bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration in Growth Regulation of Hepatocytes in Primary Culture Obtained From Cirrhotic Rat: Poor Response to Transforming Growth Factor–β1 and Interferons
Authors: Kiso Shinichi , Kawata Sumio , Tamura Shinji , Ito Nobuyuki , Takaishi Kenji , Shirai Yasuhiro , Tsushima Hirofumi , Matsuzawa Yuji
Published: March 2007

Cell growth appears to be controlled by positive and negative cell growth regulation. Little is known about the growth regulation of hepatocytes in the cirrhotic liver. Clarifying the responses of hepatocytes obtained from cirrhotic liver to various growth factors and growth inhibitory factors might aid understanding of alterations in growth regulation of the hepatocytes in the cirrhotic liver. We investigated the effects of hepatocyte growth factor, epidermal growth factor, heparin–binding epidermal growth factor–like growth factor, transforming growth factor–β1, interferon–α and interferon–γ on the DNA synthesis of hepatocytes from cirrhotic and normal rats in primary culture. Cirrhosis was induced in male Sprague–Dawley rats by means of oral administration of 0.05% thioacetamide in drinking water for 4 mo. Hepatocytes were isolated by means of an

in situ

perfusion method, and DNA synthesis was assessed from the amount of DNA–incorporated [H]thymidine. Stimulation of the DNA synthesis of hepatocytes by hepatocyte growth factor, epidermal growth factor and heparin–binding epidermal growth factor–like growth factor was not different between normal and cirrhotic rat liver. Transforming growth factor–β1 inhibited the DNA synthesis of hepatocytes in both. However, the concentration of transforming growth factor–β1 giving a 50% inhibition of DNA synthesis was about two times higher in cirrhotic hepatocytes (0.11 ng/ml) than in normal hepatocytes (0.06 ng/ml). In cirrhotic hepatocytes, the expression of transforming growth factor–β type II receptor gene was about 50% of that in normal hepatocytes. The percent inhibitions of DNA synthesis by 1.25 × 104 U/ml of interferon–α were 51.6% ± 3.2% and 14.1% ± 7.7% in normal and cirrhotic hepatocytes, respectively, by 1.25 × 103 U/ml of interferon–γ 44.8% ± 10.3% and 19.9% ± 3.4%, respectively. These results suggest that inhibitory regulation of cell growth may be impaired in the hepatocytes from cirrhotic liver. (Hepatology 1994;20:1303–1308).
Mechanism of Activation of the Na+/H+ Exchanger by Arginine Vasopressin in Hepatocytes
Authors: Anwer Sawkat M.
Published: March 2007

Arginine vasopressin has been shown to activate the Na/H+ exchanger in hepatocytes by calcium/calmodulin–dependent processes. Whether this activation also involves protein kinase C and is associated with changes in the intracellular pH setpoint was investigated in this study. Changes in pHi and intracellular Ca++ concentration were measured with the fluorescent probes BCECF and quin–2, respectively. Intracellular pH recovery rate was calculated from timedependent changes in intracellular pH in hepatocytes acid–loaded with sodium propionate. Arginine vasopressin, phorbol myristate acetate and thapsigargin stimulated intracellular pH recovery but did not increased basal intracellular pH. Arginine vasopressin and thapsigargin, but not phorbol myristol acetate, increased intracellular Ca++ concentration. The protein kinase C inhibitors staurosporine and calphostin C inhibited arginine vasopressin– and phorbol myristol acetate—induced, but not thapsigargin–induced, intracellular pH recovery. Neither staurosporine nor calphostin C affected arginine vasopressin– and thapsigargin–induced increases in intracellular Ca++ concentration, and no inhibitor affected basal intracellular pH recovery. Arginine vasopressin, phorbol myristol acetate and thapsigargin increased intracellular pH dependency of intracellular pH recovery without affecting intracellular pH setpoint. These results indicate that the activation of the Na+/H+ exchanger by arginine vasopressin is mediated both by Ca++/calmodulin and protein kinase C and may be due to enhanced interaction of H+ with the internal modifier site of the exchanger. (Hepatology 1994;20:1309-1317).
Serum Hyaluronate in the Assessment of Liver Endothelial Cell Function After Orthotopic Liver Transplantation in the Rat
Authors: Shimizu Hiroaki , He Wei , Guo Ping , Dziadkoviec Irena , Miyazaki Masaru , Falk Rudolf E.
Published: March 2007

