bluuebunny/crossref_metadata_2025 huggingface dataset:
What does “reduced central blood volume in cirrhosis” really mean?
Authors: Morali G. A. , Blendis L. M.
Published: March 2007

The pathogenesis of ascites formation in cirrhosis is uncertain. It is still under debate whether the effective blood volume is reduced (underfilling theory) or whether the intravascular compartment is expanded (overflow theory). This problem has not yet been solved because of insufficient tools for measuring the central blood volume. We have developed a method that enables us to determine directly the central blood volume, i.e., the blood volume in the heart cavities, lungs, and central arterial tree. In 60 patients with cirrhosis and 16 control subjects the central blood volume was assessed according to the kinetic theory as the product of cardiac output and mean transit time of the central vascular bed. Central blood volume was significantly smaller in patients with cirrhosis than in controls (mean 21 vs. 27 ml/kg estimated ideal body weight, p < 0.001; 25% vs. 33% of the total blood volume, p <0.0001). The lowest values (18 ml/kg) were found in patients with gross ascites and a reduced systemic vascular resistance. In patients with cirrhosis central blood volume was inversely correlated to the hepatic venous pressure gradient (r = −0.41, p <0.01), and the total blood volume was inversely correlated to the systemic vascular resistance (r = −0.49, p < 0.001), the latter being significantly reduced in the patient group. Patients with cirrhosis apparently are unable to maintain a normal central blood volume. This may be due to arteriolar vasodilation, portosystemic collateral flow, or sequestration of fluid in the peritoneal cavity, or any combination thereof. The present results indicate that central circulatory underfilling is an integral part of the hemodynamic and homeostatic derangement observed in cirrhosis.
Alveolar echinococcosis of the liver: A parasitic disease in search of a treatment
Authors: Vuitton Dominique
Published: March 2007

The efficacy of albendazole (50 mg/kg/d), mebendazole (50 mg/kg/d) and praziquantel (500 mg/kg/d) against established intraperitoneal infections of Echinococcus multilocularis in gerbils was compared by monitoring parasite weight and making ultrastructural observations on treated and untreated material. Praziquantel was the most active protoscolicidal agent, reducing protoscolex viability to <2%, although it did not inhibit cyst growth. Albendazole was the most effective agent in reducing cyst growth and was, when compared with other regimes, significantly more effective than mebendazole (p < 0.05), praziquantel (p < 0.01) or untreated controls (p < 0.01).
Changes of serum hepatitis B virus DNA and aminotransferase levels during the course of chronic hepatitis B virus infection in children
Authors: Lee Ping-Ing , Chang Mei-Hwei , Lee Chin-Yun , Hsu Hong-Yuan , Chen Juei-San , Chen Pei-Jer , Chen Ding-Shinn
Published: March 2007

During a follow-up period of 3.2 ± 1.6 (1 to 8.6) yr, 1,087 serum specimens from 230 HBsAg carrier children were tested for hepatitis B virus markers. Dividing the serum specimens into four groups according to the status of HBeAg and hepatitis B virus DNA, the frequency of abnormally elevated ALT levels in serum was in the following order: HBeAg(+)/hepatitis B virus DNA(−) serum (60%), HBeAg(−)/hepatitis B virus DNA(+) serum (53%), HBeAg(+)/hepatitis B virus DNA(+) serum (41%), HBeAg(−)/hepatitis B virus DNA(−) serum (11%). Analysis of the data before HBeAg clearance showed that both a high serum ALT level and a low serum hepatitis B virus DNA level correlated with an imminent clearance of HBeAg. Approximately two thirds of children with serum ALT levels higher than 100 IU/L cleared HBeAg within the following year. Clearance of HBeAg occurred within the following year in 65% (13 of 20) of cases with serum hepatitis B virus DNA level ≤ 1,000 pg/ml, in contrast to 19% (30 of 157) of those with serum hepatitis B virus DNA level > 1,000 pg/ml. Among 53 children who lost HBeAg and hepatitis B virus DNA during follow-up, only nine cases did not have an identified period of abnormal serum ALT levels. For the remaining 44 children, abnormal serum ALT levels fell to normal with clearance of both HBeAg and hepatitis B virus DNA in 33 children but remained elevated in the remaining 11 cases after seroconversion. This study also demonstrated that (a) serum ALT elevations in HBsAg carrier children were usually mild in degree and infrequently exceeded 100 IU/L, (b) hepatitis B virus DNA was detectable in only 1% (4 of 352) of the anti-HBe(+) sera and all showed normal ALT levels. These findings are in contrast to the adult carriers and denote some unique features of HBsAg carrier children. (HEPATOLOGY 1990;12:657-660).
Recombinant γ-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients†
Authors: Quiroga Juan Antonio , Castillo Inmaculada , Porres Juan Carlos , Casado Santos , Sáez Federico , Martínez María Gracia , Gómez Mariano , Inglada Luis , Sánchez-Sicilia Luis , Mora Adela , Galiana Fernando , Barril Guillermina , Carreño Vicente
Published: March 2007

