bluuebunny/crossref_metadata_2025 huggingface dataset:
A Prospective Clinical Trial of D–Penicillamine in the Treatment of Primary Biliary Cirrhosis
Authors: Bodenheimer Henry C. , Schaffner Fenton , Sternlieb Irmin , Klion Franklin M. , Vernace Salvatore , Pezzullo John
Published: March 2007

We conducted a prospective clinical trial to assess the relative efficacy and safety of high– vs. low–dose D–penicillamine in patients with primary biliary cirrhosis. Following clinical tests and liver biopsy diagnostic of primary biliary cirrhosis, 56 patients were randomized to receive either 250 or 750 mg D–penicillamine daily. Patients were monitored with clinical tests and annual liver biopsy. Randomization produced two groups without differences in demographic, clinical or histologic characteristics. During the trial, no differences were seen between the mean change in liver test results in patients in either treatment group. The 11% per year rise of bilirubin in the 750 mg dose group during the first 3 years was not significantly different from the 18% per year rise in the 250 mg dose group. No patient showed improvement on liver biopsy although patients on 750 mg D–penicillamine deteriorated more slowly. Side effects, particularly rash and dysgeusia, were more common in the 750 mg dose group. The frequency and severity of side effects were responsible for the early conclusion of our trial. Twenty–six patients experienced side effects necessitating discontinuation of D–penicillamine. No evidence of increased efficacy was demonstrated by high–dose D–penicillamine therapy, and side effects were observed in patients on 250 mg D–penicillamine daily. With the severity of adverse effects and continued progression of disease, D–penicillamine is not a clinically useful therapy in primary biliary cirrhosis.
Halothane Hepatitis Without Halothane: Role of Inapparent Circuit Contamination and Its Prevention
Authors: Varma Rajiv R. , Whitesell Robert C. , Iskandarani Marwan M.
Published: March 2007

Halothane and other halogenated anesthetic agents are liquids which are highly soluble in rubber and plastic materials widely used as components of anesthesia machines. These agents must be administered using machines equipped with vaporizers. We report a patient with a past history of halothane hepatitis in whom recurrence was suspected despite the fact that halothane had been avoided purposely during the subsequent operation. Circumstances led us to believe that inapparent circuit contamination of vaporizer–equipped anesthesia machine with halothane may be responsible for the inadvertant rechallenge and recurrence of halothane hepatitis. Vaporizer–equipped machines were tested for inapparent contamination with halothane and enflurane using Perkin–Elmer mass spectrometer. Oxygen alone was passed through the anesthesia circuits, and gas in the efferent limbs of the machines was tested for halothane (in eight machines) and enflurane (in two machines) which were found in various concentrations in all machines so tested. Our findings suggest that inapparent contamination may be widely prevalent in vaporizer–equipped anesthesia machines. The validity of this conclusion was confirmed in five patients with previous diagnosis of halothane hepatitis who subsequently underwent opererations under general anesthesia during which machines never equipped with vaporizers were successful in preventing recurrence of hepatitis. We conclude that patients with a prior history of halothane hepatitis are at risk of inapparent circuit contamination–induced recurrent hepatitis. Unless such contamination can be confidently excluded, vaporizer–equipped machines should not be used to administer general anesthesia in these susceptible patients.
Intracellular Processing of Human Vs. Rat Immunoglobulin A in the Rat Liver
Authors: Jones Albert L. , Hradek Gary T. , Schmucker Douglas L.
Published: March 2007

It is well established that in the rat, rat dimeric IgA is transported from blood to bile across rat liver parenchymal cells via a series of minute smooth membrane–limited vesicles. This pathway is unique from that taken by a number of other ligands, which are internalized for degradation, in that there appears to be little involvement of coated vesicles, multivesicular bodies and lysosomes. The transmembrane receptor for IgA, secretory component, is not recycled but is secreted in part with the ligand into bile and must be produced continuously within the liver cell. Several recent studies have suggested that the receptor for asialoglycoproteins, as well as the structures involved in its processing, may play an important role in IgA processing. It was noted, however, that in all of these studies human polymeric IgA1 was used in the rat model. Using purified rat and human IgA preparations, we have demonstrated by light and quantitative electron microscopic autora–diography, as well as by certain biochemical procedures, that the two ligands are processed quite differently from one another in the rat. Human IgA disappears from the plasma at a slower rate and is much less efficiently transported into the bile. In addition, up to as much as 30% of the human IgA is diverted to the lysosomal pathway. This diversion of human polymeric IgA may be related to either the association of a serine–linked oligosaccharide at the hinge region of the human polymeric IgA1 or that large polymers, often found in human IgA preparations may initiate secretory component receptor aggregation, which in turn, interferes with the normal physiological processing of the IgA molecule.
Congenital Portacaval Shunt in Rats: Liver Adaptation to Lack of Portal Vein—A Light and Electron Microscopic Study
Authors: Bioulac-Sage Paulette , Saric Jean , Boussarie Lilianne , Balabaud Charles
Published: March 2007