This study was designed to evaluate the use of serum hyaluronate as a marker of liver endothelial cell function after liver transplantation. We performed orthotopic liver transplantation in both isogeneic and allogeneic rejector models. After transplantation, hepatocyte function was assessed on the basis of serum ALT and total bilirubin levels, and liver endothelial cell function was judged on the basis of serum hyaluronate levels. Significant increase of hyaluronate in the rejector model, compared with the isogeneic model, was seen before any significant results could be obtained from conventional liver function tests. The impaired metabolism of hyaluronate in the rejector model was observed after intravenous injection of trace amounts of radioactive material. Serial studies demonstrate that the endothelial cell is a more susceptible target for the immune response than the hepatocyte. Serum hyaluronate concentration may be a better indicator in the early assessment of graft function. We also examined serum hyaluronate levels to evaluate cold ischemia–reperfusion injury to the liver endothelial cells in the isogeneic model. At 2 hr after reperfusion, hyaluronate levels in the 6–hr cold ischemia (nonviable allograft) group were significantly higher than in the 1–hr and 3–hr cold ischemia (viable allograft) groups. However, there was little difference between the viable allograft groups. After an intravenous injection of 1 mg/kg hyaluronate, the hyaluronate elimination rate in the 3–hr group was distinctly slower than that in the 1–hr group. These data indicate that the hyaluronate elimination rate may be a more sensitive marker of liver endothelial cell function in viable liver after a short period of ischemia. (Hepatology 1994;20:1323-1329).
The Mallory Body: Theories on Development and Pathological Significance (Part 2 of A Literature Survey)
Authors: Jensen Kenneth , Gluud Christian
Published: March 2007

Drawing on data from a previously published literature survey on the clinical and experimental epidemiology of the Mallory body, we discuss current theories on its development in a

pro et contra

manner. Conclusions have been largely left open to the interpretations of the reader because many are still speculative. The main results of this study characterize Mallory bodies as stereotypical histological byproducts to diverse hepatic injuries (mostly alcohol associated) of questionable pathogenic importance. The temporal characteristics of Mallory bodies cast doubt on their role in hepatic neoplasia both as a disease marker and a causative agent, and prognosis studies suggest that they may be considered preterminal markers in some nonalcoholic liver diseases but remain prognostically unimportant in most studies on alcoholic patients. By similar line of inquiry, no consistent relationships may be found with disease severity or duration in alcoholic liver diseases. The roles of vitamin A deficiency and protein–calorie malnutrition are circumstantial. Drugs known to have calcium–antagonist properties and the physiological characteristics of the stress–response protein ubiquitin support the concept of defective protein systems in Mallory body pathogenesis. Disproportionate hepatic copper accumulation seems both epidemiologically and topographically associated with Mallory bodies, but these connections are largely unsupported by exposure studies. Many arguments still downplay the importance of uncoordinated changes in hepatic oxygen delivery and consumption, but ischemia–reperfusion studies suggest a role of oxygen–derived free radicals in the liver injuries under scrutiny. Finally, the role of Mallory bodies in the control system of hepatocyte function is addressed, and indirect evidence lends credence to a cybernetic approach in future study designs. It is reasonable to assume that different elements of a multifactorial setting operate with varying intensity over time as this may account for some of the controversies that exist. In conclusion, the biological significance of Mallory bodies is still mystery. It is not known whether Mallory bodies represent an epiphenomenon or play a role themselves in the initiation and continuation of liver damage.
The Hepatitis B Virus Receptor: Book'em, Dano?
Authors: Peeples Mark E.
Published: March 2007

In a previous study, we have identified endonexin II (E–II) on human liver plasma membranes as a specific, Ca–dependent, small hepatitis B surface antigen (HBsAg)–binding protein. In this article, we describe the spontaneous development of anti–HBs antibodies in rabbits immunized with native or recombinant human liver E–II and in chickens immunized with the F(ab′)2 fragment of rabbit anti–human liver E–II immunoglobulin G. Anti–HBs activity was not observed in rabbits immunized with rat liver E–II. Cross–reactivity of anti–E–II antibodies to HBsAg epitopes was excluded, since anti–HBs and anti–E–II activities can be separated by E–II affinity chromatography. The existence of an anti–idiotypic antibody is further demonstrated by competitive binding of human liver E–II and this antibody (Ab2) to small HBsAg, suggesting that Ab2 mimics a specific E–II epitope that interacts with small HBsAg. In addition, it was demonstrated that anti–HBs antibodies developed in rabbits after immunization with intact human liver E–II or in chickens after immunization with F(ab′)2 fragments of rabbit anti–human liver E–II immunoglobulin G recognize the same epitopes on small HBsAg. These findings strongly indicate that human liver E–II is a very specific small HBsAg–binding protein and support the assumption that human liver E–II is the hepatitis B virus receptor protein.

Binding of viral envelope proteins to specific receptors on human hepatocytes is considered to be an important step in HBV infection. In this study, we demonstrate that a 34–kDa human liver plasma membrane protein specifically binds to small HBsAg in a Ca2+–dependent manner. By partial amino acid sequence analysis of preparatively isolated 34–kDa protein comigrating with HBsAg–binding protein obtained from binding assay on IEF/SDS–PAGE, we have identified this HBsAg–binding protein as Endonexin II (E–II). Native human liver E–II inhibits binding of HBsAg to intact human hepatocytes and shows specific binding to small HBsAg. This binding can be inhibited by human liver plasma membrane proteins, recombinant E–II, or anti–E–II antibodies. Despite 90% sequence homology, rat liver E–II does not bind to small HBsAg and does not inhibit significantly (less than 20%) binding of HBsAg to intact hepatocytes. Cross–linking of small HBsAg and radiolabeled human liver E–II resulted in a specific additional protein complex on PAGE with an apparent molecular weight of 90 kDa, corresponding to a complex of E–II and small HBsAg with a ratio of 2 to 1 or 1 to 2. These findings indicate that E–II, found in human liver, is a specific HBsAg–binding protein and might play an important role in the initiation of HBV infection.
Tumor Vaccination Against Hepatoma: How Does It Work?
Authors: Hanada Shuichi , Wakita Takaji , Takahashi Hiroshi
Published: March 2007

