bluuebunny/crossref_metadata_2025 huggingface dataset:
Long–Term Effects of Distal Splenorenal Shunt on Hepatic Hemodynamics and Liver Function in Patients With Cirrhosis: Importance of Reversal of Portal Blood Flow
Authors: Lacy Antonio M. , Navasa Miguel , Gilabert Rosa , Brü Concepción , García-Pagán Juan C. , García-Valdecasas Juan C. , Grande Luis , Feu Fausto , Fuster José , Terés José , Visa José , Bosch Jaime
Published: March 2007

We studied 23 patients with cirrhosis who had undergone retroperitoneal distal splenorenal shunt without portal–azygos disconnection more than 2 yr earlier. We investigated the suitability of the Doppler technique (ultrasound + Doppler) to assess the patency and blood flow direction through the portal vein and the distal splenorenal shunt and its correlation with the continuous thermal dilution technique. The study also assessed the influence of the distal splenorenal shunt and time after surgery on portal perfusion and liver function. Ultrasound + Doppler distal splenorenal shunt thrombosis in two patients; however, none was confirmed by continuous thermal dilution. Ultrasound + Doppler flowmetry was possible in 19 patients (83%) (mean, 1.58 ± 0.53 L/min). Distal splenorenal shunt continuous thermal dilution measurements were performed in all patients (100%), (mean, 1.65 ± 0.5 L/min). Good correlation was seen between them (r = 0.66). Ultrasound + Doppler of the portal vein showed a hepatopetal flow in 16 patients (69.9%). Hepatic blood flow was significantly higher in patients with hepatopetal flow (p = 0.003). Hepatic clearance and intrinsic hepatic clearance of indocyanine green were significantly lower in patients with hepatofugal flow. Patients with hepatofugal flow had a higher incidence of chronic encephalopathy. None of the patients with a follow–up of less than 4 yr exhibited hepatofugal flow, whereas 7 of the 16 patients with a longer follow–up had hepatofugal flow (43.7%). The difference was statistically significant (p = 0.04). This study suggests that ultrasound + Doppler sonography may provide useful data in the evaluation of the patency and blood flow direction through the portal vein and the distal splenorenal shunt. Direction of portal blood flow and time after surgery significantly affect hepatic portal perfusion and liver function. (Hepatology 1992;15:616-622).
The Effects of Partial Hepatectomy on Serum Sex Steroids in Humans
Authors: Liddle Christopher , Hollands Michael , Little Miles J. , Farrell Geoffrey C.
Published: March 2007

In both rats and humans, partial hepatectomy results in a substantial increase in serum estradiol concentrations. Because mammalian liver of both sexes contains estrogen receptor, it has been suggested that this surge in serum estrogen concentration may initiate or facilitate liver regeneration. We have reexamined the potential role of sex steroids in human liver regeneration by measuring serum estradiol and testosterone concentrations in men and postmenopausal women before and after hepatic resection. The results were compared with those obtained in patients subjected to other forms of major surgery. In both men and postmenopausal women, serum estradiol levels increased after partial hepatectomy. However, the magnitude of increase was not related to the amount of liver removed. Moreover, similar increases occurred in patients undergoing other major surgical procedures not involving the liver. Serum testosterone concentrations decreased in men and increased in postmenopausal women undergoing all forms of surgery. It is concluded that effects of partial hepatectomy on serum sex steroid levels are nonspecific and probably related to stress. These observations diminish the likelihood that such changes are an important factor in the control of liver regeneration in humans. (Hepatology 1992;15:623-628).
Vitronectin in Liver Disorders: Biochemical and Immunohistochemical Studies
Authors: Inuzuka Sadataka , Ueno Takato , Torimura Takuji , Tamaki Seishu , Sakata Ryuichiro , Sata Michio , Yoshida Hiroshi , Tanikawa Kyuichi
Published: March 2007

The concentration of plasma vitronectin was determined and compared with various parameters of liver function including the blood coagulation system in patients with liver diseases. The severity of cirrhosis was graded according to Child's criteria and compared with the plasma vitronectin level. Furthermore, the distribution of vitronectin in the liver of patients with liver diseases was studied by light and electron microscopy using the indirect immunoperoxidase method.

The plasma vitronectin level was low in all liver disease groups as compared with the healthy controls. The difference from the controls was significant in patients with hepatocellular carcinoma and decompensated cirrhosis. Moreover, the plasma vitronectin level was positively correlated with the levels of serum cholinesterase, albumin, plasma α2 plasmin inhibitor–plasmin complex and the prothrombin time and results of the hepatoplastin test. Plasma vitronectin decreased with increasing severity of cirrhosis according to Child's criteria. These results suggest that the plasma vitronectin level is a useful parameter of hepatic synthetic function in patients with liver diseases; it may also reflect the severity of cirrhosis.

Light microscopy revealed vitronectin in the area of focal necrosis and the portal tracts in the liver of patients with acute viral hepatitis, in the area of piecemeal necrosis in the liver of patients with chronic hepatitis and along the area of fiber deposition in the liver of patients with cirrhosis. Immunoelectron microscopy showed vitronectin in the rough endoplasmic reticulum of hepatocytes. Moreover, vitronectin was seen around inflammatory cells, endothelial cells, Ito cells and hepatocytes in the perisinusoidal area near focal necrosis and piecemeal necrosis and on collagen fibers.

