bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency, Significance and Therapy of the Mallory–Weiss Syndrome in Patients With Portal Hypertension
Authors: Paquet Karl J. , Mercado-Diaz Miguel , Kalk Johann F.
Published: March 2007

The files of patients who underwent emergency endoscopy in a 2–yr period (January 1985 to January 1987) in the Heinz–Kalk Hospital were analyzed to establish the frequency, significance and therapy of the Mallory–Weiss syndrome associated with portal hypertension, an association observed in 55 of 339 patients (16.2%). Portal hypertension was caused by cirrhosis in 53 patients and by a prehepatic block in two patients. For 21 of these patients (37%) with portal hypertension, Mallory–Weiss syndrome was the first bleeding manifestation. They numbered 6.2% of the whole population. In the remaining 34 patients (63%) sclerotherapy treatment had been previously performed. No lesions that suggested peptic esophagitis were seen in these 55 patients, although in 25 of them (45.4%) a gastroesophageal reflux was observed. The frequency of bleeding from a Mallory– Weiss tear was significantly higher in patients with advanced liver disease, particularly with Child–Pugh classifications C and B. In patients with prehepatic block, a hemorrhage from a Mallory–Weiss tear may occur, but the frequency is significantly lower than it is in patients with cirrhosis. The bleeding tear was treated by transendoscopic esophageal and cardial wall sclerosis (paravariceal technique) and was, in all cases, successfully controlled. Mallory–Weiss syndrome is observed more frequently in patients with portal hypertension and cirrhosis. Gastroesophageal reflux apparently does not play a major role in the pathogenesis of this syndrome. It may simply be the manifestation of an abnormal gastroesophageal function. Mallory–Weiss syndrome can also be observed as a cause of rebleeding in patients treated with chronic sclerotherapy. Paravariceal endoscopic sclerotherapy is apparently the treatment of first choice to stop hemorrhage.
Apolipoproteinemia A and α–Fetoprotein in the Diagnosis of Hepatocellular Carcinoma and Cirrhosis: Several Interpretations
Authors: Poynard Thierry
Published: March 2007

The serum apolipoprotein A (Apo A) and α–fetoprotein (AFP) were evaluated in histologically verified 30* cases of alcoholic cirrhosis and 18 cases of hepatocellular carcinoma (HCC). The latter were also divided into subgroups depending on the presence or absence of associated cirrhosis. Serum Apo A levels were found to be significantly decreased in cirrhotics (p < 0.001) compared to controls and non–cirrhotic HCC patients. In 22 cases of alcoholic cirrhosis (AFP < 10 ng/ml) and 12 cases of HCC (AFP > 600 ng/ml), the AFP levels itself* were diagnostic, but in the remaining cases, AFP levels (100–600 ng/ml) were not able to differentiate between cirrhosis and malignancy. In this later group of patients with low pathological range of AFP, serum Apo A levels found to be significantly decreased in alcoholic cirrhotic patients (p < 0.001) compared to HCC patients. Thus, estimation of Apo A levels may be helpful to interpret the AFP values at lower pathological range due to suspected liver pathology.
Ascitic Fluid Acidosis in Bacterial Peritonitis: A Poor Prognostic Sign?
Authors: Gitlin Norman
Published: March 2007

The aim of this retrospective study was to define prognostic factors for cure and survival after spontaneous bacterial peritonitis. In a 4–year period from 1982 to 1986, spontaneous bacterial peritonitis wasdiagnosed in 38 consecutive hospitalized cirrhotic patients (positive ascites culture and polymorphonuclear cell concentrations greater than 250 cells per mm3). Twenty–five patients recovered from their infection (69 p. 100) in a mean time of 9 ± 7 days. The cumulative survival was 68 p. 100 at one week, 50 p. 100 at one month, and 25 p. 100 at one year. The best independant prognostic factors for lack of cure from peritonitis were a low ascitic pH value (p < 0.001), an elevated serum creatinine level (p = 0.001), an elevated serum creatinine level (p = 0.01) and the presence of hepatocellular carcinoma (p < 0.05). The best prognostic factors for death were low ascitic pH value (p = 0.001) and gastrointestinal hemorrhage (p = 0.005). A low ascitic pH value was correlated with other signs of severe infection (signs of generalized infection, ongoing infection during the first week after diagnosis), with signs of severe liver disease (encephalopathy, hepatocellular carcinoma) or severe renal dysfunction (high serum creatinine level, low arterial pH value). Because of the late high–death rate associated with spontaneous bacterial peritonitis, liver transplantation should be considered in these patients.
Evaluation of Protocol Before Transplantation and After Reperfusion Biopsies From Human Orthotopic Liver Allografts: Considerations of Preservation and Early Immunological Injury
Authors: Kakizoe Saburo , Yanaga Katsuhiko , Starzl Thomas E. , Demetris Jake A.
Published: March 2007

Light microscopic, immunohistochemical and ultrastructural analysis of protocol before transplantation and after reperfusion biopsy specimens from 87 randomly selected patients was performed to assess the contribution of preservation and immunological injury to early graft failure. Most biopsy specimens were essentially normal by light microscopy before transplantatio, and no particular feature could be relied on to predict function after transplantation. Ultrastructural examination of biopsy specimens before transplantation demonstrated preferential degeneration of sinusoidal lining cells, but no strict correlation was seen between ultrastructural sinusoidal integrity before transplantation and function after transplantation. The presence of zonal or severe focal necrosis and a severe neutrophilic exudate in biopsy specimens after reperfusion presaged a poor early postoperative course in most, but not all, patients. The presence of preformed lymphocytotoxic antibodies had no effect on the early clinical course, but was associated with Kupffer cell hypertrophy in needle biopsy specimens taken after transplantation. No definite evidence was seen of hyperacute rejection as a result of preformed lymphocytotoxic antibodies as detected in conventional assays. These findings suggest that preservation injury accounts for only a subset of grafts that fail to function after transplantation. Other perioperative or “recipient” factors may be of equal or greater importance in early graft dysfunction or failure.(HEPATOLOGY 1990;11:932–941.).
Hepatic Vein Thrombosis in Behçet's Disease
Authors: Bismuth Eric , Hadengue Antoine , Hammel Pascal , Benhamou Jean-Pierre
Published: March 2007