Fusion of BERH–2 rat hepatocellular carcinoma cells with activated B cells produced hybrid cells that lost their tumorigenicity and became immunogenic. Syngeneic rats injected with BERH–2–B hybrid cells became resistant to challenge with parental BERH–2 cells, and rats with established BERH–2 hepatomas were cured by subsequent injection of BERH–2–B cells. Both CD4 and CD8+ cells were essential for the induction of protective immunity; however, only CD8+ cells were required for the eradication of BERH–2 tumors. The generation of hybrid tumor cells that elicit antitumor immune responses may be a useful strategy for cancer immunotherapy.
Indications for orthotopic liver transplantation in fulminant liver failure
Authors: Williams Roger , Wendon Julia
Published: March 2007

The decision to undertake transplantation in a patient with fulminant liver failure requires consideration of many factors so that the physician may arrive at the most appropriate course of action. There are several definitions of fulminant liver failure used in current practice, all excluding patients with chronic liver disease. In the one most recently proposed, the terms hyperacute, acute and subacute liver failure are used to categorize groups of patients with different clinical appearances and progress. Patients in the hyperacute group have a better outcome with medical treatment than others, despite deeper levels of encephalopathy. The decision to proceed to transplantation should be undertaken in patients who fulfil criteria for a poor prognosis with medical management. For two groups, Hôpital Paul Brousse, Paris, and King's College Hospital, London, criteria are based on analysis of large patient numbers, which can be applied at the bedside without recourse to complex analysis. Once a patient has been listed for transplantation, regular systems review must be undertaken because the development of irreversible multiple organ failure may preclude transplantation. Hepatectomy may occasionally have a role in stabilizing a patient awaiting a suitable organ. In less severe cases, auxiliary liver transplantation has been undertaken, and in some patients regeneration of the native liver has occurred, allowing withdrawal of immunosuppressive therapy. The results of orthotopic liver transplantation in fulminant liver failure have steadily improved over recent years, with reported 1-year survival rates of up to 80% in some series, yielding a good prognosis for certain groups of patients who previously had unacceptably high mortality (Hepatology 1994;20:5S-10S.)
Liver transplantation for hepatitis B virus—associated cirrhosis: A progress report
Authors: Van Thiel David H. , Wright Harlan I. , Fagiuoli Stefano
Published: March 2007

Because of its importance as an indication for liver transplantation, the epidemiology of chronic hepatitis B disease is presented. Current knowledge relative to the pathobiological mechanisms of hepatitis B virus—related liver disease are presented, followed by a discussion of the treatment modalities currently available for use in hepatitis B virus—related liver disease. This is followed by an examination of their use in both potential transplant recipients and those who have been given liver transplants for hepatitis B virus disease. Finally, a summary of the current status of hepatitis B virus disease and liver transplantation is presented. (Hepatology 1994;20:20S-23S.)
Liver transplantation for hepatitis C virus-related cirrhosis
Authors: Ascher Nancy L. , Lake John R. , Emond Jean , Roberts John
Published: March 2007

Since the introduction of techniques to reliably identify antibody to the hepatitis C virus and quantitation of hepatitis C virus, there has been an increasing interest in the behavior of chronic hepatitis C infection with liver transplantation. Ninety-seven patients with chronic active hepatitis C and fifty-nine patients with cryptogenic cirrhosis underwent 100 and 62 liver transplantation procedures, respectively, at a single institution. This represents 35% of the total liver transplantations performed during this time period. Twenty-three percent of transplants were performed in patients with evidence of chronic active hepatitis C. Patients and graft survival were excellent in both groups. One-, 2- and 3-yr patient survival rates for chronic active hepatitis C and cryptogenic cirrhosis were 94%, 89% and 87% and 84%, 84% and 73%, respectively. Hepatitis C can frequently be identified after transplantation. More than 95% of patients show persistence of antibody to the hepatitis C virus. Forty-one of 95 patients (surviving>1 mo) showed recurrent hepatitis (initially seen 3 to 20 mo after transplantation), and 12 progressed to chronic active hepatitis. In 16 patients of the cryptogenic group in whom hepatitis developed, 11 were associated with de novo hepatitis C infection. Seven of these 11 cases went on to a chronic state. Of 11 deaths after transplant in the hepatitis C group, 2 were directly related to recurrent disease. There were 15 deaths in the cryptogenic group, 2 related to de novo hepatitis C. Patients were not serotyped. Interferon therapy was attempted in a small number of patients with disease, with inconclusive results. These data indicate that patients with chronic active hepatitis C have excellent shortterm results after liver transplantation. With longer follow-up, we may see an increasing number of patients with recurrent hepatitis or poor outcome with specific viral serotypes. (Hepatology 1994;20:24S-27S.)
Indications for liver transplantation in hepatobiliary malignancy
Authors: Pichlmayr Rudolf , Weimann Arved , Ringe Burckhardt
Published: March 2007