These results suggest that vitronectin may be produced by hepatocytes and that they play an important role as an extracellular matrix component in the injured liver. (Hepatology 1992;15:629-636).
Serum Procollagen Peptides and Collagen Type Vi for the Assessment of Activity and Degree of Hepatic Fibrosis in Schistosomiasis and Alcoholic Liver Disease
Authors: Shahin Manal , Schuppan Detlef , Waldherr Rüdiger , Risteli Juha , Risteli Leila , Savolainen Eeva-Riitta , Oesterling Christine , Abdel Rahman Hosna M. , El Sahly Abdul M. , Abdel Razek Samia M. , Ruby Omar El , Koch Armin , Seitz Helmut K.
Published: March 2007

Schistosomiasis, in contrast to alcoholic liver disease, leads to presinusoidal hepatic fibrosis, which determines the prognosis of the disease. Because conventional liver function tests and liver biopsy specimens provide little information about the dynamics of the fibrotic process, we measured the serum concentrations of procollagen type III N–propeptide and procollagen type I C–propeptide, believed to mainly reflect collagen synthesis, and procollagen type IV C–propeptide and collagen type VI, two presumptive markers of collagen degradation. Determinations were performed in 15 healthy control subjects, 69 patients with various stages of infection with Schistosoma mansoni/Schistosoma haematobium (28) with an early active infection and no organ involvement, 27 with hepatosplenic involvement and 14 with complications of portal hypertension) and 16 patients with alcoholic cirrhosis. In addition, liver biopsy specimens were obtained from 30 schistosomal patients (18 with hepatosplenic involvement and 12 with complications of portal hypertension for histopathological grading and collagen histochemistry. Procollagen type III N–propeptide was significantly elevated in the three patient groups with schistosomiasis when compared with controls (p < 0.01). Also, patients with higher histological grading showed significantly higher procollagen type III N–propeptide values (p < 0.05). In alcoholic patients, procollagen type III N–propeptide was even higher and increased parallel to the severity of the disease, determined by using a combined clinical and laboratory index. Procollagen type I C–propeptide was only elevated in early infection (p < 0.05) and steadily decreased with disease progression. In contrast, procollagen type IV C–propeptide and collagen type VI were not significantly elevated in those patients with no organ involvement but increased significantly in those patients with hepatosplenic involvement (p < 0.01) and those patients with complications of portal hypertension (p < 0.01 and p < 0.02, respectively). Immunohistological findings for the above mentioned collagen types did not correlate with their corresponding serum levels. The data show that a serum elevation of procollagen type III N–propeptide may indicate early fibrogenic activity in patients with schistosomal infection; in addition, the combined measurement of procollagen type III N–propeptide with procollagen type IV C–propeptide and collagen type VI seems to provide additional information to predict progressive hepatic fibrosis. (Hepatology 1992;15:637-644).
Metabolism of Ursocholic Acid in Humans: Conversion of Ursocholic Acid to Deoxycholic Acid
Authors: Tint Stephen G. , Batta Ashok K. , Dayal Bishambar , Kovell Nina , Shefer Sarah , Salen Gerald
Published: March 2007

To study the metabolism of ursocholic acid, control subjects were injected with radiolabeled cholic and ursocholic acids before and after 1 wk of 900 mg/day oral ursocholic acid. Daily samples of bile were obtained, and biliary bile acids were extracted and purified to determine bile acid kinetics. During ursocholic acid therapy ursocholic acid became the principal bile acid (35% ± 3% of total bile acids, mean ± S.E.M.), and the percentage of biliary cholic and chenodeoxycholic acids decreased (p < 0.05). Cholic acid production fell from 190 ± 15 mg/day to 135 ± 20 mg/day (p = 0.078). The total bile acid pool was increased twofold (p < 0.05), whereas the deoxycholic acid pool was enlarged from 440 ± 170 mg to 1,175 ± 90 mg (p < 0.02). As much as 28% of the fed ursocholic acid was excreted in the urine, 85% as the free acid and 15% as the glycine conjugate. During treatment, ursocholic acid became the source for 69% ± 11% of biliary deoxycholic acid. The time course of the deoxycholic acid specific activity was modeled as a single pool precursor–product system with a variable time delay for the C–7–dehydroxylation of cholic and ursocholic acids (mean delay 0.86 ± 0.11 days, p < 0.001 vs. zero delay). Most of this delay probably arises from a slow process of bacterial C–7–dehydroxylation within the colon. These results demonstrate that during ursocholic acid therapy the synthesis of primary bile acids continues whereas the formation of secondary bile acids is greatly increased. (Hepatology 1992;15:645-650).
Surival and Prognostic Factors in 212 Italian Patients With Genetic Hemochromatosis
Authors: Fargion Silvia , Mandelli Clara , Piperno Alberto , Cesana Bruno , Fracanzani Anna L. , Fraquelli Mirella , Bianchi Paolo A. , Fiorelli Gemino , Conte Dario
Published: March 2007