We describe four patients with hepatic vein thrombosis caused by Behçet's disease and review the 17 previously published cases. In addition, we compared these 21 cases of hepatic vein thrombosis to our 24 cases of hepatic vein thrombosis caused by primary myeloproliferative disorders. In patients with Behçet's disease, a male predominance (male/female ratio, 19:1) contrasted with the female predominance found in patients with hepatic vein thrombosis complicating primary myeloproliferative disorders (sex ratio = 1:3). The mean age at clinical onset was younger in patients with Behçet's disease than in those with primary myeloproliferative disorders (29 vs. 35 yr). Obstruction of the inferior vena cava was found in 90% of patients with hepatic vein thrombosis caused by Behçet's disease. Inferior vena caval thrombosis appears to be the main pathophysiological mechanism of hepatic vein thrombosis in patients with Behçet's disease. Unlike patients with primary myeloproliferative disorders who often had a progressive course, one third of patients with Behçet's disease had acute liver failure and died within 2 wk of clinical onset. These findings suggest that, in patients with Behçet's disease, hepatic vein thrombosis is a sudden event usually related to the extension of a caval thrombus to the ostium of the hepatic veins.(HEPATOLOGY 1990;11:969–974.).
Cholesterol and Bile Acid Metabolism in Cultures of Primary Rat Bile Ductular Epithelial Cells
Authors: Hylemon Philip B. , Bohdan Patricia M. , Sirica Alphonse E. , Heuman Douglas M. , Vlahcevic Reno Z.
Published: March 2007

The role of hepatocytes in bile acid and cholesterol metabolism has been extensively studied. By contrast, nothing is known about the role of bile ductular epithelial cells in cholesterol and bile acid metabolism. The purpose of the current studies was to establish whether bile ductular epithelial cells synthesize cholesterol, bile acids or both and to determine whether these cells are capable of metabolizing (hydroxylating, conjugating) bile acids. Bile ductular epithelial cells were isolated from rat liver after ligation of the common bile duct for 6 to 8 wk. Bile ductular epithelial cells were essentially free ( > 99%) of hepatocytes and were histochemically positive ( > 80%) for γ–glutamyl transpeptidase activity. Cholestatic hepatocytes were simultaneously isolated and characterized with regard to their ability to synthesize and metabolize bile acids. Incubation of bile ductular epithelial cells with [14C] acetate resulted in rapid labeling of cellular cholesterol, suggesting that these cells have a complete cholesterol biosynthetic pathway. The addition of [4–14C]–cholesterol to bile ductular epithelial cells did not lead to detectable synthesis of [14C]–bile acids. [24–14C]–Cholic acid, [24–14C]–deoxycholic acid, [24–14C]–lithocholic acid and [3H]–ursodeoxycholic acid were individually added to bile ductular epithelial cells and incubated for 24 or 48 hr. Bile acid metabolites were extracted and separated by C–18 reverse–phase high performance liquid chromatography or thin–layer chromatography. Bile ductular epithelial cells conjugated deoxycholic acid, ursodeoxycholic acid and lithcholic acid to glycine and taurine. Surprisingly, no conjugation of cholic acid was detected. Conjugated lithocholic acid was further metabolized to highly polar metabolite(s), possibly β–muricholic acid. In contrast, cholestatic hepatocytes synthesized bile acid from exogenously added cholesterol. In addition, cholestatic hepatocytes converted deoxycholic acid to taurocholic acid and ursodeoxycholic acid and lithocholic acid to tauro–β–muricholic acid. We conclude that bile ductular epithelial cells differ significantly from the hepatocyte in regard to bile acid metabolism. Finally, we provide evidence that bile ductular epithelial cells can be used to study metabolic and transport processes occurring in the biliary tree.(HEPATOLOGY 1990;11:982–988.).
Ph Regulation in Human Gallbladder Bile: Study in Patients With and Without Gallstones
Authors: Marteau Chantal , Sastre Bernard , Iconomidis Nicola , Portugal Henri , Pauli Anne-Marie , Gérolami André
Published: March 2007

