bluuebunny/crossref_metadata_2025 huggingface dataset:
Spontaneous Exacerbation of Disease Activity in Patients With Chronic Delta Hepatitis Infection: the Role of Hepatitis B, C or D?
Authors: Ackerman Zvi , Valinluck Boontar , McHutchison John G. , Redeker Allan G. , Govindarajan Sugantha
Published: March 2007

Forty–six patients with chronic hepatitis delta virus infection were followed between 6 and 116 mo (mean = 32.8 mo; median = 24 mo). Nineteen patients (41%) demonstrated clinical courses with episodes of biochemical reactivation (ALT levels ≥ 10 times baseline values [group A]). Twenty–seven patients (59%) had stable clinical courses without biochemical reactivation (group B). Patients in group A were younger than those in group B (30.5 vs. 35.3 yr; p = 0.03), were less likely to be intravenous drug abusers (16% vs. 52%; p = 0.01) and were more likely to be homosexual (58% vs. 22%; p = 0.01). Serum hepatitis B virus DNA, hepatitis delta virus RNA, IgM antibody to HBc, HBeAg, antibody to HBe and IgG and IgM antibody to hepatitis delta virus were measured in all patients. In group A, these markers were studied before and during reactivation and during remission. In group B, these parameters were studied in a random fashion at 7– to 10–mo intervals. The presence of antibodies to human immunodeficiency virus and hepatitis C virus was assessed in all patients. A total of 38 biochemical reactivation episodes was noted among the 19 patients in group A. Eleven had sequential changes in hepatitis delta virus markers, suggesting that the exacerbations were due to hepatitis delta virus. In three, the sequential changes of viral markers were consistent with the exacerbations due to hepatitis B virus. In five other patients, no sequential changes in viral markers could be demonstrated to correlate with the biochemical exacerbations. Hepatitis C virus markers were found in 2 of the 19 patients; these two patients were in the group of 11 who had evidence of sequential changes of hepatitis delta virus markers with biochemical exacerbations. Of the patients in the control group (group B) who had stable biochemical courses, 10 had replication of hepatitis delta virus alone, four demonstrated replication of both hepatitis delta virus and hepatitis B virus and two demonstrated replication of hepatitis B virus alone. The viral markers did not reveal sequential or significant fluctuations in this group. In conclusion, the overall prevalence of biochemical reactivation episodes among our subjects with chronic hepatitis delta virus infection was 41%. In 58% of these patients, the episodes were related to hepatitis delta virus activity, whereas in 16% they were related to hepatitis B virus activity. Hepatitis C virus coinfection was rare in this study group. (Hepatology 1992;16:625-629.)
Liver/Kidney Microsome Antibody Type 1 and Hepatitis C Virus Infection
Authors: Lunel Francloise , Abuaf Nisen , Frangeul Lionel , Grippon Patrick , Perrin Michèle , Coz Yann Le , Valla Dominique , Borotto Eric , Yamamoto Anne-Marie , Huraux Jean-Marie , Opolon Pierre , Homberg Jean-Claude
Published: March 2007

Recent studies have shown that hepatitis C virus antibodies are present in a large proportion of patients with autoimmune hepatitis type 2. We have studied 83 patients with liver/kidney microsome antibody–positive type 1 hepatitis. Hepatitis C virus antibodies were sought in every case by second–generation tests (hepatitis C virus enzyme–linked immunosorbent assay and recombinant immunoblot assay). Hepatitis C virus RNA sequences were sought in 22 patients (12 with recombinant immunoblot assay–positive results and 10 with recombinant immunoblot assay–negative results) by means of polymerase chain reaction and by use of primers located in the 5′ noncoding region. Sixty–four patients (77%) had positive results for hepatitis C virus antibodies in the enzyme–linked immunosorbent assay test, and 41 (49.3%) were confirmed by recombinant immunoblot assay. Hepatitis C virus RNA sequences were found in all the recombinant immunoblot assaypositive patients but in none of the 10 who were recombinant immunoblot assay–negative. The recombinant immunoblot assay–negative patients were younger than those who were positive (13 ± 11 vs. 50 ± 11 years) and had higher γ–globulin levels and liver/kidney microsome antibody–positive type 1 titers (61% had a titer of 1:1,000 or more, vs. only 17% of the recombinant immunoblot assay–positive patients). On the basis of these results, chronic hepatitis with liver/kidney microsome antibody–positive type 1 can be divided into two subgroups: (a) true autoimmune hepatitis type 2 (mainly observed in young women), with high titers of liver/kidney microsome antibody–positive type 1, and in which direct autoimmune mechanisms appear to be prominent; and (b) hepatitis C virus–associated hepatitis with liver/kidney microsome antibody–positive type 1 (generally affecting older patients, especially men), with low titers of liver/kidney microsome antibody–positive type 1, and in which the autoimmune process could be a consequence of hepatitis C virus infection. (Hepatology 1992;16:630-636.)
Hbsag Retention Sensitizes the Hepatocyte to Injury by Physiological Concentrations of Interferon–γ
Authors: Gilles Patrick N. , Guerrette Deborah L. , Ulevitch Richard J. , Schreiber Robert D. , Chisari Francis V.
Published: March 2007

