AIMS/BACKGROUND: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-alpha (TNF-alpha) w...AIMS/BACKGROUND: To determine the relationship between host factors and host response to interferon (IFN) therapy, serum soluble Fas (sFas), soluble Fas ligand (sFas ligand), and tumor necrosis factor-alpha (TNF-alpha) were analyzed in 41 patients with chronic hepatitis C (CH-C) treated with IFN-alpha. METHODS: Serum levels of sFas, sFas ligand, and TNF-alpha were measured at 0, 4, and 24 weeks of IFN therapy. RESULTS: Eighteen patients were complete responders (CR) and 23 patients were non-responders (NR). Serum levels of sFas and TNF-alpha in patients with CHC were significantly higher than those in healthy controls (p<0.01 and p<0.01, respectively). Serum sFas ligand levels were significantly lower in CH-C patients than in healthy controls (p<0.01). Before IFN therapy, serum levels of sFas in NR were significantly higher than those in CR (p<0.05). At 4 weeks of IFN therapy, serum levels of sFas of CR were significantly elevated compared with levels before IFN therapy (p<0.05). Serum levels of sFas correlated with the histological activity of the liver (p<0.05) and alanine aminotransferase (p<0.05). None of the three parameters, serum sFas, sFas ligand, or TNF-alpha levels, correlated with each other, with HCV-RNA genotype or with serum HCV-RNA load. Multiple logistic regression analysis showed that serum sFas levels before IFN therapy were a contributive factor to predict efficacy of IFN therapy. CONCLUSIONS: Serum sFas/sFas ligand and TNF-alpha play a possible role in pathogenesis of CH-C and also in IFN therapy. Serum sFas levels before IFN therapy may be one of the host-related factors used for evaluating the response of CH-C patients to IFN therapy.
BACKGROUND: Connective tissue growth factor (CTGF) belongs to a family of factors that regulate fibrogenesis and wound healing. While the significance of transforming growth factor beta (TGF-beta) in liver fibrosis is we...BACKGROUND: Connective tissue growth factor (CTGF) belongs to a family of factors that regulate fibrogenesis and wound healing. While the significance of transforming growth factor beta (TGF-beta) in liver fibrosis is well established, the role of CTGF in fibrosing hepatopathy is still unknown. METHODS: CTGF was analyzed in 10 normal and in 16 cirrhotic liver tissue samples. Northern blot analysis was used to examine the concomitant expression of CTGF and TGF-beta1 mRNAs, and the cellular localization of CTGF mRNA was studied by in situ hybridization. For identification of myofibroblasts and activated hepatic stellate cells, alpha-smooth muscle actin (alpha-SMA) immunohistochemistry was used. RESULTS: Northern blot analysis showed 6.5-fold enhanced expression of CTGF mRNA and 7.8-fold enhanced expression of TGF-beta1 mRNA in liver cirrhosis in comparison with normal controls (p<0.01). By in situ hybridization, CTGF mRNA was detectable in only a few spindle cells in the portal tracts in normal liver samples. In contrast, there was strong expression of CTGF mRNA in fibroblasts and myofibroblast-like cells present in fibrous septa surrounding the cirrhotic nodules, in stellate cells, in endothelial cells and in mesenchymal cells around ductular proliferations, and in ductular epithelial cells. There was a strong correlation between CTGF mRNA and TGF-beta1 mRNA as well as the degree of fibrosis (p<0.01). CONCLUSIONS: Overexpression of CTGF in liver cirrhosis, especially in fibroblasts/myofibroblasts and stellate cells, suggests that this novel factor may play an important role in hepatic fibrosis.
Yabuuchi I, Imai Y, Kawata S
… +12 more, Tamura S, Noda S, Inada M, Maeda Y, Shirai Y, Fukuzaki T, Kaji I, Ishikawa H, Matsuda Y, Nishikawa M, Seki K, Matsuzawa Y
AIMS/BACKGROUND: The aim of this study was to determine the characteristics of patients with chronic hepatitis C showing long-term normalization of alanine aminotransferase (ALT) without eradication of HCV RNA, as well a...AIMS/BACKGROUND: The aim of this study was to determine the characteristics of patients with chronic hepatitis C showing long-term normalization of alanine aminotransferase (ALT) without eradication of HCV RNA, as well as to investigate the incidence of hepatocellular carcinoma (HCC) in such patients. METHODS: Four hundred and nineteen patients with histologically-proven chronic hepatitis C who had received interferon (IFN) therapy were studied. Complete response (CR) was defined as persistent normalization of ALT levels with eradication of serum HCV RNA (n= 126). Long-term biochemical response with positive HCV RNA (HCV-positive BR) was defined as a normal ALT level at 6 months after IFN therapy with further persistent normalization of ALT levels for 2 or more years without eradication of serum HCV RNA (n=49). All other patterns were classified as non-response (NR, n=244). RESULTS: Mean follow-up periods of CR, HCV-positive BR and NR groups were 4.9, 5.2 and 4.9 years, respectively. The HCV-positive BR group had significantly higher serum HCV RNA levels and a higher rate of HCV serological group 1 classification than the CR group. The other characteristics of the HCV-positive BR group were lower histologic activity, lower ALT levels, and a higher rate of females when compared with both the CR and NR groups. Histologic staging in the HCV-positive BR group was significantly lower than that in the NR group. Cumulative incidences of HCC estimated by the Kaplan-Meier method in both the CR and HCV-positive BR groups were significantly lower than those in the NR group (log-rank test, CR vs NR p<0.001, HCV-positive BR vs NR p=0.026). CONCLUSION: The patients with HCV-positive BR were virologically different from those with CR, and had lower ALT levels and histologic activity when compared to those with CR and NR.