In five rats with congenital portacaval shunt, liver atrophy, hyperplastic foci in the periportal zone, atrophic hepatocytes in the centrolobular zone, well–preserved hepatocyte ultrastructure with abundant rough endoplasmic reticulum, packed mitochondria and numerous peroxisomes were observed as in surgical portacaval shunt. However, portal triads were abnormal in contrast to surgical shunt. In large portal triads, hepatic arteries were prominent, bile ducts numerous and portal veins were lacking. Instead, small or large capillaries were seen in the portal tracts usually at the periphery. These capillaries appeared to be in continuity with nearby sinusoids presenting the ultrastructural characteristics of capillaries. These observations suggest that absence of the portal vein is compensated by formation of neocapillaries. It is assumed that these capillaries originate from periportal sinusoids and are necessary to distribute blood to all sinusoids and form a reservoir to lower arterial pressure.
On the Pathogenesis of Focal Nodular Hyperplasia of the Liver
Authors: Wanless Ian R. , Mawdsley Carolyn , Adams Ronald
Published: March 2007

Fifty–one focal nodular hyperplasia lesions from 36 patients were examined histologically. Serial sections and three–dimensional models were studied in selected cases. Lesions were multiple in 19% of patients. Thirty–four patients were female. One case had 11 focal nodular hyperplasia lesions and 7 hemangiomata in the liver. Three had astrocytoma and one had anomalous pulmonary venous drainage. Morphometric analysis revealed that the lesions were supplied by an anomalous artery larger than expected for the locale in the liver. This artery branched to form a spider–like structure and was usually not accompanied by a portal vein or duct. Each terminal arterial branch supplied a separate nodule 1 mm in diameter; adjacent nodules coalesced to form the focal nodular hyperplasia lesion. The arterial blood appeared to drain directly into the sinusoids of the nodule.

We propose that focal nodular hyperplasia is an hyperplastic response of the hepatic parenchyma to a preexisting arterial spider–like malformation. The frequent coexistence of focal nodular hyperplasia with other vascular and neuroendocrine anomalies suggest that the malformations are developmental in origin. The basic requirement for development of hepatic hyperplasia may be greater blood flow to a region compared to the adjacent parenchyma. This requirement appears to be met in the other forms of nodular transformation of the liver, i.e., nodular regenerative hyperplasia and partial nodular transformation.
Expression Of β 2-Microglobulin on Hepatocytes in Acute and Chronic Type B Hepatitis
Authors: Nagafuchi Yukihisa , Scheuer Peter J.
Published: March 2007

β2-Microglobulin display was examined in 131 liver biopsies from patients with acute and chronic type B hepatitis, using an indirect immunoperoxidase method. Enhanced expression of β2-microglobulin on hepatocyte membranes was observed in patients with acute hepatitis, chronic active hepatitis with moderate to severe activity and cirrhosis, when compared with normal liver. In acute hepatitis, β2-microglobulin–positive hepatocytes were mainly observed in perivenular areas in association with bridging necrosis. In chronic hepatitis, β2-microglobulin–positive hepatocytes were observed mainly in periportal zones and in some areas of lobular activty.

Diffuse–enhanced display of β2-microglobulin on hepatocytes was observed in 5 of 6 patients treated with lymphoblastoid interferon as part of a trial of antiviral therapy. The mechanism by which β2-microglobulin display is enhanced on hepatocytes in patients not treated with interferon is uncertain. However, display of β2-microglobulin on hepatocytes probably reflects display of HLA–A, B and C antigens and may influence the course of hepatitis B virus infection by increasing susceptibility of the affectedcells to T cell–mediated immune attack.
Value of Hepatic Iron Measurements in Early Hemochromatosis and Determination of the Critical Iron Level Associated With Fibrosis
Authors: Bassett Mark L. , Halliday June W. , Powell Lawrie W.
Published: March 2007

The role of the measurement of hepatic iron in the diagnosis of genetic hemochromatosis was studied, with particular reference to the differentiation of early hemochromatosis from alcoholic siderosis and the critical hepatic iron concentration associated with fibrosis in hemochromatosis. Hepatic iron was measured in 30 homozygous relatives of 17 hemochromatosis probands, 8 heterozygous relatives, 51 patients with alcoholic liver disease and 40 control subjects. Hepatic iron concentrations were greatly increased in the majority of homozygous hemochromatosis subjects, and there was little overlapwith the other groups. In the absence of alcoholism, fibrosis or cirrhosis in hemochromatosis was present only with hepatic iron concentrations above a threshold of approximately 400 μmoles per gm (22.3 mg per gm) dry weight. In some heterozygous hemochromatosis subjects and in some alcoholic patients, hepatic iron concentrations were in the range seen in young homozygous subjects. However, an age–related rise in hepatic iron was seen only in hemochromatosis homozygotes, and calculation of an hepatic iron index (hepatic iron/age) resulted in a clear distinction between homozygotes and the other three groups. It is concluded: (a) that chemical measurement of hepatic iron concentration, when corrected for the age of the subject, reliably distinguishes early hemochromatosis from alcoholic siderosis, and (b), that there appears to be a threshold level of hepatic iron above which there is a high risk of fibrosis.
Ultrastructural Evidence for the Presence of Ferritin–Iron in the Biliary System of Patients With Iron Overload
Authors: Cleton Maud I. , Sindram Jan W. , Rademakers Louk H.P.M. , Zuyderhoudt Floris M.J. , De Bruijn Willem C. , Marx Joannes J.M.
Published: March 2007

Ferritin–like particles were observed in bile canaliculi of patients with iron overload. These particles have been further investigated by: (1) a staining method enhancing the size and contrast of ferritin protein, and (2) electronprobe microanalysis detecting the presence of the elements iron and phosphorus.

