bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonsyndromatic paucity of interlobular bile ducts: Light and electron microscopic evaluation of sequential liver biopsies in early childhood
Authors: Kahn Ellen , Daum Fredric , Markowitz James , Teichberg Saul , Duffy Lynn , Harper Rita , Aiges Harvey
Published: March 2007

Liver biopsies and/or autopsy specimens from 17 children (ages 1 week to 5 years) with nonsyndromatic paucity of the interlobular bile ducts were studied by light and electron microscopy. Initial biopsies were obtained before 90 days of age from all patients, and two or more specimens were available from nine. No specific underlying condition was found in nine infants. The remaining cases were associated with Down's syndrome (n = 2), hypopituitarism (n = 2), cystic fibrosis (n = 1), α1-antitrypsin deficiency (n = 1), cytomegalovirus (n = 1) and Ivemark syndrome (n = 1).

Before 90 days of age, portal changes included duct paucity and fibrosis. Lobular changes were nonspecific, consisting of cholestasis, giant cell transformation, extramedullary hematopoiesis and perisinusoidal fibrosis. Duct paucity, portal fibrosis and perisinusoidal fibrosis persisted after 90 days. Cholestasis was mild or no longer apparent. Portal changes before 90 days of age appear to be sufficiently distinctive to microscopically distinguish nonsyndromatic from syndromatic paucity.

Electron microscopic findings suggest that paucity in nonsyndromatic patients may result from a primary ductal insult: ultrastructural studies revealed bile duct destruction characterized by undulation and breaks in the basal lamina and infiltration of the epithelium by lymphocytes. Bile canalicular dilatation with blunting of microvilli and electron-dense material in the lumen, predominantly seen before 90 days, also reinforces the hypothesis of a primary ductal defect.
Cellular localization of α-interferon in hepatitis B virus-infected liver tissue
Authors: Jilbert Allison R. , Burrell Christopher J. , Gowans Eric J. , Hertzog Paul J. , Linnane Anthony W. , Marmion Barrie P.
Published: March 2007

Cells expressing α2-interferon were identified by indirect immunofluorescence using both a polyclonal and a monoclonal anti-α-interferon antibody reagent. In hepatitis B or delta virus infection, focal clusters of α-interferon-positive infiltrating mononuclear cells and (to a lesser extent) fibroblasts were regularly seen in liver sections from patients who had chronic active hepatitis and cirrhosis and evidence of virus replication, but in a minority of patients with chronic persistent hepatitis B and not in nonvirally infected livers. This report provides evidence for local α-interferon production near the site of virus replication in hepatitis B infection, identifies mononuclear cells and fibroblasts (but not hepatocytes) as the main cell types producing interferon in this infection and suggests that locally produced α-interferon may be a natural regulator of virus replication in HBsAg-positive chronic active hepatitis. Furthermore, serological characterization of the interferon species produced locally may predict which particular interferon species could be of the greatest therapeutic benefit in specific disease states or individual patients.
Simultaneous passive and active immunization against hepatitis B: Noninterference of hepatitis B immune globulin with the anti-HBs response to reduced doses of heat-inactivated hepatitis B vaccine
Authors: Lelie Nico P. , Reesink Henk W. , Grijm Rob , de Jong-Van Manen Sonja Th. , Reerink-Brongers Eveline E.
Published: March 2007

The effect of simultaneous administration of hepatitis B immune globulin on the antibody response to a low dose of heat-inactivated hepatitis B vaccine was investigated in 175 health care workers. Subjects were divided into four groups: Groups I and II received 3 monthly injections of a reduced dose (0.6 μg) of a heat-inactivated hepatitis B vaccine (the usual dose being 3 μg) along with 500 IU of hepatitis B immune globulin simultaneously with the first injection of vaccine; Groups III and IV received the vaccine only. In addition, Groups I and III received a final booster injection with 0.6 μg of the vaccine 8 months after the initial injection.

Anti-HBs passively acquired from hepatitis B immune globulin did not interfere with the development of an active antibody response to the vaccine: the anti-HBs conversion rates were similar in persons treated with the combined regimen (89%) as in those who received the vaccine only (91%). At 3 and 5 months after the first injection, however, anti-HBs titers in the recipients of vaccine alone were slightly but statistically significantly higher than those of persons who received both hepatitis B immune globulin and vaccine; but at 8 months, this difference was no longer statistically significant. After a booster inoculation at 8 months, the geometric mean titer of anti-HBs increased 7- to 8-fold in antibody-positive vaccinees, regardless of whether hepatitis B immune globulin had been given earlier. Moreover, 6 of 13 nonresponders to the initial three vaccine injections developed anti-HBs after the booster inoculation.

Thus, passively acquired anti-HBs does not interfere with an active antibody response to hepatitis B vaccine even when a low dose of vaccine is used. Furthermore, a final booster vaccine inoculation, several months after the initial series of injections, is important in providing high response rates and sustained high titers of anti-HBs.
In situ distribution of major histocompatibility complex products and viral antigens in chronic hepatitis B virus infection: Evidence that HBc-containing hepatocytes may express HLA-DR antigens
Authors: van den Oord Joost J. , De Vos Rita , Desmet Valeer J.
Published: March 2007

Using a double-staining immunohistochemical procedure, the topographical relationship between viral antigens on the one hand and the expression of major histocompatibility complex products by hepatocytes on the other hand was analyzed in a series of 19 liver biopsies from patients with chronic hepatitis B virus infection.