Patients undergoing long-term hemodialysis are at high risk of acquiring hepatitis B yet tend to have poor rates of response to hepatitis B vaccine. The effect of recombinant human γ-interferon (2 million units/m2) on the response to a recombinant hepatitis B vaccine was evaluated in a prospective, randomized controlled trial in 81 hemodialysis patients. A similar proportion of both groups of vaccinees ultimately developed antibody to HBsAg including 81% of the 41 recipients of vaccine alone (group I) and 89% of the 40 recipients of vaccine with γ-interferon (group II). However, the antibody to HBsAg response occurred earlier in recipients of vaccine with γ-interferon, so that at 4 mo 63% of group I and 88% of group II had antibody to HBsAg (p < 0.025). Furthermore, titers of antibody to HBsAg tended to be higher in the vaccinees given interferon; the final geometric mean titers were 232 IU/L in group I and 330 IU/L in group II (p = not significant). Retrospective testing for antibody to hepatitis C virus revealed that 21 (26%) hemodialysis patients were seropositive at entry into this trial, but the presence of antibody to hepatitis C virus did not appear to affect the response rate to the hepatitis B vaccine. These results suggest that the effects of γ-interferon as an adjuvant in increasing the response rate to hepatitis B vaccination deserve further evaluation perhaps most appropriately in persons who have not responded to an initial course of vaccine. (HEPATOLOGY 1990;12:661-663).
Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide—induced acute liver failure
Authors: Yurdaydin Cihan , Hörtnagl Heide , Steindl Petra , Zimmermann Christof , Pifl Christian , Singer Ernst A. , Roth Erich , Ferenci Peter
Published: March 2007

Functional changes of various neurotransmitter systems have been implicated in the pathogenesis of hepatic encephalopathy. In this study the role of brain monoaminergic neurotransmitter systems in hepatic encephalopathy was investigated in rats with thioacetamide-induced acute liver failure. Concentrations of serotonin, dopamine, noradrenaline and of their metabolites 5-hydroxyindoleacetic acid, dihydroxyphenylalanine (following inhibition of dihydroxyphenylalanine-decarboxylase), dihydroxy-phenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenyl-glycol, were measured in the cerebral cortex, striatum and hippocampus by high performance liquid chromatography with electrochemical detection. In hepatic encephalopathy concentrations of 5-hydroxyindoleacetic acid were increased in all three brain areas (196%, 204% and 264% of salinetreated controls, p < 0.01), and concentrations of serotonin were increased in the frontal cortex (121%, p < 0.01). In the frontal cortex and hippocampus of encephalopathic rats dopamine levels were increased (157% and 289%, p < 0.05), and levels of noradrenaline (53% and 46%, p < 0.05) were decreased associated with increased 3-methoxy-4-hydroxyphenylglycol levels (173% and 206%, p < 0.05). The extent of these changes correlated with the stage of hepatic encephalopathy. In hepatic encephalopathy dihydroxyphenylalanine accumulation was increased in the hippocampus and unchanged in the cerebral cortex. Dopamine, noradrenaline, dihydroxyphenylacetic acid and homovanillic acid concentrations were unchanged in the striatum. The results of this study indicate that hepatic encephalopathy in thioacetamide-induced acute liver failure in rats is associated with neurochemical changes, suggesting an increased activity of the noradrenergic and serotoninergic neurotransmitter systems. (HEPATOLOGY 1990;12:695-700).
Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: Results of a double-blind, placebo-controlled trial
Authors: Ginés Pere , Rimola Antoni , Planas Ramón , Vargas Victor , Marco Francesc , Almela Manuel , Forne Montserrat , Miranda Maria Luisa , Llach Josep , Salmerón Joan Manuel , Esteve Maria , Marques Josep Maria , de Anta Maria Teresa Jiménez , Arroyo Vicente , Rodés Joan
Published: March 2007

Eighty cirrhotic patients who had recovered from an episode of spontaneous bacterial peritonitis were included in a multicenter, double-blind trial aimed at comparing long-term norfloxacin administration (400 mg/day; 40 patients) vs. placebo (40 patients) in the prevention of spontaneous bacterial peritonitis recurrence. At entry, both groups were similar with respect to clinical and laboratory data, ascitic fluid protein and polymorphonuclear concentrations, number of previous episodes of spontaneous bacterial peritonitis and causative organisms of the index spontaneous bacterial peritonitis. Norfloxacin administration produced a selective intestinal decontamination (elimination of aerobic gram-negative bacilli from the fecal flora without significant changes in other microorganisms) throughout the study in six patients in whom the effect of norfloxacin on the fecal flora was periodically assessed. Fourteen patients from the placebo group (35%) and five from the norfloxacin group (12%) developed spontaneous bacterial peritonitis recurrence during follow-up (χ2 = 5.97; p = 0.014) (mean follow-up period = 6.4 ± 0.6 mo; range = 1 to 19 mo). Ten of the 14 spontaneous bacterial peritonitis recurrences in the placebo group and only one of the five spontaneous bacterial peritonitis recurrences in the norfloxacin group were caused by aerobic gramnegative bacilli (χ2 = 8.87; p = 0.0029). The overall probability of spontaneous bacterial peritonitis recurrence at 1 yr of follow-up was 20% in the norfloxacin group and 68% in the placebo group (p = 0.0063) and the probability of spontaneous bacterial peritonitis recurrence caused by aerobic gram-negative bacilli at 1 yr of follow-up was 3% and 60%, respectively (p = 0.0013). Only one patient treated with norfloxacin experienced side effects related to treatment (oral and esophageal candidiasis). These results indicate that long-term selective intestinal decontamination with norfloxacin is an effective and safe measure to prevent spontaneous bacterial peritonitis recurrence caused by aerobic gram-negative bacilli in cirrhosis. (HEPATOLOGY 1990;12:716-724).
Albumin absorption and protein secretion by the gallbladder in man and in the pig†
Authors: Toth Julius L. , Harvey Robert P. C. , Upadyha Aravinda G. , Strasberg Steven M.
Published: March 2007