Two hundred twelve Italian patients with genetic hemochromatosis (181 men, mean age 50 ± 11 yr; and 31 women, mean age 49 ± 10 yr) were followed for a median period of 44 mo (range = 3 to 218 mo). Alcohol abuse was present in 31 subjects (15%), and chronic HBV and HCV infection were seen in 19 (9%) and 35 (24%) of 145 cases tested, respectively. Twenty–four patients (11%) had concomitant p–thalassemia trait. Liver biopsy revealed cirrhosis in 146 and a noncirrhotic pattern in the other 66. Perls' stain was degree I11 in 37 patients and IV in 171 patients. One hundred eighty–five patients underwent weekly venesection, and iron depletion was achieved in 122 cases after total iron removal of 3 to 41 gm. Death occurred in 44 patients after 3 to 198 mo and was due to hepatocellular carcinoma in 20 cases, liver failure in 10, extrahepatic cancer in six, heart failure in three and hemochromatosis unrelated causes in five. Cancer has developed in seven other patients still alive (hepatocellular in five and extrahepatic in two). No deaths were observed among noncirrhotic patients; cumulative survival rates in cirrhotic patients were 85%, 75%, 60% and 47% at 3, 5, 8 and 10 yr, respectively. Univariate analysis in the 146 cirrhotic patients showed that age greater than 60 yr, alcohol abuse, cardiomyopathy, skin pigmentation, portal hypertension, hypoalbuminemia, hypergammaglobulinemia and Child class B or C had significant negative prognostic value. At multivariate analysis, only alcohol abuse, γ–globulins greater than 2.0 gm/dl and Child class B or C maintained their negative prognostic values (p < 0.01, hazard ratio 2.7; p < 0.001, hazard ratio 2.8; and p < 0.001, hazard ratio 4.3, respectively). (Hepatology 1992;15:655-659).
Genotype Analysis for ΔF508, G551d and R553x Mutations in Children and Young Adults With Cystic Fibrosis With and Without Chronic Liver Disease
Authors: Duthie Ann , Doherty Derek G. , Williams Carolyn , Scott-Jupp Robert , Warner J. O. , Tanner Stuart M. , Williamson Robert , Mowat Alex P.
Published: March 2007

Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations - ΔF508, G551D and R553X - in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty–nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the ΔF508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis. (Hepatology 1992;15:660-664).
Hyperfibrinolysis Increases the Risk of Gastrointestinal Hemorrhage in Patients With Advanced Cirrhosis
Authors: Violi Francesco , Ferro Domenico , Basili Stefania , Quintarelli Claudio , Saliola Mirella , Alessandri Cesare , Cordova Corrado , Balsano Francesco
Published: March 2007

Sixty–one patients with different degrees of liver failure, 23 with Child–Pugh class B and 38 with Child–Pugh class C, were studied and observed for 3 yr. Coagulation index analysis showed significantly lower values of prothrombin activity, more prolonged activated partial thromboplastin time, higher bilirubin and fibrinogen degradation products values in class C patients. Among all patients, 28 had fibrinogen degradation products values greater than 10 μg/ml, and in these patients a hyperfibrinolytic state was confirmed by higher values of circulating plasminogen activator antigen (17.3 ± 8.7 ng/ml vs. 5.41 ± 1.9 ng/ml; p < 0.0001) and activity (6.6 ± 2.1 IU/ml vs. 1.92 ± 1.12 IU/mi; p < 0.0001) and significantly lower plasminogen activator inhibitor antigen (6.4 ± 3.5 ng/ml vs. 15.8 ± 5.6 ng/ml; p < 0.0001) and activity (3.6 ± 2.2 IU/ml vs. 8.5 ± 3.9 IU/ml; p < 0.0001). Patients with positive fibrinogen degradation products had higher serum bilirubin (6 ± 4 mg/dl vs. 2 ± 2 mg/dl; p < 0.0001) and lower fibrinogen (156 ± 52 mg/dl vs. 194 ± 62 mg/dl; p < 0.02) than patients without hyperfibrinolysis. During the follow–up period, 41 patients died, 22 from fatal gastrointestinal hemorrhage and 19 from liver failure. Thirty patients experienced fatal (22 patients) and nonfatal (8 patients) gastrointestinal hemorrhage. Patients with positive fibrinogen degradation products or class C had a higher risk of gastrointestinal bleeding than patients with negative fibrinogen degradation products (odds ratio = 8) or class B (odds ratio = 3.5), respectively. Cox's multiple regression model showed that positive fibrinogen degradation products was the best bleeding predictor (β coefficient = 3.9 ± 0.7 S.E.M., p < 0.001).

This study indicates that in cirrhosis the presence of hyperfibrinolysis should be regarded as an important warning sign of gastrointestinal bleeding. (Hepatology 1992;15:672-676).
Scintigraphic Documentation of An Improvement in Hepatobiliary Excretory Function After Treatment With Ursodeoxycholic Acid in Patients With Cystic Fibrosis and Associated Liver Disease
Authors: Colombo Carla , Castellani Maria Rita , Balistreri William F. , Seregni Ettore , Assaisso Maria Luisa , Giunta Annamaria
Published: March 2007

We have previously documented that ursodeoxycholic acid exerts a beneficial effect on liver function and bile acid metabolism in patients with cystic fibrosis. We hypothesized that the mechanism of action may be related in part to the choleretic properties of the administered bile acid. We therefore compared hepatobiliary scintigraphic images obtained before and 1 yr after initiation of ursodeoxycholic acid therapy to document an improvement in bile flow in 13 patients with cystic fibrosis and hepatobiliary involvement. Before therapy, hepatobiliary scintigraphy documented biliary stasis with retention of the isotope in intrahepatic and extrahepatic bile ducts in nine patients; during therapy, duct dilatation decreased substantially in eight patients, with decreased intrahepatic retention and more rapid biliary outflow of the tracer. The time of appearance of isotope in the intestine decreased (from a mean of 36.9 ± 17.8 min to 18.8 ± 9.0 min; p < 0.01) in all patients in whom it had been abnormal, and the half–time of hepatic washout decreased from a mean of 35 ± 20.7 min to 26 ± 15.6 min (p < 0.05). During ursodeoxycholic acid administration enrichment of bile was achieved, with the mean ursodeoxycholic acid percent composition increasing from 5.8% ± 2.9% to 35.7% ± 8.5%. Ursodeoxycholic acid became the predominant bile acid in serum. Liver function improved in all 10 of the patients with abnormal values at baseline. We conclude that hepatobiliary scintigraphy is of value in monitoring the therapeutic responses of cystic fibrosis patients with liver disease to ursodeoxycholic acid therapy. These scintigraphic changes observed in our patients after treatment with ursodeoxycholic acid confirm the therapeutic effect of this bile acid in cystic fibrosis patients with associated liver disease. The effect may be mediated through an improvement in canalicular excretory function and biliary drainage. (Hepatology 1992;15:677-684).
Evaluation of Hepatitis Delta Virus Rna Levels During Interferon Therapy by Analysis of Polymerase Chain Reaction Products With A Nonradioisotopic Hybridization Assay
Authors: Cariani Elisabetta , Ravaggi Antonella , Puoti Massimo , Mantero Giovanni , Albertini Alberto , Primi Daniele
Published: March 2007