Samples of gallbladder bile obtained from 25 controls and 34 patients with pigment (28 cases) or cholesterol (6 cases) gallstones were studied to establish whether disturbances in regulation of the biliary pH are likely to play a role in the pathogenesis of gallstones. Samples were assayed for pH, Pco2 and concentrations of sodium, bicarbonate and calcium (total and ionized). Saturation of bile in calcium carbonate was calculated. The main results of the study were as follows: (a) mean (± S. D.) Pco2 was significantly higher in gallbladder bile (6.72 ± 0.36 kPa (in controls) and 7.63 ± 0.29 kPa in patients) than in blood. This is consonant with previous results in animal species; it suggests that also in man a mucosal Na+ H+ antiport acidifies the gallbladder bile generating CO2 from biliary bicarbonate. (b) Biliary pH decreased when sodium concentration increased over a range of 140 to 280 mM. The pH decreased slightly when sodium increased from 140 to 200 mM and rapidly beyond this value; the rapid pH decrease in concentrated bile was associated with bicarbonate concentrations lower than 1 to 2 mM. The results showed that bicarbonate is the main buffer of gallbladder bile. (c) The pH decrease during bile concentration was similar in patients and controls. In both groups, fully concentrated bile was unsaturated in calcium carbonate. The results suggest that gallstone formation is not due to disturbances of biliary pH regulation. However, the normal concentration process that increases Ca++ concentration up to 4 mM and lowers pH values is likely to favor, in fully concentrated biles, the precipitation of calcium salts such as calcium bilirubinate.(HEPATOLOGY 1990;11:997–1002.).
Sexual Transmission of Hepatitis D Virus Infection in Taiwan
Authors: Wu Jaw-Ching , Lee Shou-Dong , Govindarajan Sugantha , Lin Hwa-Chen , Chou Pesus , Wang Yan-Jenn , Lee Shoou-Yih , Tsai Yang-Te , Lo Kwang-Juei , Ting Ling-Pai
Published: March 2007

Multivariate analysis of the risk factors for hepatitis D virus infection among 53 men with acute hepatitis D virus superinfection, 59 men with acute exacerbation of chronic hepatitis B and 54 asymptomatic male hepatitis B carriers revealed that sexual contact with prostitutes and use of nondisposable needles were the factors significantly associated with hepatitis D virus infection in Taiwan (odds ratio = 5.5, 95% confidence interval = 3.3 to 9.2; odds ratio = 2.4, 95% confidence interval = 1.3 to 4.4, respectively). The prevalence of antibody to hepatitis D virus antigen among hepatitis B virus carriers with histories of sexual exposure to prostitutes was 10.3% (14 of 136) and the prevalence of hepatitis D virus antigen among the female prostitutes who were hepatitis B virus carriers was 59% (24 of 51). Among those who admitted to sexual contact with prostitutes, testing for hepatitis D virus antigen revealed positive correlations with the frequency of such sexual contacts and with the frequency of history of venereal diseases. Among the female prostitutes, the prevalence of hepatitis D virus antigen had a positive correlation with the frequency of sexual contact and a negative correlation with age. Analysis of serum hepatitis D virus RNA among those with hepatitis D virus antigen revealed that 4 of the 9 with sexual exposure to prostitutes and 3 of the 24 prostitutes were positive. From these findings, we conclude that these two groups are not only at high risk for hepatitis D virus infection but also form a reservoir of this virus.(HEPATOLOGY 1990;11:1057–1061.).
Parenteral Nutrition With Branched–Chain Amino Acids in Hepatic Encephalopathy: Meta Analysis
Authors: Dersimonian Rebecca
Published: March 2007

The authors undertook a meta analysis of nine randomized clinical trials (RCTs) in which modified amino acid solutions that contained supplemental amounts of branched–chain amino acida (BCAA) were compared with other forms of therapy of hepatic encephalopathy (HE). When five RCTs were pooled, analysis showed highly significant improvement in the degree of HE (p < 0.001). Various interpretations of the data gave similar reslts. The mortality data differed so widely in these RCTs that pooling of the data could not be meaningfully performed. In two RCTs BCAA therapy resulted in increased mortality, whereas in two others BCAA treatment was associated with increased survival. An aggregate relative risk reduction of 0.59 was calcilated with 95% confidence intervals of 0.23 to 0.80 (p < 0.002). When the data from one additional study that had not yet been published and that showed BCAA therapy to be beneficial was added to the analysis, the pooled relative reduction was even greater i. e., 0.82 [p < 0.0001]. The mortality in these studies was significantly reduced regardless of the type of statistical analysis performed (p = 0.023), Nevertheless, because of the short duration of follow–up in these studies and the striking differences in the effects of BCAA on mortality, the authors recommended that additional RCTs with prolonged follow–up be performed.
Chronic Hepatitis Caused by the Hepatitis A Virus
Authors: Liaw Yun-Fan
Published: March 2007

The case of a young man with hepatitis A and a chronic course is presented. The patient recived a short course of steroid therapy for recurrence of symptoms following acute hepatitis A. Thereafter liver enzymes have remained marginally elevated for 4 years and annual liver biopsies have shown evidence of chronicity. HAV IgM Ab persisted for 1034 days with subsequent development of HAV IgG Ab. The possiblity of other viruses in the aetiology and the role of steroids in the development of chronicity are discussed.
Renal and Systemic Hemodynamics in Experimental Cirrhosis in Rats: Relation to Hepatic Function
Authors: Wensing Georg , Sabra Ramzi , Branch Robert A.
Published: March 2007