Our personal experience with 172 patients, the results from the European Liver Transplant Registry and a review of the recent literature are summarized and discussed to define present indications for liver transplantation in hepatobiliary malignancy. The following conditions should be considered contraindications: advanced primary liver tumors with any extrahepatic spread, cholangiocellular carcinoma, hemangiosarcoma and liver metastases from nonendocrine primary tumor. Currently, “favorable” indications include uncommon tumors such as fibrolamellar carcinoma, epithelioid hemangioendothelioma, hepatoblastoma and metastases from endocrine tumors. Further indications may be nonresectable hepatocellular and proximal bile duct carcinoma in tumor stage II. Borderline indications are hepatocellular and proximal bile duct carcinoma in tumor stage III. In advanced tumors confined to the liver, transplantation should be restricted to multimodality treatment protocols. Although there are strong arguments for transplantation in early resectable hepatocellular carcinoma with underlying cirrhosis, it remains an open issue requiring further investigation in a controlled study using the same tumor classification. With regard to limited resources of donor organs, split-liver transplantation permits transplantation in tumor patients without neglecting those with benign diseases. (Hepatology 1994;20:33S-40S.)
Living donor for liver transplantation
Authors: Broelsch Christoph E. , Burdelski Martin , Rogiers Xavier , Gundlach Matthias , Knoefel Wolfram T. , Langwieler Thomas , Fischer Lutz , Latta Astrid , Hellwege Horst , Schulte Franz-Joseph , Schmiegel Wolff , Sterneck Martina , Greten Heiner , Kuechler Thomas , Krupski Gerrit , Loeliger Cornelius , Kuehnl Peter , Pothmann Werner , Esch Jochen Schulte Am
Published: March 2007

Since living related liver transplantation was first performed in 1989, more than 150 cases have been performed worldwide, mostly in the United States and Japan. This paper reports the first series of living related liver transplantation in Europe. Twenty living related liver transplantation surgeries were performed over a 13-mo period, with an overall patient survival of 85%. For patients who underwent elective transplantation (n=13), the survival rate was 100%. Technical complications included one arterial thrombosis necessitating retransplantation and five bile leaks requiring surgical revision. The technical improvements that permit avoidance of these complications are discussed. A detailed description of the living related liver procurement is given. All procurements yielded grafts of excellent quality. No intraoperative complications occurred, and no reoperations were necessary. No heterologous blood transfusion was needed. In two patients, incisional hernias developed after wound infection. Living related liver transplantation does not absolve the transplant community of efforts to promote cadaveric organ procurement. Nevertheless, living related liver transplantation does have the advantage of a readily available graft of excellent quality, permitting transplantation with optimal timing under elective conditions. Several centers are now preparing living related segmental liver transplants, following the model of our protocol, for three reasons: (a) to obtain superior results compared with cadaveric liver transplantation; (b) to overcome cadaveric organ shortage and further reduce pretransplantation mortality and (c) to provide viable organs in countries where cadaveric organ procurement is not established. When performed by a team experienced in pediatric liver transplantation and in adult liver resection, living related liver transplantation is an excellent modality for the treatment of end-stage liver disease in children. (Hepatology 1994;20:49S-55S.)
Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti-hepatitis b e—positive chronic hepatitis
Authors: Dienes Hans Peter , Gerken Guido , Goergen Bernd , Heermann Klaus , Gerlich Wolfram , zum Büschenfelde Meyer K. H.
Published: March 2007

A number of naturally occurring hepatitis B virus (HBV) mutants unable to synthesize the hepatitis B e antigen (HBeAg) have been identified in patients characterized by HBV DNA and anti-HBe in their serum. Because the analysis of the HBV-associated DNA and antigens in the liver tissue is still not complete, we investigated the precore sequence of HBV DNA and its encoded proteins in the liver tissue of 32 patients positive for HBV DNA and anti-HBe in their serum. Three different groups of patients were identified. Group I (n = 14) was characterized by viral DNA sequences with a G-A transition in the distal precore gene region, thus creating a termination codon (TAG). Liver tissue from this group was negative for HBeAg but positive for hepatitis B core antigen (HBcAg) and a peptide containing the last 10 aminoacids of the precore and the first four aminoacids of the c region. Group II (n = 6) showed variable mutations in base sequences further upstream and negative for HBeAg and the precore peptide. Group III (n = 12) contained wild-type HBV DNA sequences in the tissue and positivity for precore- and core-encoded proteins. We conclude from our study that the group of patients with HBV DNA and anti-HBe in the serum is rather heterogeneous, including HBV DNA mutations in the precore region as well as infection with the wildtype virus being negative for HBeAg in the serum. The precore peptide is produced and expressed in the tissue even when the formation of a stop codon at base 1896 prevents the complete translation of the entire HBe protein. (Hepatology 1995;21:1-7).
Hepatitis B virus precore mutant infection is associated with severe recurrent disease after liver transplantation
Authors: Angus Peter W. , Locarnini Stephen A. , McCaughan Geoffrey W. , Jones Robert M. , McMillan Janine S. , Bowden Scott D.
Published: March 2007

