood pressures were measured by a direct cannulation method at several key points in the hepatic vascular pathway in normal and cirrhotic rats. Cirrhosis was produced by feeding a choline–deficient diet. Blood pressures in normal rats were 110 mm H2O in the portal vein, 68 mm H2O in the terminal portal venule, 28 mm H2O in the terminal hepatic venule and 20 mm H2O in the inferior vena cava. In cirrhotic rats, blood pressures in the portal vein and the terminal portal venule were 173 and 100 mm H2O, respectively, while those in the terminal hepatic venule and the inferior vena cava were elevated only slightly above normal. These hemodynamic data suggest that an increase in vascular resistance in cirrhotic liver is present in the intrahepatic portal vein and sinusoids, but not in intrahepatic hepatic vein. In cirrhotic liver, stenosis and distortion were found in peripheral branches of the portal vein, and sinusoidal stenoses and a decrease in sinusoidal space were recognized. Accordingly, it is suggested that the increase in vascular resistance in the intrahepatic portal vein and sinusoids correlate with these structural changes. Although severe stenoses and distortion were found in hepatic vein branches, it was thought that they do not contribute to portal hypertension because of lack of increase in vascular resistance in the intrahepatic hepatic vein.
Portal Venous Bile Acids in Cholesterol Gallstone Disease: Effect of Treatment With Chenodeoxycholic and Cholic Acids
Authors: Einarsson Kurt , Ahlberg Jon , Angelin Bo , Björkhem Ingemar , Ewerth Staffan
Published: March 2007

We determined the serum concentrations of cholic, chenodeoxycholic and deoxycholic acids in portal and peripheral venous blood in 9 gallstone–free patients and 39 patients with cholesterol gallstones during standardized cholecystectomy. An accurate and specific gas chromatographic–mass spectrometric technique was used. The portal venous concentration of total bile acids was similar in gallstone–free and untreated gallstone patients (n = 20); there was no evidence of a reduced hepatic uptake of bile acids in the latter. Treatment with cholic acid (n = 10) was associated with a 70% increase in cholic acid and normal concentration of total bile acids. In chenodeoxycholic acid–treated patients (n = 9), the portal venous concentration of this bile acid was increased 3–fold; total bile acids were increased about 60%. The estimated hepatic uptake of cholic acid was slightly decreased during chenodeoxycholic acid treatment. The results indicate that neither bile acid inflow to the liver nor hepatic bile acid uptake is reduced in fasting patients with cholesterol gallstones, and treatment with chenodeoxycholic acid increases fasting inflow of bile acids to the liver. The latter may contribute to unsaturation of fasting hepatic bile during treatment with chenodeoxycholic acid.
Functional Properties of Isolated Hepatocytes From Ethanol–Treated Rat Liver
Authors: Schüller Amador , Moscat Jorge , Diez Emilio , Fernandez-Checa Jose C. , Gavilanes Francisco G. , Municio Angel M.
Published: March 2007

Gluconeogenesis and palmitate incorporation into triacylglycerols and phosphatidylcholine were measured in isolated hepatocytes from control and ethanol–treated rats. Basal gluconeogenesis and its hormonal response decreased in hepatocytes from ethanol–treated animals; palmitate incorporation into triacylglycerols increased. In ethanol–treated rat liver, 45Ca2+ uptake and methylating capacity were reduced, and the hormonal response exhibited differences in binding parameters of insulin.
Acetaminophen Hepatotoxicity and Targeted Rescue: A Model for Specific Chemotherapy of Hepatocellular Carcinoma
Authors: Wu George Y. , Wu Catherine H. , Rubin Mark I.
Published: March 2007