We developed a nonradioisotopic assay for detection of hepatitis delta virus RNA in serum by combining reverse transcription of RNA, polymerase chain reaction of the resultant complementary DNA and enzyme linked immunoassay detection of the polymerase chain reaction products using a monoclonal antibody specific for double–stranded DNA. This DNA enzyme immunoassay had a limit of detection of cloned hepatitis delta virus RNA similar to that of standard PCR followed by Southern–blot hybridization (˜ 10 copies/sample) and was 103 to 104 times more sensitive than direct dot–blot hybridization (˜ 105 copies/sample). Serial serum samples from six patients with chronic hepatitis delta virus infection undergoing interferon therapy were analyzed by reverse transcription-polymerase chain reaction followed by both standard hybridization and DNA enzyme immunoassay. The results of both methods were comparable, revealing disappearance of hepatitis delta virus RNA after 3 to 6 mo of therapy in three patients, two of whom had also a significant decrease in ALT activity. The DNA enzyme immunoassay test is therefore a potentially useful method for therapeutic monitoring in chronic hepatitis delta virus infection and may contribute to a wider application of polymerase chain reaction in clinical laboratories. (Hepatology 1992;15:685-689).
Three Different Patterns of Hepatitis C Virus Infection in Chimpanzees
Authors: Abe Kenji , Inchauspe Genevieve , Shikata Toshio , Prince Alfred M.
Published: March 2007

The relationship between hepatitis C virus RNA and hepatitis C virus–associated antibodies (antibody against the putative capsid protein and C–100 antibody) was determined by nested polymerase chain reaction and enzyme–linked immunosorbent assay in serial serum samples obtained from eight chimpanzees experimentally infected with hepatitis C virus. Three different patterns emerged from the polymerase chain reaction data: the first (group 1) was acute resolving hepatitis with transient appearance of HCV RNA (two cases). The second (group 2) had chronic hepatitis with persistent hepatitis C virus RNA positivity (four cases) and the third (group 3) had chronic hepatitis with intermittent appearance of hepatitis C virus RNA (two cases). In four of eight animals, hepatitis C virus RNA was first detectable in serum 1 wk after inoculation. Although serum HCV RNA was detected in all infected chimpanzees, two were positive only for antibody against the putative capsid protein, whereas two were positive only for antibody to C–100 antigen. In four of eight cases, antibody against the putative capsid protein appeared earlier than did antibody to C–100 antigen, was detected just before or coincident with rising glutamate pyruvate transaminase values and remained positive for a long time even after recovery. Six of eight animals (75%) were still hepatitis C virus RNA positive 1 yr after inoculation, suggesting that the risk of development of the chronic carrier state is high in hepatitis C virus infection. Furthermore, there did not appear to be a good correlation between antibody titer in serum and hepatitis C virus infectivity titer. (Hepatology 1992;690-695).
Atrial Natriuretic Peptide in Portal Vein-Ligated Rats: Alterations in Cardiac Production, Plasma Level and Glomerular Receptor Density and Affinity
Authors: Jonas Gavin M. , Morgan Timothy R. , Morgan Kengathevy , Thillainadarajah Inthirany , Hornacek Cynthia
Published: March 2007

The atrial natriuretic peptide hormonal system is altered to a variable degree in patients with cirrhosis. Portal pressure and portal–systemic shunting are also varied in cirrhosis. We used a portal vein-ligated rat model with predictable portal hypertension to study the effects of portal hypertension alone on the atrial natriuretic peptide hormonal system. Sham–operated rats were used as controls. Mean portal pressure was significantly increased in portal vein-ligated rats (portal vein-ligated rats, 21.7 ± 0.74 cm H2O; sham–operated rats, 13.7 ± 0.47 cm H2O; p < 0.0001). Plasma atrial natriuretic peptide decreased 50% in the portal vein-ligated rats (p < 0.0001). Atrial natriuretic peptide messenger RNA level was decreased by 40% to 60% in the left and right atria and in the ventricles of portal vein-ligated rats (p < 0.05 for each chamber). Only one class of glomerular binding site was identified by competitive binding studies. The atrial natriuretic peptide glomerular receptor density increased in the portal vein-ligated rats (portal vein-ligated rats, 1,660 ± 393; sham–operated 725 ± 147 fmol/mg protein, p < 0.02), whereas affinity decreased (portal vein-ligated, 1.69 ± 0.49; sham–operated, 0.55 ± 0.12 nmol/L, p < 0.02). No difference was seen in the amount of cyclic GMP generated by atrial natriuretic peptide stimulation in isolated glomeruli from portal vein-ligated and sham–operated rats. Thus, in the rat model of portal hypertension without liver disease, decreased plasma atrial natriuretic peptide level is associated with decreased cardiac atrial natriuretic peptide messenger RNA and increased density (but decreased affinity) of glomerular atrial natriuretic peptide binding sites. Portal hypertension alone may account for the increased density of glomerular atrial natriuretic peptide binding sites reported in cirrhosis, but it does not account for the changes in cardiac atrial natriuretic peptide and plasma atrial natriuretic peptide reported by most investigators. (Hepatology 1992;15:696-701).
Differential Colchicine Effects on the Transport of Membrane and Secretory Proteins in Rat Hepatocytes In Vivo : Bipolar Secretion of Albumin
Authors: Saucan Lucian , Palade George E.
Published: March 2007