In areas of piecemeal necrosis, periportal hepatocytes demonstrated Class I major histocompatibility complex products or HLA-A, B and C antigens, but did not show a preferential expression of either HBcAg or HBsAg. The cellular infiltrate of piecemeal necrosis consisted of helper/inducer and suppressor/cytotoxic T-lymphocytes, and was admixed in four cases with branching dendritic processes of sinusoidal lining cells which strongly expressed Class II major histocompatibility complex products or HLA-DR antigens. The latter surrounded small groups of periportal hepatocytes.

In areas of spotty necrosis, the hepatocytes expressed HLA-A, B and C antigens in all cases, and were admixed with variable numbers of suppressor/cytotoxic T-lymphocytes. In 14 cases, the clustered hepatocytes in areas of spotty necrosis expressed HLA-DR antigens, associated in 11 of the cases with immunoreactive HBcAg in the nuclei of some of the HLA-DR-positive hepatocytes. Immunoelectron microscopy, performed in one such case, demonstrated the presence of HLA-DR antigen in a discontinuous pattern at the plasma membrane of some hepatocytes, together with the presence of core particles in the nucleus of HLA-DR-positive hepatocytes.

Our findings further contribute to the growing evidence that HBcAg represents the major target antigen for T-cell attack in areas of spotty necrosis. It is suggested that lymphokines, e.g., γ-intereron, secreted by nearby lymphocytes represent the eliciting agent for HLA-DR production and expression by hepatocytes in areas of spotty necrosis in chronic hepatitis B virus infection.
Interactions between liver allografts and lymphocytotoxic alloantibodies in inbred rats
Authors: Houssin Didier , Bellon Blanche , Brunaud Marie-Dominique , Gugenheim Jean , Settaf Abdellatif , Meriggi Francesco , Emond Jean
Published: March 2007

Several clinical and experimental findings suggest that liver allografts are less sensitive than other organ allografts to lymphocytotoxic antibodies. In this experimental study in hypersensitized inbred rat recipients, rejection of liver allografts was delayed compared to that of heart allografts. Furthermore, there was a marked decrease in the level of cytotoxic antibodies after liver allografting but not after heart allografting in these animals. The decrease in the level of antibodies also occurred after donor-specific extracorporeal liver hemoperfusion in hypersensitized recipients. Whether the decrease was caused by a massive absorption of antibodies on the liver or related to excretion of major histocompatibility complex antigens in a soluble form remains to be demonstrated. These results support the hypothesis that the liver has a privileged position in regard to rejection and are consistent with clinical observations made following ABO incompatible or crossmatch positive liver transplantations.
Special delivery of insulin to the liver
Authors: Defronzo Ralph A.
Published: March 2007

Insulin encapsulated in lipid vesicles and targeted to hepatocytes by means of a digalactosy diglyceride moiety [(designated vesicle encapsulated insulin (VEI)] was administered intrave nously to conscious catheterized diabetic dogs to determine the effects on hepatic and extrahepatic glucose utilization. Our results indicate that VE administered intravenously to diabetic dogs ove a dose range of 0.5 to 2.0 mU · kg−1·min−1 reduce hepatic glucose output or induces hepatic glucos uptake without causing any significant alteratios in the rate of extrahepatic glucose utilization. Steady-state comparisons of 1.0 mU·kg−1·min−1 VEI with intraportal and peripherally administered insulin revealed that VEI and intraportal insulin result in significantly less extrahepatic glucose utilization than does an equivalent dose of peripherally administered insulin (6.36 ± 1.21 and 5.08 ± 0.97 vs. 8.82 ± 1.61 mg.kg−1.min−1; P < 0.03). Through the use of VEI, we were able to significantly alter the deposition of intravenously administered glucose from 11% hepatic and 89% extrahepatic noted with peripheral insulin to 35% hepatic and 65% extrahepatic with VEI (P < 0.03). Thus, by encapsulating insulin into a lipid carrier specifically targeted to the liver, selective hepatic insulinization can be achieved. As a result of this approach, one can alter the distribution of a glucose load to favor hepatic deposition.
Porphyria cutanea tarda and hepatocellular carcinoma: Correlations
Authors: Okuda Kunio
Published: March 2007

In order to assess the incidence of hepatocellular carcinoma (HCC) in porphyria cutanea tarda (PCT), 83 patients (77 males, 6 females, mean age 57.4 years) were studied. Thirteen patients (15.7%) had HCC, all of whom were male and cirrhotics with a mean age of 58.5 years. HCC patients showed a statistically significant (P < 0.0005) longer evolution time (23 years since onset of the cutaneous disease) than patients without HCC (9.4 years), while the age of onset was similar in both groups. Differences in alcohol intake and hepatitis B virus (HBV) markers were non-significant, although high prevalence (54%) of past HBV infection was found in both groups. In HCC development, attributable risks of 100% were found for cirrhosis (P < 0.001), male sex (P = NS) and for age over 51 (P < 0.025). Therefore, PCT harbours a high incidence of HCC; evolution time, cirrhosis and age over 51 appear to be the most important contributing factors.
Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension†
Authors: Mastai Ricardo , Grande Luis , Bosch Jaime , Bruix Jordi , Rigau Joaquim , Kravetz David , Navasa Miguel , Pera Cristobal , Rodés Joan
Published: March 2007

The effects of pharmacological manipulation of the lower esophageal sphincter pressure on the esophageal circulation in patients with cirrhosis and portal hypertension were investigated in 33 patients by measuring the azygos venous blood flow, which is an index of blood flow through esophageal varices and periesophageal collaterals draining into the azygos venous system. Measurements were performed in baseline conditions and after the blind administration of metoclopramide (20 mg i.v.) (12 patients), domperidone (10 mg i.v.) (12 patients) and placebo (9 patients).