We have taken advantage of the presence of hepatic receptors for galactose–terminal (asialo–)glycoproteins to achieve targeted rescue of differentiated hepatocytes from acetaminophen–induced toxicity in vitro. To accomplish this, a conjugate was formed by covalent coupling of N–acetylcysteine (an acetaminophen antagonist) to galactose–terminal (asialo–)fetuin. We used two human hepatocyte–derived cell lines to test our targeted–rescue method: Hep G2 cells are capable of receptor–mediated endocytosis of galactose–terminal glycoproteins and PLC/PRF/5 cells are not. In the presence of acetaminophen alone, both cell lines demonstrated a similar concentration–dependent sensitivity. Growth rates of both cell lines became normal when N–acetylcysteine was administered in equimolar quantities with acetaminophen indicating that both cell lines had the potential of responding to the antagonist. When asialofetuin–N–acetylcysteine conjugate was given to both cell lines in the presence of acetaminophen, PLC/PRF/5, receptor (-) cells failed to respond. However, Hep G2, receptor (+) cells treated with asialofetuin–N–acetylcysteine conjugate under identical conditions, increased their populations and eventually reached confluence. Control conjugate fetuin–N–acetylcysteine as well as asialofetuin alone had no effect on either cell line.
Detection of An Igm Antiidiotype Directed Against Anti–Hbs in Hepatitis B Patients
Authors: Troisi Catherine L. , Hollinger Blaine F.
Published: March 2007

An IgM–specific anti–[anti–HBs] antibody was detected by radioimmunoassay using anti–IgM–coated beads and 125I–labeled anti–HBs. This antiidiotype was found only in the sera of hepatitis B virus–infected patients, both acute and chronic. However, not all HBsAg–positive patients exhibited this reaction, and activity was correlated with the presence of HBeAg. Approximately 93% of sera that contained antiidiotype activity also contained HBeAg. Conversely, 70% of the sera positive for HBeAg reacted in the IgM assay. No correlation was observed between the presence of antiidiotype and rheumatoid factor or elevated SGPT levels.

Two approaches were used to determine whether the reactive moiety was an IgM anti–[anti–HBs] as postulated or an IgM anti–HBs/HBsAg complex. It was shown that chicken anti–HBs sera, which does not share the common idiotype of human and other mammalian anti–HBs, did not block a positive reaction in this radioimmunoassay even though it specifically bound HBsAg. It was also demonstrated that treatment with polyethylene gylcol, which will precipitate IgM anti–HBs/HBsAg activity, did not precipitate the reactive moiety in 6 of 7 sera tested, lending further evidence to the existence of an IgM antiidiotype in these patients.

It is suggested that this antiidiotype directed against anti–HBs may be involved in a defective feedback mechanism resulting in the suppression of production of anti–HBs and maintenance of the carrier state.
Changes of Laboratory Variables With Time in Cirrhosis: Prognostic and Therapeutic Significance
Authors: Christensen Erik , Schlichting Poul , Fauerholdt Lis , Juhl Erik , Poulsen Hemming , Tygstrup Niels
Published: March 2007

The time change of laboratory variables in cirrhosis was studied by analysis of data from 488 patients with cirrhosis included in a controlled clinical trial of long–term prednisone vs. placebo.

In the placebo group, a marked regression towards normal was seen within 3 months of entry into the trial (increase in serum albumin, acetylcholinesterase, cholesterol, hemoglobin and decrease in erythrocyte sedimentation rate). The subsequent course did not show a clear pattern, except for a slight increase in serum bilirubin and decrease in albumin. When studied in relation to the time of death in patients dying from a “hepatic” cause, marked increase in bilirubin and decrease in prothrombin index, albumin and cholesterol were seen in the year prior to death with little change before that time.

In the prednisone group, a more marked decrease in bilirubin, SGOT, alkaline phosphatase, γ–globulin, sulfobromophthalein retention, erythrocyte sedimentation rate and increase in leukocytes, prothrombin index and cholesterol were seen during the first 3 months. In relation to time of death from a “hepatic” cause, similar changes were seen as in the placebo group except that alkaline phosphatase increased and cholesterol did not decrease.

A beneficial effect of prednisone on survival, as expressed by a previously developed therapeutic index, was associated with decrease in SGOT, alkaline phosphatase and γ–globulin within the first 3 months. An increase in SGOT during prednisone seemed to be associated with harmful effects of therapy.
A Randomized Comparison of Metoclopramide and Domperidone on Plasma Aldosterone Concentration and on Spironolactone–Induced Diuresis in Ascitic Cirrhotic Patients
Authors: D-Arienzo Agesilao , Ambrogio Gabriella , Siervi Pasqualina Di , Perna Enzo , Squame Giovanni , Mazzacca Gabriele
Published: March 2007

The effect of metoclopramide and domperidone, two dopamine antagonists, administered to cirrhotic patients with ascites and secondary hyperaldosteronism, was examined to evaluate the changes in plasma aldosterone levels and in spironolactone–induced diuresis.