The role that inflammatory cytokines may play in the life cycle of the hepatitis B virus and in the pathogenesis of its associated liver disease has not been carefully delineated. In this report, we demonstrate that bacterial lipopolysaccharide, a potent inducer of inflammatory cytokines in vivo, causes a severe acute liver disease in transgenic mice whose hepatocytes produce the hepatitis B virus large envelope polypeptide and retain HBsAg within the endoplasmic reticulum. In contrast, 100–fold higher doses of bacterial lipopolysaccharide do not induce liver cell injury in nontransgenic littermate controls or in transgenic mice whose hepatocytes secrete HBsAg rather than retain it. Coincident with the hepatocellular injury and the influx of inflammatory cells into the liver, a marked reduction occurs in the intrahepatic content of hepatitis B virus steady–state messenger RNA, thereby confirming the selectivity of this process for the HBsAg–positive hepatocyte. Bacterial lipopolysaccharide–induced hepatocellular injury appears to be principally mediated by interferon–γ because it can be markedly reduced by the prior administration of neutralizing interferon–γ-specific monoclonal antibodies and because recombinant interferon–γ is also selectively cytotoxic for the HBsAg–positive transgenic hepatocyte in vivo. Tumor necrosis factor-α is also involved in this process because bacterial lipopolysaccharide–induced liver cell injury is significantly reduced by tumor necrosis factor-α specific monoclonal antibodies. The role of tumor necrosis factor-α in bacterial lipopolysaccharide-induced liver cell injury is less clear than interferon–γ, however, because unlike interferon–γ it is also toxic for nontransgenic hepatocytes. These results demonstrate that the HBsAg–positive transgenic mouse hepatocyte is selectively sensitive to destruction by interferon–γ in vivo. Because this cytokine has been shown to be produced by intrahepatic lymphocytes during viral hepatitis in humans, these results raise the possibility that a similar pathway may contribute to the clearance of HBsAg–positive hepatocytes and to the pathogenesis of liver cell injury in human HBV infection as well. (Hepatology 1992;16:655-663.)
Increased Spontaneous and Lymphokine–Conditioned Iga and Igg Synthesis by B Cells From Alcoholic Cirrhotic Patients
Authors: Girón José Antonio , Alvarez-Mon Melchor , Menéndez-Caro José Luis , Abreu Luis , Albillos Agustín , Manzano Luis , Durántez Alberto
Published: March 2007

Immunoglobulin secretion by B lymphocytes is a complex process in which lymphokines secreted by T lymphocytes play an important regulatory role. Increased serum levels of IgA and IgG have been characteristically detected in patients with alcoholic cirrhosis. We have studied the functional alterations of T and B lymphocytes implicated in the physiopathology of this common immunoglobulin abnormality. After activation with phytohemagglutinin, purified T cells from alcoholic cirrhotic patients showed significantly enhanced secretion of B–cell differentiation factors for IgG and IgA with respect to those secreted by T cells from healthy controls (p < 0.05). Simultaneously, normal secretion of B–cell differentiation factor for IgM was demonstrated in T lymphocytes from these patients. The pattern of secretion of the lymphokines involved in the regulation of the B–cell differentiation pathway found in alcoholic cirrhotic patients was different from that of the primary biliary cirrhotic patients studied. Purified B cells from patients with alcoholic cirrhosis secreted significantly higher amounts of IgA and IgG than did those found in healthy controls, both spontaneously (p < 0.05) and after sequential activation with immunoglobulin ligands (Staphylococcus aureus Cowan I) and a standard B–cell differentiation factor preparation (p < 0.05). By contrast, the IgM secretion and regulatory pathway were normal in alcoholic cirrhotic patients. These results support a physiopathological explanation for the characteristic hyperimmunoglobulinemia found in patients with alcoholic cirrhosis. (Hepatology 1992;16:664-670.)
Biochemical and Histopathological Correlation in Liver Transplant: the First 180 Days
Authors: Henley Keith S. , Lucey Michael R. , Appelman Henry D. , Baliga Prabhakar , Brown Kimberly A. , Burtch Gordon D. , Campbell Darrell A. , Ham John M. , Merion Robert M. , Turcotte Jeremiah G.
Published: March 2007

It is not known whether the histopathology of the liver allograft can be predicted from biochemical measurements in serum with the same confidence as in the native liver. To answer this question we compared the histopathological diagnoses in 170 biopsy specimens from 70 adult transplant recipients obtained during the first 180 days, with the concentrations of the serum bilirubin and the activities of AST, ALT and alkaline phosphatase measured at the same time. The most frequent diagnosis was cholestasis (n = 45), which was mild, moderate or severe and which may have been complicated by rejection (n = 28) or ischemia (n = 14). Hepatitis (n = 14), ischemia with rejection (n = 6) and spotty focal necrosis (n = 6) were diagnosed less frequently. Fifteen biopsy specimens were reported as histopathologically normal. In general, biochemical measurements discriminated poorly between different histopathological diagnoses. The histopathologically normal liver often showed an abnormal pattern of enzymes and an increase in the serum bilirubin level. As a result histopathologically normal biopsy specimens were indistinguishable biochemically from those with hepatitis. When two pathological conditions were found to coexist (e.g., cholestasis with either rejection or ischemic necrosis, or ischemic necrosis with rejection), the effect on the serum biochemistry was usually not additive and in some instances returned the biochemical abnormalities toward normal. With the exception of the serum bilirubin level, which increased with the severity of uncomplicated cholestasis, we could not identify a specific pattern of biochemical changes corresponding to a given histopathological diagnosis. We suggest that until more specific noninvasive methods of monitoring the transplanted liver are developed protocol liver biopsies offer the best means of identifying significant pathological conditions in liver allografts. (Hepatology 1992;16:688-693.)
Comparison of Hepatectomy and Transcatheter Arterial Chemoembolization for the Treatment of Hepatocellular Carcinoma: Necessity for Prospective Randomized Trial
Authors: Yoshimi Fuyo , Nagao Takeshi , Inoue Sumio , Kawano Nobuhiro , Muto Tetsuichiro , Gunji Toshiaki , Ohnishi Shin , Imawari Michio
Published: March 2007