Morphological observation of coated vesicles in the cytoplasm adjacent to the bile canaliculi and coated pits in the canalicular membrane suggests a transport mechanism via membrane–bound organelles.

Support is given to the theory that part of the iron, stored in the liver, leaves the hepatocyte by excretion of ferritininto the bile.
Ccl4-Induced Toxicity in Isolated Hepatocytes: the Importance of Direct Solvent Injury
Authors: Berger Marc L. , Bhatt Harshika , Combes Burton , Estabrook Ronald W.
Published: March 2007

CCl4 is proposed to induce cellular injury through its metabolites that are generated by a cytochrome P–450 dependent step. These free radical products can interact with membrane structures, thereby generating lipid peroxides. The latter process has been implicated as a major mechanism of CCl4 hepatoxicity, although this relationship has been difficult to demonstrate when using isolated hepatocyte preparations. This report demonstrates that there are at least two mechanisms by which CCl4 induces injury in isolated hepatocytes. One occurs within minutes of exposure to CCl4 and is characterized by modest malondialdehyde formation and no decline in cellular–reduced glutathione. SKF 525A, metyrapone and promethazine did not protect against this early damage. A second phase of damage, evident particularly after 3 hr, is characterized by a marked increase in malondialdehyde formation, a fall in cellular glutathione and substantial further cellular damage. These changes could be moderated by the cytochrome P–450 inhibitors and promethazine, and antioxidant. Further examination of the initial phase of damage reveals an immediate dose–related inhibition of O2 consumption. This could not be prevented by SKF 525A or metyrapone and was associatedwith loss of ability to stimulate mitochondrial respiration with dinitrophenol. Rapid recovery to initial O2 consumption rates occurred with time as CCl4 evaporated from the incubation system. This was associated with a partial return of dinitrophenol stimulation of mitochondrial O2 consumption despite significant glutamate dehydrogenase release. A portion of this recovery could be inhibited by SKF 525A, suggesting that some O2 consumption was due to CCl4 metabolism and ensuing lipid peroxidation. These data suggest that early CCl4 toxicity is adirect consequence of its solvent properties and is partially reversible; subsequent damage may be mediated by lipid peroxidation. This solvent injury has not been previously recognized and may have relevance not only to a reversible toxicityas demonstrated with isolated hepatocytes but also in vivo as well.
Hemostasis and Fibrinolysis in Severe Liver Failure and Their Relation to Hemorrhage
Authors: Boks Anton L. , Brommer Emile J.P. , Schalm Solko W. , Van Vliet Huub H.D.M.
Published: March 2007

In a study of severe, decompensated liver failure, we tried to find a correlation between hemorrhage and parameters ofhemostasis and fibrinolysis. Three groups of patients were studied: alcoholic cirrhosis; nonalcoholic cirrhosis, and acute liver failure without known prior liver disease. The two cirrhotic groups did not differ significantly from each other in coagulation or in fibrinolytic parameters, although liver function was more impaired in nonalcoholic cirrhosis. The levels of clotting factors, antithrombin III, prekallikrein, plasminogen and α2-antiplasmin were significantly lower in the third group. Mean values of fibrinolytic activity (fibrin plate method) were slightly reduced as compared to normal in all three groups. Tissue plasminogen activator–related antigen tended to be elevated especially in alcoholic cirrhosis. The free fast–acting plasminogen activator inhibitor showed extremely high and extremely low levels in some patients among all three groups.

Nonvariceal, capillary–type bleeding, including mucosal bleeding, hematomas and bleeding from puncture sites correlated with low thrombotest and normotest levels (p < 0.01), low fibrinogen concentration (p < 0.05) and with a high quotient of fibrinolytic activity (square root of lysis area) and normotest (p < 0.001). The ratio between fibrinformation and dissolution appears to be an important parameter of hemorrhagic tendency in liver disease. Variceal bleeding appeared not to be related to impairment of hemostasis or fibrinolysis.
Effect of Propranolol on Hepatic and Systemic Hemodynamics in Dogs With Chronic Bile Duct Ligation
Authors: Willems Bernard , Villeneuve Jean-Pierre , Huet P.-Michel
Published: March 2007

Propranolol has been reported to reduce portal and wedged hepatic vein pressures in man and may be useful for the prevention of variceal bleeding. However, its mechanism of action remains unclear. We have examined the effect of propranolol on the systemic and hepatic circulations in dogs with chronic bile duct ligation and secondary biliary cirrhosis. Underanesthesia, eight dogs received four increasing doses of propranolol as an i.v. bolus followed by continuous infusion. Systemic and hepatic hemodynamic parameters were measured in basal conditions and after a 30 min infusion for each dose. Portal vein and hepatic artery blood flows were measured with electromagnetic flow meters. All dogs had portal hypertension(portal venous pressure 15.3 ± 0.8 mm Hg), a hyperdynamic circulation and severe liver disease resulting in a marked decrease of propranolol systemic clearance (8.75 ml per min per kg) and extraction (40%). The first dose of propranolol induced a decrease in heart rate (-27%) and in cardiac index(-21%), and an increase in systemic vascular resistance (+20%). With increasing doses, the systemic vascular resistance decreased with an increase in the cardiac index. Propranolol was not associated with significant modifications of hepatic hemodynamics: portal, wedged and free hepatic venous pressures and hepatic artery blood flow were stable, and portal blood flow decreased slightly at very high propranolol levels. In seven dogs studied without dissection of the hepatic vessels, there was a small decrease in portal pressure, but not in wedged and free hepatic venous pressures with increasing doses of propranolol. Thus, in dogs with intrahepatic portal hypertension, propranolol has significant effects on systemic hemodynamics, but only minimal effects on the hepatic circulation.
Portal Venous–Esophageal Luminal Pressure Gradient in Cirrhosis
Authors: Reding Pierre , Urbain Daniel , Grivegnee André , Frere Daniel
Published: March 2007

