bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate analysis of prognostic factors in fulminant hepatitis B
Authors: Bernuau Jacques , Goudeau Alain , Poynard Thierry , Dubois Frederic , Lesage Gerard , Yvonnet Bernard , Degott Claude , Bezeaud Annie , Rueff Bernard , Benhamou Jean-Pierre
Published: March 2007

We assessed prognostic factors in 115 patients with serologically defined fulminant hepatitis B. The diagnosis in each case was based on the finding of IgM antibody to the hepatitis B core antigen in serum. Multivariate analysis showed that factor V level (p < 0.001), patient's age (p = 0.001), absence of detectable HBsAg by radioimmunoassay (p = 0.06) and serum α-fetoprotein concentration (p = 0.07) were independent predictors of survival. The survival rate in the 21 patients in whom HBsAg was not detected was 47%, which was significantly higher than the survival rate of 17% observed in the 94 HBsAg-positive patients (p = 0.006). In patients with fulminant hepatitis B, the absence of HBsAg in serum as detected by radioimmunoassay has an independent, favorable prognostic value.
Noninvasive measurement of the pressure of esophageal varices using an endoscopic gauge: Comparison with measurements by variceal puncture in patients undergoing endoscopic sclerotherapy
Authors: Bosch Jaime , Bordas José M. , Rigau Joaquín , Viola Carmen , Mastai Ricardo , Kravetz David , Navasa Miguel , Rodés Joan
Published: March 2007

Measurements of variceal pressure with a noninvasive endoscopic pressure gauge and by direct variceal puncture were performed in 20 cirrhotic patients with portal hypertension in the course of the first session of therapeutic sclerotherapy following an episode of variceal bleeding.

Endoscopic gauge measurements of the pressure of esophageal varices gave similar values (15.5 ± 2.7 mm Hg) than measurements by variceal puncture (15.4 ± 2.4 mm Hg; not statistically significant), and there was a highly significant linear correlation between both measurements (r = 0.9, p < 0.001). Azygos blood flow, that was markedly increased in these patients (852 ± 399 ml per min), was directly related to variceal pressure (r = 0.73, p < 0.01). Variceal pressure was significantly lower than portal pressure (18.8 ± 5.0 mm Hg) (p < 0.05), indicating that measurements of variceal pressure cannot substitute measurements of portal pressure.

The study demonstrates that the noninvasive endoscopic gauge technique allows an accurate estimation of variceal pressure in patients with portal hypertension. This technique may provide additional useful information in the evaluation of portal hypertension as well as on the mechanism of variceal bleeding.
Use of propranolol to reduce the rebleeding rate during injection sclerotherapy prior to variceal obliteration
Authors: Westaby David , Melia Walter , Hegarty John , Gimson Alexander E. S. , Stellon Anthony J. , Williams Roger
Published: March 2007

In a prospective, randomized controlled trial, 53 patients with variceal hemorrhage from portal hypertension, including 44 with cirrhosis, were allocated, after initial control of the bleeding, to treatment by sclerotherapy alone, or by this together with oral propranolol in a dose sufficient to reduce resting pulse rate by 25% during the period up to the time when varices were obliterated. Eight of the 27 patients undergoing sclerotherapy alone rebled during this period as compared to 7 of the 26 patients in the additional propranolol group (p > 0.80), two patients from each group dying from uncontrollable variceal hemorrhage. Propranolol precipitated encephalopathy in one patient and complicated resuscitation following bleeding in a second, and as there was no evidence in this study that use of the drug reduced the frequency or severity of the variceal bleeding, its administration cannot be recommended during the period prior to obliteration of varices by sclerotherapy.
Subcapsular hepatic necrosis in orthotopic liver allografts
Authors: Russo Pierre A. , Yunis Eduardo J.
Published: March 2007

Five cases of subcapsular liver necrosis were found in a series of 55 hepatic orthotopic allografts examined at hepatectomy or autopsy during a 3-yr period at Children's Hospital of Pittsburgh. There was a pronounced rise in liver enzymes in the first few days in all of the cases after transplantation followed by a decrease in values in four of the cases over the next few days. All were characterized by an irregular subcapsular band of necrotic tissue involving both lobes, to a variable degree, but most frequently the right lobe. There were no obstructions or occlusions of the extrahepatic arteries, portal or hepatic veins. Hepatocyte necrosis was frequently observed in periportal areas, although centrilobular necrosis was also common. Varying degrees of steatosis were seen in the rest of the liver. Various etiological possibilities are discussed, particularly the role of hypoperfusion. Focal subcapsular necrosis of liver allografts may be more frequent than is presently realized. Awareness that hepatic necrosis in allografts may occur as localized subcapsular phenomenon may prevent misinterpretation of superficial biopsy findings as being representative of the entire organ, thus overestimating the degree of damage.
Evaluation of aztreonam in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis
Authors: Ariza Javier , Gudiol Francisco , Dolz Carlos , Xiol Javier , Liñares Josefina , Bosch Jorge , Pallares Roman
Published: March 2007

To determine the efficacy of aztreonam in the treatment of spontaneous bacterial peritonitis in patients with hepatic cirrhosis, 14 patients (7 males, 7 females) with 16 Gram-negative infective episodes (12 Escherichia coli and 4 Klebsiella pneumoniae) were treated with aztreonam infusions at doses of 1 gm per 8 hr for a planned 14-day period. Ages ranged from 40 to 75 years with a mean of 57 ± 10 years.