The factors that predispose patients undergoing liver transplantation for hepatitis B virus (HBV) disease to severe recurrence of infection are unclear. In this study we examined the effect of pretransplantation infection with HBV and precore variant strains of HBV on posttransplantation outcome and allograft histology in 24 patients who survived more than 3 months after liver transplantation. Based on pretransplantation serum HBV DNA status as detected by the polymerase chain reaction (PCR) and direct sequencing, the 24 patients could be assigned to three groups. In group 1 there were 4 patients HBV DNA-negative before transplantation and none of these patients suffered recurrence of infection posttransplantation. In group 2, of 10 patients with pretransplantation infection with wild-type virus, 7 became reinfected, and 1 of these developed HBV-related graft failure. In group 3, 9 of 10 patients infected with precore mutant HBV strains became reinfected. However, in contrast to the patients in group 2, 7 patients in group 3 developed HBV-related graft loss, and 5 of these patients had fibrosing cholestatic hepatitis (FCH). These results indicate that infection with precore mutant strains of HBV predisposes a patient to early graft loss following transplantation. (Hepatology 1995;21:14-18).
Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance
Authors: Lok Anna S. F. , Akarca Ulus S. , Greene Sheila
Published: March 2007

We previously reported two mutually exclusive mutations in the precore region of hepatitis B virus: M1 (T-1856, proline-serine substitution at codon 15) and M2 (A-1896, stop codon at codon 28). This study was conducted to determine if the presence of precore mutants affect spontaneous or interferon (IFN)-induced hepatitis B e antigen (HBeAg) clearance. Sera from 201 hepatitis B e antigen posititis B virus (HBV) infection were analyzed by direct sequencing of HBV DNA after amplification by polymerase chain reaction (PCR) assay. Forty-three (21%) patients had M1 (T-1856), and 20 patients (10%) had M2 (A-1896). During a follow-up period of 1 to 7 years, 75%, 28%, and 26% of those with M2 (A-1896), M1 (T-1856), and wild type sequence respectively, cleared HBeAg (P<.0001). Eighteen (67%) of 27 patients with wild-type sequence but none of 10 patients who had M1 (T-1856) in their initial samples developed M2 (A-1896) after loss of HBeAg (P<.0001). Sustained antiviral response was achieved in 55%, 0%, and 17% of interferontreated patients who had M2 (A-1896), M1 (T-1856), and wild-type sequence, respectively, initially (P = 0.04). However, patients with M2 (A-1896) were also more likely to have elevated pretreatment aminotransferase levels (P = 0.02). In summary, HBeAg-positive Chinese patients with M2 (A-1896) were more likely to clear HBeAg, and to do so earlier. Neverthless, development or selection of M2 (A-1896) was not a prerequisite for HBeAg clearance. Interferon therapy did not increase the rate of HBeAg clearance in patients with M2 (A-1896) when stratified for aminotransferase levels. (Hepatology 1995;21:19-24).
Grading of cellular rejection after orthotopic liver transplantation
Authors: Gupta Siddhartha Datta , Hudson Mark , Burroughs Andrew K. , Morris Richard , Rolles Keith , Amlot Peter , Scheuer Peter J. , Dhillon Amar P.
Published: March 2007

All 684 post-orthotopic liver transplantation (OLT) liver biopsies performed at the Royal Free Hospital (RFH) between 1988 and 1993, from 120 patients, were reviewed in order to try to define the relative importance of the histological features of immunosuppressionresponsive cellular rejection. Twenty histological features considered to be possible contributors to the diagnosis of cellular rejection were documented in a binary (present/absent) fashion. These features in 106 biopsy specimens obtained 1 to 8 days after OLT were analyzed using stepwise logistic discriminant analysis. All clinical and treatment records were reviewed, and each biopsy specimen was assigned to a diagnostic category depending on these records and follow-up information. Important determinants of the histological diagnosis of cellular rejection (which occurred in 84 of the 106 cases) were moderate/severe mixed portal inflammation, eosinophils, endotheliitis, and bile duct damage. When these all occurred together, the odds of rejection increased 3.6-fold. The original histological diagnosis was recorded, and each biopsy specimen showing cellular rejection was regraded according to the specific criteria of Snover et al., Demetris et al., and a novel RFH scoring system. The latter consists of evaluating portal inflammation, endotheliitis, eosinophils, and bile duct damage, each on a 0 to 3 scale (none, mild, moderate, or severe, respectively) and summation. The resulting cellular rejection score thus can range from 0 to 12. The agreement between the different scoring systems was analyzed using K statistics, and there was good concordance (K, 0.64 to 0.78), despite different histological criteria being used to derive each score. Each system showed a similar degree of sensitivity (87% to 96%). The specificity ranged from 59% to 77%. We conclude that the histological diagnosis of cellular rejection relies mainly on the previously described features of mixed portal inflammation, endotheliitis, eosinophils, and duct damage. There is scope for unification and simplification of the existing grading systems, which depend on differing criteria, and we suggest one such scheme. (Hepatology 1995;21:46-57).
A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation
Authors: Sankary Howard N. , McChesney Lawrence , Frye Elizabeth , Cohn Steven , Foster Preston , Williams James
Published: March 2007