The portal venous–esophageal luminal pressure gradient may be more important than the absolute portal venous pressure in explaining hemorrhages caused by esophageal varices. A continuous recording of portal venous pressure and the esophageal luminal pressure enabled the authors to study the gradient between these pressures in 12 cirrhotic patients with varices of different size and under different circumstances, in particular inspiration, expiration, coughing and a Valsalva maneuver.

A significant increase of portal venous pressure occurred during inspiration (+15%), coughing (+77%) and Valsalva maneuver (+157%). The value of portal venous–esophageal luminal pressure gradient increased during inspiration (+38%), coughing (+90%) and Valsalva maneuver (+69%) while it decreased during expiration (-14%).
Impaired Antibody Synthesis in Patients With Chronic Hepatitis B Infection
Authors: Nowicki Marek J. , Tong Myron J. , Nair Prem V. , Stevenson Douglas
Published: March 2007

In vitro synthesis of the anti–HBc, anti–HBs and polyclonal IgG and IgM classes of antibodies were determined from supernatants of peripheral blood mononuclear cells cultured in the presence of pokeweed mitogen. Thirty–seven patients with chronic hepatitis B and 10 healthy control subjects whose sera were positive for anti–HBs formed the study group. Twenty–four of 37 patients showed histologic evidence of chronic active hepatitis B while the remaining 13 patients had chronic persistent hepatitis B. Lymphocytes from chronic persistent hepatitis B, chronic active hepatitis B and healthy controls secreted similar levels of IgM. However, IgG synthesis was markedly impaired (p < 0.002) in the chronic persistent hepatitis B group as compared with healthy controls or chronic active hepatitis B patients. In vitro anti–HBc production and serum anti–HBc titers correlated directly with hepatocellular inflammation and inversely with serum hepatitis B virus DNA. Anti–HBc synthesis was significantly higher in chronic active hepatitis B patients who exhibited a more pronounced hepatocellular damage when compared to chronic persistent hepatitis B patients who had little or no liver cell injury.
Studies of Gene Transcription and Translation in Regenerating Rat Liver
Authors: Huber Brian E. , Heilman Carole A. , Wirth Peter J. , Miller Mark J. , Thorgeirsson Snorri S.
Published: March 2007

Specific transcriptional and translational products associated with regenerating liver were analyzed by differential hybridization to a cDNA library and by two–dimensional electrophoresis of hepatic proteins, respectively. Comparisons of approximately 800 soluble and 800 particulate liver proteins from normal and 70% partially hepatectomized Fischer rats resulted in the identification of only three apparently unique polypeptides in 70% partially hepatectomized livers, although many quantitative changes were observed. A subset of these quantitative changes were also observed after sham operation. A cDNA library was generated from polyadenylated RNA isolated 18 hr post–70% partial hepatectomy. Comparative analysis of 6,000 transformantswith single–stranded cDNA probes prepared from 18 hr post–70% partial hepatectomy and sham–operated animals identified three clones whose sequences were preferentially expressed 4– to 6–fold 18 hr post–70%partial hepatectomy. Southern blot analysis of one clone, REG–A, showed no homology to albumin, α–fetoprotein, three different forms of cytochrome P–450, ornithine decarboxylase, globin, or to a putative tumor promotion associated gene called PRO–2. A single, REG–A specific 2.5 kb band was identified by Northern blot analysis of liver samples. REG–A expression was increased 2–fold 18 hr postsham operation; 4–fold 18 hr post–70% partialhepatectomy and following chronic 2,3,7,8–tetrachlorodibenzo–p–dioxin or phenobarbital treatment. REG–A expression returned to control levels 1 week after 70% partial hepatectomy. Furthermore, expression of REG–Awas reduced in chemically induced preneoplastic nodules and in primary and transplantable hepatomas. Hybrid selection studies indicated that the REG–A sequence selected a mRNA(s) species, that in an in vitro translation assay, produced two major polypeptides of 21,000 and 25,000 molecular weight with a pI of 6.9.

Thus, these data support the hypothesis that liver regeneration is characterized byquantitative changes in genes normally expressed at low levels in the Go hepatocyte andis not the result of major qualitative changes in gene expression.
Cell Types Involved in Collagen and Fibronectin Production in Normal and Fibrotic Human Liver
Authors: Clement Bruno , Grimaud Jean-Alexis , Campion Jean-Pierre , Deugnier Yves , Guillouzo Andre
Published: March 2007

Three collagen types (I, III and IV) and fibronectin were localized in normal and alcoholic human liver by light and electron microscopy using the indirect immunoperoxidase technique. In normal liver, most of the bundles of collagen fibers stained for type pro–III collagen while only a few reacted for type I. Basement membranes stainedfor type IV collagen which formed discontinuous discrete deposits in sinusoids. Only fibronectin appeared as an almost continuous layer in the space of Disse. At the intracellular level, hepatocytes were found to contain little type I collagen and large amountsof fibronectin. Fat–storing cells strongly stained for type IV collagen and expressed low amounts of types I and III collagen and fibronectin. Endothelial cells contained low amounts of all the components.