All organisms were highly susceptible to aztreonam (minimal inhibitory concentration ≤ 0.06 to 0.12 μg per ml). Serum antibiotic levels were 61.9 ± 25.5 μg per ml (peak) and 27 ± 18.5 μg per ml (trough). Ascitic fluid antibiotic levels were 33.6 ± 22.5 μg per ml (peak) and 32.7 ± 16.8 μg per ml (trough).

Although the symptoms of infection were controlled within 3 days and ascitic fluid cultures became negative after 48 hr, 10 patients (62.5%) died, with hepatorenal syndrome and digestive tract hemorrhage as the principal causes of death. Three patients developed streptococcal superinfections during treatment; Streptococcus faecalis peritonitis in one case and spontaneous bacteremia due to Streptococcus equinus and Streptococcus mutans in the other two.

Aztreonam was well tolerated and clinically and bacteriologically efficacious in controlling the infection. Serum and ascitic fluid levels were considerably higher than the minimal inhibitory concentration for the causative organisms, suggesting that lower doses may achieve suitable therapeutic levels.

A negative aspect of the antibiotic therapy was the superinfections. The high mortality rate was attributable to the generally poor underlying condition of the patients.
Effect of 16,16-dimethyl prostaglandin E2 on oxygen uptake and microcirculation in the perfused rat liver
Authors: Meren Haruya , Varin France , Ruwart Mary , Thurman Ronald G.
Published: March 2007

Previous work demonstrated that collagen deposition in the liver of rats fed a nutritionally deficient diet for 3 to 4 months was diminished markedly by 16,16-dimethyl prostaglandin E2 treatment. In this study, rats were fed a high-fat diet or a high-fat diet deficient in lipotropes for 2 to 4 weeks prior to liver perfusion. Rates of O2 uptake by the liver were not changed by dietary manipulation. Infusion of 16,16-dimethyl prostaglandin E2 (10 μM), however, decreased O2 uptake by the whole organ by 20 to 40% in both groups. O2 tension was measured at the liver surface with a miniature O2 electrode placed alternatively on periportal and pericentral regions of the liver lobule. Mean O2 tensions in both periportal and pericentral regions were reduced 2- to 3-fold during the infusion of 16,16-dimethyl prostaglandin E2 suggesting an action on the microcirculation. This hypothesis was supported by the observation that fluorescein isothiocyanate-dextran fluorescence detected from the liver surface as well as hepatic vascular volume determined by dye dilution techniques were decreased 30 to 50% by 16,16-dimethyl prostaglandin E2. In addition, 16,16-dimethyl prostaglandin E2 increased portal pressure by about 10 mm Hg in a reversible manner. Thus, it is concluded that pharmacological levels of 16,16-dimethyl prostaglandin E2 affects the microcirculation dramatically in the isolated perfused liver.
Prognostic value of the aminopyrine breath test in cirrhotic patients
Authors: Villeneuve Jean-Pierre , Infante-Rivard Claire , Ampelas Michel , Pomier-Layrargues Gilles , Huet Michel P. , Marleau Denis
Published: March 2007

The aminopyrine breath test has been proposed as a quantitative test of hepatic function, but its long-term prognostic value in patients with cirrhosis has not been determined. The aim of this study was to examine the usefulness of the aminopyrine breath test in assessing prognosis and to compare it with traditional methods of evaluating liver function. One-hundred eighty-seven patients with histologically confirmed cirrhosis were studied prospectively. An aminopyrine breath test was obtained at the time of inclusion in the study and results were expressed as per cent of the dose excreted in 2 hr. At inclusion, the severity of liver disease was also assessed according to the Pugh modification of the Child-Turcotte classification based on ascites, neurological status, serum albumin, serum bilirubin and prothrombin time. Mean follow-up was 844 days. During that period, 59 of 187 patients died of their liver disease. Two-year survival decreased with increasing Child-Turcotte classification score: survival was 98% in Child Class A patients (n = 62), 66% in Child Class B (n = 76) and 36% in Child Class C (n = 49) (χ2 = 65.6, p < 0.001). Two-year survival also decreased significantly with increasing degree of aminopyrine breath test abnormalities: survival was 90% in patients with aminopyrine breath test > 4% (n = 56); 78% in patients with aminopyrine breath test = 2 to 4% (n = 66), and 43% in patients with aminopyrine breath test < 2% (n = 65) (χ2 = 36.9, p < 0.001). To test whether the aminopyrine breath test contributed significantly to the likelihood of survival once the Child-Turcotte criteria are taken into account, a step-wise survival analysis using the Cox proportional hazard model was performed. At the final step, ascites, encephalopathy, albumin and bilirubin (but not the aminopyrine breath test) were found to be independent variables significantly related to survival. Our results suggest that the Child-Turcotte classification provides valuable prognostic information whereas the aminopyrine breath test does not add any information to our ability to predict once the Child-Turcotte classification score has been used.
Evidence for a deficiency of interferon production in patients with chronic hepatitis B virus infection acquired in adult life
Authors: Ikeda Tadashi , Lever Andrew M. L. , Thomas Howard C.
Published: March 2007