BACKGROUND/AIMS: Infection with Schistosoma mansoni is endemic in Egypt leading to hepatic schistosomiasis and eventually portal hypertension. The prevalence of antibodies against hepatitis virus C among Egyptians is 14-...BACKGROUND/AIMS: Infection with Schistosoma mansoni is endemic in Egypt leading to hepatic schistosomiasis and eventually portal hypertension. The prevalence of antibodies against hepatitis virus C among Egyptians is 14-51%. The aim of the present study was to investigate the influence of schistosomiasis on chronic hepatitis C with respect to the natural course of the disease, immunology, virology and histology. PATIENTS AND METHODS: One hundred and twenty-six Egyptian patients classified into three groups: group A: chronic hepatitis C (n=33); group B: chronic schistosomiasis (n=30) and group C: chronic hepatitis C and chronic schistosomiasis (n=63) were enrolled and prospectively followed for 62.7 +/- 22 months. Patients infected with other hepatic viruses and/or parasites were excluded. Detailed history, clinical examination, CD4+ and CD8+ lymphocyte counts in blood, hematological and blood chemical values, abdominal ultrasonography, upper endoscopy, HCV RNA titer by RT/PCR, genotype and histological activity index in the liver biopsy were determined. RESULTS: Thirty patients (48%) with HCV and schistosomiasis had liver cirrhosis and Child-Pugh class C vs. five (15%) in HCV patients and none in the schistosomal group. HCV RNA levels ranged between 0.07 and 13 x 10(5) copies/ml in group A, and between 1 and 25 x 10(5) copies/ml in group C. HCV genotype 4 was detected in 58 patients with co-infection (92%) and 21 patients with HCV alone (64%). Patients with coinfection showed higher grading and staging scores in their liver biopsies. Hepatocellular carcinoma was detected only in patients with coinfection. During follow-up, the mortality rate was 12%, 3% and 48% in group A, B and C, respectively. CONCLUSIONS: Patients with concomitant HCV and schistosomiasis infection were characterized by more advanced liver disease, higher HCV RNA titers, predominance of HCV genotype 4, higher histologic activity, higher incidence of cirrhosis and hepatocellular carcinoma as well as a much higher mortality rate.
Shiratori Y, Moriyama M, Imazeki F
… +12 more, Ohkubo H, Tanaka N, Arakawa Y, Yoshida H, Yokosuka O, Shibuya A, Matsuzaki K, Hashimoto E, Hayashi N, Hirata K, Ohashi Y, Omata M
BACKGROUND/AIMS: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interfe...BACKGROUND/AIMS: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. METHODS: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with "low" viral load (< or = 10(5.8) copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with "high" viral load (< or = 10(6.3) copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1,404 MU). RESULTS: HCV-RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with "low" viral load, in contrast to 14% in patients with "high" viral load. Sustained virological response was found in 40% of patients with "low" viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with "high" viral load. Viral eradication was found in approximately 50% of patients having a low virus load (< or = 10(4.3) copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. CONCLUSIONS: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12-month course of intensive IFN therapy. This result indicates that there is a certain cut-off level of HCV RNA load which can not be eradicated.