Transcatheter arterial chemoembolization is now widely used in cases of surgically unresectable hepatocellular carcinoma. However, it is unclear whether patients with surgically resectable hepatocellular carcinoma should always be treated with hepatectomy as opposed to transcatheter arterial chemoembolization. Sixty–six patients with hepatocellular carcinoma underwent hepatectomy, whereas 29 patients with more advanced hepatocellular carcinoma were treated with transcatheter arterial chemoembolization at our hospital from 1984 to 1990. All cases were associated with cirrhosis of Child class A or B. All of them underwent hepatectomy or transcatheter arterial chemoembolization for the first time. Their outcomes were determined on March 31, 1991. The backgrounds and survival curves for hepatectomy and transcatheter arterial chemoembolization were compared in both Child A and Child B patients. For both Child A and B patients, no significant difference was found between hepatectomy and transcatheter arterial chemoembolization with respect to age, sex, cause of underlying cirrhosis, liver function assessed by indocyanine green test and maximum diameter of the main tumor. The incidence of multiple hepatocellular carcinoma, more advanced hepatocellular carcinoma (TNM stage III or IV) or both was significantly higher in the transcatheter arterial chemoembolization group than in the hepatectomy group for both Child A and Child B patients. The survival curves of both the hepatectomy and the transcatheter arterial chemoembolization groups showed no significant difference for both Child A and Child B patients. A prospective study is therefore warranted to elucidate whether hepatectomy or transcatheter arterial chemoembolization is more effective for treating resectable hepatocellular carcinoma associated with cirrhosis. (Hepatology 1992;16:702-706.)
Ursodeoxycholic Acid for Treatment of Primary Sclerosing Cholangitis: A Placebo–Controlled Trial
Authors: Beuers Ulrich , Spengler Ulrich , Kruis Wolfgang , Aydemir ülker , Wiebecke Baldur , Heldwein Walter , Weinzierl Marlene , Pape Gerd R. , Sauerbruch Tilman , Paumgartner Gustav
Published: March 2007

The efficacy and safety of ursodeoxycholic acid for the treatment of primary sclerosing cholangitis were evaluated in a prospective, randomized, double–blind, placebo–controlled trial. Fourteen patients with primary sclerosing cholangitis documented by cholestatic serum enzyme pattern, liver histological appearance and endoscopic retrograde cholangiography were included in the trial. Six patients received ursodeoxycholic acid (13 to 15 mg/kg body wt/day), and eight patients received placebo. Two patients had to be withdrawn from the study, one because of UDCA–related diarrhea and the other because of worsening of the disease during placebo treatment. Patients in the ursodeoxycholic acid group improved significantly during 1 yr of treatment with respect to serum levels of bilirubin (median = - 50%), alkaline phosphatase (median = - 67%), γ–glutamyltransferase (median = - 53%), AST (median = - 54%) and ALT (median = - 36%) compared with the placebo group, but not with respect to serum levels of hydrophobic bile acids. During ursodeoxycholic acid treatment, histopathological features also improved significantly, as evaluated by multiparametric score. Expression of human leukocyte antigen class I molecules appeared to be markedly reduced on liver cells after ursodeoxycholic acid treatment. We conclude that ursodeoxycholic acid is beneficial in reducing disease activity in patients with primary sclerosing cholangitis (Hepatology 1992;16:707-714.)
Hemodynamics During Liver Transplantation: the Interactions Between Cardiac Output and Portal Venous and Hepatic Arterial Flows
Authors: Henderson Michael J. , Gilmore Thomas G. , Mackay Gregory J. , Galloway John R. , Dodson Thomas F. , Kutner Michael H.
Published: March 2007

Liver blood flow and systemic hemodynamics were measured intraoperatively in 34 patients after liver transplantation. Ultrasound transit–time flow probes measured hepatic arterial and portal venous flow over 10 to 75 min 1 to 3 hr after reperfusion. Cardiac output was measured by thermodilution. Mean cardiac output was 9.5 ± 2.8 L/min; the mean total liver blood flow of 2,091 ± 932 ml/min was 23% ± 11% of cardiac output. Mean portal flow of 1,808 ± 929 ml/min was disproportionately high at 85% ± 10% of total liver blood flow. Correlation analysis showed a significant (p < 0.01; r = 0.42) correlation between cardiac output and portal venous flow and a trend toward negative correlation (p = 0.087) between cardiac output and hepatic arterial flow. These data show that increased flow in the newly transplanted liver is predominantly portal venous flow and is associated with high cardiac output and reduced hepatic arterial flow. In the last 13 patients studied, portal flow was reduced by 50% and the hepatic artery response was measured. We saw a significant (p < 0.05) increase in hepatic artery flow from 322 ± 228 to 419 ± 271 ml/min, indicating an intact hepatic arterial buffer response. The hepatic artery response also showed that it is a reversible rather than a fixed resistance that contributes to the low hepatic artery flow in these patients. (Hepatology 1992;16:715-718.)
Incidence and Predictive Factors of First Episode of Spontaneous Bacterial Peritonitis in Cirrhosis With Ascites: Relevance of Ascitic Fluid Protein Concentration
Authors: Llach Josep , Rimola Antoni , Navasa Miquel , Ginès Pere , Salmerón Joan M. , Ginès Angels , Arroyo Vicente , Rodés Joan
Published: March 2007