To study albumin absorption by the gallbladder in man, an in vitro model was first established in the pig and compared with in vivo function in the same species. Water and electrolyte transport and 125I-albumin absorption and protein secretion in vivo and in vitro were compared. Then similar in vitro studies were performed on human gallbladders obtained at surgery. The in vivo study in the pig was performed without disturbing the gallbladder except to tie a cannula in the cystic duct end. The in vitro model was identical in the pig and human gallbladders. Gallbladders were excised using a technique causing minimal injury and anoxia. They were oxygenated on both mucosal and serosal surfaces in a temperature-controlled environment. Luminal and external bath test solutions consisted of modified Ringers bicarbonate with added glucose; luminal solutions also contained 125I-albumin from different species, depending on the study. Active absorption of sodium and water occurred in both types of studies in the pig but in vivo absorption rates were considerably greater than in vitro rates. Albumin absorption in vivo was substantial; although present in vitro, the absorption of albumin was diminished relatively more than electrolyte transport rates. Protein secretion rates into the gallbladder were similar in vitro and in vivo. The results of studies in the human gallbladders in vitro were similar to the pig, except albumin absorption was greater. Some human gallbladders were obtained from control patients and some from patients with cholesterol gallstones. There were no significant differences between the two groups for any of the variables studied; however, the numbers were small and some control gallbladders were not normal gallbladders. (HEPATOLOGY 1990;12:729-737).
Amyloid deposition in intrahepatic large bile ducts and peribiliary glands in systemic amyloidosis
Authors: Sasaki Motoko , Nakanuma Yasuni , Terada Tadashi , Hoso Masahiro , Saito Katsuhiko , Hayashi Morimoto , Kurumaya Hiroshi
Published: March 2007

Amyloid deposition in the hepatic parenchyma and portal tracts in the liver is well known in systemic amyloidosis. We recently experienced an autopsy case of systemic amyloidosis presenting the amyloid deposits in the intrahepatic biliary tree. This experience prompted us to survey 19 autopsy cases of systemic amyloidosis. Amyloid deposition was found just under the lining epithelium of the intrahepatic large bile duct in 10 of 19 cases and around the peribiliary glandular acini in 7 of the 19 cases, respectively. Amyloid deposition in the intrahepatic large bile duct and peribiliary glands was positively correlated with the degree of amyloid deposition in the liver but not with type of amyloid protein. Double-staining of amyloid and vascular endothelium disclosed that amyloid deposition was more closely related to the inner part of the peribiliary vascular plexus and to the vascular plexus encircling the peribiliary glands than the lining biliary epithelium and peribiliary glandular acinar cells themselves. The exact pathogenesis of amyloid deposition in these anatomical components, however, remains unclear. Although our cases failed to show any overt clinical symptomatologies related to amyloid deposition in these biliary components, it seems conceivable that more massive amyloid deposition in these anatomical components could give rise to some clinical symptoms. (HEPATOLOGY 1990;12:743-746).
Diagnostic value of brush cytology in the diagnosis of bile duct carcinoma: A study in 65 patients with bile duct strictures
Authors: Rabinovitz Mordechai , Zajko Albert B. , Hassanein Tarek , Shetty Balu , Bron Klaus M. , Schade Robert R. , Gavaler Judith S. , Block Geoffrey , van Thiel David H. , Dekker Andrew
Published: March 2007

Malignant strictures of the extrahepatic bile ducts are difficult to distinguish from benign strictures, particularly in patients with primary sclerosing cholangitis. Because attempts at diagnosing small cancers with fine-needle aspiration biopsy are not possible in the absence of an associated mass lesion and because the sensitivity of exfoliative biliary cytology is controversial, brush cytology has been used as a potential means of establishing a specific diagnosis of bile duct carcinoma. Herein we report our experience with this technique when performed on 65 patients over a 5-yr period. Each had at least one brushing. Thirty-seven were found to have bile duct carcinoma and 28 were found to have benign strictures. Of these 37, the first brushing was positive for malignancy in 15 (40%), whereas four (11%) had cells suspected but not diagnostic of malignancy. Thirteen patients with bile duct carcinoma whose initial brushings were negative for malignancy had second brushings. Of these, five (38%) had malignant cells, whereas three (24%) yielded suspicious cells. Three of the eight whose first two brushings were negative for malignancy were found to have malignant cells on the third brushing. In contrast, of the 28 patients with benign strictures, malignant cells were never found. However, in two patients, suspicious cells were reported with the first but not the second brushing. A single negative or suspicious cytological finding decreased the probability of bile duct carcinoma to 43%. Two and three sequential negative tests reduced the probability to 32% and 0%, respectively. When suspicious cytological findings were excluded from the negative results, the probability of having bile duct carcinoma was further reduced to 41%, 20% and 0%, respectively.