Both metoclopramide and domperidone caused a significant reduction of azygos blood flow, that decreased by 11.5% (p < 0.01) and 15.6% (p < 0.02) respectively, while no change was observed in patients receiving placebo (+1.4%, not statistically significant). Reduction of azygos blood flow represents a selective effect of metoclopramide and domperidone on the esophageal circulation, since portal pressure, hepatic blood flow, cardiac output, heart rate and arterial blood pressure were unchanged by the administration of metoclopramide, domperidone or placebo.

These results indicate that the administration of drugs that increase the lower esophageal sphincter pressure may reduce the inflow of blood into the esophageal varices in cirrhotic patients with portal hypertension.
Positive antimitochondrial antibody but normal alkaline phosphatase: Is this primary biliary cirrhosis?
Authors: Mitchison Harriet C. , Bassendine Margaret F. , Hendrick Alex , Bennett Mark K. , Bird Graham , Watson Alexander J. , James Oliver F. W.
Published: March 2007

Twenty-nine patients with a positive antimitochondrial antibody titer ≥1/40, who were detected during screening for other autoimmune disease, are described who had a normal serum bilirubin, alkaline phosphatase and transaminase and who had no symptoms of liver disease at presentation. Liver biopsies in 12 of the 29 fulfilled diagnostic criteria for primary biliary cirrhosis; a further 12 were consistent with primary biliary cirrhosis, but only 2 were normal. There was a high incidence of other autoantibodies and autoimmune diseases, especially thyroid antibodies and disorders. Sixteen of these patients have been followed for over 4 years since diagnosis (mean = 6 years, range = 4 to 9 years) and for a mean of 8.7 years since initial detection of the antimitochondrial antibody (range = 4 to 13). Five of 16 developed symptoms suggestive of primary biliary cirrhosis, and 11 of 16 developed elevation of alkaline phosphatase. The antimitochondrial antibody activity in these patients was in the same IgG subclasses (predominantly IgG1 and IgG3) as that seen in a group of 23 patients with clinically, biochemically and histologically advanced primary biliary cirrhosis. All showed the same abnormalities on quantitative estimation of the total IgG subclasses in serum; relative excess of IgG3 and, to a lesser extent, IgG2 was exhibited. It is concluded that, in this study, the finding of an antimitochondrial antibody titer ≥1/40 is strongly suggestive of primary biliary cirrhosis even in the absence of symptoms and the presence of a normal alkaline phosphatase.
Epidemiologic aspects of Santa Marta hepatitis over a 40-year period
Authors: Buitrago Bernardo , Hadler Stephen C. , Popper Hans , Thung Swan N. , Gerber Michael A. , Purcell Robert H. , Maynard James E.
Published: March 2007

“Santa Marta” hepatitis has been recognized as an unusual type of severe hepatitis occurring in northern Colombia since 1930. Liver specimens from a historic viscerotomy series, used by Gast-Galvis to identify cases and describe epidemiologic features of this disease, were available for review and histopathologic staining for δ-virus. Of 86 liver specimens examined from cases of fulminant Santa Marta hepatitis, 81 showed a distinct histopathologic picture, in various stages of progression, with features of eosinophilic necrosis, microvesicular fat infiltration of the liver parenchyma and morula cells; 69% were positive for δ-antigen by immunoperoxidase staining. This disease occurred predominantly in several small towns within 50 km of Santa Marta, with mortality reaching 1.25 per 1,000 inhabitants per year during the 1940′s. Children under age 15 were most commonly affected and males affected twice as frequently as females. Liver specimens obtained from children, or within 15 hr of death, or which showed early histologic stages of disease were most likely to be positive for δ-antigen.

This and the accompanying study confirm the existence of a distinct type of fulminant hepatitis in Colombia for over 50 years. The epidemiologic and histopathologic features are comparable to severe hepatitis in Venezuela Indians and in the Amazon basin of Brazil, suggesting that all are caused by δ-superinfection of hepatitis B virus carriers.
Cell-mediated cytotoxicity in hepatitis A virus infection†
Authors: Vallbracht Angelika , Gabriel Peter , Maier Katharina , Hartmann Franz , Steinhardt Hans Jörg , Müller Claudia , Wolf Alexis , Manncke Klaus Herbert , Flehmig Bertram
Published: March 2007