To investigate the long–term probability of the appearance of the first episode of spontaneous bacterial peritonitis in cirrhosis with ascites and to identify predictors of this complication, we closely followed throughout their illness 127 patients consecutively admitted to our unit for the treatment of an episode of ascites without prior spontaneous bacterial peritonitis (follow–up period: 21 ± 22 mo). Thirteen patients (10%) had the first spontaneous bacterial peritonitis episode during follow–up. The appearance probability of this complication is 11% at 1 yr and 15% at 3 yr. Thirty–three variables obtained at admission (including clinical data, standard liver and kidney function test results, ascitic fluid protein concentrations and hemodynamic parameters) were analyzed in relation to their value in predicting spontaneous bacterial peritonitis development. In univariate analysis (Kaplan–Meier curves) five variables reached statistical significance (p < 0.05) as predictive factors for the development of the first spontaneous bacterial peritonitis episode. These five variables were poor nutritional status, increased serum bilirubin levels, increased serum AST levels, decreased prothrombin activity and reduced total protein concentration in ascitic fluid. When these five variables were introduced in a multivariate analysis, only the ascitic fluid protein concentration was found to correlate independently with spontaneous bacterial peritonitis development (p = 0.002). The probability of first spontaneous bacterial peritonitis after 3 yr of follow–up was 24% and 4% in patients with ascitic fluid protein content lower than 1 gm/dl and greater than or equal to 1 gm/dl, respectively. We concluded that the most important predictor of the development of the first spontaneous bacterial peritonitis episode in cirrhosis with ascites is the total protein concentration in ascitic fluid. (Hepatology 1992;16:724-727.)
Reversible Inhibition of Albumin Production by Rat Hepatocytes Maintained on A Laminin–Rich Gel (Engelbreth–Holm–Swarm) in Response to Secretory Products of Kupffer Cells and Cytokines
Authors: Kowalski-Saunders Peter W.J. , Winwood Paul J. , Arthur Michael J.P. , Wright Ralph
Published: March 2007

Decreased albumin synthesis by hepatocytes in liver injury is thought to occur in response to Kupffer cell-derived acute–phase cytokines. In this study we used hepatocytes maintained in a differentiated phenotype, by culture on a laminin–rich gel substratum (Engelbreth–Holm–Swarm matrix), to investigate the effects of Kupffer cell-conditioned medium and purified cytokines (interleukin–1, interleukin–6 and tumor necrosis factor-a) on albumin synthesis. Kupffer cell-conditioned medium caused a reversible decrease in albumin synthesis to 64.7% of control (p < 0.01, Wilcoxon's rank sum test, n = 11) on day 2. Repeated doses caused further dose–dependent reversible responses. The same result was obtained when protease inhibitors (α1–antitrypsin and α2–macroglobulin) were added to Kupffer cell-conditioned medium (n = 3), thus eliminating the potential effect of matrix degradation. Pure interleukin–1, interleukin–6 and tumor necrosis factor-α also inhibited albumin synthesis (p < 0.05, Wilcoxon's rank sum test, n = 5), interleukin–6 having the greatest effect. After exposure to interleukin–1 (30 U · ml-1) and tumor necrosis factor-α (300 U · ml-1), decreased albumin synthesis was followed by a rebound increase (n = 3). Our results support the hypothesis that reduced albumin synthesis in the acute–phase response is modulated by cytokines released from Kupffer cells. Moreover, our results suggest that hepatocytes may exhibit a compensatory increase in albumin synthesis after cytokine withdrawal. These findings may be of physiological importance in the recovery from injury and the acutephase response in vivo. (Hepatology 1992;16:733-741.)
Loss of Mitochondrial Respiratory Function and Its Suppression During Cold Ischemic Preservation of Rat Livers With University of Wisconsin Solution
Authors: Kim Seon-Kyeong , Belzer Folkert O. , Southard James H.
Published: March 2007

Preservation of the liver involves a period of cold (0° to 4°C) ischemia; the longer the ischemic period, the greater the injury to the liver. The mechanisms for cold–induced ischemic injury are not known, but it is clear that after preservation the liver has a reduced capacity to regenerate high–energy phosphate compounds (ATP). One cause for the delayed rate of ATP synthesis could be injury to the mitochondria. The effects of long–term (more than 24 hr) preservation on liver mitochondrial function have not been previously studied. In this study, rat livers were preserved in University of Wisconsin solution at 4° C for up to 96 hr. After preservation, mitochondrial respiratory function was assayed in a homogenate and in isolated mitochondria. We saw a progressive increase in oligomycin–sensitive respiration with time of preservation (from 1.2 ± 0.09 m¨mol · min-1 · gm tissue-1 at 0 hr to 3.8 ± 0.2 m¨mol · min-1 · gm tissue-1 after 96 hr). The increase after 24–hr preservation (2.1 ± 0.2 m¨mol · min-1 · gm tissue-1) was also significantly greater than 0 time values (p < 0.05). No decrease was found in uncoupler–stimulated respiration for up to 48 hr of preservation; only a small decrease was seen after 72 hr of preservation (about 30%). The cause of the increase in oligomycin–sensitive respiration appeared to be related to free fatty acids (or another uncoupling factor) generated during preservation. This was suggested from the fact that bovine serum albumin prevented the increase in oligomycin–sensitive respiration after all periods of preservation. The increase in oligomycin–sensitive respiration suggests an uncoupling of mitochondrial respiratory functions that could lead to a decreased rate of resynthesis of ATP on transplantation of the liver. Chlorpromazine and verapamil also prevented the increased oligomycinsensitive respiration caused by preservation, suggesting that calcium–activated phospholipases contributed to the generation of free fatty acids (or other factors) that caused mitochondrial injury. Rat livers flushed out with Ringer's lactate containing bovine serum albumin after 48 hr of preservation showed improved mitochondrial function, and no increase was found in oligomycin–sensitive respiration. This suggests that before transplantation the liver should be flushed out with a solution containing albumin to remove the uncoupling factors and improve mitochondrial function. (Hepatology 1992;16:742-748.)
High Concentrations of Soluble Tumor Necrosis Factor Receptors in Ascites
Authors: Andus Tilo , Gross Volker , Holstege Axel , Ott Margit , Weber Marlies , David Martina , Gallati Harald , Gerok Wolfgang , Schölmerich Jürgen
Published: March 2007