Using these results, we conclude that (a) a single cytological brushing of a bile duct stricture has a low yield, (b) the sensitivity of the test increases with repeated attempts, (c) the probability of having bile duct carcinoma after three sequential negative cytological brushings is very low (<6%) and (d) these data provide evidence for the usefulness of percutaneous transhepatic cholangiography and bile duct cytological findings in establishing a diagnosis of bile duct cancer. (HEPATOLOGY 1990;12:747-752).
Prognostic factors of hepatocellular carcinoma in the west: A multivariate analysis in 206 patients
Authors: Calvet Xavier , Bruix Jordi , Ginés Pere , Bru Concepció , Sole Manel , Vilana Ramón , Rodés Joan
Published: March 2007

To investigate the prognostic factors in Western patients with hepatocellular carcinoma, 206 patients with confirmed diagnoses of hepatocellular carcinoma were studied in terms of survival. All patients were diagnosed between 1983 and 1987. A multivariate survival analysis (Cox regression model) using clinical, biochemical, ultrasonographical and pathological data obtained at diagnosis disclosed that bilirubin (p = 0.0001), ascites (p = 0.0001), toxic syndrome (defined by the presence of weight loss > 10% premorbid weight, malaise and anorexia) (p = 0.009), blood urea nitrogen (p = 0.025), tumor size (p = 0.001), γ-glutamyltranspeptidase (p = 0.0006), age (p = 0.0005), serum sodium (p = 0.003) and presence of metastases (p = 0.002) were independent predictors of survival. According to the contribution of each of these factors to the final model, a prognostic index was constructed allowing division of patients in different groups according to their relative risk of death: RRD = EXP (Age × 0.03 + Ascites × 0.8281 + BUN × 0.0137 + Serum sodium × (− 0.0538) + γ-Glutamyltranspeptidase × 0.0019 + Bilirubin × 0.0734 + Tumor size × 0.33 + Toxic syndrome × 0.4965 + Metastases × 0.55).

These results facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials. (HEPATOLOGY 1990;12:753-760).
Liver cell carcinoma with osteoclast-like giant cells: Nonepitheliogenic giant cells in diverse malignancies
Authors: Rosai Juan
Published: March 2007

Hepatocellular carcinoma with osteoclast-like giant cells (hepatic giant cell carcinoma ([HGCC]) is a rare entity, with only three cases reported. The tumor is histologically similar to giant cell tumor (GCT) of bone, and the origin of the multinucleated giant cells and mononuclear stromal cells has not been determined. The purpose of this report is to present a case of this rare tumor and compare its ultrastructural and immunohistochemical features with those of a conventional GCT of bone. Histologically, the HGCC consists of sheets of osteoclast-like giant cells with a background of mononuclear cells. The giant cells lack the pleomorphism seen in hepatocellular carcinomas with anaplastic giant cells. At the light microscopic level, most of this tumor was nearly identical to a GCT of bone, but several microscopic fields (less than 5% of the tumor) had the histologic appearance of a “usual” hepatocellular carcinoma. The hepatic tumor was negative for HAM 56, epithelial cytokeratins, muramidase, and alpha-1-antitrypsin, with only focal positivity for chymotrypsin in mononuclear and giant cells. The GCT was strongly positive for alpha-1-antitrypsin and chymotrypsin in both the mononuclear and giant cells and showed focal, weak staining for AE1 and AE3 in the mononuclear stromal cells. Ultrastructurally, both mononuclear and giant cells of the HGCC showed features typical of hepatocellular carcinoma. Although the patient presented in this report died, the pattern of growth was different from most hepatocellular carcinomas. The overall histologic features of this tumor are distinctive and appear to justify separating this variant from other types of hepatocellular carcinoma.
Effects of oxygen inhalation in ascitic cirrhotic patients: Therapeutic implications?
Authors: Henriksen Jens H.
Published: March 2007

In patients with cirrhosis, O2 uptake, i.e., O2 consumption, is abnormally deceased. We administered 50% O2 for 30 min in eight patients with alcoholic cirrhosis to determine whether the subsequent increase in arterial O2 content may correct the low O2 consumption. In addition, we studied in these patients the reflex control of cardiac output and blood pressure by arterial baroreceptors, as O2 inhalation induces a systemic vasoconstriction. Arterial O2 tension, oxyhaemoglobin saturation and arterial O2 content significantly increased as well as systemic vascular resistance and arterial pressure. In contrast, O2 consumption (which was below normal values) under basal conditions, O2 transport, O2 extraction ratio, heart rate, right atrial and pulmonary wedged pressures, cardiac output, hepatic venous pressures, hepatic and azygos blood flows were unaffected by O2 administration. In three patients receiving air, no significant change was observed. Our results show that, in patients with cirrhosis, inhalation of 50% O2 does not correct O2 consumption. We may conclude that reflex control of cardiac output and arterial pressure by arterial baroreceptors is impaired in these patients.
Role of ethanol-inducible cytochrome P-450 IIE1 in carbon tetrachloride—induced damage to centrilobular hepatocytes from ethanol-treated rats
Authors: Lindros Kai O. , Cai Yuan , Penttilä Kai E.
Published: March 2007