We studied cell-mediated cytotoxicity to hepatitis A virus-infected cells in seven patients with acute type A hepatitis and two controls. Skin fibroblast cultures obtained from the skin biopsies of seven patients after acute hepatitis A virus infection and from two persons without history of current or past hepatitis A virus infection were inoculated with hepatitis A virus. Infection of fibroblast cultures always resulted in an inapparent, persistent infection with production and release of infectious hepatitis A virus. Peripheral blood lymphocytes were collected from the same patients at different times after onset of icterus and were stored in liquid nitrogen. Cytolytic activity of peripheral blood lymphocytes was determined by a microcytotoxicity assay using autologous 51Cr-labeled hepatitis A virus-infected and uninfected target cells. Cytotoxic peripheral blood lymphocytes capable of lysing autologous hepatitis A virusinfected skin fibroblasts were detected in all patients with hepatitis A but were not demonstrable in the controls without antibodies against hepatitis A virus. The clinical course of the hepatitis A virus infection was normal in five patients; and in these patients, cytolytic activity of peripheral blood lymphocytes against hepatitis A virus-infected autologous targets peaked 2 to 3 weeks after onset of icterus. A clinically protracted form of the disease with persistent elevation of aminotransferase for at least 5 months after onset was present in two patients. In these cases, the highest cytolytic activity was demonstrated in peripheral blood lymphocytes collected 8 to 12 weeks after onset of icterus. Natural killer cell activity, as measured by specific lysis of K562 cells, did not show peak activity during the acute or convalescent phases of the disease. Our experimental findings suggest that cytolytic T cells play an important role in the pathogenesis of hepatitis A virus infection.
Demonstration of pre-S polypeptides of hepatitis B virus in infected livers
Authors: Thung Swan N. , Gerber Michael A. , Kasambalides Efthimios J. , Gilja Bal K. , Keh William , Gerlich Wolfram H.
Published: March 2007

The large (pre-S1), middle (pre-S2) and major (P24) polypeptides of HBsAg have been defined in detail, but their role in hepatitis B virus infection is not known. Therefore, we studied the expression of pre-S1, pre-S2 and P24 in the liver of 15 patients with acute or chronic hepatitis B virus infection using monoclonal and polyclonal antibodies in a double staining immunofluorescence method. The pre-S and major HBsAg polypeptides were co-expressed in the hepatocyte cytoplasm of all patients except for one case of chronic active hepatitis and cirrhosis. HBcAg was present in hepatocyte nuclei of nine patients suggestive of active hepatitis B virus replication. These studies support the hypothesis that the pre-S polypeptides represent essential components of the envelope of hepatitis B virus.
Diagnostic usefulness of testing for anti-HBc IgM in acute hepatitis B
Authors: Lindsay Karen L. , Nizze Anne J. , Koretz Ronald , Gitnick Gary
Published: March 2007

Numerous tests to detect anti-HBc IgM have been developed and shown to have different degrees of sensitivity and specificity. One of these assays, Corzyme®-M (Abbott Laboratories, North Chicago, Ill.), recently became commercially available. The present study was undertaken to evaluate the clinical utility of this anti-HBc IgM test in establishing the diagnosis of acute hepatitis B using sera from a group of 42 prospectively followed individuals who had been exposed to hepatitis B virus. The Corzyme®-M test was highly sensitive in detecting recent hepatitis B virus infection. All 30 patients with symptomatic and 12 with asymptomatic acute hepatitis B virus infection developed anti-HBc IgM. However, the timing of sample testing relative to onset of symptoms in symptomatic patients was important, inasmuch as 2 of 23 patients were negative for anti-HBc IgM early in the symptomatic period, although all were HBsAg positive. The duration of anti-HBc IgM positivity after acute infection was variable, ranging from 2 to 134 weeks. In 14% of patients, anti-HBc IgM remained detectable for more than 1 year. From the data, recommendations are given regarding the usefulness of anti-HBc IgM testing in the diagnosis of acute hepatitis B virus infection.
Characterization of the molecular forms of fibronectin in fulminant hepatic failure
Authors: Almasio Piero L. , Hughes Robin D. , Williams Roger
Published: March 2007

The plasma levels of the opsonic glycoprotein fibronectin are decreased in patients with fulminant hepatic failure, which may be an important factor in their impaired host-defense. Twenty-nine patients in fulminant hepatic failure were studied on admission, and the mean fibronectin level in Grade 0-2 encephalopathy was 82 μg per ml (range = 0 to 150) and in Grade 3-4 encephalopathy 61 μg per ml (range = 5 to 158) as compared to normal controls (268 μg per ml, range = 178 to 380, n = 62). No fibronectin degradation products could be detected in fulminant hepatic failure plasma by sodium dodecyl sulfate-gel electrophoresis on a polyacrylamide gradient (5 to 15%) followed by immunoblotting onto nitrocellulose with detection using a rabbit antihuman fibronectin antiserum visualized with a peroxidase conjugate. The plasma levels of the marker proteolytic enzyme cathepsin D were significantly elevated in fulminant hepatic failure (120 ± 31 mU per ml per hr) as compared to the normal controls (18 ± 2.1 mU per ml per hr, n = 10, p < 0.01). Cross-immunoelectrophoresis of fulminant hepatic failure plasma for fibronectin on agarose plates gave an additional slower migrating peak in 15 of the 29 patients, as well as that of fibronectin, which corresponded to the fibronectin complex reported by other workers in leukemia. An intermediate gel containing antihuman fibrinogen demonstrated fibrinogen to be one component of this complex. Binding of other substances to fibronectin will reduce its apparent biological activity and may be the result of their lack of clearance by the damaged liver.
Effect of growth hormone on alcohol dehydrogenase activity in hepatocyte culture
Authors: Mezey Esteban , Potter James J. , Rhodes Deborah L.
Published: March 2007