Ascites and plasma concentrations of soluble tumor necrosis factor receptors p55 and p75 were measured in a prospective study in 34 patients (35 occasions of ascites) with hepatic (5 infected and 21 uninfected) and malignancy–related (9) ascites. All patients had high concentrations of both soluble tumor necrosis factor receptors in ascites and plasma; these were about 500 times higher than the corresponding tumor necrosis factor–α concentrations. Ascites levels of soluble tumor necrosis factor receptors p55 and soluble tumor necrosis factor receptors p75 were significantly elevated in patients with malignancy–related (p55: 26.0 ± 8.6 ng/ml; p75: 20.5 ± 17.4 ng/ml; mean S.D.) and infected ascites (p55: 25.1 ± 10.9 ng/ml, p75: 22.6 ± 11.0 ng/ml) compared with patients with uncomplicated hepatic ascites (p55: 10.1 ± 4.4 ng/ml; p75: 6.0 ± 2.6 ng/ml). Patients with infected or malignancy–related ascites also showed higher soluble tumor necrosis factor receptor concentrations in plasma than did patients with plain hepatic ascites. Successful antibiotic treatment of peritonitis reduced soluble tumor necrosis factor receptor p55 and p75 ascites levels in three patients from 24.2 ± 15.2 ng/ml to 10.7 ± 1.9 ng/ml and from 20.2 ± 14.4 ng/ml to 7.5 ± 1.8 ng/ml, respectively. Soluble tumor necrosis factor receptors p55 and p75 at cutoff levels of 16.5 ng/ml and 9.5 ng/ml, respectively, differentiated between infected or malignant and plain hepatic ascites with diagnostic accuracies of 94% and 89%, respectively. They did not differentiate between infected and malignant ascites. The concentrations of soluble tumor necrosis factor receptor p55 were usually higher in ascites than in plasma in all subgroups of patients. Levels of soluble tumor necrosis factor receptor p75 were also higher in ascites than in plasma in patients with malignant and infected ascites, but soluble tumor necrosis factor receptor p75 levels were usually higher in plasma than in ascites in patients with uncomplicated hepatic ascites. The concentrations of both tumor necrosis factor receptors correlated well in ascites (r = 0.83, p < 0.001) and plasma (r = 0.85, p < 0.001) but only weakly with tumor necrosis factor–α levels in ascites (p55: r = 0.32, p = 0.03; p75: r = 0.29, p = 0.047) and not with tumor necrosis factor–α in plasma.

The high soluble tumor necrosis factor receptor concentrations found in ascites may influence the local bioavailability of tumor necrosis factor and might have an impact on the treatment of peritoneal carcinomatosis with recombinant tumor necrosis factor. Furthermore, the determination of soluble tumor necrosis factor receptors could be of value for the differential diagnosis of ascites. (Hepatology 1992;16:749-755.)
Prenatal Diagnosis of Bilirubin–Udp–Glucuronosyltransferase Deficiency in Rats by Genomic Dna Analysis
Authors: Huang Tian-Jun , Chowdhury Jayanta Roy , Lahiri Pulak , Yerneni Purna C. , Bommineni Vasudeva R. , Arias Irwin M. , Chowdhury Namita Roy
Published: March 2007

Hepatic bilirubin excretion requires UDP–glucuronosyltransferase-mediated glucuronidation. Patients with type I Crigler–Najjar syndrome and mutant rats (Gunn strain) inherit deficiency of UDP–glucuronyltransferase activity toward bilirubin as an autosomal recessive trait and, as a result, exhibit marked nonhemolytic unconjugated hyperbilirubinemia throughout postnatal life. Heterozygous carriers of the trait have normal serum bilirubin levels. Because of placental excretion of unconjugated bilirubin, type 1 Crigler–Najjar syndrome patients and Gunn rats are not jaundiced in utero, making prenatal diagnosis difficult. Here we report a diagnostic method in Gunn rats based on genomic DNA analysis for prenatal recognition of deficiency of UDP–glucuronyltransferase activity toward bilirubin in Gunn rats and identification of heterozygous carriers. We and others have shown that two distinct messenger RNA species (UDP–glucuronyltransferase activity toward bilirubin and the 3–methylcholanthrene–inducible phenol-UDP–glucuronyltransferase messenger RNA) in Gunn rat liver contain identical deletions of a single guanosine residue in their common 3′ regions. Loss of the restriction site for the endonuclease BstNI, which results from this deletion, was used as the basis for a diagnostic test. Female heterozygous Gunn rats were mated with male homozygous Gunn rats. Genomic DNA was extracted from the chorionic aspect of placenta of 17–day fetuses or from leukocytes from normal rats, obligate heterozygotes and homozygous Gunn rats. The DNA was sequentially digested with the restriction enzymes EcoRI and BstNI and subjected to Southern–blot analysis with a double–stranded DNA probe for the common region of UDP–glucuronyltransferase activity toward bilirubin and the 3–methylcholanthrene-inducible UDP–glucuronyltransferase messenger RNAs. DNA samples from Gunn rats showed 600–bp fragments, whereas normal rat DNA showed a 400–bp and a 200–bp band. In heterozygous Gunn rats, three bands at 600 bp, 400 bp and 200 bp were observed. Homozygosity and heterozygosity of the fetal rats was confirmed by analysis of bile pigments excreted in the meconium. This principle may be adapted for the intrauterine diagnosis of type 1 Crigler–Najjar syndrome and identification of carriers who should receive genetic counseling. However, because individual patients with type 1 Crigler–Najjar syndrome may have genetic lesions at different regions, more extensive genetic analysis will be required. (Hepatology 1992;16:756-762.)
Flow–Limited Tracer Oxygen Distribution in the Isolated Perfused Rat Liver: Effects of Temperature and Hematocrit
Authors: Kassissia Ibrahim , Rose Colin P. , Goresky Carl A. , Schwab Andreas J. , Bach Glen G. , Guirguis Suzette
Published: March 2007