The ethanol-inducible form of cytochrome P-450 (IIE1) is expressed and induced by ethanol, predominantly in the centrilobular region. Because this isoenzyme has a particularly high capacity to convert carbon tetrachloride and several other hepatotoxins into reactive intermediates, its role in producing damage was studied by comparing the effect of carbon tetrachloride exposure on hepatocytes isolated from either the periportal or the perivenous region by digitonin-collagenase perfusion. After exposure for 18 hr of primary culture to 600 μmol/L of carbon tetrachloride, periportal cells were only slightly damaged, as estimated from dye exclusion and lactate dehydrogenase leakage. In marked contrast, perivenous cells, which contained a several-fold higher amount of immunoreactive P-450 IIE1 apoprotein, were partly damaged after exposure to 60 to 150 μmol/L of carbon tetrachloride and severely damaged after 600 μmol/L. Similarly, lipid peroxidation after carbon tetrachloride was much more prominent in perivenous cells. The differences between perivenous and periportal cells in carbon tetrachloride—induced injury were larger when cells were isolated from chronically ethanol-treated rats. Isoniazid, an efficient inhibitor of P-450 IIE1, protected against damage by carbon tetrachloride more efficiently than the general P-450 inhibitor cimetidine. Our results suggest that the greater susceptibility of the perivenous hepatocytes to carbon tetrachloride—induced damage is associated with the high expression of P-450 IIE1 in these cells. This enzyme may also be involved in damage elicited by several other typical centrilobular hepatotoxins. (HEPATOLOGY 1990;12:1092-1097).
A study of the inhibition of adrenaline-induced vasoconstriction in the isolated perfused liver of rabbit
Authors: Martínková Jiřina , Bulas Josef , Krejčí Vladimír , Hartman Miroslav , Tilšer Ivan , Hůlek Petr
Published: March 2007

We have studied the action of a series of vasoactive and antispasmodic agents on the intrahepatic vasoconstriction induced by adrenaline in the isolated perfused liver of rabbits. The arterial and portal venous resistance, oxygen consumption, liver weight and bile flow were investigated. The drugs used were as follows: nonspecific α-adrenergic antagonists (DH-ergocristine, dibenamine, phenoxybenzamine), vasodilators with a direct miscellaneous action (theophylline, papaverine, dipyridamole, glucagon, Aiu-cor by Instituto Gentilli, Italy [inosine, ATP, IPI, UTP]) and antispasmodics (piperylone, tropenziline, noraminophenazone).

Adrenaline increased arterial and portal venous resistance followed by a diminution of oxygen consumption, liver weight and bile flow. α-Adrenergic antagonists inhibited the effects of adrenaline on portal venous resistance and oxygen consumption and especially the effects on hepatic arterial resistance. The most potent agent was phenoxybenzamine.

In contrast to α-adrenoceptor blockade, the effects of other vasoactive agents were without a sustained influence on hepatic arterial resistance (excepting those of glucagon and dipyridamole). Some of them were effective as antagonists on responses in the portal venous bed (papaverine, Aiu-cor). Moreover, there were drugs exerting an enhancement of the vasoconstrictor responses of hepatic artery to low concentrations of adrenaline with no effect on the portal venous bed (piperylone, tropenziline). Theophylline and noraminophenazone exerted no effect either on the arterial or portal venous bed.

No vasodilator agent antagonized the changes of the bile flow after adrenaline administration. (HEPATOLOGY 1990;12:1157-1165).
Selective intestinal decontamination increases serum and ascitic fluid C3 levels in cirrhosis
Authors: Such Jose , Guarner Carlos , Soriano German , Teixidó Montserrat , Barrios José , Tena Francisco , Méndez Carmen , Enríquez Jaime , Rodríguez José Luis , Vilardell Francisco
Published: March 2007

Selective intestinal decontamination for 7 days with norfloxacin was performed in 14 cirrhotic patients with ascites and low ascitic fluid total protein. Variations in serum and ascitic fluid of C3 and C4 and ascitic fluid total protein after therapy were compared with those of a control group of 14 untreated patients with similar characteristics. After oral norfloxacin administration, we saw a significant increase of C3 in serum (p < 0.05) and ascitic fluid (p = 0.01). A significant increase was also observed in ascitic fluid total protein (p < 0.05) but not in serum and ascitic fluid C4. There were no changes in serum C3, ascitic fluid C3, ascitic fluid C4 or in ascitic fluid total protein in group 2. These data demonstrate that selective intestinal decontamination increases serum and ascitic fluid C3 levels and, therefore, might be useful in preventing spontaneous infections in cirrhotic patients at high risk of infection. (HEPATOLOGY 1990;12:1175-1178).
Involvement of tumor necrosis factor-α in development of hepatic injury in galactosamine-sensitized mice
Authors: Hishinuma Ieharu , Nagakawa Jun-Ichi , Hirota Kazuo , Miyamoto Kaname , Tsukidate Kazuo , Yamanaka Takashi , Katayama Kou-Ichi , Yamatsu Isao
Published: March 2007

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 μg/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor—like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor—sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor—α with polyvalent rabbit anti-mouse tumor necrosis factor—α antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor—α on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor—α, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.