In 15 patients with ascites and secondry hyperaldosteronism, the intravenous administration of 10 mg metoclopramide significantly increased plasma aldosterone levels (23%, p < 0.01). This effect was observed when an equivalent dose of domperidone was administered.

In 20 ascitic patients treated with spironolactone (300 mg per day), the administration of metoclopramide (20 mg) significantly reduced urinary output (24%, p < 0.001) and urinary sodium (35%, p < 0.001) while simultaneously increasing urinary potassium (24%, p < 0.001) and plasma aldosterone (40%, p < 0.001). This effect was not observed with domperidone in an equivalent dose.

Therefore, it is recommended that metoclopramide should be avoided during diuretic therapy in cirrhotic patients with ascites. In these circumstances, domperidone is preferred.
Histopathology of Early and Late Human Hepatic Allograft Rejection: Evidence of Progressive Destruction of Interlobular Bile Ducts
Authors: Vierling John M. , Fennell Robert H.
Published: March 2007

Cholestasis and injury of interlobular bile ducts occur during rejection of human hepatic allografts. However, knowledge of the nature and progression of bile duct injury during rejection remains incomplete. To define the role of inflammation in bile duct damage, we assessed the light microscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Nine patients with rejection were easily separated into two groups based on the duration of the allograft survival. The first group (early rejection) consisted of five patients in whom rejection occurred between 13 and 36 days. The second group (late rejection) consisted of four patients in whom rejection occurred between 170 and 912 days. Early rejection was characterized by distortion of bile ducts by adjacent inflammatory cell infiltrates, cytological changes of bile duct epithelial cells and occasionally by frank mononuclear cell inflammation of the epithelium with destruction of the duct. Late rejection was characterized by nonsuppurative destructive cholangitis culminating in the disappearance of interlobular bile ducts. Both groups exhibited histological cholestasis, intact limiting plates, preservation of hepatocytes and positive orcein stains for copper–binding protein. We conclude that the dominant histopathological feature of hepatic allograft rejection is progressive, nonsuppurative destructive cholangitis.
Hepatitis B Virus, Hepatitis Non–A, Non–B Virus and Hepatitis Delta Virus in Lyophilized Antihemophilic Factor: Relative Sensitivity to Heat
Authors: Purcell Robert H. , Gerin John L. , Popper Hans , London William T. , Cicmanec John , Eichberg Jorg W. , Newman Jack , Hrinda Michael E.
Published: March 2007

Lyophilized plasma derivatives are more stable to heat than when they are in the liquid state. Commercial Factor VIII (antihemophilic factor) was seeded with a measured quantity of hepatitis B virus. The contaminated material was then lyophilized and subjected to heat of 60°c for 30 hr. Chimpanzees were inoculated with the heat–treated antihemophilic factor or sham–treated antihemophilic factor that had been held at 4°c. Surprisingly, hepatitis B virus survived the heating procedure with no apparent loss in titer: the incubation period to appearance of HBsAg was that expected for the challenge dose of virus. Even more surprising, one chimpanzee (the recipient of the unheated antihemophilic factor) also developed non–A, non–B hepatitis and two chimpanzees (recipients of the heated antihemophilic factor) also developed delta hepatitis. Neither of these agents was a contaminant of the hepatitis B virus challenge pool, since the purity of this hepatitis B virus pool was established previously in chimpanzees. Thus, both a non–A, non–B agent and the delta agent apparently contaminated the commercial antihemophilic factor. This is the first direct evidence for contamination of antihemophilic factor with the delta agent and confirms previous seroepidemiologic evidence for its presence in pooled plasma derivatives. Subsequent inactivation studies were performed with antihemophilic factor experimentally contaminated with the Hutchinson strain of non–A, non–B hepatitis virus. In these studies, heating at 60°c for 30 hr in the dry state rendered antihemophilic factor free of detectable non–A, non–B hepatitis virus.
Transformation of Bile Acids Into Iso–Bile Acids By Clostridium Perfringens : Possible Transport of 3β–Hydrogen Via the Coenzyme
Authors: Batta Ashok K. , Salen Gerald , Shefer Sarah
Published: March 2007