The onset of sodium retention in the phenobarbital and carbon tetrachloride model of cirrhosis in the rat is preceded by a linear decrease in hepatic function as measured by the aminopyrine breath test. Sodium retention occurs when liver function decreases below a critical threshold. Changes in systemic hemodynamics may be responsible for initiating the development of renal sodium retention. The objective of this study was to investigate the relationship between hepatic function and systemic and renal hemodynamics of experimental cirrhosis in rats maintained on a constant salt diet. Cirrhosis was induced in phenobarbitaltreated rats by weekly administration of carbon tetrachloride. The aminopyrine breath test served as a measure of hepatic function. Three groups of animals were studied to evaluate the contribution of changes in systemic and renal hemodynamics to the onset of sodium retention: a group with sodium retention and aminopyrine breath test results just below the critical threshold, a group without sodium retention and aminopyrine breath test results just above the critical threshold and a phenobarbital–treated control group. In each group, urinary sodium excretion, renal plasma flow, glomerular filtration rate, mean arterial pressure and arterial and renal venous plasma renin activities were determined. A progressive, significant reduction in mean arterial pressure was seen, comparing controls with the other two groups. No differences in renal plasma flow were observed between the three groups, but glomerular filtration rate and filtration fraction were slightly reduced in the sodium–retaining group compared with the non–retaining group and controls. A trend toward increased renin activity was observed in both groups of cirrhotic animals, but the differences were not statistically significant, compared with controls. A positive, curvilinear relationship was found between aminopyrine breath test results and mean arterial pressure and glomerular filtration rates, and a negative association was found between aminopyrine breath test results and plasma renin activity. Our data demonstrate, that in carbon tetrachloride-induced cirrhosis in the rat, changes in mean arterial pressure, glomerular filtration rate and plasma renin activity are closely related to the impairment in hepatic function. The significant decrease in mean arterial pressure in nonsodium–retaining cirrhotic rats suggests that peripheral vasodilatation is the initial event in the development of salt retention in this model of cirrhosis. These observations suggest the hypothesis that changes in tubular function, rather than changes in renal hemodynamics and glomerular function, are responsible for the onset of sodium retention. (Hepatology 1990;12:13-19).
Cytotoxic Interactions of Cardioactive Cationic Amphiphilic Compounds in Primary Rat Hepatocytes in Culture
Authors: Bandyopadhyay Subhankar , Klaunig James E. , Somani Pitambar
Published: March 2007

Hepatocytes from adult male Sprague–Dawley rats were isolated by the two–stage collagenase perfusion technique; 1 × 106 cells/plate were incubated in primary cell culture in Leibovitz's L–15 medium for 24 hr with or without various concentrations (12.5 to 400 μmol/L) of cardioactive cationic amphiphilic compounds such as propranolol, verapamil, sotalol, atenolol and procainamide. Propranolol and verapamil caused a significant release of lactate dehydrogenase (used as cytotoxic index in this study) in the culture media in a concentration–dependent manner, with LC50 values of 220 ± 10 and 224 ± 7 μmol/L, respectively. Atenolol, sotalol and procainamide had no effect on lactate dehydrogenase release. Electron microscopy of the hepatocytes showed that subtoxic concentrations of propranolol (12.5 to 125 μmol/L) and verapamil (12.5 to 100 μmol/L) induced multilamellar inclusion bodies after 24 hr of incubation. The two higher concentrations of propranolol (50 and 125 μmol/L) and 100 μmol/L of verapamil produced a significant decrease in the percentage of volume density of the mitochondria as quantitated by morphometrical analysis. An unusual feature of the electron microscopical changes with propranolol and verapamil was the presence of mitochondria within the multilamellar inclusion bodies. When these two drugs were used together or with subtoxic concentrations of amiodarone or desethylamiodarone, release of lactate dehydrogenase was significantly enhanced. No correlation was evident between the cytotoxic response and the volume density of cellular inclusions in hepatocytes treated with different concentrations of propranolol, verapamil, amiodarone or desethylamiodarone. Sotalol, atenolol and procainamide in concentrations up to 400 μmol/L did not produce any ultrastructural changes in hepatocytes after 24 hr of incubation. These results show that (a) cationic amphiphilic structure per se is not the only requirement for induction of multilamellar inclusions, (b) propranolol and verapamil can induce the formation of multilamellar inclusion bodies and cause a concentration–dependent release of lactate dehydrogenase from hepatocytes and (c) combination of different cationic amphiphiles in subtoxic concentrations can enhance cytotoxicity and increase the volume density of multilamellar inclusions. (Hepatology 1990;12:48-58).
Physicochemical Determinants in Hepatic Extraction of Small Peptides
Authors: Hunter Ellen B. , Powers Stephen P. , Kost Louis J. , Pinon Delia I. , Miller Laurence J. , LaRusso Nicholas F.
Published: March 2007

Although the liver is known to extract amino acids and organic anions by well–characterized transport systems, the factors that regulate the hepatic uptake of small, circulating peptides are poorly understood. We previously reported that cholecystokinin octapeptide, a biologically active form of cholecystokinin, is efficiently cleared by the liver and that uptake depends on its carboxyl–terminal tetrapeptide (Trp–Met–Asp–PheNH2). Here we further define the physicochemical determinants for hepatic clearance of cholecystokinin. A series of 13 tetrapeptides, including eight analogs of the carboxyl–terminal tetrapeptide of cholecystokinin–8 with different charges, hydrophobicity and aminoacid sequences, were prepared by solid–phase synthesis, purified by high–performance liquid chromatography and characterized by amino–acid analysis and mass spectrometry. Radioiodination was performed by oxidative or nonoxidative techniques. Hydrophobicity of individual radiolabeled peptides was calculated using published hydrophobicity data or measured directly by determining their partition between octanol and aqueous triethylammonium acetate. First–pass hepatic extraction of radiolabeled peptides was determined with a nonrecirculating, isolated, perfused rat liver model. First–pass hepatic extraction of injected, labeled peptides varied from 4% to 86% and correlated significantly (r = 0.85; p < 0.0002) with hydrophobicity. Hydrophobic peptides with positive, neutral or negative charges were avidly extracted (30% to 86%) by the liver; first–pass clearance of hydrophobic peptides with similar charges varied with amino–acid sequence. In contrast, the first–pass hepatic extraction of positively or negatively charged hydrophilic tetrapeptides was negligible (<10%). These results suggest that hydrophobicity and amino–acid sequence-but not anionic or cationic nature-are the major determinants of hepatic extraction of cholecystokinin, and perhaps other small, circulating peptides. (Hepatology 1990;12:76-82).
Inhibition of Hepatocytary Vesicular Transport by Cyclosporin A in the Rat: Relationship With Cholestasis and Hyperbilirubinemia
Authors: Roman Irene D. , Monte Maria J. , Gonzalez-Buitrago Jose M. , Esteller Alejandro , Jiménez Rafael
Published: March 2007