The effect of growth hormone on the activity of alcohol dehydrogenase was determined in hepatocyte culture from normal and hypophysectomized male rats. Alcohol dehydrogenase activity was highest in hepatocytes harvested from hypophysectomized rats. The enzyme activity remained stable in hepatocytes harvested from normal rats during 2 to 6 days of culture but declined steadily in hepatocytes cultured from hypophysectomized rats. The combination of growth hormone (1 μg per ml) and corticosterone (1 μM) increased alcohol dehydrogenase activity in hepatocytes from normal rats, while neither hormone alone had an effect. Corticosterone (1 μM) prevented the decline of the enzyme activity in hepatocytes from hypophysectomized rats, and the combination of growth hormone (1 μg per ml) and corticosterone (1 μM) resulted in a further increase in enzyme activity. The increases in alcohol dehydrogenase, due to the exposure of the hepatocytes to the combination of growth hormone and corticosterone, were associated with increases in the rate of ethanol elimination. These observations indicate that growth hormone enhances liver alcohol dehydrogenase activity and ethanol elimination, and that this effect is dependent on the permissive influence of corticosterone.
Monoclonal antibodies against antigens expressed on human hepatocellular carcinoma cells
Authors: Hu Cheng-Po , Han Shou-Hwa , Lui Wing-Yiu , Hsu Hey-Chi , Lin Yeh-Ming , Lin Pei-Hui , Chen Liang-Ru , Hsieh Hsian-Guey , Kuo Pseng-Tong , P'eng Fang-Ku , Chang Chungming
Published: March 2007

Monoclonal antibodies with selectivity for human hepatoma cell lines were produced by immunizing BALB/c mice with human hepatoma cell lines, HA22T/VGH or Hep 3B, and fusing sensitized mouse spleen cells with mouse myeloma cells. Two monoclonal antibodies recognizing antigens present only on human hepatoma cell lines were investigated. The monoclonal antibody IB1 was found to react with 3 of 9 hepatoma cell lines. Monoclonal antibody 9B2 reacted with all nine hepatoma cell lines. None of the other 20 cell lines tested was bound by IB1 and 9B2. The immunoperoxidase staining of monoclonal antibodies on frozen sections of paired hepatoma and normal liver tissues from the same individuals were studied. Antibody IB1 reacted with 3 of 13 hepatoma tissues, but with none of the normal liver and other tissues, and antibody 9B2 was reactive with antigens appearing on the bile canalicular domain of hepatoma and normal liver tissues. The antibody 9B2 stained no normal tissues with the exception of proximal tubules of kidney. Radioimmunoprecipitation tests identified two antigens reacting with 9B2. The major antigen had an apparent molecular weight of 140,000 and a minor one of 130,000. Therefore, antibody IB1 seems to be specific for antigens present on a group of human hepatoma cells and may be useful for classification and diagnosis of human hepatomas. Antibody 9B2 is quite specific to human liver cells and may be used to provide clues for the characterization of tumor cell lines, identification of metastatic tumors with hepatocytic origin, and study of the structure and function of bile canaliculi.
Hemochromatosis: Precirrhotic therapy restores normal life expectancy
Authors: Powell Lawrie W.
Published: March 2007

We analyzed survival and causes of death among 163 patients with primary hemochromatosis diagnosed between 1959 and 1983. The mean follow-up period was 10.5 ± 5.6 years (±S.D.). Cu- mulative survival was 92 per cent at 5 years, 76 per cent at 10 years, 59 per cent at 15 years, and 49 per cent at 20 years. Life expectancy was re- duced in patients with cirrhosis of the liver as compared with those without cirrhosis (P≤0.05), in patients with diabetes mellitus as compared with those without diabetes (P≤0.002), and in pa- tients who could not be depleted of iron during the first 18 months of venesection therapy as com- pared with those who could be depleted (P≤0.001). Prognosis was not influenced by sex (P>0.5). Pa- tients without cirrhosis had a life expectancy that was not different from that expected in an age- and sex-matched normal population. Analysis of the causes of death in 53 patients, as compared with the normal population, showed that liver can- cer was 219 times more frequent among the pa- tients (16 patients), cardiomyopathy was 306 times more frequent (3 patients), liver cirrhosis was 13 times more frequent (10 patients), and diabetes mellitus was 7 times more frequent (3 patients). Death rates for other causes, including extrahepatic carcinomas (seven patients), were not different from the rates expected. We conclude that patients with hemochromatosis diagnosed in the precirrhotic stage and treated by venesection have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.
Transient neonatal hyperammonemia: Squeezing an iceberg into a pigeon hole
Authors: Hsia Yugen Edward
Published: March 2007

Transient neonatal hyperammonemia (TNH) was reviewed in six cases seen by the authors and in 27 selected from the literature. These 33 cases were compared with 13 infants with urea cycle enzyme deficiencies (UCED). The two groups were similar in sex distribution, routes of delivery, time of onset of seizures, Apgar scores and in the prevalence of perinatal complications. Patients with TNH had significantly lower birth weights (2,282±78 gm vs. 3,336±222; mean±SEM; P < 0.001) and gestational ages (35±0.5 vs. 40±0.5 weeks; p e 0.001). The mean time of onset of respiratory distress (4±1 vs. 72 2 26 hr; P < 0.001), need for ventilatory support (P < 0.001), time of onset of lethargy (P < 0.006) and coma (P < 0.005) all occurred earlier in patients with TNH than in those with UCED. Plasma ammonium concentra- tions were higher in patients with TNH than UCED (1,871±209 vs. 973±169 μM;P < 0.02). Respiratory distress occurred in all except one patient with TNH within the first 24 hr, while it occurred in none of the UCED patients within the first 30 hr and only one occurred in 62%of the latter group at any time. The clinical presentations of these two syndromes permit differentiation on clinical grounds alone.
Prevention of variceal rebleeding by propranolol: Can “nonresponders” be identified?
Authors: Burroughs A. K.
Published: March 2007