Alcoholic livers were studied at three stages: steatosis, fibrosis and cirrhosis. Qualitative and quantitative differences were observed in extracellular and intracellulardistributions of matrix proteins. Increased amounts of all components were usually found in fibrotic and cirrhotic livers compared to normal liver. In two fibrotic livers which contained numerous bundles of collagen in the sinusoids, fat–storing cells stained more intensely for type III collagen. In a cryptogenic fibrotic liver, abundant type IV collagen was observed in hepatocytes.

These results suggest that hepatocytes, fat–storing cells and endothelial cells are engaged in production of extracellular matrix components in normal human liver. In fibrosis, hepatocytes which normally did not synthesize types III and IV collagen mayproduce these collagens.
Sodium Excretion in Advanced Cirrhosis: Effect of Expansion of Central Blood Volume and Suppression of Plasma Aldosterone
Authors: Nicholls Kathleen M. , Shapiro Michael D. , Kluge Rudiger , Chung Hsaio-Min , Bichet Daniel G. , Schrier Robert W.
Published: March 2007

Sodium excretion in 13 patients with decompensated cirrhosis was measured under baseline conditions of water loading (n = 13) and during conditions designed to improve effective blood volume including: head–out water immersion alone (n = 13); norepinephrine infusion alone (n = 6), and combined norepinephrine and head–out water immersion (n = 6). All 13 patients were in positive sodium balance under baseline conditions, with a mean plasma aldosterone concentration of 78.7 ± 15.6 ng per dl. In only four patients was plasma aldosterone less than 50 ng per dl. During head–out water immersion alone, 5 patients achieved negative sodium balance and, in all 5, plasma aldosterone was less than 50 ng per dl (mean = 23.0 ± 5.3 ng per dl). However, the mean plasma aldosterone during head–out water immersion in the eight patients who remained in positive sodium balance during this maneuver was 64.0 ± 11.9 ng per dl (p < 0.01). During norepinephrine alone, positive sodium balance was maintained in all patients, and plasma aldosterone was not significantly different from baseline. Combining norepinephrine and head–outwater immersion resulted in the largest and most consistent negative sodium balance. The mean plasma aldosterone concentration was decreased significantly (78.7 ± 15.6 to 32.6 ± 9.9) ng per dl (p < 0.05). Regardless of the maneuver performed, nopatient in whom aldosterone exceeded 50 ng per dl achieved negative sodium balance. Furthermore, only in those studies utilizing head–out water immersion, with or without norepinephrine, was negative sodium balance seen. The results, therefore, suggest that expansion of central blood volume with suppression of plasma aldosterone overcomes sodium avidity in decompensated cirrhosis.
Abnormalities of Neutrophil Phagocytosis, Intracellular Killing and Metabolic Activity in Alcoholic Cirrhosis and Hepatitis
Authors: Rajkovic I. A. , Williams Roger
Published: March 2007

Neutrophil functions of phagocytosis and intracellular killing of bacteria were examined in 40 patients with alcoholic cirrhosis of whom 18 had a superimposed acute alcoholic hepatitis. In 65% of these, defective neutrophil phagocytosis was demonstrable, and in 62.5% there was a defect of intracellular killing of either Staphylococcus aureus or Escherichia coli. Studies of the patients' serum failed to reveal inhibitors of neutrophil function. Additional assays of superoxide (O2
-) and hydrogen peroxide production, hexose monophosphate shunt activity, degranulation and cellular levels of granule enzymes and glutathione revealed that these neutrophil defects are caused by both reduced production of superoxide and defects of degranulation. The hydrogen peroxide/superoxide molar ratio was raised in patients' neutrophils, and the strong inverse correlation found between the value of this ratio and intracellular levels of reduced glutathione would be consistent with thehypothesis that the neutrophils from patients with cirrhosis are unable to detoxify hydrogen peroxide effectively and that this is a result of reduced levels of glutathione in the cells. The consequent increase in oxidant stress, both intra–and extracellularly, may be the cause of phagocytic and degranulation defects. The reduced responsesof patients' neutrophils may be caused by previous exposure of the cells to activating stimuli in circulation, as evidenced by depleted intracellular levels of granule enzymes and glutathione.

Neutrophils from the patients with a superimposed acute alcoholic hepatitis had depressed phagocytosis in the early stages of incubation but, on the whole, neutrophils from these patients had a greater capacity for ingestion and killing of bacteria than neutrophils from patients with cirrhosis alone. Other neutrophil functions and metabolic activities were also significantly better than in patients with cirrhosis alone, and the reason for this may lie in the greater proportion of young neutrophils in the circulation of patients with superimposed acute alcoholic hepatitis.