Ninety per cent of patients infected in adult life with the hepatitis B virus clear the virus completely and 10% develop chronic infection. There is evidence for the involvement of interferon in the clearance of acute hepatitis B virus infection. We report that, in in vitro tests, some hepatitis B virus carriers have a reduced capacity to produce α- and γ-interferon which is unrelated to the level of viral replication and to the severity of the liver disease and that the level of 2-5 oligoadenylate synthetase in their livers is only minimally elevated compared to controls. Treatment with lymphoblastoid (α−) interferon leads to a marked rise in 2-5 oligoadenylate synthetase activity. These data indicate that some patients with chronic hepatitis B virus infection acquired in adult life have a partial deficiency of production of α-interferon but can respond to exogenous α-interferon. These observations provide a logical basis for attempts to treat this condition with interferons.
Relationship between guanase activity in donor blood and the incidence of posttransfusional non-A, non-B hepatitis, and a possible method for preventing posttransfusional hepatitis
Authors: Ito Susumu , Tsuji Yasuhiro , Iwasaki Akiharu , Kitagawa Naoyuki , Tamura Yoshiyuki , Fujii Setsuro
Published: March 2007

A total of 107 recipients, who did not show any evidence of hepatic disorders in pretransfusional liver function tests and gave a negative reaction for HBsAg, were observed from 3 weeks to 3 months after blood transfusion of 711 units of blood. The blood was judged suitable for use in transfusion because it had a normal level of ALT activity and gave a negative reaction for HBsAg. The guanase activities of the blood used for transfusion were examined. Cases in which an increase of ALT to at least twice the upper limit of normal persisted for at least 3 weeks and the ALT value increased to more than five times the normal upper limit at least once during this period, which also gave a negative reaction for HBsAg, were judged to have posttransfusional non-A, non-B hepatitis. Of 107 recipients, 18 developed posttransfusional non-A, non-B hepatitis. It was detected in 2 of 71 recipients (3%) with blood guanase activities below 3.5 units per liter and in 16 of 36 recipients (44%) with blood guanase activities above 3.6 units per liter. Thus, the incidence of posttransfusional non-A, non-B hepatitis was significantly higher in recipients with blood guanase activities above 3.6 units per liter. The incidence of posttransfusional non-A, non-B hepatitis increased linearly with increase in the level of guanase activity in donor blood. Thus, a high guanase activity in donor blood is considered to be an important predicting factor for posttransfusional non-A, non-B hepatitis. It is proposed that development of posttransfusional non-A, non-B hepatitis could be reduced by avoiding use of donor blood with guanase activities above 3.6 units per liter.
Orthotopic liver transplantation for type I Crigler-Najjar syndrome
Authors: Kaufman Stuart S. , Wood Patrick R. , Shaw Byers W. , Markin Rodney S. , Rosenthal Philip , Gridelli Bruno , Vanderhoof Jon A.
Published: March 2007

A neurologically normal 3-year-old girl with Type I Crigler-Najjar syndrome was successfully treated with orthotopic liver transplantation. Preoperative serum bilirubin concentrations as high as 31 mg per dl were not diminished with phenobarbital or phototherapy. Bilirubin fractionation of duodenal bile prior to transplantation revealed 87.1% unconjugated bilirubin and 12.9% monoconjugates as determined by alkaline methanolysis-high-performance liquid chromatography. Postoperatively, the serum bilirubin concentration quickly fell to normal. Uridine diphosphate glucuronyl transferase activity in the recipient liver was not detectable. The gallbladder bile bilirubin concentration of 23.9 mg per dl was less than 15% of previously reported normal values. Since devastating kernicteric brain injury is the invariable outcome of Type I Crigler-Najjar syndrome, liver transplantation should be performed when phototherapy cannot maintain the serum bilirubin concentration at an unequivocally safe level.
Correction of vitamin E deficiency in children with chronic cholestasis. II. Effect on gastrointestinal and hepatic function†
Authors: Sokol Ronald J. , Heubi James E. , McGraw Catherine , Balistreri William F.
Published: March 2007

Although secondary vitamin E deficiency causes a reversible neurologic disorder in children with chronic cholestasis, the effect of this deficiency state on other organ systems is unknown. We studied the effects of vitamin E therapy on selected gastrointestinal and hepatic functions in five children with chronic cholestasis and well-documented biochemical and neurologic evidence of vitamin E deficiency. After 2 to 3 years of oral or parenteral vitamin E therapy, there was no improvement in fecal fat losses, severity of vitamin E malabsorption (as measured by an oral vitamin E tolerance test) or total serum fatty acid concentrations. Serial analyses of liver function blood tests demonstrated a marked decline in fasting serum cholylglycine concentrations during 18 to 31 months of vitamin E therapy, while other liver function tests showed no consistent changes. We conclude that vitamin E deficiency does not appear to alter intestinal absorption of fat or vitamin E; however, vitamin E deficiency may further impair already compromised hepatic function during pathologic conditions such as cholestasis.
Medium-chain and long-chain acyl CoA dehydrogenase deficiency: Clinical, pathologic and ultrastructural differentiation from Reye's syndrome†
Authors: Treem William R. , Witzleben Camillus A. , Piccoli David A. , Stanley Charles A. , Hale Daniel E. , Coates Paul M. , Watkins John B.
Published: March 2007

The clinical and pathologic findings in 12 patients with medium-chain acyl CoA dehydrogenase deficiency and three patients with long-chain acyl CoA dehydrogenase deficiency are summarized. Although these inborn errors of intramitochondrial β-oxidation of fatty acids present with similar findings to Reye's syndrome, there are clinical, laboratory and hepatic histologic differences. Younger age at presentation, history of unexplained sibling death, a previous episode of lethargy, hypoglycemia or acidosis precipitated by fasting stress and only mildly elevated serum transaminases with normal or only mildly prolonged prothrombin time may all suggest an acyl CoA dehydrogenase deficiency. Long-chain acyl CoA dehydrogenase deficiency is differentiated from medium-chain acyl CoA dehydrogenase deficiency by younger age at presentation, more profound cardiorespiratory depression, evidence of cardiomyopathy, and sequelae of muscle weakness, hypotonia and developmental delay. Definitive diagnosis is made by assay of medium-chain or long-chain enzyme activity in cultured skin fibroblasts or in leukocytes.