Nonanastomotic strictures after liver transplantations are a source of significant morbidity, often necessitating retransplantation. The purpose of this study was twofold: first to identify features associated with the development of this lesion; second, to make technical modifications that will decrease the incidence of this problem. In the first part of this study, 15 of 131 patients were diagnosed with nonanastomotic biliary stricture. A stepwise logistic-regression analaysis associated donor cold ischemie time and dopamine dose with the development of nonanastomotic biliary strictures. All these patients had arterial reconstruction after partial revascularization of the liver with portal venous blood. Because the bile duct receives its blood supply from only the hepatic artery, we hypothesized staged reconstruction of the vascular supply would promote the development of this lesion. In a second a part of this study, the stricture rate in 45 patients with simultaneous revascularization using both the hepatic artery and portal vein was compared with that in 83 patients from the first part of this study, initially revascularized with portal venous blood. All patients in the second study had grafts preserved using UW solution. Only 1 patient with simultaneous revascularization developed a nonanstomotic biliary stricture. Because we were unable to identify any significant complications related to this method of revascularization, we propose that the hepatic artery and portal vein should be released simultaneously, especially in patients receiving a graft with prolonged storage time. (Hepatology 1995;21:63-69).
Occurrence of hepatocellular carcinoma and decompensation in western european patients with cirrhosis type B
Authors: Fattovich Giovanna , Giustina Giuliano , Schalm Solko W. , Hadziyannis Stephanos , Sanchez-Tapias Josè , Almasio Piero , Christensen Erik , Krogsgaard Kim , Degos Francoise , De Moura Miguel Carneiro , Solinas Antonio , Noventa Franco , Realdi Giuseppe
Published: March 2007

To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation. At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that idependently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC. Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease. (Hepatology 1995;21:77-82).
Failure of hepatopulmonary syndrome to resolve after liver transplantation and successful treatment with embolotherapy
Authors: Poterucha John J. , Krowka Michael J. , Dickson Rolland E. , Cortese Denis A. , Stanson Anthony W. , Krom Ruud A. F.
Published: March 2007

The hepatopulmonary syndrome is an uncommon accompaniment of chronic liver disease. The outcome of this disorder after orthotopic liver transplantation is varibable. We describe a patient with the hepatopulmonary syndrome who underwent orthotopic liver transplantation for autoimmune hepatitis. Her platypnea and orthodeoxia failed to improve postoperatively. Pulmonary angiography showed large pulmonary arteriovenous shunts that were successfully treated with coil embolotherapy. (Hepatology 1995;21:96-100).
Predicting survival in fulminant hepatic failure using serum gc protein concentrations
Authors: Lee William M. , Galbraith Robert M. , Watt Graeme H. , Hughes Robin D. , McIntire Donald D. , Hoffman Brenda J. , Williams Roger
Published: March 2007

Plasma Gc protein sequesters actin released into the circulation after massive hepatocyte necrosis, but is greatly depleted in the process. In fulminant hepatic failure (FHF), Gc is present in serum both as a complex with actin and as unbound protein, the latter becoming completely exhausted in those patients with the most severe FHF. In the present study, 47 consecutive patients with FHF, 39 of whom were the result of acetaminophen (AC) overdose, were evaluated to determine whether measurement of Gc protein levels could be used to predict survival. Using serum samples obtained shortly after admission as well as later samples, levels for total Gc protein, percentage of Gc complexed with actin, and calculated unbound Gc remaining in serum were compared for survivors and those who died of their illness. The most marked changes were present in unbound Gc levels in nonsurvivors, the mean of which for follow-up samples was 10% of normal mean values, as compared with 23% of normal mean values in those who survived (P<.01). Using a cutoff value for unbound Gc protein of ±34 μg/mL to predict survival, outcome was correctly predicted in 32 of 47 (68%) patients using early samples, and in 24 of 27 (89%) patients using later sera. No differences were observed between values and/or outcome in AC and non-AC cases. Measurement of Gc protein level correctly predicted all patients dying of hepatic failure. This single measurement compares favorably with multifactorial predictive models, such as the King's College model, and might be a useful test for patients being considered for transplantation. (Hepathology 1995;21:101-105).
Cytokine patterns and cytotoxic mediators in primary biliary cirrhosis
Authors: Martinez Olivia M. , Villanueva Janeth C. , Gershwin Eric M. , Krams Sheri M.
Published: March 2007