We carried out a comparative investigation on the effects of colchicine (25 μmoles/100 gm body wt) on the intracellular transport, processing and discharge by secretion or proteolytic processing of a membrane protein (i.e., the polymeric IgA receptor) and a secretory protein (i.e., albumin) in rat hepatocytes. The results obtained indicated the following: (a) the transport and processing of polymeric IgA receptor is strongly inhibited and delayed, but the appearance of secretory component in the bile is not arrested; (b) polymeric IgA receptor reaches the sinusoidal plasmalemma in colchicine–treated specimens, as it does in controls; (c) albumin discharge into the plasma is strongly inhibited and markedly delayed in colchicinetreated as compared with control animals; (d) the reverse applies for albumin secretion in the bile, which is increased by a large factor; (e) newly synthesized albumin secreted directly from hepatocytes in control and in colchicine–treated animals is the major source of bile albumin; and (f) colchicine affects in different ways the polymeric IgA receptor and albumin arrival at the sinusoidal front and especially at the biliary front of the hepatocyte. (Hepatology 1992;15:714-721).
Predicting Postprocedure Bleeding in Liver Disease
Authors: Davenport Robertson D.
Published: March 2007

Prophylactic transfusions of fresh frozen plasma and platelets are sometimes given to patients with mild elevations in prothrombin time (PT) and partial thromboplastin time (PTF) and mild thrombocytopenia before percutaneous liver biopsy. To determine whether PTs and PTFs 1.1-1.5 times midrange normal levels and platelet counts 50-99 × 109/L are associated with increased bleeding complications, hospital records of all patients who underwent percutaneous liver biopsy during 56 consecutive months (n = 291) were reviewed. Complete information was available for 177 inpatient procedures (155 standard, 22 fine needle). Overall, the frequency of bleeding complications in patients with platelet counts ± 50 × 109/L was 3.4% (6 of 175), with no significant difference between patients with mild hemostatic abnormalities and patients with normal parameters. These data suggest that prophylactic transfusions may not be necessary. One factor was highly associated with bleeding complications: a patient diagnosis of malignancy, 14% (7 of 50) compared with 0.8% (1 of 127) among other patients (P < 0.001). These patients should be monitored closely after biopsy.

To determine whether untreated mild coagulopathy in patients with no evidence of clinical bleeding is associated with an increased risk of hemorrhage after paracentesis or thoracentesis, retrospective examination was conducted of 608 consecutive procedures for which prothrombin time (PT), partial thromboplastin time (PTT), platelet (Plt) counts, and preprocedure and postprocedure hemoglobin concentrations were available. There was no increased bleeding in patients with mild to moderate coagulopathy (defined as PT or PTT up to twice the midpoint normal range or plt count of 50 to 99 × 103 per μL [50-99 × 109 L]). However, patients with markedly elevated serum creatinine levels (6.0 to 14.0 mg/dL [530-1240 μmol/L]) had a significantly greater average hemoglobin loss (–0.82 ± 1.3 g/dL [–8 ± 13 g/L], n = 11) than patients with normal serum creatinine levels (–0.12 ± 088 g/dL [–1 ± 9 g/L], n = 450) (p = 0.011). Overall, the frequency of bleeding complications requiring red cell transfusions was very low: 0.2 percent of events. The most common diagnosis for patients who had paracentesis was alcoholic liver disease (72%); for those having thoracentesis, it was infection (37%). It can be concluded that, for these patients, prophylactic plasma or platelet transfusions are not necessary. Patients with markedly elevated serum creatinine deserve close postprocedure observation.
Genetic Structure and Heterogeneity of Hepatitis C Virus: A Vaccine Impediment?
Authors: Daugherty Daryl
Published: March 2007

The nucleotide sequence of the RNA genome of the human hepatitis C virus (HCV) has been determined from overlapping cDNA clones. The sequence (9379 nucleotides) has a single large open reading frame that could encode a viral polyprotein precursor of 3011 amino acids. While there is little overall amino acid and nucleotide sequence homology with other viruses, the 5′ HCV nucleotide sequence upstream of this large open reading frame has substantial similarity to the 5′ termini of pestiviral genomes. The polyprotein also has significant sequence similarity to helicases encoded by animal pestiviruses, plant potyviruses, and human flaviviruses, and it contains sequence motifs widely conserved among viral replicases and trypsin–like proteases. A basic, presumed nucleocapsid domain is located at the N terminus upstream of a region containing numerous potential N–linked glycosylation sites. These HCV domains are located in the same relative position as observed in the pestiviruses and flaviviruses and the hydrophobic profiles of all three viral polyproteins are similar. These combined data indicate that HCV is an unusual virus that is most related to the pestiviruses. Significant genome diversity is apparent within the putative 5′ structural gene region of different HCV isolates, suggesting the presence of closely related but distinct viral genotypes.