These results suggest that endogenous tumor necrosis factor—α participates in the pathogenesis of lipopolysaccharide-elicited hepatic injury, and that tumor necrosis factor plays a crucial role in the development of liver necrosis in galactosamine-sensitized mice. (HEPATOLOGY 1990;12:1187-1191).
Infection of mice with lactate dehydrogenase—elevating virus destroys the subpopulation of kupffer cells involved in receptor-mediated endocytosis of lactate dehydrogenase and other enzymes
Authors: Smit Martin J. , Duursma Anneke M. , Koudstaal Jan , Hardonk Machiel J. , Bouma Joop M. W.
Published: March 2007

In previous experiments in rats, we have shown that the rapid plasma clearance of a number of clinically important enzymes is due to receptor-mediated endocytosis by Kupffer cells and other resident macrophages. Others have shown that infection of mice with lactate dehydrogenase—elevating virus, a virus that proliferates in macrophages, leads to reduced plasma elimination of these enzymes. This paper integrates these two sets of experiments. Plasma elimination of intravenously injected, radioactively labeled lactate dehydrogenase M4 and mitochondrial malate dehydrogenase in mice was shown to be caused in part by uptake in liver, spleen and bone. Uptake of lactate dehydrogenase M4 by these tissues was, to a large extent, saturable and the two dehydrogenases competitively inhibited each other's clearance. These results suggest that, also in mice, these enzymes are partly cleared from plasma by endocytosis by way of a common receptor on cells (probably macrophages) from liver, spleen and bone marrow. Morphometrical data showed that normal mouse liver contains 23 × 106 Kupffer cells/cm3. This number was reduced to about 30% of that of controls 24 hr after infection of mice with lactate dehydrogenase—elevating virus but returned to normal within the next 9 days. The saturable component of uptake of lactate dehydrogenase M4 by liver, spleen and bone had disappeared 24 hr after infection with the virus, and did not return after the Kupffer cell population had recovered. Our findings suggest that lactate dehydrogenase M4 is, to a large extent, removed from the circulation by way of a receptor on a subpopulation of macrophages that is permissive for replication of lactate dehydrogenase—elevating virus. This subpopulation is destroyed within 24 hr after infection and is replaced during the next 9 days by cells that are not permissive for the virus and lack the receptor. (HEPATOLOGY 1990;12:1192-1199).
Pathological observations of intrahepatic peribiliary glands in 1,000 consecutive autopsy livers. III. Survey of necroinflammation and cystic dilatation
Authors: Terada Tadashi , Nakanuma Yasuni
Published: March 2007

Pathological changes and significance of intrahepatic peribiliary glands, hitherto poorly recognized intrahepatic elements, have been evaluated in our laboratory. In this report, we surveyed necroinflammatory and cystic changes of the peribiliary glands in 1,000 consecutive autopsy livers because these two changes coexisted frequently in the same liver. The necroinflammatory change was found in 228 livers (22.8%) and the cystic change in 202 livers (20.2%), and 103 cases showed both changes in the same liver. The necroinflammatory change was frequently found in intrahepatic cholangitis and extrahepatic biliary obstruction with bacterial infection, suggesting that biliary bacterial inflammation extends into these peribiliary glands. This change was also frequent in systemic infection or septicemia without biliary bacterial infection, implying that the peribiliary glands were also damaged in such conditions without direct infection. The cystic change was frequent in livers with portal hypertension or obstruction, adult polycystic disease and necroinflammation of the glands, suggesting that the cystic change of the glands could occur as the result of the disturbance of intrahepatic circulation or as the result of inflammatory destruction of the glandular conduits. Some of peribiliary cysts may be of congenital origin. Dysfunction related to these pathological changes in the glands may diminish seromucous secretion and cause alterations in hepatic bile composition. The cystic change of the glands may retard bile flow by compressing bile duct lumina. (HEPATOLOGY 1990;12:1229-1233).
A biphasic pattern of anti-pre-s responses in acute hepatitis B virus infection
Authors: Budkowska Agata , Dubreuil Pascal , Maillard Patrick , Poynard Thierry , Pillot Jacques
Published: March 2007

The clinical relevance of the immune response to the translation products of the pre-S1 and pre-S2 regions of hepatitis B virus was examined by testing sequential serum samples from 17 patients with acute self-limited hepatitis B and from two patients in whom chronic liver disease developed. Anti-pre-S antibodies were determined by enzyme immunoassays based on the inhibition of binding of monoclonal antibodies to epitopes in the pre-S1 and pre-S2 sequence.

In acute, self-limited infection, anti-pre-S antibodies appeared in a biphasic pattern. The early antibodies were detected at the time of clinical signs of acute disease when HBsAg and often HBeAg were present, but hepatitis B virus DNA was no longer detectable in serum. Anti-pre-S levels then fell, but subsequently reappeared as the late antibody during the recovery phase, after development of anti-HBe, but before anti-HBs. Anti-pre-S responses were detected in 15 of 17 patients who recovered (88.2%) and in both patients with acute hepatitis B virus infection evolving to chronic liver disease.

Although the early antibodies to pre-S1 and pre-S2 proteins appeared at the time of decreasing levels of infectious virus in serum in cases of self-limited infection, these antibodies also were transiently or continuously present with high levels of serum hepatitis B virus DNA in patients in whom chronic hepatitis B infection developed. Thus the anti-pre-S response in acute hepatitis is not a prognostic marker for clinical resolution. Mechanisms other than a lack of humoral anti-pre-S responses must be responsible for the failure to eliminate virus in acute hepatitis B evolving into chronic infection. (HEPATOLOGY 1990;12:1271-1277).
Normalization of ventilation/perfusion relationships after liver transplantation in patients with decompensated cirrhosis: Evidence for a hepatopulmonary syndrome
Authors: Eriksson Ljusk Siw , Söderman Charlotte , Ericzon Bo-Göran , Eleborg Lennart , Wahren John , Hedenstierna Göran
Published: March 2007

To examine the effect of liver transplantation on the respiratory and cardiovascular functions, ventilation/perfusion relationships were determined by multiple inert gas elimination technique in six patients with end-stage liver disease 1 to 19 mo before and 2 to 6 mo after liver transplantation. Cardiac output and pulmonary vascular pressures were measured after catheterization of the pulmonary artery. All patients had normal spirometry and chest x-ray films before transplantation.