Between October, 1981 and December 1983, 46 consecutive unselected cirrhotic patients who had been admitted for variceal hemorrhage were assigned to propranolol for the prevention of variceal rebleeding and followed for a mean period of 13.3 months (ranges: 1 day, 45 months). At the time of inclusion, 87 p. 100 of patients had alcoholic cirrhosis: ascites was present in 43 p. 100, jaundice in 43 p. 100 and encephalopathy in 33 p. 100 of cases. The goal of this retrospective study was to assess the effectiveness of propranolol in these unselected patients and to determine variables associated with a high rebleeding rate. Twenty-four patients (52 p. 100) rebled from esophageal varices within a mean time of 8.2 months (range: 6 days, 39 months) and 12 of these patients died. The percentage of patients who rebled from varices was 27 p. 100 at 6 months, 43 p. 100 at 1 year, 52 p. 100 at 18 months. Patients with ascites at the time of inclusion were 3.5 times more likely to rebleed than patients without ascites (p = 0.007). Patients with jaundice (total bilirubin ≥ 50 μmol/l) were 3.1 times more likely to rebleed than patients without jaundice (p = 0.01). One year after the beginning of this treatment, the probability of rebleeding was 19 p. 100 in the 17 Pugh-Child class A cirrhotic patients, 60 p. 100 in the 15 class B patients, 55 p. 100 in the 14 class C patients. Neither proper acceptance in taking propranolol nor alcohol withdrawal were associated with significantly modified risks of rebleeding in these unselected alcoholic patients.
Virological significance of HBeAg subtypes (HBeAg/1 and HBeAg/2) in patients with type B hepatitis
Authors: Kanno Atsushi , Ohori Hitoshi , Matsuda Keizaburoh , Nakayama Haruo , Miyazaki Yutaka , Ishii Motoyasu , Suzuki Hiroshi , Ohtsuki Masao , Goto Yoshio
Published: March 2007

In order to establish the virological significance of HBeAg subtypes (HBeAg/1 and HBeAg/2) during hepatitis B virus infection, HBsAg, HBeAg and hepatitis B virus DNA in serum and HBeAg in liver were determined quantitatively in relation to the detection of HBeAg subtypes in agar gel diffusion. Thirty-eight chronic HBsAg carriers with HBeAg, including 16 non-specific reactive hepatitis, 8 chronic persistent hepatitis, 11 chronic active hepatitis and 3 liver cirrhosis, who were seen at Tohoku University Hospital from 1983 to 1985, were examined. Significantly larger amounts of HBsAg, HBeAg and hepatitis B virus DNA in serum and HBeAg in liver were found in patients positive for both HBeAg/1 and HBeAg/2 in serum than in those positive for only HBeAg/1 or negative for both subtypes. These results suggest that the presence of HBeAg/2 in serum may reflect the occurrence of active viral replication.

When the detection pattern of HBeAg subtypes was examined during serial follow-up for at least 1 year, three groups of patients were classified with respect to the presence of HBeAg/2, i.e., Type I, consistently positive for HBeAg/2, Type II, consistently negative for HBeAg/2, and Type III, intermittently positive for HBeAg/2. More than 80% of Type I patients were histologically diagnosed having as nonspecific reactive hepatitis, while more than 80% of Type II and III patients had more progressive liver diseases such as chronic persistent hepatitis, chronic active hepatitis and liver cirrhosis. These results suggest that the serial examination of HBeAg subtypes in serum may be important for more detailed evaluations of type B hepatitis.
Effects of adenine arabinoside on serum and intrahepatic replicative forms of duck hepatitis B virus in chronic infection
Authors: Hirota Katsutaro , Sherker Averell H. , Omata Masao , Yokosuka Osamu , Okuda Kunio
Published: March 2007

Adenine arabinoside is an antiviral agent which has been used in a number of clinical studies for the treatment of chronic infections with hepatitis B virus. In order to better understand its effects and mode of action, we treated ducks chronically infected with duck hepatitis B virus with a 2-week course and monitored the effects of the drug on viral replication by studying duck hepatitis B virus DNA in liver and serum using molecular biological techniques. We found the drug to be effective in ducks only at much higher doses than those used in humans. At high doses, adenine arabinoside had a dose-related inhibitory effect on viral replication during treatment, but there was a rapid return toward baseline values soon after the cessation of treatment. The supercoiled form of viral DNA was found to be most resistant to adenine arabinoside therapy, and the drug had a disproportionate inhibitory effect on viral plus (noncoding) strand synthesis. We conclude that adenine arabinoside likely exerts its effect in hepadna virus infections predominantly through inhibition of viral DNA polymerase. On the basis of our current study and previous trials in hepatitis B virus-infected patients, we predict that adenine arabinoside will not efficiently eliminate viral replication in chronic hepadna virus infection, when used as the sole therapeutic modality. Adenine arabinoside may have a role to play as an adjunct to immunomodulation or interferon therapy in chronic hepatitis B virus infection in man.
Primary hepatocellular carcinoma and hepatitis B infection during childhood
Authors: Wu Tzee Chung , Tong Myron J. , Hwang Betau , Lee Shou-Dong , Hu Mu Mei
Published: March 2007

Twenty pediatric patients with primary hepatocellular carcinoma in Taiwan were tested for HBsAg, and all were found to be positive. The youngest case was 8 months of age, five cases occurred between 9 and 10 years of age, and 14 cases occurred between 11 and 16 years of age. The serum α-fetoprotein was elevated in all 20 primary hepatocellular carcinoma patients, and the average survival of these cases after diagnosis was 4.7 months.