BACKGROUND/AIMS: The presence or absence of hepatitis C virus (HCV) RNA in the semen of infected man remains controversial, mainly due to technical difficulties associated with nucleic acid detection. The aims of this st...BACKGROUND/AIMS: The presence or absence of hepatitis C virus (HCV) RNA in the semen of infected man remains controversial, mainly due to technical difficulties associated with nucleic acid detection. The aims of this study were to assess the presence of HCV RNA in spermatozoa and in seminal fluid using different polymerase chain reaction (PCR)- and non-PCR-dependent methods and, in the case of HCV presence, to correlate this detection with the viraemia. METHODS: Serum and semen from 25 chronically infected hepatitis C patients were studied. The semen was separated into spermatozoa and seminal fluid and HCV RNA was analysed in the two fractions using RT-PCR and branched DNA. The presence of HCV RNA in pelleted cells was also assessed using in situ hybridization. RESULTS: All three approaches failed to demonstrate HCV RNA in semen. The presence of an inhibitor of the PCR was demonstrated in seminal fluid but not in spermatoza. CONCLUSION: Our results confirmed the lack of detection of HCV RNA in semen by PCR- and non-PCR-dependent techniques and support the view that viral contamination in semen remains, if present, at a very low level. Nevertheless, epidemiological studies are required to definitively assess the absence of sexual transmission of HCV
BACKGROUND: It has been suggested that gastric varices bleed at lower portosystemic pressure gradients (PSPG) than oesophageal varices and that transjugular intrahepatic portosystemic shunt (TIPS) is a particularly effec...BACKGROUND: It has been suggested that gastric varices bleed at lower portosystemic pressure gradients (PSPG) than oesophageal varices and that transjugular intrahepatic portosystemic shunt (TIPS) is a particularly effective treatment in these patients. AIMS: This study was undertaken to assess the difference in PSPG measured at the time of TIPS insertion between patients bleeding from gastric and those bleeding from oesophageal varices. Rebleeding and mortality rates between the two groups were also compared. PATIENTS AND METHODS: In a five year period, 64 patients (36 males and 28 females) undergoing TIPS for acute variceal bleeding had PSPG measured at the time of TIPS insertion. 12 patients underwent TIPS for gastric variceal haemorrhage (GVH) and 52 for oesophageal variceal haemorrhage (OVH). The median age was 53 years and 40/64 patients (63%) had alcoholic liver disease. The median Child's Pugh score was 8 for GVH and 9 for OVH patients. Median follow up was 75 weeks. RESULTS: There was no significant difference in median PSPG between patients with GVH, 21 mmHg (range 15-30 mmHg) and OVH, 22 mmHg (range 12-45 mmHg). Following TIPS, PSPG was 8.5 mmHg (range 3-11 mmHg) and 9 mmHg (range 4-20 mmHg) in GVH and OVH patients respectively. Rebleeding occurred in 2/12 (16%) GVH patients and 12/52 (23%) OVH patients (p= 1.0). Mortality during follow up was 25% (4/12) in the GVH and 25% (13/52) in the OVH patients. CONCLUSION: In this study, there was no difference between the pressures at which gastric and oesophageal varices bled. Rebleeding and mortality rates were similar in the two groups. TIPS is equally effective in the treatment of both oesophageal and gastric variceal haemorrhage.
AIM: The aim of this study was to clarify the relationship between TT virus (TTV) infection and the development of hepatocellular carcinoma. METHODS: TTV from serum was examined in 224 patients with hepatocellular carcin...AIM: The aim of this study was to clarify the relationship between TT virus (TTV) infection and the development of hepatocellular carcinoma. METHODS: TTV from serum was examined in 224 patients with hepatocellular carcinoma (HCC) and 106 patients with chronic liver disease (CLD) but without HCC who were admitted to our hospital between 1995-1997. As controls, 48 patients without liver disease were also examined. TTV DNA was detected using nested PCR method after extraction of DNA from serum. RESULTS: TTV DNA was detected in 29/224 (13%) of patients with HCC; in 14% (4/28) of HCC patients negative for both hepatitis B virus surface antigen (HBsAg) and anti-hepatitis C virus antibody (anti-HCV), in 9% (2/22) of HCC patients positive for HBsAg, and in 12% (21/170) of HCC patients positive for anti-HCV. The prevalence of TTV DNA in HCC patients (13%) was not significantly higher than in CLD patients (22%). There were no significant differences in age, gender, liver function, tumor biology (size, TNM classification), other viral markers, or amount of alcohol intake between TTV-positive and -negative HCC patients. Only a history of blood transfusion was significantly more frequent in TTV-positive HCC patients than in TTV-negative cases (p= 0.02). Coinfection with TTV did not correlate with the severity of HCV-positive liver disease. There was no significant difference in prognosis between TTV-positive and -negative HCC patients. CONCLUSIONS: TTV does not seem to contribute to the development of HCC from chronic liver disease and is not correlated with severity of liver disease.