Hepatic light microscopic alterations are essentially limited to steatosis, which may be either macro- or microvesicular. The cases with microvesicular steatosis can be differentiated morphologically from Reye's syndrome by electron microscopy, showing the absence of the mitochondrial changes characteristic of Reye's. Four of seven cases of acyl CoA dehydrogenase deficiency showed some variations from normal in the appearance of the hepatocyte mitochondria. The relationship of these variations to the basic metabolic defect(s) remains to be determined.
Type D hepatitis: The clinical significance of hepatitis D virus RNA in serum as detected by a hybridization-based assay
Authors: Smedile Antonina , Rizzetto Mario , Denniston Katherine , Bonino Ferruccio , Wells Frances , Verme Giorgio , Consolo Fausto , Hoyer Bill , Purcell Robert H. , Gerin John L.
Published: March 2007

Hepatitis D virus is a defective human pathogen that requires hepatitis B virus for its replication. A hybridization-based assay for the 1.75 kb RNA genome of hepatitis D virus was developed using as probe a radiolabeled transcript of a cloned cDNA fragment (pKD3 hepatitis D virus DNA). Sera from 120 chronic carriers of HBsAg with confirmed hepatitis D virus infection were analyzed for the presence of hepatitis D virus RNA. Serum hepatitis D virus RNA was detected in 43 of 74 (58%) patients with chronic liver disease; some patients were positive for hepatitis D virus RNA in multiple samples over a period of several years. Serum hepatitis D virus RNA was present in 17 of 28 (61%) patients during the acute phase of clinical hepatitis and was not detected after recovery from acute disease or in 18 asymptomatic chronic HBsAg carriers with antibody to hepatitis D virus. The presence of hepatitis D virus RNA correlated with other known markers of active hepatitis D virus replication; all chronic active liver disease patients with serum hepatitis D virus RNA were positive for antihepatitis D antigen IgM, and 34 of 37 (92%) had hepatitis D antigen in their liver biopsy specimens.

The assay for hepatitis D virus RNA provides a direct and noninvasive method for the detection of hepatitis D virus in serum and will be useful in the study of the natural history of type D hepatitis, the identification of chronic hepatitis D virus carriers likely to transmit hepatitis D virus and the selection and monitoring of patients for potential antiviral therapy.
A histological study of hepatitis delta virus liver disease
Authors: Verme Giorgio , Amoroso Pietro , Lettieri Gennaro , Pierri Paola , David Ezio , Sessa Fausto , Rizzi Roberto , Bonino Ferruccio , Recchia Serafino , Rizzetto Mario
Published: March 2007

The histopathology of hepatitis delta virus disease was studied in carriers of HBsAg with chronic hepatitis delta antigen-positive hepatitis and in serial biopsies of patients with acute hepatitis delta virus hepatitis that progressed to chronicity.

There was no histologic feature distinctive of hepatitis delta virus from other types of viral hepatitis. Biopsy specimens of patients with chronic disease exhibited portal and periportal inflammation with piecemeal necrosis, conforming to a picture of aggressive hepatitis often accompanied by cirrhosis. Characteristic was a marked intralobular infiltration by mononuclear cells and a degenerative eosinophilic change of the hepatocytic cytoplasms conducive to the formation of acidophilic bodies.

Liver specimens from patients with hepatitis delta virus hepatitis exhibited aspects of focal, confluent and bridging necrosis. The disease progressed to chronicity irrespective of the original histological features.

The expression of intrahepatic hepatitis delta antigen was reduced in the phase of the acute hepatitis but increased in parallel with the development of chronic active liver disease. In late-stage cirrhosis, expression of hepatitis delta antigen was usually low.
A pilot study on the effects of prednisone withdrawal on serum hepatitis B virus DNA and HBeAg in chronic active hepatitis B
Authors: Nair Prem V. , Tong Myron J. , Stevenson Douglas , Roskamp Deborah , Boone Cissy
Published: March 2007

We investigated the efficacy of a short course of prednisone therapy in 20 patients with histologic evidence of chronic active hepatitis B. Sixteen of 20 prednisone-treated patients who were initially serum hepatitis B virus DNA-positive had a transient elevation of their serum ALT activity on withdrawal of prednisone. Subsequently, 14 of these 16 patients (87.5%) became persistently negative for serum hepatitis B virus DNA, and 10 also lost their HBeAg. In addition, there was a significant fall in serum ALT levels and HBsAg titers up to 12 months of follow-up in the prednisone-treated group. Five of 20 (25%) prednisone-treated patients experienced a transient episode of hepatic decompensation coinciding with the peak of enzyme elevation.