Seventy per cent of the mothers of the pediatric primary hepatocellular carcinoma cases and 52.9% of their siblings who were tested also were positive for HBsAg. In addition, two families had clustering of primary hepatocellular carcinoma cases.

The occurrence of primary hepatoceullar carcinoma in the pediatric age group suggests the need for close follow-up of young HBsAg-positive carriers. Also, prevention of perinatal transmission of hepatitis B virus by immunoprophylaxis will significantly decrease both the hepatitis B virus carrier rate and the incidence of primary hepatocellular carcinoma in the asian population.
Fetal and adult human liver differ markedly in the fluidity and lipid composition of their microsomal membranes
Authors: Kapitulnik Jaime , Weil Evelyn , Rabinowitz Ron , Krausz Michael M.
Published: March 2007

The fluidity and lipid composition of the human hepatic microsomal membrane were studied in 11 livers from 16- to 21-week-old fetuses and in 5 adult livers, and compared with those of fetal and adult rat liver microsomes. Membrane fluidity was analyzed by measurement of fluorescence polarization using the fluorophore 1,6-diphenyl-1,3,5-hexatriene. The lipid apparent microviscosity (η) of human fetal liver microsomes was 2.17 ± 0.13 poise, as compared with 1.08 ± 0.08 poise in adult liver (p < 0.001). Similar differences in fluidity were found between fetal and adult rat liver microsomes. The more “fluid” adult microsomes had higher phospholipid/cholesterol and phosphatidylcholine/sphingomyelin molar ratios than those of the more “rigid” fetal microsomes. The degree of unsaturation of the adult microsomal lipids was much higher than that of the fetal lipids. The ratios of unsaturated/saturated fatty acids in microsomal lipids highly correlated with the η values obtained for the combined group of fetal and adult human livers, suggesting that the developmental increase in degree of unsaturation of the microsomal lipids is a major determinant of the increased fluidity of adult as compared with fetal liver microsomes. These differences in fluidity and lipid composition between fetal and adult human liver microsomes may be a critical factor in the regulation of hepatic microsomal drug and carcinogen metabolizing enzyme activity, and could so determine the extent of toxicity and teratogenicity of drugs and/or their metabolites in the developing human fetus.
Alcoholic liver injury: Defenestration in noncirrhotic livers—a scanning electron microscopic study
Authors: Horn Thomas , Christoffersen Per , Henriksen Jens H.
Published: March 2007

The fenestration of hepatic sinusoidal endothelial cells in 15 needle biopsies obtained from chronic alcoholics without cirrhosis was studied by scanning electron microscopy. As compared to nonalcoholics, a significant reduction in the number of fenestrae and porosity of the sinusoidal lining wall (fractional area of fenestrae) was observed in acinar Zone 3, both in biopsies with and without Zone 3 fibrosis as judged by light microscopy. A significant reduction of porosity as shown in this study may influence the blood hepatocytic exchange and contribute to the alcohol-induced liver injury.
Cerebral CT scan abnormalities in cholestatic and hepatocellular disease and their relationship to neuropsychologic test performance
Authors: Bernthal Patricia , Hays Amy , Tarter Ralph E. , Van Thiel David , Lecky James , Hegedus Andrea
Published: March 2007

Forty-nine nonalcoholic cirrhotic patients, on whom cranial CT scans were available, were administered a battery of neuropsychological tests. Although none of the subjects exhibited clinical signs or symptoms of hepatic encephalopathy, quantification of the CT scan image implicated cerebral edema and cortical atrophy. In addition numerous significant correlations were observed between the CT variables and neuropsychological test performance. The findings are conjectured to reflect previously unrecognized cerebral morphologic changes associated with chronic subclinical portal-systemic encephalopathy.
Low bone turnover state in primary biliary cirrhosis
Authors: Stellon Anthony J. , Webb Adrian , Compston Juliet , Williams Roger
Published: March 2007

To determine whether bone loss in patients with chronic cholestatic liver disease is the consequence of a high or low bone turnover state, 30 female patients with biopsy-proven primary biliary cirrhosis underwent iliac crest biopsy following double tetracycline labeling. The mean trabecular bone volume was decreased as a result of trabecular plate thinning in both the premenopausal (p < 0.02) and postmenopausal (p < 0.05) patients, compared to age- and sex-matched controls. Indications that osteoblastic function was impaired included a significantly lower mean wall thickness (p < 0.01) and mean osteoid seam width (p < 0.05), and this in association with a decreased mineral appositional rate and prolonged mineralization lag time was suggestive of a defect in matrix synthesis. Further evidence of impaired osteoblastic activity was the significantly lower bone formation rate at both tissue (p < 0.001) and basic multicellular unit levels (p < 0.05) in the postmenopausal patients. Total resorption surfaces and fasting urinary calcium/creatinine ratios were significantly increased (p < 0.005 and 0.05, respectively) in the premenopausal patients and mean interstitial bone thickness reduced in both pre- and postmenopausal patients, suggesting that increased resorption may also contribute to bone loss in primary biliary cirrhosis.
Hereditary defect of hepatobiliary cysteinyl leukotriene elimination in mutant rats with defective hepatic anion excretion
Authors: Huber Michael , Guhlmann Albrecht , Jansen Peter L. M. , Keppler Dietrich
Published: March 2007