The exhaustion of the neutrophils' bactericidal capacity in severe alcoholic liver disease, most marked in patients with cirrhosis alone, could be a significant factor in the well–described increased susceptibility of these patients to bacterial infection.
The Relationship Between Glucagon and Prostaglandin F in Stimulating Canine Hepatic Bile Flow
Authors: Kaminski D. L. , Deshpande Y. G.
Published: March 2007

Both glucagon and prostaglandin F2α have been shown to stimulate a chloride–rich choleresis in dogs. This study was performed to ascertain the interrelationship between glucagon and prostaglandin F2α in stimulating bile flow. The experiments were performed using dogs with chronic biliary and gastric fistulas. Initially, the effects of prostaglandin F2α on serum glucagon levels were evaluated. Glucagon administration increased bile volume andchloride secretion as did prostaglandin F2α. Serum glucagon levels during prostaglandin F2α administration were increased significantly over baseline values. During prostaglandin F2α administration, the increase in serum glucagon concentration correlated well with the increase in hepatic bile flow. Administration of somatostatin, a hormone known to inhibit glucagon release, prevented the choleresis produced by prostaglandin F2α while simultaneously eliminating the hyperglucagonemia. Subsequently, the effects of glucagon on bile prostaglandin F secretion and the effect of prostaglandin synthetase inhibition on glucagon choleresis were evaluated. Bile prostaglandin F secretion increased from control values of 101 ± 27 pg per min (mean ± S.D.) during bile salt infusion alone to 1,498 ± 1,086 pg per min during the administration of 1 μg kg-1 hr-1 glucagon. The prostaglandin synthetase inhibitor, indomethacin, significantly decreased the choleresis, the increased bile chloride secretion and the increased bile prostaglandin F secretion produced by glucagon. The results of this study indicate that prostaglandin F2α-stimulated bile flow is primarily the result of glucagon release and suggest that prostaglandin F2α may be involved in glucagon secretion. The inhibition of glucagon choleresis by indomethacin is compatible with the hypothesis that prostaglandin F2α partially mediates the response of the hormone associated with increased chloride secretion. Prostaglandin F2α may be involved in glucagon choleresis both during release of the hormone and at the site of its action.
The Effects of Aging on the Hepatic Microsomal Mixed–Function Oxidase System of Male and Female Monkeys
Authors: Maloney Alan G. , Schmucker Douglas L. , Vessey Donald S. , Wang Rose K.
Published: March 2007

Studies were conducted to determine the effects of aging on certain biochemical andbiophysical properties of the hepatic microsomes and on the kinetic properties of a constituent drug–metabolizing enzyme and a heme protein in a nonhuman primate. Outbred male and female rhesus monkeys (Macaque mulatta) ranging in age from 1 to 25 years were employed as animal models. There was considerable individual variability, but no significant age or sex–related changes in (1) the concentration of microsomal protein or (2) the content of the cytochromes P–450. Although the oldest animals examined for NADPH cytochrome c (P–450) reductase activity were only 19 years of age, the specific activity of this important enzyme increased rather than decreased during aging. There were only minor changes in the total phospholipid content of the microsomes and none in the distribution profile of the major phospholipid classes. However, the microsomal cholesterol content increased sufficiently to cause a rise in the cholesterol/phospholipid ratio between 16 and 25 years of age. The fluidity of the membrane lipid domain exhibited a concomitant decline as measured by electron spin resonance spectroscopy. There was no apparent correlation between age–related changes in these physicochemical properties of the microsomes and the in vitro activities of the constituent drug–metabolizing enzymes or heme proteins. Furthermore, the marked disparities between the data obtained in inbred male rodents and those from outbred primates suggest that the extrapolation of the former to humans is of questionable value with respect to liver drug metabolism.
Late Onset Hepatic Failure: Clinical, Serological and Histological Features
Authors: Gimson Alexander E.S. , O'Grady John , Ede Roland J. , Portmann Bernard , Williams Roger
Published: March 2007

The clinical, laboratory and histological features of 47 patients with what is defined as late onset hepatic failure are reviewed. Twenty–five of the patients werefemale and 22 male with a median age of 45 years. Hepatic dysfunction was severe as evidenced by the prolongation of prothrombin time (median = 32 sec, range = 17 to 120 sec). In only four cases was a viral etiology proven (2 hepatitis B, 2 hepatitis A) although the similarity of the clinical features to patients with fulminant viral hepatitis—apart from the longer period of illness prior to the onset of encephalopathy (median = 9 weeks, range = 8 to 24 weeks)—made non–A, non–B infection a possibility in the remainder. There were also similarities to chronic active hepatitis with low titer antibodies to smooth muscle or antinuclear factor in 17% and elevation of the serum IgG in 49%. Liver biopsy in 5 of 8survivors more than 1 year after initial presentation showed chronic active hepatitis in three. Lobular inflammatory infiltrate, bridging necrosis and multilobular collapse were the features of the acute stage of illness in both the survivors and fatal cases. The patients given corticosteroids did not have a statistically significant improvement in survival, and overall mortality for the series was 81%. Hepatic transplantation, successfully performed in one patient, would appear to offer the best chance of survival for the majority of these patients.
Elevated Serum Aminotransferase Induced by Isoniazid in Relation to Isoniazid Acetylator Phenotype
Authors: Yamamoto Tetsuo , Suou Takeaki , Hirayama Chisato
Published: March 2007