To contrast, only 3 of 15 (20%) initially hepatitis B virus DNA-positive matched untreated patients followed during the same time period became negative for serum hepatitis B virus DNA, and no significant changes in serum ALT values or HBsAg titers were noted over the 12-month study period. Thus, patients with chronic active hepatitis B appear to be responsive to immunologic manipulation with prednisone as indicated by a pronounced rebound immune response and clearance of hepatitis B virus DNA with improvement in liver disease activity.
If the proper study of mankind is man, the proper study of cholesterol is the liver
Authors: Tint G. S.
Published: March 2007

A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 μmol per liter (normal, <0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts.

In the subsequent pregnancy of the patient's mother, gas chromatography-mass spectrometry demonstrated a marked elevation of mevalonic acid in the mother's urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans.
Mallory bodies in hepatic neoplasms: What does it mean?
Authors: French Samuel W.
Published: March 2007

Evidence has been accumulating that Mallory body (MB) is a heritable phenotype of hepatocellular carcinoma (HCC) and is closely related to hepatocarcinogenesis in some carcinogen-fed animals. This prompted us to try to evaluate the MB phenomenon in human HCCs, in which its significance remains unclear to date. Whole liver slices were obtained from 28 autopsied livers in which MB-positive HCC was found, and distribution of MBs within the HCC was examined. There were three distribution patterns: clustering, diffuse, and sparse types. The clustering type was the most frequent and was found in 21 of the 28 cases. In this type, there was a formation of groups of the MB-containing cells within the HCC, and the cluster of MB-positive cells was variable in number, size, and shape. There was often a sharp border line between MB-positive clusters and the surrounding MB-negative HCC cell areas where a collision line could occasionally be seen. Some of the MB-containing HCC cells were positive for γ-glutamyl transpeptidase and α-fetoprotein. These data led the authors to speculate that MB-positive HCC cells in human livers are capable of proliferation to form the clusters and that therefore, MBs are expressed as a kind of heritable phenotype in such clusters.
Costs of liver transplantation: Primum non obfuscare
Authors: McMahon Laurence F.
Published: March 2007

The costs and benefits of liver transplantation in adult patients at the University of Pittsburgh were reviewed for the period from 1981 through 1984. Indirect costs such as those to support the surgical and hepatology programs, the operating rooms and the clinical pathology department were ignored, and only those costs generated by the liver transplant program were considered in this analysis. Benefits to the patients are survival itself. Over 8.5% of those who leave the hospital return to full-time employment or other useful activity, including normal, albeit complicated, pregnancies. Most deaths occur during the first 3 months, after which there is a slow decline during the first year. Costs to the patient and/or the third party payers are enormous, and include evaluation as a transplant candidate, procurement of the donor liver, the transplantation itself and lifelong medical-surgical follow-up and immunosuppression plus the management of the undesirable consequences of the whole procedure. Laboratory tests alone average over $52,000 per patient. The consumption of blood and blood products is great and averages 30 units per patient. Duration of hospital admissions averaged about 55 days per patient, of which about 10 were in intensive care units. Total dollar costs were not calculated, however. The benefits to medicine are considerable in the acquisition of new knowledge and skills applicable to other disorders and other patients. The authors conclude that with further experience, the costs will decrease and the benefits will increase.
Occurrence and ultrastructural localization of duck hepatitis B virus in the liver of ducks after experimental infection
Authors: Uchida Toshikazu , Suzuki Koyu , Esumi Mariko , Arii Masayuki , Oomura Masashi , Shikata Toshio
Published: March 2007

A sequential study was performed to investigate the occurrence and localization of duck hepatitis B virus in the liver of domestic ducks utilizing the indirect immunoperoxidase method and electron microscopy. Seventeen ducklings were injected intravenously with duck hepatitis B virus-positive serum within 24 hr after hatching and were subsequently sacrificed on the 2nd, 3rd, 4th, 5th, 27th and 44th day after injection. Nine ducklings were not injected and were used as a negative control.

Duck hepatitis B virus DNA by spot hybridization using a [32P]-labeled probe occurred in trace amounts on the 2nd day and in large amounts on the 4th day after inoculation. Immunoreactivity for DHBV was seen in the hepatocytes, sporadically on the 2nd day and diffusely on the 4th day, and also in the biliary epithelial cells on the 27th day. Both kinds of cells revealed staining in the cytoplasm but not in the nucleus.

Virus particles were recognized by electron microscopy in the hepatocytes beginning on the 4th day. The hepatocytes had many incomplete virus particles, 40 to 61 nm in diameter, and a few complete virus particles, 40 nm in diameter, in the cisternae of the rough and smooth endoplasmic reticula. Such particles and the endoplasmic reticulum showed reaction products for duck hepatitis B virus by immunoelectron microscopy. There were clusters of core particles, 27 nm in diameter, in the hyaloplasm around peroxisomes where an assembly of cores appeared to occur. No conspicuous virus particles were recognized in the biliary epithelial cells. The similarities and differences in virus localization between duck hepatitis B virus and hepatitis B virus are discussed.
δ-Infection and suppression of hepatitis B virus replication in chronic HBsAg carriers
Authors: Krogsgaard Kim , Kryger Peter , Aldershvile Jan , Andersson Poul , Sørensen Thorkild I. A. , Nielsen Jens Ole
Published: March 2007