Hepatobiliary and renal elimination of cysteinyl leu-kotrienes were investigated in a mutant rat strain with a hereditary defect in the hepatobiliary excretion of conjugated bilirubin, dibromosulfophthalein and oua-bain. After intravenous injection of [3H]leukotriene C4, the initial half-life of radioactivity circulating in blood was 79 ± 15 sec (S.D.) in transport mutant rats as compared to 31 ± 6 sec (S.D.) in normal Wistar rats. The intrahepatic leukotriene radioactivity was increased 5-fold after 1 hr in mutant rats, while the biliary elimination of [3H]Ieukotrienes was reduced to 1.8% of control. In normal rats, 77 ± 7% (S.D.) of the administered leukotriene radioactivity were recovered in bile within 1 hr. The total recovery of radioactivity from bile, urine, liver, intestine, stomach, kidneys, muscular system and blood 1 hr after intravenous [3H]leukotriene C4 was 89 ± 6% (S.D.) in normal rats and 46 ± 4% (S.D.) in transport mutants. Enterohepatic circulation was studied after intraduodenal administration of N-acetyl-[3H]leukotriene E4, a major cysteinyl leukotriene metabolite in rat bile. In transport mutants, hepatobiliary elimination of the intestinally absorbed [3H]leukotriene was reduced to 5%, whereas urinary excretion was not significantly affected. [3H]Leukotriene metabolites in bile, liver and urine were separated by reversed-phase high-performance liquid chromatography. The proportion of N-acetyl-[3H]leukotriene E4 relative to polar leukotriene metabolites was higher in the bile of transport mutants as compared to control Wistar rats when analyzed within 30 to 60 min after intravenous injection of [3H]leukotriene C4. Our results indicate that the cysteinyl leukotrienes are physiological substrates of the can-alicular transport system for organic anions such as dibromosulfophthalein. The transport mutant rats serve to characterize the hepatobiliary excretion system for cysteinyl leukotrienes.
Bile salts induce calcium uptake in vitro by human erythrocytes
Authors: Oelberg David G. , Dubinsky William P. , Sackman Jeffrey W. , Wang Leslie B. , Adcock Eugene W. , Lester Roger
Published: March 2007

At high concentrations, bile salts induce hemolysis by comicellization of lipid components of the cell membrane. However, bile salts are also associated with hemolysis at lower concentrations by mechanisms which have not been characterized. To investigate the possibility that bile salts promote calcium uptake by red blood cells and that bile salt-associated hemolysis is, in part, calcium-mediated, calcium uptake by red blood cells was measured in the presence of individual bile salts, and hemolysis dependence upon calcium availability was examined.

Washed human red blood cells with or without ATP depletion were incubated with 1 mM CaCl2 and tracer amounts of 45CaCl2 in the presence of selected bile salts at concentrations (0.01 to 0.3 mM reported to be below critical micellar concentrations. Calcium uptake (defined for the purposes of this study as 45Ca retained in red blood cells) was monitored over 5 hr, after which hemolysis and membrane phospholipid content were determined. The presence of bile salts stimulated calcium uptake 4- to 25-fold—the magnitude of which was partly related to the lipid solubility of the bile salts. ATP depletion or exposure to trifluoperazine, procedures which inhibit calcium pump activity in red blood cells, enhanced bile salt-induced calcium uptake relative to controls. The percentage of associated hemolysis (2 to 14%) at the end of 5 hr correlated directly with the observed calcium uptake. Removal of calcium from the extracellular space reduced hemolysis in the presence of bile salts to control levels. After red blood cells exposed to bile salts and calcium were hemolyzed, 10% of the measured calcium uptake by intact cells and 60% of the measured bile salt uptake by intact cells remained with the membrane fraction. Overall, the above results are compatible with the hypothesis that, at concentrations below critical micellar concentrations, bile salts are associated with calcium-dependent hemolysis which results, in part, from increased calcium uptake by cells.
An extrahepatic bile duct growth factor: In vivo effect and preliminary characterization
Authors: Glaser Joy H. , Morecki Rachel , Fallon-Friedlander Sheila , Horwitz Marshall S.
Published: March 2007

Rabbit sera injected intraperitoneally into BALB/c mice were noted to produce a considerable and selective enlargement of extrahepatic bile ducts. The gallbladder, intrahepatic ducts, liver and other organs showed no stimulaion of growth. Duct enlargement leading to widening of its outer diameter which, on average, was 3.6 times that of normal, was due entirely to an increased number of epithelial cells with prominent proliferation of intramural glandular components. There was no evidence of inflammatory bile duct injury, fibrosis or obstruction. All of the above changes were reversible and regressed slowly after discontinuation of injections. The bile duct growth-promoting factor was detected in sera of many animal species including humans and birds. Host response to this factor was determined by the number of injections and appeared to be strain-related since it was not observed in C57BL or C3H mice. The sex and age of the donor or recipient were not of any relevance to the growth response.

In order to isolate and characterize the bile duct growth factor, rabbit serum was separated into various fractions, and the effect of each fraction was tested in the animal model. Proteins in the 33 to 65% ammonium sulfate precipitate of whole rabbit sera had activity equal to that of native sera. Activity was abolished by treating this serum fraction with 1% sodium dodecyl sulfate plus proteinase K, suggesting that the bile duct growth factor is a protein. Lipids extracted from whole sera using chloroform:methanol or ultracentrifugation were devoid of activity.

These studies point to the existence of a serum protein which acts as a selective in vivo growth factor for extrahepatic bile ducts in genetically susceptible mice.