PaO2 before transplantation was 78.8 ± 7.4 mm Hg (range = 51.8 to 102.8 mm Hg). All patients had perfusion of poorly ventilated lung regions (low ventilation/perfusion relationships) varying from 3% to 19% of cardiac output (mean = 8.5% ± 2.4% of cardiac output) and two patients had intrapulmonary shunting (3% and 20% of cardiac output). Measured and calculated PaI2 agreed closely, indicating absence of pulmonary diffusion abnormality, as well as of extrapulmonary shunting. After transplantation, PaO2 normalized in all patients, and both shunting and low ventilation/perfusion relationships disappeared. Cardiac output decreased from 9.1 ± 1.4 to 6.6 ± 0.5 L/min (p < 0.05), and the pulmonary vascular resistance increased from 0.69 ± 0.14 to 1.64 ± 0.43 mm Hg/L/min (p < 0.05). The systemic vascular resistance also increased (before = 8.7 ± 1.0; after = 15.3 ± 1.1 mm Hg/L/min; p < 0.001).

Normalization of respiratory and cardiovascular alterations, after liver transplantation, in patients with end-stage liver disease indicates that these changes have a direct functional relationship to the diseased liver. It is hypothesized that this is part of a “hepatopulmonary syndrome,” which in similarity to the hepatorenal syndrome disappears with improved liver function. (HEPATOLOGY 1990;12:1350-1357).
Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: Results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo
Authors: Andreani Toni , Poupon Reneé E. , Balkau Beverley J. , Trinchet Jean-Claude , Grange Jean-Didier , Peigney Nicolas , Beaugrand Michel , Poupon Raoul
Published: March 2007

Propranolol and endoscopic sclerosis of esophageal varices are the two approaches currently used in prophylaxis of the first gastrointestinal hemorrhage in the cirrhotic patient. One hundred twenty-six cirrhotic patients with esophageal varices and no histories of bleeding were included in the trial regardless of the gravity of the cirrhosis or the size of the esophageal varices. Patients with hepatocarcinomas or other cancers, clearly impossible follow-up, previous treatment for portal hypertension or contraindication to β-blockers were excluded. After randomization, 43 patients received propranolol twice daily at a dose reducing the heart rate by 25%; 42 patients were treated with intravariceal and extravariceal injections of Polidocanol; 41 control patients received vitamin K orally as placebo. The patients were seen at 3-mo intervals for 2 yr. On entry to the trial the three groups were comparable in terms of clinical and biological parameters, including size of esophageal varices (grade I = 51, grade II = 54, grade III = 17), Child-Pugh classification (A = 29, B = 61, C = 32) and the origin of cirrhosis (alcoholic in 79% of cases).

Twenty-four patients bled (two bled in the propranolol group, nine bled in the endoscopic sclerosis of esophageal varices group and 13 bled in the placebo group). Actuarial estimates (Kaplan-Meier) of the time of onset of first bleeding showed that the differences were significant between propranolol and placebo (p < 0.004) and between propranolol and sclerotherapy (p < 0.03) but not between sclerotherapy and placebo. The multivariate Cox model indicated that the size of esophageal varices and the Child-Pugh class were prognostic factors for the onset of GI bleeding; the treatment effect remained after adjusting for these factors. No significant difference in survival was observed among the three treatment groups. The multivariate Cox model indicated that female gender and Child-Pugh class were factors predictive of survival and that treatment played no part in predicting survival. In conclusion, our study suggests that propranolol is effective in preventing the first gastrointestinal bleeding in the cirrhotic patient but does not improve the survival rate. (HEPATOLOGY 1990;12:1413-1419).
Intrahepatic expression of HBcAg in chronic HBV hepatitis: Lessons from molecular biology
Authors: Chu Chia-Ming , Liaw Yun-Fan
Published: March 2007

The precore and core proteins of hepatitis B virus have identical deduced amino acid sequences other than a 29-residue amino-terminal extension (precore region) on the precore protein. The first 19 of these residues serve as a signal sequence to direct the precore protein to the endoplasmic reticulum, where they are cleaved off with formation of precore protein derivative P22 for secretion. In this report, we show that P22 can alternatively be transported into the nucleus following signal peptide cleavage. Experiments with deletion mutants indicated that this nuclear transport proceeds via the cytosol and is dependent on the amino-terminal portion of P22. Thus, the hepatitis B virus precore protein is a secreted, cytosolic, and nuclear protein.
Antibodies in Anti-HBe—positive patient sera bind to an HBe protein expressed on the cell surface of human hepatoma cells: Implications for virus clearance
Authors: Schlicht Hans-jürgen , von Brunn Albrecht , Theilmann Lorenz
Published: March 2007

The relevance of the recently described membrane-bound form of the HBe protein for the antiviral immune response was examined. The data show that antibodies in anti-HBe, but not in anti-HBc—positive human sera efficiently bind to the membrane expressed HBe. No evidence was obtained that the HBc can reach the cell surface in a form that can be detected with human antibodies. The findings suggest that the decline of virus titer that is usually observed after seroconversion from HBe to anti-HBe might be the result of an antibody-mediated elimination of infected cells. (Hepatology 1991;13:57-61).
Distribution of cholesterol between vesicles and micelles in human gallbladder bile: Influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid
Authors: Sahlin Staffan , Thyberg Per , Ahlberg Jon , Angelin Bo , Einarsson Kurt
Published: March 2007