In an attempt to understand the hepatotoxicity associated with immunosuppressive therapy with cyclosporin A, we investigated the effects of acute cyclosporin A administration on biliary secretion, serum bile acid and bilirubin levels and the histological changes in the hepatic parenchyma in anesthetized male Wistar rats. The animals were divided into three experimental groups that received equal volumes (1 ml, intravenously) of physiological saline (controls), cyclosporin A vehicle (a fat emulsion, Intralipid, mixed with absolute ethanol) or cyclosporin A dissolved in the aforementioned mixture. In another series of assays, horseradish peroxidase was coinjected with cyclosporin A vehicle or with the solution containing cyclosporin A. Only after cyclosporin A administration was an immediate inhibition in bile flow and in the biliary concentrations and secretion of bile acids and bilirubin found. In addition, a delay in the peak time of the appearance of horseradish peroxidase together with a reduction in the biliary excretion rate and in the total amount of horseradish peroxidase excreted were observed during cholestasis. At 40 to 50 min after drug administration, all biliary parameters evaluated had returned to the pretest values. The relationship between bile flow and bile acid secretion showed that cyclosporin A-induced cholestasis is related to a decrease of both the bile acid-dependent and bile acid-independent fractions of bile flow. At the end of the cyclosporin A assays, the serum bile acid, total bilirubin and conjugated bilirubin concentrations were greater than those observed in the controls and Intralipid–treated animals. These effects were dose–dependent. Light microscopy and transmission electron microscopy studies did not reveal architectural hepatic abnormalities. We conclude that cyclosporin A interferes with the hepatocellular vesicle–mediated transport processes and postulate that apart from the previously proposed inhibition of the hepatic uptake of bile acids, the cyclosporin A-induced hyperbilirubinemia, cholestasis and bilirubinostasis in the rat are also related to an inhibition of transhepatocytary vesicular transport processes. (Hepatology 1990;12:83-91).
Early Diagnosis of Cytomegalovirus Hepatitis in Liver Transplant Recipients: Role of Immunostaining, Dna Hybridization and Culture of Hepatic Tissue
Authors: Paya Carlos V. , Holley Keith E. , Wiesner Russell H. , Balasubramaniam Kumaravelu , Smith Thomas F. , Espy Mark J. , Ludwig Jurgen , Batts Kenneth P. , Hermans Paul E. , Krom Ruud A.F.
Published: March 2007

Immunostaining techniques that use a monoclonal antibody against an early cytomegalovirus antigen or a polyclonal antibody, in situ DNA hybridization and inoculation of cell cultures for the detection of cytomegalovirus from liver biopsy specimens were studied in 20 liver transplant patients with cytomegalovirus hepatitis, as defined by histological criteria. A total of 108 liver biopsy specimens from 20 patients with a diagnosis of cytomegalovirus hepatitis (obtained per protocol at 7, 21, 90, and 180 days or whenever liver dysfunction occurred), which had previously been examined histologically and in cell culture, were again studied by recutting the liver tissue for histological examination, DNA hybridization and immunostaining with monoclonal or polyclonal antibodies to cytomegalovirus. In 5 of 20 patients, the diagnosis of cytomegalovirus hepatitis could have been made earlier (mean = 9.6 days) by immunostaining with a monoclonal antibody. Of 47 biopsy specimens with cytomegalovirus inclusion bodies, the sensitivity and specificity of the diagnostic procedures were immunostaining with monoclonal antibody (84% and 90%) and polyclonal antibody (72% and 97%), in situ DNA hybridization (72% and 100%) and cell culture detection (52% and 95%), respectively. Immunostaining with a monoclonal antibody against an early CMV antigen frequently detected cytomegalovirus infection in the liver allograft earlier than identification of typical histological inclusion bodies. DNA in situ hybridization was less sensitive than other techniques but highly specific; cytomegalovirus cell culture lacked sensitivity compared with the other procedures. (Hepatology 1990;12:119-126).
Patients With Type Ii Autoimmune Hepatitis Express Functionally Intact Cytochrome P–450 Db1 That Is Inhibited by Lkm–1 Autoantibodies In Vitro But Not In Vivo
Authors: Manns Michael , Zanger Ulrich , Gerken Guido , Sullivan Kevin F. , Zum Büschenfelde Meyer Karl-H. , Meyer Urs A. , Eichelbaum Michel
Published: March 2007