The presence of hepatitis B virus DNA and anti-δ was examined in a longitudinal study of 24 patients known to be δ-infected during the course from acute to chronic hepatitis B virus infection. Fifteen patients (63%) were hepatitis B virus DNA positive in the first serum sample. Eleven of 14 patients, who cleared hepatitis B virus DNA, did so following or at the same time as onset of δ-infection. Duration of hepatitis B virus DNA positivity in these 11 patients was shorter than in 11 anti-δ-negative controls matched according to duration of preceding hepatitis B virus DNA positivity, but the difference was not statistically significant. Considering only patients positive for IgM anti-δ in the last serum sample (eight patients), a statistically significant shorter duration of hepatitis B virus DNA positivity was found in δ-infected patients than in the controls (p < 0.02). The study indicates that the δ-agent may have the capacity to inhibit hepatitis B virus replication and that a chronic δ-infection may lead to a termination of the period of active viral replication.
Selective hepatobiliary transport defect for organic anions and neutral steroids in mutant rats with hereditary-conjugated hyperbilirubinemia
Authors: Jansen Peter L. M. , Groothuis Geny M. M. , Peters Wilbert H. M. , Meijer Dirk F. M.
Published: March 2007

Mutant rats (TM rats) with abnormal hepatic excretory function were used to study biliary transport of dibromosulfophthalein, ouabain, tributylmethyl ammonium, cholate and taurocholate. In whole animals, dibromosulfophthalein and ouabain clearance is reduced to 7 and 37% of normal, respectively, due to severely impaired excretion from liver to bile. Initial uptake rates of these agents are relatively little affected. In the isolated perfused liver preparation, dibromosulfophthalein is retained within liver and perfusion medium, and the 60-min recovery on bile is reduced to 1.5 vs 75% in normal controls. Biliary excretion of cholate, taurocholate and the quaternary ammonium cation, [14C]tributylmethyl ammonium, is not impaired. These results provide evidence for a selective defect of organic anion and neutral steroid transport in TM rats and confirm that multiple pathways exist for the hepatobiliary excretion of organic anions, neutral steroids, bile acids and cations. Bile flow in whole animals and in the isolated perfused liver is reduced to 50 and 30% of normal, respectively. This suggests that a normal function of the excretory systems for organic anions and neutral steroids is important for the maintenance of normal bile flow.
Characteristics of serum IgA and liver IgA deposits in alcoholic liver disease
Authors: Van De Wiel Albert , Delacroix Dominique L. , Van Hattum Jan , Schuurman Henk-Jan , Kater Louis
Published: March 2007

Patients with alcoholic liver disease frequently reveal an increase in IgA serum concentration and IgA deposits in a continuous pattern along hepatic sinusoids. We investigated whether the hepatic IgA deposits are a passive reflection of changes in concentration or composition of IgA in the circulation, or represent a distinct effect of alcohol on the liver. Forty-one patients with alcoholic liver disease (daily alcohol intake at least 50 gm for more than five consecutive years) were compared with 41 patients with nonalcoholic liver disease. Patients in both groups were matched for serum IgA and histopathological changes in the liver biopsy. IgA deposits in the liver were found in 78% of the alcoholic patients and in 12% of the nonalcoholic patients. The presence of deposits was not related to histopathological changes in the liver or to the serum IgA concentration. In serum IgA subclass distribution, alcoholic patients differed from nonalcoholic patients by a slight but significant shift to IgA2; in contrast, the hepatic IgA deposits in alcoholic patients were almost of the IgA1 subclass. Serum secretory component (which is an equivalent of serum secretory IgA) was elevated in both alcoholic and nonalcoholic patients; patients with a liver biopsy revealing hepatitis showed the highest level. In contrast, the hepatic deposits did not contain secretory component. We conclude that the continuous deposits of IgA along liver sinusoids are not a passive reflection of changes in concentration or composition of circulating IgA, but may represent a distinct effect of alcohol on the liver related to the role of this organ in IgA metabolism.
Predictive value of random sample urine bile acids corrected by creatinine in liver disease
Authors: Simko Vlado , Michael Shoukry , Kelley Robert E.
Published: March 2007

Bile acids, in a random sample of urine, discriminated normal controls from liver disease, with a probability similar to fasting plasma bile acids (p < 0.01 and p < 0.001, depending on the analytical technique). A high degree of correlation between urinary and plasma bile acids (up to r = 0.93) was achieved only when the urine flow was corrected by using a urinary bile acids/creatinine ratio but not with urinary bile acids as simple volume concentration. These findings originated from 10 patients with severe liver disease and 10 with mild liver disease, all biopsy-confirmed, compared with controls. In 24 normal controls and 24 histologically confirmed compensated liver disease, the predictive value of urinary bile acids/creatinine equaled or exceeded fasting plasma bile acids and routine liver tests. In a patient recovering from subacute hepatic necrosis, the urinary bile acids/creatinine closely resembled changes in plasma bile acids and in the routine liver tests. When sulfated urinary bile acids were included, the discrimination between liver disease and controls did not improve. Gallbladder contraction induced by parenteral analogs of cholecystokinin did not change urinary bile acids/creatinine, despite a significant increase in the plasma bile acids. Collection of fasting urine is thus not necessary. Urinary bile acids/creatinine in 12 subjects with renal insufficiency and moderate impairment of creatinine clearance was not different from controls. The weight/height index did not affect this urinary test: there was no significant correlation between the two. Available radioimmunoassays for plasma bile acids can be easily adapted for urine. Enzymatic-spectrophotometric assay of bile acids is also useful. Urinary bile acids/creatinine from a random sample of urine provides valuable information not only on the presence of liver disease but also about its extent, making it useful for screening and for a follow-up of liver disease.
Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation
Authors: Haagsma Elizabeth B. , Manns Michael , Klein Reinhild , Grond Joris , Huizenga Johannes R. , Slooff Maarten J. H. , Zum Büschenfelde Karl-Hermann Meyer , Berg Peter A. , Gips Chris H.
Published: March 2007