Of 143 patients with pulmonary tuberculosis receiving isoniazid therapy, 52 (36%) had a transient elevation in serum aminotransferases. Among 74 patients taking isoniazid, rifampicin and streptomycin, 35 (47%) had such an increase, while of 69 patients taking isoniazid, amino–salicylic acid and streptomycin, 17 (24%) did; this difference was significant. Isoniazid therapy could be continued in all patients with the abnormal test results. In 36 of the patients receiving isoniazid, rifampicin and streptomycin, isoniazid and its metabolites were studied in the serum and urine using high–performance liquid chromatography after the oral administration of 10 mg per kg of isoniazid. We had chosen for this test 18 patients with normal aminotransferase levels and 18 with abnormal levels. There were 14 rapid acetylators in the patients with abnormal aminotransferase levels and 7 rapid acetylators in the patients with normal levels; this difference was significant. These results indicate that liver dysfunction is more often caused by an isoniazid/rifampicin regimen, and patients who are rapid acetylators are more susceptible.
Ultrastructure of Experimental Cocaine Hepatotoxicity
Authors: Gottfried Marcia R. , Kloss Michelle W. , Graham Doyle , Rauckman Elmer J. , Rosen Gerald M.
Published: March 2007

Cocaine is a potent hepatotoxin in mice. It is converted in the liver by a minor oxidative pathway to the active metabolite, norcocaine nitroxide. Previous studies have shown evidence of a lipid peroxidative mechanism of toxicity, including increased conjugated diene absorption by hepatic microsomal lipids following a single 60 mg per kg i.p. dose of cocaine in DBA/2Ha mice. To explore this mechanism further, morphologic changesin the livers of DBA/2Ha mice were examined following the same dose of cocaine. The first ultrastructural change seen was dilatation of rough endoplasmic reticulum in centrilobular hepatocytes 1 hr following cocaine injection, coincident with the previously observed onset of increased conjugated diene absorption in microsomal lipids. During the previously observed period of peak conjugated diene absorption (2 to 4 hr), ultrastructural changes in centrilobular hepatocytes progressed. These included focal mitochondrial membrane disruption followed by more extensive mitochondrial swelling and disruption with increased swelling of rough endoplasmic reticulum. Changes in size, shape and concentration of histochemically labeled, morphometrically studied peroxisomes were also seen during this interval. Injury of centrilobular hepatocytes advanced to cell death in 6 to 8 hr. The time course and nature of these morphologic findings correlate with previously observed evidence of lipid peroxidation, supporting the hypothesis that this is the mechanism of cocaine hepatoxicity.
The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis
Authors: Graham W. , Cooksley E. , Bradbear Robin A. , Robinson William , Harrison Mark , Halliday June W. , Powell Lawrie W. , Ng Han-Seung , Seah Chen-Siang , Okuda Kunio , Scheuer Peter J. , Sherlock Sheila
Published: March 2007

Sixty-nine patients with chronic active hepatitis without cirrhosis were studied to define the prognostic implications of bridging necrosis of various types. There were 19 patients without bridging necrosis compared with 50 patients with bridging necrosis. The two groups did not differ significantly at presentation in age, sex, clinical or laboratory features. In the group without bridging necrosis, no patient died from the disease and none of 13 having a later biopsy developed cirrhosis. In the group with bridging necrosis, one patient died from hepatic failure and 7 of 36 developed cirrhosis (19%). When analyzed statistically, a significant (p<0.05) relationship is seen between increasing severity of initial lesion and the subsequent development of cirrhosis. It is concluded that patients with piecemeal necrosis without bridging should not be grouped together with patients with bridging necrosis or cirrhosis when considering management decisions.
HLA class I antigens on the hepatocyte membrane during recovery from acute hepatitis B virus infection and during interferon therapy in chronic hepatitis B virus infection†
Authors: Pignatelli Massimo , Waters Jenny , Brown Dave , Lever Andrew , Iwarson Sten , Schaff Zsuzsa , Gerety Robert , Thomas Howard C.
Published: March 2007

In a chimpanzee model of acute type B hepatitis, at the time of onset of hepatitis B virus replication and before the development of immunity to hepatitis B virus, interferon is present in the plasma. This is followed by an increase in the display of HLA class I, but not class II proteins, on the hepatocyte membrane.

In chronic hepatitis B virus infection, there is a low density of HLA class I protein display on the infected hepatocyte. Administration of α-interferon enhances HLA display and in many cases is followed by a transaminase elevation, seroconversion of HBe antigen to antibody and disappearance of hepatitis B virus DNA from serum, changes implying clearance of infected hepatocytes. Successful response to interferon therapy may be predicted by a rapidly rising serum β-microglobulin, a component of the HLA class I molecule, during the first 2 weeks of therapy, before the rise in transaminases.
Prevention of maternal-infant hepatitis B virus transmission by immunization: The role of serum hepatitis B virus DNA
Authors: Lee Shou-Dong , Lo Kwang-Juei , Wu Jaw-Ching , Tsai Yang-Te , Wang Jiin-Yu , Ting Ling-Pai , Tong Myron J.
Published: March 2007

Sera from 108 HBsAg carrier mothers at delivery and their respective offspring at birth and at 6 months of age were examined for hepatitis B virus DNA by the dot-blot hybridization technique. Hepatitis B virus DNA was detected in 83% of 88 carrier mothers who were HBeAg positive, and in 10% of 20 carrier mothers who were HBeAg negative. All five infants born to HBeAg-positive carrier mothers with hepatitis B virus DNA levels over 80 pg per 10 μl of serum were infected by hepatitis B virus, in spite of receiving hepatitis B immunization. All 17 infants without hepatitis B immunization who were born to HBeAg and hepatitis B virus DNA-positive carrier mothers developed hepatitis B virus infection. Of 56 infants born to HBeAg and hepatitis B virus DNA-positive carrier mothers and who had received hepatitis B immunization, a higher hepatitis B virus infection rate was found in a group of infants whose sera hepatitis B virus DNA were positive (15/16, 93.8%) than in infants whose sera were negative (17/40, 42.5%) at birth (p<0.0005). These data suggest that the assay for hepatitis B virus DNA in sera of HBsAg carrier mothers at delivery or their infants at birth will predict the efficacy of hepatitis B immunization for prevention of maternal-infant hepatitis B virus transmission.
Diuresis of cirrhotic ascites increases its opsonic activity and may help prevent spontaneous bacterial peritonitis
Authors: Runyon Bruce A. , Van Epps Dennis E.
Published: March 2007