Liver–kidney microsomal–1 autoantibodies characterize a subgroup of autoimmune chronic active hepatitis. The liver antigen of liver–kidney microsomal–1 antibodies has been identified as cytochrome P450 db1, a microsomal enzyme catalyzing the oxidative metabolism of more than 20 drugs, including debrisoquine, sparteine and bufuralol. A genetic polymorphism (debrisoquin–sparteine polymorphism) is responsible for the lack of P450 db1 protein in the livers of 5% to 10% of Caucasians, leading to impaired drug metabolism and a distinct poor metabolizer phenotype. We investigated whether liver–kidney microsomal–1 positive autoimmune chronic active hepatitis patients express functionally intact P450 db1 in their livers. In four patients with liver–kidney microsomal–1 positive chronic active hepatitis, but not in five patients with various liver–kidney microsomal–1 negative liver diseases, the presence of circulating liver–kidney microsomal–1 antibodies was confirmed by immunofluorescence, radioimmunoassay and immunoblotting analysis using recombinant P450 db1. Moreover, only sera from liver–kidney microsomal–1 positive autoimmune chronic active hepatitis patients strongly inhibited the enzymatic activity of P450 db1 in human liver microsomes in vitro. Immunoblotting detected 50–kd P450 db1 protein in liver biopsy specimens from all patients. The in vivo function of P450 db1 was investigated by determining the metabolic ratio for sparteine and its 2–dehydro and 5–dehydro metabolites in 12–hr urine samples after oral administration of sparteine sulfate. In vivo P450 db1-mediated drug metabolism was of the extensive metabolizer phenotype and did not differ significantly between liver–kidney microsomal–1 positive (metabolic ratio = 1.15 ± 0.32) and liver–kidney microsomal–1 negative (metabolic ratio = 1.18 ± 0.48) patients. Thus patients with liver–kidney microsomal–1 positive chronic active hepatitis express functionally intact P450 db1 in their livers. However, the activity of this enzyme is not significantly diminished in vivo by circulating liver–kidney microsomal–1 autoantibodies that react with the active site of P450 db1 and inhibit its function in vitro. (Hepatology 1990;12:127-132).
Higher Blood Alcohol Levels in Women Than in Men: Vive La Petite Diféfrence
Authors: Batey R. , Conn Harold O.
Published: March 2007

After consuming comparable amounts of ethanol, women have higher blood ethanol concentrations than men, even with allowance for differences in size, and are more susceptible to alcoholic liver disease. Recently, we documented significant “first–pass metabolism” of ethanol due to its oxidation by gastric tissue. We report a study of the possible contribution of this metabolism to the sex–related difference in blood alcohol concentrations in 20 men and 23 women. Six in each group were alcoholics.

The first–pass metabolism was determined on the basis of the difference in areas under the curves of blood alcohol concentrations after intravenous and oral administration of ethanol (0.3 g per kilogram of body weight). Alcohol dehydrogenase activity was also measured in endoscopic gastric biopsies. In nonalcoholic subjects, the first–pass metabolism and gastric alcohol dehydrogenase activity of the women were 23 and 59 percent, respectively, of those in the men, and there was a significant correlation (r8 = 0.659) between first–pass metabolism and gastric mucosal alcohol dehydrogenase activity. In the alcoholic men, the first–pass metabolism and gastric alcohol dehydrogenase activity were about half those in the nonalcoholic men; in the alcoholic women, the gastric mucosal alcohol dehydrogenase activity was even lower than in the alcoholic men, and first–pass metabolism was virtually abolished.

We conclude that the increased bioavailability of ethanol resulting from decreased gastric oxidation of ethanol may contribute to the enhanced vulnerability of women to acute and chronic complications of alcoholism.
Perinatal Hemochromatosis: One Disease, Several Diseases or A Spectrum?
Authors: Collins Janna , Goldfischer Sidney
Published: March 2007

A clinicopathologic picture of severe neonatal liver disease associated with heavy stainable iron stores in a “hemochromatotic” distribution has been designated as neonatal or perinatal iron storage disease or hemochromatosis. In an attempt to determine the specificity of these findings, we determined the amount and distribution of stainable iron in four groups of autopsied infants: those with severe subacute/chronic liver disease of undetermined etiology, those with subacute/chronic liver disease of known etiology, those with severe acute liver disease, and those with no liver disease. Fourteen of 15 infants with severe subacute/chronic liver disease of unknown etiology showed heavy iron accumulation in a hemochromatotic distribution in more than one organ, in contrast to only one of 37 cases in the other three groups. The findings are compatible with the possibility that the combination of morphologic findings defines a single disease entity (of currently unknown etiology), and also with the possibility that this disease entity is specific only to the extent of establishing a relationship between severe early (in utero) liver injury and a hemochromatotic distribution of iron in multiple organs.
Extrahepatic Hepatitis B Virus Dna Sequences in Patients With Acute Hepatitis B Infection
Authors: Yoffe Boris , Burns Dennis K. , Bhatt Harshika S. , Combes Burton
Published: March 2007

Recent studies have demonstrated the presence of hepadnavirus–related nucleic acids in extrahepatic tissues in various animal models. The prevalence and biological significance of extrahepatic infection in humans remains undetermined. To characterize the tissue distribution and physical state of extrahepatic hepatitis B virus nucleic acids in acute hepatitis infection, we examined serum, liver and multiple extrahepatic tissues obtained at autopsy from two patients with fulminant hepatitis and one patient with resolving hepatitis who died of an unrelated cause. Southern–blot hybridization analysis was used to analyze the physical state of hepatitis B virus–related DNA. Hepatitis B virus–related RNA sequences were examined by slot–blotting total RNA extracted from corresponding tissues. Hepatitis B virus nucleic acids were demonstrated in lymph nodes, spleen, gonads, thyroid gland, kidneys, pancreas and adrenal glands. The most intense signal of hybridization was obtained with DNA extracted from lymph nodes. In general, the levels of hepatitis B virus RNA correlated with the amount of viral DNA. Fast–migrating DNA sequences resembling replicative intermediates and ranging in size from 1 to 3.2 kb were detected in EcoRI digests. Faint high–molecular–weight smears suggesting random integration also were observed. Remarkably, little or no hepatitis B virus nucleic acid was detected in the serum or liver. In control specimens obtained from hepatitis B virus carriers, most hybridizable hepatitis B virus nucleic acid was present in liver, but hepatitis B virus DNA was also detected in extrahepatic tissues. Finally, no specific histological changes were observed in extrahepatic tissues harboring hepatitis B virus. These findings demonstrate hepatitis B virus nucleic acids in extrahepatic sites in humans during acute infection and provide new insights into the pathogenesis of fulminant hepatitis. (Hepatology 1990;12:187-192).
Characterization and Biological Properties of A Hepatitis B Virus Isolated From A Patient Without Hepatitis B Virus Serologic Markers
Authors: Liang Jake T. , Blum Hubert E. , Wands Jack R.
Published: March 2007