The nucleotide sequences of cDNAs (275 base–pairs) in the non–structural protein 5 regions of Japanese isolates of hepatitis C virus (HCV–J) from the plasma of 11 patients with non–A, non–B hepatitis and the livers of five patients with hepatocellular carcinoma were analyzed. Approximately 14 to 17% of nucleotide sequences of the HCV–Js examined differed from that of the original isolate in the United States (HCV–US). Furthermore, 2.5 to 11% sequence diversity was found among the HCV–Js. The nucleotide sequences of the HCV–Js showed characteristic common differences from that of HCV–US, although they also showed some random substitutions. Plural HCV–J genomes were found in two of the cDNAs derived from liver specimens, and a deletion of 102 nucleotides was found in the eDNA derived from one plasma specimen. These results suggest that HCV–J is a strain different from the HCV–US and that mutation of the viral genome occurs at as high a frequency as in that of the human immunodeficiency virus.
Gallbladder Emptying Stimuli in Obese and Normal–Weight Subjects
Authors: Stone Bradford G. , Ansel Howard J. , Peterson Francis J. , Gebhard Roger L.
Published: March 2007

ABSTRPlCT

Gallbladder stasis may be an important factor in the pathogenesis of cholesterol–gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone–free, healthy subjects with normal (22 ± 1 kg/m2) and high (36 ± 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 ± 4.4 ml) and residual volume after maximal emptying (8.4 ± 2.3 ml) in high-body–mass index subjects were not significantly different from those of normal-body–mass index subjects (20.5 ± 2.5 ml and 4.2 ± 1.3 ml, respectively). The percentage of gallbladder emptying (71% ± 5%) and the rate of gallbladder emptying (–1.9 ± 0.3 × 10-2 min-1) in high-body–mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78% ± 6%) and rate of emptying (-2.3 ± 0.6 × 10-2 min-1) in normal-body–mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal–stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose–response relationships to fat are similar in obese and normal–weight individuals. Furthermore, these findings suggest that a threshold quantity of fat-no more than 10 gm-included in a liquid–meal stimulus might be able to restore gallbladder emptying to normal. It does not appear that an intrinsic defect in gallbladder contractility is responsible for the increased incidence of gallstones in obesity. (Hepatology 1992;15:795-798).
Total Effective Vascular Compliance in Patients With Cirrhosis: A Study of the Response to Acute Blood Volume Expansion
Authors: Hadengue Antoine , Moreau Richard , Gaudin Christophe , Bacq Yannick , Champigneulle Bruno , Lebrec Didier
Published: March 2007

ABSTRPlCT

Although arterial vasodilation is a well–known feature in patients with cirrhosis, the venous system remains unexplored. To measure total effective vascular compliance, a reflection of the properties of the venous system, rapid volume expansion (300 ml of a gelatin solution in 3 min) was performed in 23 patients. Eleven patients had compensated cirrhosis (Child–Pugh grade A or B), and eight had decompensated cirrhosis (Child–Pugh grade C). Four control patients had mild chronic hepatitis, normal hepatic venous pressure and normal liver architecture. Cardiac index, hepatic venous pressures, hepatic and azygos blood flow and renal plasma flow were measured before and immediately after volume expansion. Right atrial pressure was recorded during volume expansion. This allowed the calculation of total effective vascular compliance, which was higher in patients with decompensated cirrhosis than in those with compensated cirrhosis (4.65 ± 4.21 vs. 1.34 ± 0.63 ml ± mm Hg-1 · kg-1; p < 0.05). In response to volume expansion, renal vascular resistance decreased significantly in patients with compensated cirrhosis, but not in those with decompensated cirrhosis (-30% ± 33% vs. +2% ± 23%; p < 0.05). No change was seen in glomerular filtration rate. Systemic oxygen consumption increased in patients with compensated cirrhosis, but not in those patients with decompensated cirrhosis (25% ± 33% vs. -4% ± 9%; p < 0.05). Although in all patients with cirrhosis volume expansion increased central venous pressures, azygos blood flow and the hepatic venous pressure gradient did not change. We conclude that in patients with cirrhosis and severe liver failure, total vascular compliance is elevated and probably accounts for blunted systemic and renal effects of volume expansion. (Hepatology 1992; 15:809–815).
Alterations in Hepatic Fructose Metabolism in Cirrhotic Patients Demonstrated by Dynamic 31Phosphorus Spectroscopy
Authors: Dufour Jean-François , Stoupis Christopher , Lazeyras François , Vock Peter , Terrier François , Reichen Jürg
Published: March 2007

ABSTRPlCT

Quantitative liver function tests are based on the clearance concept and measure the plasma disappearance of a test compound such as galactose. Metabolism is inferred to be predominantly hepatic, and usually no knowledge is obtained of the true time course of metabolite formation. Dynamic 31phosphorus magnetic resonance spectroscopy after intravenous administration of fructose directly measures hepatic sugar metabolism. To determine the feasability and the utility of 31P magnetic resonance spectroscopy, we studied the responses of six healthy subjects and nine patients with nonalcoholic cirrhosis to a fructose load. Results were related to the impairment of hepatic function assessed by the galactose–elimination capacity test. Liver spectra were acquired in a 1.5 T whole–body nuclear magnetic resonance unit with a surface coil (9–cm diameter) placed ventrally on the liver; the one–dimensional chemical–shift imaging technique was used to obtain spectra from tissue slices parallel to the surface coil. After a basal spectrum had been obtained, fructose (250 mg/kg) was injected intravenously, and further spectra were collected sequentially every 6 min for 1 hr. Formation of monophosphate esters (9% ± 5% vs. 20% ± 8% of total area; p < 0.01) and utilization of inorganic phosphate (5% ± 4% vs. 11% ± 3% of total area; p < 0.005) were markedly decreased in cirrhotic patients. These measures correlated with the severity of the impairment of liver function measured by the galactose–elimination capacity (r = 0.53 to 0.69; p < 0.05). We conclude that dynamic 31P magnetic resonance spectroscopy is a safe, clinically feasible test that allows detailed insights into biochemical events in liver disease. (Hepatology 1992;15:835-842).
Hypercholesterolemia and Atherosclerosis in Primary Biliary Cirrhosis: What Is the Risk?
Authors: Crippin Jeffrey S. , Lindor Kieth D. , Jorgensen Roberta , Kottke Bruce A. , Harrison Jay M. , Murtaugh Paul A. , Dickson Rolland E.
Published: March 2007