We used the multiple–indicator dilution technique to examine the kinetics of tracer oxygen distribution and uptake in the rat liver perfused in a nonrecirculating fashion with blood. 51Cr–labeled 18O2–saturated erythrocytes, labeled albumin, sucrose and water (the tracers for oxygen and vascular, interstitial and cellular references) were injected simultaneously into the portal vein. Timed anerobic samples were collected from the hepatic vein and analyzed by mass spectrometry for relative 18O2 enrichment and radioactivity. In a set of experiments performed at 32° C, oxygen uptake was substantially diminished; tracer oxygen profiles approached those expected for a completely recovered, flow–limited substance. At 37° C, much larger tracer oxygen sequestration occurred. Experiments were carried out at each temperature at higher and lower hematocrit, and oxygen consumption at each temperature was found to be independent of hematocrit. The tissue space of distribution for tracer oxygen relative to the total sinusoidal vascular content was influenced by the hematocrit: it was smaller at higher hematocrit and larger at lower hematocrit, as expected. The derived partition coefficient of oxygen for liver cells relative to plasma (expressed in terms of the liver and plasma water spaces) was, on average, 2.62 ml/ml; it was independent of the hematocrit. Analysis of the indicator dilution experiments indicates that the tracer oxygen is distributed into tissue in a flow–limited rather than a barrier–limited fashion, and that with this, an ongoing concomitant intracellular sequestration of tracer can be seen. (Hepatology 1992;16:763-775.)
Zinc Supplementation Reduces Blood Ammonia and Increases Liver Ornithine Transcarbamylase Activity in Experimental Cirrhosis
Authors: Riggio Oliviero , Merli Manuela , Capocaccia Livio , Caschera Massimo , Zullo Angelo , Pinto Giorgio , Gaudio Eugenio , Franchitto Antonio , Spagnoli Roberta , D'aquilino Elvira , Seri Siro , Moretti Renzo , Cantafora Alfredo
Published: March 2007

Zinc deficiency is common in cirrhosis and may be involved in the alteration of ammonia metabolism. Rats with carbon tetrachloride-induced cirrhosis have high plasma ammonia and low serum and tissue zinc levels. We used this model to examine the effects of oral zinc supplementation on activities of plasma ammonia and liver ornithine transcarbamylase (a key enzyme in the urea cycle). These parameters were examined in two consecutive experiments. Each experiment included two groups of rats treated with carbon tetrachloride; one group received zinc in the drinking water during the induction of cirrhosis, and another served as a control group. Regardless of zinc supplementation, all carbon tetrachloride-treated rats exhibited similar micronodular cirrhosis, with similar histological appearance and liver function impairment.

Cirrhotic rats without zinc supplementation showed high plasma ammonia and low serum and hepatic zinc levels and reduced liver ornithine transcarbamylase activity. Serum, hepatic zinc and liver ornithine transcarbamylase activity increased significantly in the zinc–supplemented group, and these rats' plasma ammonia levels became normal. Plasma ammonia level was significantly inversely correlated with liver ornithine transcarbamylase activity and positively correlated with serum and hepatic zinc content. Our results suggest that zinc deficiency may modify hepatic ornithine transcarbamylase activity and, therefore, ammonia disposal. (Hepatology 1992;16:785-789.)
Role of the Liver in Splanchnic Extraction of Atrial Natriuretic Factor in the Rat
Authors: Gerbes Alexander L. , Witthaut Rochus , Gülberg Veit , Thibault Gaétan , Bilzer Manfred , Jüngst Dieter
Published: March 2007

Mesenteric, hepatic and splanchnic extraction of C–terminal and N–terminal atrial natriuretic factor was investigated in male Sprague–Dawley rats. Plasma concentrations (mean ± S.E.M.) of C–terminal atrial natriuretic factor were 55.0 ± 6.1 fmol/ml, 31.2 ± 4.0 fmol/ml and 23.5 ± 3.3 fmol/ml (n = 12) in the abdominal aorta, the portal vein and the hepatic vein, respectively. N–terminal atrial natriuretic factor plasma levels in these vessels were 3031 ± 756 fmol/ml, 2264 ± 661 fmol/ml and 1618 ± 496 fmol/ml (n = 6), respectively. Although the mesenteric extraction ratio was higher (p < 0.05) for C–terminal atrial natriuretic factor (42% ± 6%) than for N–terminal atrial natriuretic factor (28% ± 4%), there were no significant differences in the hepatic extraction ratio (41% ± 5% vs. 39% ± 6%) and the splanchnic extraction ratio (56% ± 5% vs. 50% ± 7%). These data suggest a major role of the liver in the splanchnic extraction of C–terminal and of N–terminal atrial natriuretic factor in the rat. (Hepatology 1992;16:790-793.)
Assessment of Hepatic Phagocytic Activity By In Vivo Microscopy After Liver Transplantation in the Rat
Authors: Post Stefan , Gonzalez Alberto P. , Palma Pablo , Rentsch Markus , Stiehl Adolf , Menger Michael D.
Published: March 2007