We have developed a rapid method to characterize genomic diversity of low–level hepatitis B and related viral agents after their identification in serum by high–affinity HBsAg–antibody monoclonal antibody capture and subsequent polymerase chain reaction amplification. Serum from an individual with chronic liver disease and without hepatitis B virus serological markers but reactive by monoclonal antibody capture/polymerase chain reaction amplification was inoculated into a chimpanzee. After inoculation, an acute hepatitis B virus–like hepatitis developed in the chimpanzee. Analysis of serial liver biopsy samples showed the persistence of hepatitis B virus DNA for more than 17 mo after resolution of acute hepatitis and seroconversion. Applying the technique of restriction enzyme fragment analysis to serial chimpanzee liver biopsy samples and acute–phase sera, along with the serum inoculum, we established that all hepatitis B virus DNA sequences are derived from the same viral agent. We present evidence that the viral DNA persisted as a nonreplicating episomal form in the nucleus of hepatocytes. This study demonstrates that after clinical and serological recovery from an acute hepatitis, there may be persistence of low–level hepatitis B virus–related genome in the liver despite the presence of antibodies to HBsAg. Such persistence of viral genome may be a natural sequela of infection and may serve as a source of viral latency and possible reactivation. Finally, cloning and complete nucleic–acid sequencing of this virus have demonstrated multiple nucleotide and amino acid changes compared with all known hepatitis B virus subtypes. These changes may have contributed in part to a different antigenic composition or immunological reactivity of the host to this hepatitis B virus isolate. (Hepatology 1990;12:204-212).
Hla Phenotypes and Gene Polymorphisms in Juvenile Liver Disease Associated With α1–Antitrypsin Deficiency
Authors: Doherty Derek G. , Donaldson Peter T. , Whitehouse David B. , Mieli-Vergani Giorgina , Duthie Ann , Hopkinson David A. , Mowat Alex P.
Published: March 2007

Chronic liver disease affects up to 20% of children with α–antitrypsin deficiency owing to the PiZZ genotype. Previous observations of a familial occurrence and abnormal immune responses to liver antigens in these patients suggests that immunoregulatory genes may be involved in the pathogenesis of liver damage. We have identified HLA phenotypes and class II (HLA–DR) gene polymorphisms in 140 white PiZZ subjects, of whom 92 (83 index patients) had liver disease, and 206 first–degree relatives. DR3* was present in 35 of 75 (46.7%) unrelated patients with liver disease compared with 5 of 28 (17.8%) patients without (p < 0.01) and 23 of 100 controls (p < 0.001). DR4 was increased in patients without liver disease; it was present in 17 of 28 (60.7%) compared with 29 of 75 (38.7%) patients with liver disease (p < 0.05) and 36 of 100 controls (p < 0.025). Using Southern blot analysis with HLA–DRB and DQB DNA probes, we identified two polymorphisms of DR3, only one (Dw25) of which is raised in PiZZ individuals with liver disease (9 of 55: 16.4%) compared with 1 of 23 (4.4%) without and 2 of 52 (3.9%) controls (p < 0.05). Analysis of the segregation of HLA haplotypes in 77 families revealed no concordance for liver disease with HLA in those with affected sibships, indicating that, although DR3–Dw25 is associated with liver disease in α1–antitrypsin deficiency, other factors must play a pathogenic role. (Hepatology 1990;12:218-223).
Adenosine Partially Prevents Cirrhosis Induced by Carbon Tetrachloride in Rats
Authors: Hernández-muñoz Rolando , Díaz-muñoz Mauricio , Suárez Jorge , de Sánchez Victoria Chagoya
Published: March 2007

Adenosine administration was tested in rats with carbon tetrachloride-induced hepatic fibrosis and was able to partially prevent the enlargement of liver and spleen induced by the toxin. This amelioration of the hepatomegaly was accompanied by a 50% reduction of the liver collagen deposition and preservation of content of glycosaminoglycans. A stimulated hepatic collagenase activity is apparently the mechanism for reduction of collagen accumulation. These effects were associated with a striking improvement in liver function. Adenosine treatment did not modify the late hepatotoxic effect of the carbon tetrachloride; however, the stimulatory effect of the nucleoside on energy state appeared to counteract the drastic decreases in adenine nucleotides, ATP, ATP/ADP ratio and energy charge elicited by the hepatotoxin. Moreover, a possible beneficial action of enhanced hepatic oxygenation caused by the vasodilator properties of adenosine cannot be ruled out. Regardless of the mechanism, adenosine seems to change the cellular response to the injury induced by the hepatotoxin. (Hepatology 1990;12:242-248).
Immunohistochemistry of the Hepatic Extracellular Matrix in Acute Viral Hepatitis
Authors: Inuzuka Sadataka , Ueno Takato , Torimura Takuji , Sata Michio , Abe Hirohiko , Tanikawa Kyuichi
Published: March 2007

The distribution of several extracellular matrix components in the liver of patients with acute viral hepatitis was studied by light and electron microscopy using indirect immunoperoxidase methods.