We have examined the mechanism for the bacterial transformation of chenodeoxycholic acid and lithocholic acid into the corresponding 3β–hydroxy epimers with the use of 3α– and 3β–tritiated bile acids. The 3–oxo bile acids were transformed into the 3α– (85%) and 3β– (15%) hydroxy bile acids after 20–hr incubation with Clostridium perfringens. Approximately 75% radioactivity was recovered in the aqueous medium when [3β–3]chenodeoxycholic acid or [3β–3]lithocholic acid was incubated with the bacteria, and approximately 15% of radioactivity in the bile acid fraction was associated with the 3α–position of the iso–bile acids. When [3β–3]chenodeoxycholic acid was incubated with unlabeled 3–oxo–5β–cholanoic acid, tritiated litho– and iso–lithocholic acids were recovered. These results can be explained only when a 3–oxo intermediate is postulated, and the 3β–hydrogen in the bile acids is transferred by the bacterial coenzyme (NAD+ or NADP+) to the 3α–position in the iso–bile acids during the reduction of the 3–oxo compounds.
Acute Fatty Liver of Pregnancy: A Clinicopathologic Study of 35 Cases
Authors: Rolfes Donald B. , Ishak Kamal G.
Published: March 2007

Acute fatty liver of pregnancy is a disease of the third trimester which is generally considered to be rare and to have a grave prognosis. This study found an optimistic outlook for patients with acute fatty liver of pregnancy due to early termination of the pregnancy as well as the recognition of milder cases. In prospectively followed women, a maternal mortality of 8% and a fetal mortality of 14% were observed. The disorder also appears to be more common than previously suspected and should be considered in all women with liver dysfunction in late pregnancy, even if they are anicteric. Histologically, the characteristic fine droplet steatosis usually produces distinct vacuoli–zation in sections stained with hematoxylin–eosin. However, early in the course of the illness, liver cells have a ballooned appearance and the presence of lipid is masked. When accompanied by a significant necroinflammatory reaction, this stage may be difficult to distinguish from acute viral hepatitis. Whenever acute fatty liver of pregnancy is suspected, a small piece of the biopsy should be reserved for special stains to confirm the presence of lipid in frozen sections. Significant loss of hepatic parenchyma is a regular accompaniment of acute fatty liver of pregnancy and is due to hepatocytolysis, acidophilic degeneration and liver cell atrophy. Extramedullary hematopoiesis and giant mitochondria are often present; the latter change is probably an adaptive or degenerative response to an altered metabolic environment. Despite the frequent presence of signs and symptoms of toxemia in patients with acute fatty liver of pregnancy, no histologic overlap was observed, suggesting that they represent distinct etiologic entities.
The Morphologic Spectrum of Halothane–Induced Hepatic Injury: Analysis of 77 Cases
Authors: Benjamin Stanley B. , Goodman Zachary D. , Ishak Kamal G. , Zimmerman Hyman J. , Irey Nelson S.
Published: March 2007

Hepatic histopathology and clinical–pathologic correlations were studied in 77 patients who met clinical criteria for halothane hepatotoxicity. They were divided into groups based on the type of surgery (minor or major) and outcome (nonfatal, biopsy group or fatal, autopsy group). The two nonfatal groups (minor surgery and major surgery) and the two fatal groups (minor surgery and major surgery) were comparable with regard to age, time of onset from exposure, peak aminotransferase values and peak bilirubin determinations. A spectrum of histologic patterns was identified in these patients. It ranged from panlobular and multifocal spotty necrosis resembling viral hepatitis through submassive confluent zonal necrosis to massive necrosis. Progression of severity of injury from spotty to massive necrosis was more closely related to multiple exposures to halothane (and especially repeated exposure within less than three months), than to the extensive–ness of the associated surgical procedures.