Serial ascitic fluid samples were obtained during diuresis in seven patients with portal hypertension-related ascites. The samples were tested for concentrations of total protein, CH100, C3 and C4 as well as for in vitro opsonic activity. These parameters were all found to increase to a statistically significant degree when the initial specimen was compared to the final specimen: total protein=1.5 vs. 2.7 gm per dl; CH100=9.3 vs. 20.2 units per ml; C3=13.4 vs. 23.8 mg per dl; C4=1.9 vs. 3.6 mg per dl, and opsonic activity=0.8 vs. 1.9 log kill. This increased opsonic activity resulted in a greater than 10-fold increase in bacterial killing. This study demonstrates that diuresis of patients with cirrhotic ascites increases the concentrations of ascitic fluid complement components and increases the opsonic activity of ascitic fluid and may help protect patients from bacterial infection of their ascites.
Hemodynamic studies in long- and short-term portal hypertensive rats: The relation to systemic glucagon levels
Authors: Sikuler Emanuel , Groszmann Roberto J.
Published: March 2007

It is not known whether the hyperdynamic state which has been observed in several experimental models and in patients with portal hypertension reflects a temporary phase during the evolution of the portal hypertensive syndrome or is an expression of a permanent steady state. A hemodynamic study was performed in a group of rats with long-standing portal hypertension induced by portal vein constriction performed 6.2 ± 0.1 months earlier. A group of rats matched by age and weight with short-term (20.7 ± 0.9 days) portal hypertension and a group of long-term (6.2 ± 0.1 months) sham-operated rats were used as controls. Cardiac output and regional blood flows were measured using a radioactive microsphere technique. Arterial blood levels of glucagon, a known vasodilator that was implicated in the etiology of the hyperdynamic circulation, were also measured. Portal pressure in long- and short-term portal hypertensive groups (12.3 ± 0.4 and 13.7 ± 0.4 mm Hg; not statistically significant) was higher than in the sham group (9.0 ± 0.3 mm Hg; p<0.01). Cardiac output in the long-term portal hypertensive rats was similar to the sham-operated group and lower than in the short-term portal hypertensive group (19.4 ± 1.0 and 20.6 ± 1.5 vs. 32.7 ± 2.0 ml·min−1. 100 gm body weight−1; p<0.01). Portal venous inflow in the long-term portal hypertensive group was also similar to the sham group and lower than in the short-term portal hypertensive group (4.51 ± 0.36 and 4.58 ± 0.39 vs. 6.72 ± 0.48 ml·min−1 100 gm body weight−1; p<0.01). Systemic glucagon levels were 244 ± 17 and 297 ± 33 pg·ml−1 in long- and short-term portal hypertensive groups, respectively (not statistically significant). Glucagon level in the sham group was lower (181 ± 22 pg·ml−1; p<0.05) compared to the other two groups. These results indicate that after long-term portal vein constriction, the hyperdynamic circulation disappears while the portal hypertension persists. Whether this is unique to this model or is a universal phenomenon in portal hypertension has yet to be established. High glucagon blood levels do not induce a hyperdynamic circulation in chronic portal hypertension.
Cytosolic bile acid binding protein in rat liver: Radioimmunoassay, molecular forms, developmental characteristics and organ distribution
Authors: Stolz Andrew , Sugiyama Yuichi , Kuhlenkamp John , Osadchey Bruce , Yamada Tadataka , Belknap William , Balistreri William , Kaplowitz Neil
Published: March 2007

Rat liver efficiently extracts bile acids from the portal blood and rapidly excretes them into bile. Little is known about the process by which bile acids traverse the liver cell from the sinusoidal to the canalicular membrane. In order to begin to define this process, we recently identified a pair of similar monomeric (33 kilodalton) cytosolic bile acid binding proteins (bile acid binders I and II, J. Biol. Chem. 1983; 258:3602-3607, Abstract). These bile acid binders have comparable binding affinities for bile acid as the YaYa and YaYc members of the family of glutathione S-transferases, the previously recognized cytoplasmic bile acid binding protein. We now report the establishment of a sensitive and specific radioimmunoassay which equally detects both bile acid binders I and II. Specificity of the antiserum was verified by the co-purification of bile acid binder immunoreactivity with the bile acid binders. Liver contained the greatest concentration of bile acid binder, where it constituted 0.33% of the total cytosolic proteins. Phenobarbital administration and lithocholate feeding had no significant effect on hepatic bile acid binder content. Examination of the ontogeny of bile acid binder revealed a rapid increase after birth to near adult levels by Day 14. In summary, we have established a sensitive radioimmunoassay for the bile acid binders. Its localization mainly in liver and its increase after birth parallel bile acid transport in the liver.