Phagocytic activity of sinusoidal lining cells was studied in 32 livers of male Lewis rats by in vivo fluorescence microscopy with epiillumination. Normal livers (group 1, n = 8) were compared with orthotopic syngeneic liver grafts 90 min after reperfusion after a period of cold storage in University of Wisconsin solution for 17 hr (group 2, n = 10) or 24 hr (group 3. n = 14). After bolus injection of fluorescence–labeled latex particles (3 × 108/kg; diameter = 1.1 m¨m), zonal distribution and kinetics of adherence of latex beads were quantified by off–line video analysis. Hepatocellular function was estimated by the rate of bile production and biliary concentrations of bile acids. In normal livers 50% 37% and 13% of injected latex beads adhered in zones 1, 2 and 3, respectively, whereas in transplanted livers a more homogeneous distribution was found (group 2: 37%, 41%, 22%; group 3: 37%, 39%, 24%; p < 0.01 vs. controls by analysis of variance). Kinetic analysis of phagocytic activity showed no significant difference between group 1 (88% adherence of visible latex beads 3 min after injection) and group 2 (90% adherence). However, after long–term preservation in group 3, sinusoidal adherence was significantly faster (96.4% adherence; p < 0.001). Bile secretion in group 2 was lower than in controls and severely depressed in group 3 (group 1: 1.1 ± 0.07 m¨l/min/gm liver [mean S.E.M.]; group 2: 0.8 ± 0.07; group 3: 01 ± 0.04; p < 0.001) without significant changes in bile acid concentrations. Bile production correlated inversely with adherence of latex particles (p < 0.001, r2 = 0.44). We conclude that increased phagocytic activity after liver transplantation is associated with depressed hepatocellular excretory function. These results provide further evidence that activated Kupffer cells are involved in hepatic reperfusion injury after extended periods of cold ischemia. (Hepatology 1992;16:803-809.)
Influence of Dietary Zinc on Hepatic Collagen and Prolyl Hydroxylase Activity in Alcoholic Rats
Authors: Giménez América , Caballería Joan , Parés Albert , Alié Silvia , Deulofeu Ramón , Andreu Hernán , Rodés Joan
Published: March 2007

The effects of dietary zinc on hepatic collagen and prolyl hydroxylase activity in normal and alcoholic rats has been investigated in four groups of pair–fed male Wistar rats given either liquid ethanol or a control diet for 12 wk. Each group of pair–fed animals received a diet with a different zinc concentration (standard diet, 7.6 mg/L; low–zinc diet, 3.4 mg/L; zinc–supplemented diet, 76 mg/L; and zincextrasupplemented, 300 mg/L. There were no significant differences in hepatic collagen concentration and prolyl hydroxylase activity between alcoholic and normal rats receiving a standard diet (collagen, 77 ± 5 and 73 ± 6 m¨g/mg protein; and prolyl hydroxylase; 37 ± 26 and 36 ± 22 cpm/mg protein). Alcoholic rats fed a low–zinc diet showed increased prolyl hydroxylase activity (75 ± 10 cpm/mg protein, p < 0.05), although no changes in hepatic collagen (77 ± 10 m¨g/mg protein) were observed in comparison with rats fed a standard alcoholic diet. By contrast, hepatic collagen was significantly lower in alcoholic rats fed a zincsupplemented diet (66 ± 4 and 63 ± 3 m¨g/mg protein, p < 0.05 and p <0.01, respectively), and hepatic prolyl hydroxylase activity was particularly lower in rats receiving zinc 300 mg/L (18 ± 20 cpm/mg protein). Similar effects were observed in normal rats. We conclude that dietary zinc influences hepatic prolyl hydroxylase activity and collagen deposition in alcoholic rats, and in consequence, the control of dietary zinc is necessary to assess the effects of alcohol on collagen metabolism in rats. (Hepatology 1992;16:815-819.)
Cell–Cell Interactions: Clues to Hepatocyte Heterogeneity and Beyond?
Authors: Gumucio Jorge J. , Gebhardt Rolf
Published: March 2007

We previously demonstrated that glutamine synthetase (GS) and ornithine aminotransferase (OAT) mRNAs are expressed in the mouse liver acinus preferentially in pericentral hepatocytes, that is, those immediately surrounding terminal central veins (A. L. Bennett, K. E. Paulson, R. E. Miller, and J. E. Darnell, Jr., J. Cell Biol. 105:1073-1085, 1987, and F. C. Kuo, W. L. Hwu, D. Valle, and J. E. Darnell, Jr., Proc. Natl. Acad. Sci. USA, (in press). We now show that hepatocytes surrounding large collecting hepatic veins but not portal veins also express these two mRNAs. The pericentral hepatocytes are the most distal hepatocytes with respect to acinar blood flow, whereas this is not necessarily the case for hepatocytes next to the large collecting hepatic veins. This result implies that it is contact with some hepatic venous element which signals positional expression. In an effort to induce conditions that change relationships between hepatocytes and blood vessels, regenerating liver was studied. After surgical removal of two–thirds or more of the liver, there was no noticeable change in GS or OAT expression in the remaining liver tissue during regeneration. However, treatment with carbon tetrachloride (CCl4), which specifically kills pericentral hepatocytes, completely removed GS– and OAT–containing cells and promptly halted hepatic transcription of GS. Repair of CCl4 damage is associated with invasion of inflammatory and scavenging cells, which remove dead hepatocytes to allow regrowth. Only when hepatocytes resumed contact with pericentral veins were the pretreatment levels of OAT and GS mRNA and high levels of GS transcription restored.
Aflatoxin and Hepatocellular Carcinoma: A Useful Paradigm for Environmentally Induced Carcinogenesis
Authors: Kolars Joseph C.
Published: March 2007