ABSTRPlCT

Hypercholesterolemia is commonly associated with primary biliary cirrhosis. In the general population, elevated serum cholesterol is associated with an increased risk of atherosclerosis. The relative risk has been poorly defined in primary biliary cirrhosis patients with hyperlipidemia. In addition, the hyperlipidemic state seen with primary biliary cirrhosis has not been well studied. We prospectively observed 312 patients with primary biliary cirrhosis for a median of 7.4 yr. During this period, 128 patients died. The incidence of atherosclerotic death in patients with primary biliary cirrhosis was not statistically different when compared with an age–matched and sex–matched U.S. control population. A similar group of 50 consecutive PBC patients had detailed serum lipid profiles. Findings included progressive increases in total cholesterol and low–density lipoprotein cholesterol with an increasing histological stage or severity of disease. High–density lipoprotein cholesterol was elevated in all stages, with the highest levels in histological stage 2 and 3 disease. Triglycerides were normal or slightly elevated in all stages. Apoprotein A–I was elevated in all but histological stage 4 disease. Our study suggests the hyperlipidemia associated with primary biliary cirrhosis does not place these patients at risk for atherosclerotic death. In light of the limitations imposed by our relatively small sample size, however, additional patients should be studied. Furthermore, an examination of the pathophysiological mechanisms leading to hypercholesterolemia should be the topic of further study. (Hepatology 1992;15:858-862).
Effects of Rapamycin on Cultured Hepatocyte Proliferation and Gene Expression
Authors: Francavilla Antonio , Carr Brian I. , Starzl Thomas E. , Azzarone Alessandro , Carrieri Giuseppe , Zeng Qui-Hua
Published: March 2007

ABSTRPlCT

Rapamycin, a potent immunosuppressive drug that disrupts normal signal–transduction processes, inhibited hepatocyte proliferation without evidence of inherent cytotoxicity in rat hepatocytes cultured in conventional medium or in a medium enriched with epidermal growth factor. The antiproliferative effect was dose dependent, uninfluenced by the concentration of epidermal growth factor in the medium and long lasting after a brief exposure. The effect of rapamycin was unaltered by the concomitant presence of FK 506 in the medium, suggesting that different binding affinities of these two drugs or even a separate rapamycin binding site may exist. Hepatocytes harvested 12 and 24 hr after partial hepatectomy were progressively less responsive to the antiproliferative effect of rapamycin. The gene expression of transforming growth factor–β was reduced under in vivo rapamycin treatment, but at the same time the gene expression of albumin and glyceraldehyde–3–phosphate dehydrogenase was unchanged or increased. The experiments confirm that rapamycin has inherent growth–control qualities, and they strengthen the hypothesis that the recently defined immunophilin network is central to many aspects of cellular growth control. (Hepatology 1992;15:871-877).
Localization and Cellular Source of the Extracellular Matrix Protein Tenascin in Normal and Fibrotic Rat Liver
Authors: van Eyken Peter , Geerts Albert , de Bleser Pieter , Lazou Jean-Marc , Vrijsen Raf , Sciot Raf , Wisse Eddie , Desmet Valeer J.
Published: March 2007

ABSTRPlCT

The distribution and the cellular source of the novel extracellular matrix glycoprotein tenascin were studied in normal and fibrotic rat liver. Cryostat sections of normal rat livers, livers of rats treated with intraperitoneal injections of CCl4 and 4–day–old and 8–day–old primary fat–storing cell cultures were stained for tenascin and desmin using an immunoperoxidase procedure or a double–label immunofluorescence technique. Fat–storing cell cultures were metabolically labeled with H–proline. Radiolabeled proteins were immunoprecipitated from the supernatant with antitenascin antiserum and subjected to polyacrylamide gel electrophoresis. In normal rat livers, tenascin was detected discontinuously along the sinusoids, whereas portal tracts were devoid of staining. In fibrotic rat livers, tenascin was preferentially expressed in areas of cell damage, in slender septa or at connective tissue-parenchymal interfaces. The middle region of broad septa was negative. Desmin–positive fat–storing cells accumulated in areas strongly immunoreactive for tenascin, and double–label immunofluorescence showed cells positive for both tenascin and desmin. In fat–storing cell cultures, both intracellular positivity for tenascin and staining of extracellular fibers were seen. Gel electrophoresis of immunoprecipitated proteins revealed two major and three minor bands with molecular weights consistent with tenascin. We conclude that tenascin is a component of the extracellular matrix of both normal and fibrotic rat livers. The strong expression of tenascin in areas of cell damage, in “early” septa or at septal–parenchymal interfaces, in contrast to its absence from the middle region of mature septa, suggests a role in early matrix organization. Fat–storing cells synthesize and secrete tenascin. (Hepatology 1992;15:909-916).
Characterization of the Transport of A Synthetic Bile Salt, Iodinated Cholyl–Glycyl–Tyrosine, in Isolated Cultured Rat Hepatocytes
Authors: Deutsch John C. , Iwahashi Mieko M. , Sutherland Eileen M. , Mapoles John , Simon Francis R.
Published: March 2007