Light microscopy revealed type III and type V collagen and fibronectin in the portal tracts and the area of focal necrosis, showing cell infiltration. Type III and type V collagen were more strongly stained in the periphery of focal necrosis. Type IV collagen was seen around the vessels and hepatocytes near the focal necrosis. Electron microscopy showed many transitional Ito cells in the area of focal necrosis and fibroblasts were observed in the portal tracts, showing collagen fiber deposition. Numerous collagen fibrils were observed around fibroblasts, Ito cells and hepatocytes. Using immunoelectron microscopy, type III and type IV collagen and fibronectin were observed in the rough endoplasmic reticulum of Ito cells and hepatocytes localized near the area of focal necrosis or fiber deposition. In addition, type IV collagen was seen in the rough endoplasmic reticulum of endothelial cells forming capillary vessels.

These results suggest that several extracellular matrix components such as types III, IV and V collagen and fibronectin, produced by Ito cells, hepatocytes or endothelial cells, play important roles in the healing of liver damage in acute viral hepatitis. (Hepatology 1990; 12:249-256).
Predictive Value of Whole Blood Chemiluminescence in Patients With Alcoholic Hepatitis
Authors: Lunel Françoise , Descamps-Latscha Beatrice , Descamps Diane , Charpentier Yves Le , Grippon Patrick , Valla Dominique , Cadranel Jean-François , Trum Johannes , Opolon Pierre
Published: March 2007

Recent reports suggest that ethanol metabolism leads to reactive oxygen intermediates that may be responsible for the lesions observed in alcoholic hepatitis. This study investigated the production of reactive oxygen intermediates in peripheral blood phagocytes of patients with alcoholic hepatitis and attempts to evaluate its predictive value. Using a luminol–dependent chemiluminescence method, reactive oxygen intermediate production was measured directly within microamounts of whole blood, both in the absence (basal chemiluminescence production) and in the presence of phagocyte–stimulating agents including latex, zymosan, phorbol myristate acetate and N–formyl–methionyl–leucyl–phenylalanine. Thirty patients with well–documented and histologically proven alcoholic hepatitis were studied. Pugh's and Child's classification, Orrego's composite clinical and laboratory index and Maddrey's discriminant function were used to assess the prognosis of the liver disease. Patients were followed up monthly for 6 mo. Results were compared with those obtained in 17 patients with nonalcoholic liver disease and in 78 normal control subjects. Basal chemiluminescence production was significantly higher in patients with alcoholic hepatitis than in those with nonalcoholic liver disease and in normal subjects (p < 0.001). Chemiluminescence responses to latex, zymosan and phorbol myristate acetate were significantly lower in alcoholic hepatitis patients than in normal subjects (p < 0.001); however, when compared with nonalcoholic liver disease patients, these responses were significantly decreased only in the presence of zymosan (p < 0.05). Both basal chemiluminescence production (p < 0.001) and zymosan–induced chemiluminescence responses (p < 0.02) were closely related to alcoholic hepatitis prognosis indices (i.e.), Pugh's and Child's classification, Orrego's composite clinical and laboratory index and Maddrey's discriminant function. Patients with severe alcoholic hepatitis and unfavorable outcome exhibited more pronounced chemiluminescence alterations than patients with mild alcoholic hepatitis or those with favorable outcome. Although not based on conventional liver function tests, whole blood chemiluminescence determination appears to be a sensitive and discriminating test in evaluating the severity and prognosis of alcoholic hepatitis. (Hepatology 1990;12:264-272).
Liver Tumor Promoters Stimulate Growth of Transplanted Hepatocellular Carcinomas
Authors: Seglen Per O. , Sæter Gunnar , Schwarze Per E.
Published: March 2007

Cell suspensions or tissue fragments from primary hepatocellular carcinomas and benign neoplastic nodules, induced by treating rats with chemical carcinogens, were transplanted by intraportal injection or subcapsular implantation in the livers of syngeneic host rats. Both nodule and carcinoma transplants produced high numbers of hepatocellular carcinomas in the hosts 2 to 5 mo after transplantation. Treatment of the host rats with liver tumor promoters (phenobarbital or 2–acetylaminofluorene) greatly stimulated tumor outgrowth, demonstrating that even established carcinoma cells can be promoter–sensitive. Tumor outgrowth was also stimulated by partial hepatectomy of the hosts, the regenerative stimulus interacting synergistically with the tumor promoters. (Hepatology 1990;12:295-300).
Intrahepatic Cholestasis and Phospholipidosis Associated With the Use of Trimethoprim–Sulfamethoxazole
Authors: Muñoz Santiago J. , Martinez-Hernandez Antonino , Maddrey Willis C.
Published: March 2007

Although liver injury after administration of the trimethoprim–sulfamethoxazole combination is rare, hepatocellular necrosis and cholestasis have developed in a few cases. We describe a patient who developed a severe, prolonged cholestatic reaction after trimethoprim–sulfamethoxazole administration. The findings from serial liver biopsy samples showed characteristic abnormalities of phospholipidosis that have not been previously described for trimethoprimsulfamethoxazole-related hepatic injury. The most prominent finding on electron microscopic evaluation of the liver was the presence of prominent hepatocyte lysosomal inclusions characterized by concentric arrangements of membranous and lamellated structures. The patient improved after several courses of exchange plasmapheresis, which may have assisted in the removal of toxic drug–lipid complexes. The pathogenesis of this acquired secondary phospholipidosis is unknown. Possible mechanisms include generation of highly lipid–soluble metabolites and inhibition of the lysosomal enzyme phospholipase A1. (Hepatology 1990; 12:342-347).