Aflatoxin is believed to be a major causative agent in the high incidence of primary liver cancer seen in certain regions of the world. In Fujian Province, an aflatoxin–endemic region of China, we compared the cigarette smoking habits of 200 primary hepatoma patients with those of 200 matched nonhepatoma controls. We excluded from our study all individuals with evidence of hepatitis B virus serum antigen and/or alcoholic cirrhosis. Interestingly, two groups of hepatoma patients could be discerned. In patients more than 50 years of age, a significantly higher number of cases of primary hepatoma was found among nonsmokers than smokers (odds ratio = 2.06; 95% confidence interval = 1.32-3.20). In patients less than 50 years of age, this difference was not seen. Previous studies in the rat, mouse and duck had suggested that agents present in cigarette smoke might induce a cytochrome P450–mediated detoxication pathway, leading to protection against aflatoxin–induced primary liver cancer. Our clinical data in the present study are therefore consistent with the previous laboratory animal experiments.

Mutations of the p53 gene are found in hepatocellular carcinoma (HCC), the most common form of primary liver cancer. Specific mutations might reflect exposure to specific carcinogens and we have screened HCC samples from patients in 14 different countries to determine the frequency of a hotspot mutation at codon 249 of the tumour suppressor p53 gene.

We detected mutations in 17% of tumours (12/72) from four countries in south Africa and the southeast coast of Asia. There was no codon 249 mutation in 95 specimens of HCC from other geographical locations including North America, Europe, Middle East, and Japan. Worldwide, the presence of the codon 249 mutation in HCCs correlated with high risk of exposure to aflatoxins and the hepatitis B virus (HBV). Further studies were completed in two groups of HBV–infected patients at different risks of exposure to aflatoxins. 53% of patients (8/15) from Mozambique at high risk of aflatoxin exposure had a tumour with a codon 249 mutation, in contrast with 8% of patients from Transkei (1/12) who were at low risk.

HCC is an endemic disease in Mozambique and accounts for up to two thirds of all tumours in men. A codon 249 mutation of the p53 gene identifies an endemic form of HCC strongly associated with dietary aflatoxin intake.
A Pilot Study of 2′,3′–Dideoxyinosine for the Treatment of Chronic Hepatitis B
Authors: Fried Michael W. , Korenman Julia C. , Di Bisceglie Adrian M. , Park Yoon , Waggoner Jeanne G. , Mitsuya Hiroaki , Hartman Neil R. , Yarchoan Robert , Broder Samuel , Hoofnagle Jay H.
Published: March 2007

ABSTRACT

The nucleoside analog 2′,3′–dideoxyinosine, currently being used to treat patients infected with the human immunodeficiency virus, has been shown to inhibit viral replication in certain cell culture systems of hepatitis B virus and the duck model of chronic hepatitis B infection. We studied the effect of dideoxyinosine on viral replication in patients with chronic hepatitis B. In the initial dose–finding phase, patients received sequential 2–wk courses of dideoxyinosine in escalating doses of 3,6 and 9 mg/kg/day. In the second, long–term treatment phase, patients received dideoxyinosine at a dose of 9 mg/kg/day for 12 wk. Dideoxyinosine was given orally in three divided doses. The effects of dideoxyinosine on hepatitis B were assessed by serial measurements of ALT, hepatitis B virus DNA and DNA polymerase activity in serum. Six patients completed the dose–finding phase, and five patients continued into the long–term treatment phase. No significant differences were seen in serum aminotransferases, hepatitis B virus DNA levels or DNA polymerase activity at any time during treatment when compared with pretreatment levels. All patients remained positive for HBeAg during treatment and during 6 mo of follow–up. Thus at the doses tested, dideoxyinosine had no appreciable effect on viral replication in patients with chronic hepatitis B. (HEPATOLOGY 1992;16:861-864.)
Hepatitis C Viral Infection in Liver Transplant Recipients
Authors: Ferrell Linda D. , Wright Teresa L. , Roberts John , Ascher Nancy , Lake John
Published: March 2007

ABSTRACT

In this study we examined multiple serial liver biopsy specimens from liver transplant recipients to determine the pathological features of hepatitis C virus—induced hepatitis. Hepatitis C virus infections acquired after transplantation and previous infections that recurred in patients after transplantation were confirmed by the results of the polymerase chain reaction. Of 43 patients infected with the hepatitis C virus, 18 had a mild form of chronic hepatitis. Four patients had hepatitis that progressed to focal bridging fibrosis or cirrhosis. There were no significant clinical or pathological differences between infections acquired after transplantation and recurrent infections (as determined by polymerase chain reaction) except that acquired infections more often developed into hepatitis. Findings indicative of hepatitis C infection included portal and parenchymal mononuclear infiltrates of varying degrees, acidophilic necrosis and swollen hepatocytes. Other common findings included lymphoid aggregates, bile duct damage and fatty change. Atypical pathological conditions included extensive hepatocyte swelling or acidophilic necrosis with minimal inflammation mimicking ischemia and ductal or ductular damage and proliferation with mixed portal infiltrates mimicking rejection or obstruction. We conclude that in transplant recipients infection by the hepatitis C virus usually produces a mild disease state, but the diagnosis of hepatitis can be difficult to make because indicators of hepatitis may mimic those of rejection, ischemia, obstruction or other hepatic infections. Serial biopsy specimens with persistent pathology and polymerase chain reaction may be necessary to define the presence of a hepatitis C virus lesion. (HEPATOLOGY 1992;16:865-876.)