The present study aimed at determining the relative distribution of cholesterol between the vesicular and micellar phases in gallbladder bile of gallstone patients (n = 23) and gallstone-free subjects (n = 7). Nine of the gallstone patients were treated with chenodeoxycholic acid and seven were treated with ursodeoxycholic acid, 15 mg/kg/day, for 3 wk before cholecystectomy. The vesicular and micellar fractions in bile were separated by sucrose density gradient ultracentrifugation, and a clear separation between the two phases was obtained. The vesicles were further identified by quasielastic light scattering spectroscopy and appeared to be of a uniform size with a mean hydrodynamic radius of 760 Å. The proportion of cholesterol in the vesicular fraction was significantly higher in the untreated gallstone group (40% ± 4%) compared with the gallstone-free (28% ± 3%), ursodeoxycholic acid (28% ± 3%) and chenodeoxycholic acid (18%± 4%) groups. Despite a low cholesterol saturation of bile in the latter three groups (88% ± 12%, 51% ± 9% and 65% ± 5%, respectively), a considerable part of the biliary cholesterol was carried in the vesicular fraction. The cholesterol/phospholipid ratio in the vesicular fraction averaged between 0.49 and 0.58 in the gallstone, gallstone-free and chenode-oxycholic acid groups, whereas the ursodeoxycholic acid group had a significantly lower ratio of 0.24. The cholesterol/phospholipid ratio was about 0.15 in all micellar fractions. The nucleation time of bile from the gallstone group was short (2 ± 1 days) compared with the gallstone-free, chenodeoxycholic acid and ursodeoxycholic acid groups (23 ± 3, 24 ± 6 and 14 ± 3 days, respectively). These observations give further support to the concept that the mechanism for gallstone dissolution is complex and different for chenodeoxycholic acid and ursodeoxycholic acid. (Hepatology 1991;13:104-110).
Significance of anti-HBx antibodies in hepatitis B virus infection
Authors: Levrero Massimo , Stemler Marietta , Pasquinelli Claudio , Alberti Alfredo , Jean-Jean Olivier , Franco Alessandra , Balsano Clara , Diop Dialo , Brechot Christian , Melegari Margherita , Villa Erica , Barnaba Vincenzo , Perricaudet Michel , Will Hans
Published: March 2007

Serological responses to hepatitis B virus-X determinants have been noted in human sera, but conflicting findings concerning the correlation of anti-HBx antibodies with different stages of hepatitis B virus infection or pathological sequelae have been reported. Using an adenovirus-based eukaryotic vector, the 17 kD X protein was efficiently expressed in 293 cells. Cellular extracts containing the eukaryotic X protein have been used to screen for anti-HBx antibodies by immunoblot analysis in a large panel of sera from patients affected by hepatitis B virus chronic hepatitis, hepatocellular carcinoma and acute viral hepatitis. Sera from 32 of 171 (19%) chronic hepatitis B virus patients were positive for anti-HBx antibodies. Only one of thirty-two (3%) HBsAg-negative, anti-HBs/anti-HBc—positive chronic hepatitis serum was anti-HBx positive. Very few sera from primary hepatocellular carcinoma patients showed positivity for anti-HBx (8 of 149 or 5%). Anti-HBx were also detected in 8 of 48 (17%) acute viral hepatitis patients. In the four cases that were followed up weekly, anti-HBx anti-bodies appeared 3 to 4 wk after the onset of the clinical signs. To compare the X protein expressed in eukaryotic and prokaryotic cells as a substrate for anti-HBx antibody detection, 171 sera were screened with HBx fusion proteins expressed in Escherichia coli. The prokaryotic cell extract test seems to be more sensitive. During the chronic phase of hepatitis B virus infection, the presence of anti-HBx antibodies detected with the eukaryotic cell extract correlates with the presence of well-established markers of ongoing viral replication: serum hepatitis B virus-DNA (p < 0.001) and intrahepatic HBcAg expression (p < 0.001). (Hepatology 1991;13:143—149).
Elevated intracranial pressure and computed tomography of the brain in fulminant hepatocellular failure
Authors: Muñoz Santiago J. , Robinson Murray , Northrup Bruce , Bell Rodney , Moritz Michael , Jarrell Bruce , Martin Paul , Maddrey Willis C.
Published: March 2007

Cerebral herniation is a leading cause of death in patients with fulminant hepatocellular failure. Classical signs of elevated intracranial pressure are often absent in these patients. A reliable noninvasive method by which the presence of cerebral edema could be determined is much needed. To assess the efficacy of computed tomography of the brain in this setting, we compared the radiographic findings to the intracranial pressure measured by an epidural monitor in patients with fulminant hepatic failure. Unfortunately, a considerable difference existed between the presence of cerebral edema diagnosed by computed tomography of the brain and elevation of the intracranial pressure. Our observations suggest that in patients with fulminant hepatic failure and advanced hepatic encephalopathy, computed tomography of the brain is of little value in detecting cerebral edema. Pressure monitoring is most important to establish the presence and guide the therapy of intracranial hypertension. (HEPATOLOGY 1991;13:209-212).