Antimitochondrial antibodies are markers for primary biliary cirrhosis and probably reflect a specific defect in immunoregulation underlying this disease. Antimitochondrial antibodies and their primary biliary cirrhosis-specific subtypes were tested before and up to 6 years after orthotopic liver transplantation. Sera from 31 consecutive patients were tested, 15 patients had primary biliary cirrhosis and 16 non-primary biliary cirrhosis. Antimitochondrial antibodies were investigated under code by immunofluorescence, and primary biliary cirrhosis-specific subtypes were determined by radioimmunoassay (anti-p62, anti-p48) and complement fixation test (anti-M2, anti-M4, anti-M8). Before orthotopic liver transplantation, antimitochondrial antibodies were detected by immunofluorescence in 13 of 15 patients with primary biliary cirrhosis. Of these patients, 12 were positive for anti-p62 and 8 for anti-p48. Ten patients were positive for anti-M2, 4 patients for anti-M4 and 7 patients for anti-M8. Two primary biliary cirrhosis patients and all non-primary biliary cirrhosis patients were negative with all tests. One month after orthotopic liver transplantation, antimitochondrial antibodies titers declined or became negative by antimitochondrial antibodies immunofluorescence, 3 patients became negative by radioimmunoassay for anti-p62 and 1 for anti-p48. With complement fixation test, 4 patients became negative for anti-M2, 2 for anti-M4 and 4 for anti-M8. Antimitochondrial antibody titer reduction observed 1 month after orthotopic liver transplantation remained unchanged in most sera during the following years. A rise was observed in two patients after 4 and 5 years.

We conclude that antimitochondrial antibodies titers detected by immunofluorescence and their primary biliary cirrhosis-specific subtypes decline after orthotopic liver transplantation or become negative. Subtypes after orthotopic liver transplantation are the same as before. Antimitochondrial antibody titer height does not influence long-term results. A recurrence of primary biliary cirrhosis was not observed in our primary biliary cirrhosis patients after orthotopic liver transplantation. Disappearance of antimitochondrial antibodies may be either due to prednisolone treatment or to a cure of the disease by orthotopic liver transplantation.
Contractile activity of bile canaliculi: Contraction or collapse?
Authors: Boyer James L.
Published: March 2007

The discovery that bile canaliculi are capable of spontaneous contractile activity has led to their use in the investigation of the physiology of the liver cell. The contraction of a bile canaliculus is dependent on the network of actin, which is found in the pericanalicular region of the hepatocyte, and agents that inhibit actin filaments interfere with canalicular contraction. Injection of calcium directly into the cytoplasm of one hepatocyte of a cell pair results in contraction of the canaliculus. To determine whether the contractile activity of adjacent bile canaliculi was coordinated, calcium was injected into one cell of a group of three hepatocytes that formed two neighboring bile canaliculi. Calcium microinjection resulted in contraction of the bile canaliculus contiguous with the microinjected cell and was followed by a contraction of the second, adjacent canaliculus. These secondary contractions occurred after an interval of approximately 45 seconds. The finding that bile canalicular contractions are coordinated with contractions occurring in a sequential fashion supports the hypothesis that within the liver lobule, transport of bile within the canalicular network results from the coordinated contractions of the canaliculi.

Rat hepatocytes, when isolated and maintained in primary culture, are capable of producing forceful contractions of their bile canaliculi, with contractions occurring on a regular basis once every 5.5 minutes. To determine whether the contraction of one bile canaliculus affected the contraction of a neighboring canaliculus, cinephotomicrographic studies of pairs of contiguous canaliculi were undertaken. The activity of 10 pairs of contiguous canaliculi, and 10 pairs of noncontiguous canaliculi which served as a control group, was recorded for a period of 12.5 hours at the rate of 1 frame every 15 seconds. Using frame-by-frame analysis of this period of observation, we determined the time of contraction of each of the canaliculi in the pairs. Cross-correlations were obtained for the contraction times of each of the 10 pairs of contiguous canaliculi and 10 control pairs. A peak in activity was found, with that peak occurring five frames 75 seconds from the midline, whereas the noncontiguous controls showed no correlation in contractile activity. This finding indicates that, when one bile canaliculus contracts, a neighboring canaliculus is likely to contract after an interval of 1.25 minutes. That there is coordination of contractile activity of bile canaliculi suggests that, within the intact liver lobule, ordered motility function of the bile canaliculi may facilitate bile flow.
Different susceptibilities to the formation of cholesterol gallstones in mice
Authors: Alexander Manfred , Portman Oscar W.
Published: March 2007