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver with unknown etiology. Autoreactive T lymphocytes that infiltrate the liver may play a major role in the bile duct damage that accompanies the disease. We hypothesized that cytokines produced by T lymphocytes and other cells are central to the disease process. Therefore, we used reverse transcription-polymerase chain reaction (PCR) and Southern hybridization to identify cytokine message directly from liver tissue of 11 patients with PBC and 5 patients with autoimmune hepatitis (AI-CAH). Messenger RNA (mRNA) for interleukin (IL)-2, IL-5, IL-6, interferon gamma (IFN-γ), and transforming growth factor beta (TGF-β) were detected in the majority of the specimens from patients with PBC. The presence of IL-5 was associated with PBC (P<.001, PBC vs. AI-CAH). Because IL-5 is a potent eosinophil differentiation factor, we looked for evidence of activated eosinophils within the infiltrate. We observed the deposition of the primary cytotoxic granule protein of eosinophils, major basic protein (MBP), within the portal region of livers from patients with PBC. Moreover, we detected message for a cytotoxic T-lymphocyte (CTL) granzyme in 87.5% of these livers indicating that mature CTL are present. Thus, we present evidence for two effector pathways that may contribute to the tissue damage observed in PBC and have identified massage for cytokines that may regulate these pathways. (Hepatology 1995;21:113-119).
Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease
Authors: George Jacob , Murray Michael , Byth Karen , Farrell Geoffrey C.
Published: March 2007

To determine whether cytochrome P450 proteins were differentially altered in severe chronic liver diseases, we examined 50 livers removed at liver transplantation from patients with end-stage cirrhosis, including 18 with and 32 without cholestasis, and compared the results with 21 histologically normal livers. NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total cytochrome P450 content was significantly reduced. The catalytic activities of four xenobiotic-metabolizing P450s and the level of the corresponding proteins were differentially altered. Thus, P450 3A-supported testosterone 6β-hydroxylase activity and 3A protein appeared to be reduced, but only in the subgroup without cholestasis was this change significant. In contrast, 2E1 and the related N,N-dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C protein was reduced only in patients with severe chronic cholestasis. Finally, P450 1A2 and 1A2-supported ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced liver disease. In summary, these data demonstrate that cytochrome P450 proteins are selectively altered in severe chronic liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of cholestasis in patients with cirrhosis severe enough to require transplantation. (Hepatology 1995;21:120-128).
Pediatric liver transplantation for langerhans' cell histiocytosis
Authors: Zandi Parissa , Panis Yves , Debray Dominique , Bernard Olivier , Houssin Didier
Published: March 2007

Langerhans' cell histiocytosis (LCH) represents 15% to 20% of sclerosing cholangitis (SC) in children. In LCH-associated SC, a very poor response to chemotherapy has been reported, and spontaneous prognosis is very bad. Few cases of orthotopic liver transplantation (OLT) for LCH have been reported and little is known about the risk of recurrence and the effect of immunosuppression after OLT. Since 1986, five children (mean age ± SD, 12.6 ± 3.6 years) underwent OLT for SC complicating LCH. All patients presented with growth retardation, and severe liver disease including repeated episodes of variceal bleeding (n = 5), liver insufficiency (n = 4), jaundice (n = 5), and ascitis (n = 4). Four patients presented with previous abdominal surgery (mesocaval shunt in two and explorative laparotomy in two). OLT was performed using a whole (n = 2) or a reduced liver graft (n = 3). Pathological examination of the recipient liver showed biliary cirrhosis in all cases. Three patients are alive and well 9 to 88 months after OLT. None presented with recurrence of LCH or SC within the liver graft or in other organs. General condition (including growth and puberty) improved dramatically in the three surviving patients. Absence of recurrence after up to 7 years of follow-up after liver transplantation in our patients, as well as in all other reported cases, is encouraging and shows that OLT may be indicated in end-stage liver disease complicating LCH. Furthermore, cyclosporine may be beneficial for preventing recurrence of LCH, in which autoimmunologic mechanisms have been advocated. (Hepatology 1995;21:129-133).
Octreotide blunts postprandial splanchnic hyperemia in cirrhotic patients: A double-blind randomized echo-doppler study
Authors: Buonamico Paolo , Sabbá Carlo , Garcia-Tsao Guadalupe , Berardi Elsa , Antonica Gianfranco , Ferraioli Giovanna , Jensen Jonathan E. , Lerner Emanuel , Taylor Kenneth J. W. , Albano Ottavio , Groszmann Roberto J.
Published: March 2007