ABSTRPlCT

The uptake of tri–hydroxy conjugated bile salts by hepatocytes is principally by a sodium–dependent carrier. We examined the uptake kinetics of the high–specific–activity, hydroxylated, conjugated bile salt 125I–labeled cholyl–glycyl–tyrosine, to determine whether this synthetic bile salt was transported by the sodium–dependent bile salt system. 125I–labeled cholyl–glycyl–tyrosine was synthesized, and its transport kinetics were studied in freshly cultured rat hepatocytes. Uptake into hepatocytes was time and temperature dependent and was decreased by the inhibitors diisothiocyanodisulfonic acid stilbene, probenecid and carbonyl cyanide chlorophenyl hydrazone, demonstrating carrier mediation and energy dependence. At concentrations of iodinated cholyl–glycyl–tyrosine less than 10 μmol/L, uptake was 27% ± 5% sodium dependent, whereas at concentrations from 10 μmol/L to 40 μmol/L uptake was 52% ± 4% sodium dependent. The apparent affinity for uptake of 125I–labeled cholyl–glycyl–tyrosine was 8 ± 2 μmol/L, and the maximal velocity was 50 ± 20 pmol/μg DNA/min. Both taurocholate and indocyanine green inhibited uptake of 125I–labeled cholyl–glycyl–tyrosine. Indocyanine green inhibited the uptake of 125I–labeled cholyl–glycyl–tyrosine (Ki = 10 μm) more effectively than taurocholate (Ki = 20 μm). We conclude that 125I–labeled cholyl–glycyl–tyrosine is not a specific probe for either sodium–dependent bile salt or sodium–independent organic anion carriers, but appears to use both systems in a concentration–dependent manner in cultured rat hepatocytes. (Hepatology 1992;15:917-922).
Mirex–Induced Adaptive Liver Growth in Rats Subjected to Thyroidectomy
Authors: Yarbrough James D. , Grimley Jo M. , Thottassery Jaideep V.
Published: March 2007

ABSTRPlCT

The organochlorine compound mirex (dodecachlorooctahydro–1,3,4–metheno–2H–cyclobuta–CD–pentalene) induces an adaptive liver growth dependent on the hormonal status of the experimental animal. In the intact laboratory rat, mirex induces liver growth that is an expression of both cellular hyperplasia and hypertrophy. However, in rats subjected to adrenalectomy, mirex induces liver growth that is essentially hyperplastic. Corticosterone supplements given to rats subjected to adrenalectomy and treated with mirex restore the hypertrophic component of liver growth. Therefore it appears that the expression of the hypertrophic component of mirex–induced liver growth is corticosterone dependent.

To further explore the hormonal modulation of the expression of mirex–induced adaptive liver growth, rats subjected to thyroidectomy were studied. In male rats subjected to thyroidectomy, a single oral dose of mirex (100 mg/kg body wt) increased relative liver weight (liver wt/body wt × 100) by 62% within 72–hr after mirex administration. Liver growth occurred in the absence of [H]thymidine incorporation into liver DNA. Thus the observed liver growth was totally hypertrophic. However, in mirex–dosed rats subjected to thyroidectomy given twice–daily subcutaneous injections of thyroxine (5 mg/kg body wt), relative liver weight was increased by 204% of the control value within 72–hr after mirex administration, and there was a peak of [H]thymidine incorporation into liver DNA 54 hr after mirex administration. These studies suggest that the expression of hyperplasia in mirex–induced adaptive liver growth is thyroxine dependent. (Hepatology 1992;15:923-927).
Opposite Responses of Nuclear Spermidine N 8–Acetyltransferase and Histone Acetyltransferase Activities to Regenerative Stimuli in Rat Liver
Authors: Desiderio Maria Alfonsina
Published: March 2007

ABSTRPlCT

Experiments performed in different models of hepatic regeneration at the time of maximal DNA synthesis, determined by thymidine kinase activity assay, demonstrated that spermidine N
8–acetyltransferase activity increased 48 hr after CCl4 administration (2–fold), 72 hr after CCl4 plus phenobarbital (3–fold) and 24 hr after partial hepatectomy (4.5–fold). On the contrary, at these times histone acetyltransferase activity diminished (approximately twofold) and was unchanged compared with control values in the liver of hepatotoxin–treated and hepatectomized rats, respectively. Histone acetylation was, however, enhanced 1.5–fold before the onset of DNA replication (14 hr), and 3.4–fold after the peak of DNA synthesis (32 hr) in the liver of hepatectomized rats.

α–Difluoromethylornithine, a specific and irreversible inhibitor of ornithine decarboxylase that was administered to hepatectomized rats, blocked polyamine synthesis, thymidine kinase activity and consequently liver regeneration 24 hr after the surgery. In those conditions, spermidine N
8–acetyltransferase activity was decreased approximately twofold, whereas histone acetyltransferase activity was elevated approximately twofold. All these effects were reversed by putrescine coadministration.

Altogether, these findings showed that nuclear spermidine N
8–acetyltransferase and histone acetyltransferase activities were regulated in opposite ways during the processes associated with liver regeneration. Moreover, they suggested that the polyamines themselves might have a direct or indirect role in this regulation. (Hepatology 1992;15:928-933).