In the search for an animal model of genetic determinants of cholesterol cholelithiasis, we found strain, gender and individual differences in mice. Male black (C57BL6J) mice had a 50% incidence of cholesterol gallstones after they consumed lithogenic food similar to that used by Tepperman et al. for 2 weeks, whereas similarly treated male agouti (CBA/J) mice and females of both strains were free of gallstones. The male and female mice of both strains were fertile at 8 weeks of age, and the male black mice were first susceptible to induction of gallstones at 24 weeks of age. Male agouti mice of the same age did not form gallstones until they had consumed the lithogenic food for 8 weeks. The gallbladder biles of both strains were supersaturated with cholesterol during the lithogenic regimen. The male agouti mice had much higher fractional turnover rates of [24-14C]cholic acid than did the male black mice. In spite of their small total cholate pools, the agouti mice had higher rates of new cholate synthesis than did the black mice. The rate of disappearance of [1,2-3H]cholesterol from the blood was higher in the male agouti than in the black mice. The gallbladders of the agouti mice contained less bile and weighed less empty than gallbladders of the black mice. They also did not increase in volume in response to the lithogenic diet as much as gallbladders of the black mice.

The difference in gallstone induction times between male and female black mice was as great as the difference between the two strains. In spite of their resistance to gallstone formation, the black females had gallbladder bile that was usually supersaturated with cholesterol; however, in one experiment their increase in biliary cholesterol concentration was delayed compared to that of males. The concentrations of esterified cholesterol in the liver were higher in the females than in the males, and the plasma cholesterol concentrations were lower. The pattern of metabolism of labeled cholate and cholesterol in the black females was intermediate between that of black male and agouti male mice. The empty gallbladders of the black females were heavier and increased more in volume during the lithogenic regimen than those of the black males.

The black males that formed gallstones had bile which was more supersaturated with cholesterol after 2 weeks on the lithogenic regimen than the black males which were free of stones. They also had lower rates of new cholate synthesis and lower concentrations of esterified cholesterol in the liver than the animals which were free of stones. After 4 and 8 weeks of the experiment, the concentrations of esterified cholesterol in the livers of agouti mice with gallstones were also less than in the livers of those without stones. Thus, resistance to cholesterol gallstone formation in mice may be related to increased activities of the liver in converting cholesterol to bile acids and to esterified cholesterol.
Hepatic metabolism during acute ethanol administration: A phosphorus-31 nuclear magnetic resonance study on the perfused rat liver under normoxic or hypoxic conditions
Authors: Desmoulin Franck , Canioni Paul , Crotte Christian , Gérolami André , Cozzone Patrick J.
Published: March 2007

The effect of ethanol metabolism on the energetic parameters and intracellular pH of the isolated perfused rat liver from fed rats was studied by phosphorus-31 nuclear magnetic resonance spectroscopy. This technique allowed us to analyze nondestructively and in real time the role of low oxygen tension on the possible injurious effect of ethanol on the liver cells.

A quantitative analysis of nuclear magnetic resonance data recorded on a perfused rat liver within a 30 mm diameter probe has been performed at 80.9 MHz. Under normoxic and normothermic conditions, the levels of phosphorylated metabolites detected by nuclear magnetic resonance were 2.8, 0.3 and 2 μmoles per gm liver wet weight for ATP, ADP and inorganic orthophosphate, respectively. The cytosolic pH was 7.25 ± 0.05. During a period of 4 min of hypoxia induced by reducing the perfusion flow rate to 25% of its initial value (i.e., from 12 ml to 3 ml per min per 100 gm body weight), the level of ATP dropped to 2.2 μmoles per gm liver wet weight. Concomitantly, ADP and inorganic orthophosphate increased to 0.6 and 3.3 μmolès per gm liver wet weight. Cytosolic pH fell to 7.02 ± 0.05.

Perfusion of the liver with a Krebs medium containing 70 mM (0.4%) ethanol induced a sharp decrease in intracellular inorganic orthophosphate to reach 1.3 μmole per gm liver wet weight and after a lag time of 4 to 6 min, a decrease in ATP level (2.15 μmoles per gm liver wet weight). A large increase in phosphomonoesters (mainly sn-glycerol 3-phosphate) up to 6 μmoles per gm liver wet weight was also observed. No significant cytosolic pH variation was noted after 20 min of ethanol perfusion (pH 7.20 ± 0.05). In the presence of 70 mM ethanol, a 4-min period of hypoxia caused pronounced changes; in particular, the level of ATP dropped to 1.15 μmole per gm liver wet weight, and a large intracellular acidosis occurred (pH 6.80 ± 0.05). Ethanol oxidation during hypoxia is also correlated to a dramatic increase in the cytosolic content of sn-glycerol 3-phosphate, as compared to the level found under normoxic ethanol perfusion.

Data presented here indicate that ethanol hepatotoxicity might be enhanced under hypoxia due to accumulation of protons in the cytosol. This severe metabolic acidosis is likely to contribute to metabolic disturbances occurring during ethanol exidation. Ethanol metabolism in fed rats gives rise to a synthesis of sn-glycerol 3-phosphate correlated with a decrease in cytosolic inorganic orthophosphate which in turn becomes limiting for ATP production. Finally, the observed increase in sn-glycerol 3-phosphate under hypoxia indicates that the sn-glycerol 3-phosphate/dihydroxyacetone phosphate shuttle could play a very important role as a compensatory mechanism in hypoxic regions of the liver in order to compensate for the decreased activity of the malate/aspartate shuttle.