The effect of octreotide, a long-acting synthetic analog of somatostatin, on fasting and postprandial splanchnic hemodynamics was investigated in cirrhotic patients. Splanchnic hemodynamics were assessed using an echo-Doppler duplex system in a prospective, double-blind, placebo-controlled, crossover study performed on 2 separate days, 1 week apart, in 30 cirrhotic patients. Measurements of portal vein (PV) cross-sectional area (PV-A) and mean velocity (PV-V), and of superior mesenteric artery (SMA) mean velocity (SMA-V) and pulsatility index (SMA-PI) (an index of vascular resistance) were performed at baseline, 30 minutes after octreotide (200 μg subcutaneously) or placebo administration, and 30 and 60 minutes after the ingestion of a liquid meal. In the fasted state, octreotide induced a significant decrease in PV-V (-7%) and in SMA-V (-10%) and an increase in PI (+16%). On the day of placebo administration, meal ingestion induced a significant increase in PV-V (+21%). and in SMA-V (+43%) and a decrease in PI (-21%). In contrast, meal ingestion on octreotide day induced significantly smaller increases in PV-V (+10%) and in SMA-V (+18%) and a significantly smaller decrease in PI (-10%). Octreotide, although producing a mild reduction in PV-V and SMA-V in the fasted state, markedly blunts postprandial splanchnic hyperemia in cirrhotic patients. (Hepatology 1995;21:134-139).
Employment after liver transplantation
Authors: Adams Paul C. , Ghent Cameron N. , Grant David R. , Wall William J.
Published: March 2007

The objective of this study was to study the factors affecting employment after liver transplantation. The employment status and health status of 203 adult liver transplant recipients was assessed retrospectively in a survey comprising an employment questionnaire, the Sickness Impact Profile (SID), and the Medical Outcomes Survey (MOS). The patient population consisted of all surviving adult patients who had undergone liver transplantation between 1982 and 1992 at our institution and who had survived a minimum of 9 months. Fiftyseven percent of the recipients were employed and 43% of the recipients were unemployed. Eighteen percent of the recipients considered themselves not well enough to work. Other reasons cited for not working in the unemployed patients were early retirement (8%), return to school (3%), family reasons (3%), no work available (3%), and chose not to work (3%). Patient age, duration of disability before transplantion, and type of job before transplantation significantly affected posttransplantation employment status. Health status measurements predicting employment were ambulation, home management, physical functioning, and pain. Older recipients and those who were continuosly out of the workforce for several years before transplantation were the least likely to return to gainful employment after liver transplantation. These findings have implications for assessing the success of liver transplantation and the implementation of strategies to fully rehabilitate patients after liver grafting. (Hepatology 1995;21:140-144).
Hepatic collagen synthesis and degradation during liver regeneration after partial hepatectomy
Authors: Yamamoto Hiroko , Murawaki Yoshikazu , Kawasaki Hironaka
Published: March 2007

To elucidate hepatic collagen metabolism during liver regeneration after partial hepatectomy, we measured collagen content, collagen synthesis, and collagen-degrading enzyme activity in the remnant livers of rats 3, 5, 7, and 14 days after a partial hepatectomy of 68%. Hepatic collagen synthesis was significantly higher 3, 5, and 7 days after partial hepatectomy than it was in sham-operated control rats, but there was no such difference 14 days after surgery, the maximal hepatic collagen synthesis being observed 5 days after surgery. Although the collagen concentration in the remnant liver was similar to that in the control liver, the total collagen content of the remnant liver increased rapidly with liver increased rapidly with liver regeneration until 7 days after partial hepatectomy. Hepatic collagenase activity was similar to the control; however, hepatic cathepsin B and cathepsin L activity and the intracellular degradation of newly synthesized collagen were markedly decreased 3, 5, and 7 days after partial hepatectomy compared with the controls. Hepatic collagen synthesis was significantly and inversely correlated with cathepsin L activity and with the intracellular degradation of newly synthesized collagen. These findings suggest that a combination of increased collagen synthesis and decreased intracellular collagen degradation contributes to the rapid supply of collagen that is observed during the early phase of liver regeneration. (Hepatology 1995;21:155-161).
Hemodynamic characteristics of the intrahepatic portal vascular bed over an extended flow range: A study in the isolated perfused rat liver
Authors: Grossman Howard J. , Grossman Virginia L. , Bhathal Prithi S.
Published: March 2007

The relationship between the perfusion pressure (P) and resistance (R) of the intrahepatic portal vascular bed was determined in isolated rat liver preparations perfused with fresh, heparinized rat blood (hematocrit 30%), with rat blood containing a vasodilator agent (sodium nitroprusside, 1 × 10-3 mol/L), or with 2.5% bovine serum albumin in Krebs-Henseleit buffer (BSA-KH). Pressure-flow curves were constructed over an extended range of portal venous inflow (0 to 70 mL·min-1, corresponding to a flow rate per gram liver wet weight, Q, of approximately 0 to 7 mL·min-1·g-1). Subsequent analysis showed that two mathematical expressions adequately described the data over the full range of flow. Thus, the pressure-flow curve could be represented by (a) the sum of a linear plus a hyperbolic function, i.e., P = Q·R′ + Pmax·Q/Q + Km), where R′, Pmax, and Km are constants, or (b) by the simple equation G = C·P, where G is the conductance (Q/P), and C is a conductivity constant. The values of R′, Pmax, Km, and C were significantly different under each of the circumstances investigated, but the form of the curve was not altered. Hence, it is proposed that these parameters can be used to describe the fundamental hemodynamic properties of the portal vascular bed of the isolated rat liver. The results are discussed in terms of the microvascular recruitment and distensible resistance vessel models of the hepatic microcirculation. (Hepatology 1995;21:162-168).