AIMS/BACKGROUND: alpha1-antitrypsin (alpha1-AT) is a hepatic acute phase protein which predominantly inhibits neutrophil elastase. Besides this major function, we have also previously shown that alpha1-AT markedly increa...AIMS/BACKGROUND: alpha1-antitrypsin (alpha1-AT) is a hepatic acute phase protein which predominantly inhibits neutrophil elastase. Besides this major function, we have also previously shown that alpha1-AT markedly increased H-ferritin mRNA expression and ferritin synthesis in the human hepatoma cell line HepG 2. These actions suggest that alpha1-AT might interact with HepG 2 cells via a specific cell surface binding site. METHODS AND RESULTS: Using radio-labelled native alpha1-AT, we observed saturable binding to HepG 2 cells with a dissociation constant (Kd) of 63.3+/-6.9 nM and a maximal density of binding sites (Bmax) of 0.34+/-0.05 pmol/10(6) cells equivalent to 195,800+/-29,200 sites/cell. The binding of [125I]alpha1-AT was time dependent with a calculated association rate constant of 9.22+/-1.84x10(4)xM(-1)xmin(-1). Binding was highly specific since other acute phase proteins or protease inhibitors failed to block binding. Although alpha1-AT-trypsin, alpha1-AT-elastase and the pentapeptide FVYLI, the minimal binding sequence for the SEC receptor, increased [125I]alpha1-AT binding, in long term experiments these complexes failed to influence the number of alpha1-AT binding sites. Specific, saturable binding of [125I]alpha1-AT was also found on the human intestinal epithelial Caco 2 cells, but not on fibroblast or leukaemic cell lines. CONCLUSION: These experiments demonstrate a specific, high affinity binding site for native alpha1-AT on HepG 2 and Caco 2 cells, cell lines derived from tissues involved in the acute phase response.
AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplot...AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.
AIMS/BACKGROUND: Sex difference has been shown to play a major role in susceptibility to the development of hepatocellular carcinoma in humans and rodents. In order to clarify the necessity of androgens in hepatic tumori...AIMS/BACKGROUND: Sex difference has been shown to play a major role in susceptibility to the development of hepatocellular carcinoma in humans and rodents. In order to clarify the necessity of androgens in hepatic tumorigenesis in transgenic mice overexpressing transforming growth factor (TGF) alpha (MT42), androgen supplement after castration and the LH-RH analogue, leuprolerin acetate, were tested in an experimental model in MT42. METHODS: Male MT42 mice were castrated and supplemented with dihydrotestosterone (DHT) every three months up to 15 months and hepatic tumorigenesis was observed. Leuprolerin acetate was administered to both male and female MT42 mice once a month from 2 months after birth to 15 months to observe the effect on hepatic tumorigenesis. Northern hybridization was performed to detect messenger RNA (mRNA) of TGFalpha expression and the rate of proliferative cell nuclear antigen (PCNA) staining compared with the castrated and non-treated mice. RESULTS: Castration tended to decrease both body and liver weight in MT42 mice which was then restored by DHT. Untreated MT42 males developed 11 liver tumors in 6 mice. Hormonal treatment including castration and DHT supplementation did not change the expression of TGFalpha-mRNA. Castrated transgenic mice developed 2 liver tumors in 2 out of 6 mice and DHT supplementation after castration restored the number of liver tumors to 9 in 5 of 6 mice. PCNA labelling indexes of liver tumors and adjacent non-tumorous-liver were 7.1% (p<0.05): 0.6% in untreated MT42, 3.2%: 0.2% in castrated MT42 and 10.1% (p<0.05): 0.5% in MT42 with castration and DHT supplementation (significant difference compared with castrated mice). Leuprolerin acetate-treated MT42 males developed one liver tumor in 6 mice compared to MT42 administered with saline as a vehicle control in which group 7 liver tumors in 6 male MT42 were observed. Tumors in castrated-MT42 and leuprolerin treated-MT42 were smaller than those in control MT42 mice. CONCLUSION: TGFalpha related hepatocarcinogenesis and hepatocyte proliferation are increased by androgenic stimulation. Suppression of androgens may be useful for the treatment of TGFalpha related liver tumors.
AIMS/BACKGROUND: GB virus-C/hepatitis G virus (HGV) is a newly identified flavivirus, which may share the same mode of transmission as hepatitis C virus (HCV). The aim of this study was to investigate associated factors...AIMS/BACKGROUND: GB virus-C/hepatitis G virus (HGV) is a newly identified flavivirus, which may share the same mode of transmission as hepatitis C virus (HCV). The aim of this study was to investigate associated factors of HGV infection and clearance in a HCV endemic village in southern Taiwan. METHODS: Five hundred and ninety-four residents of a village in southern Taiwan were enrolled for hepatitis virus screening. Clinical features were recorded and a questionnaire addressing the possible routes of transmission was filled in by the participating residents. RESULTS: The prevalence of antibody to hepatitis C virus and hepatitis B surface antigen in the 594 residents was 70.7% and 19.5% respectively. Of the 399 residents tested for HGV RNA, GB virus-C/Hepatitis G virus envelop 2 protein (HGV-E2) antibody, and HCV RNA, the prevalence was 13.5%, 25.3%, 53.1% respectively. Multivariate logistic regression analysis showed that low educational attainment was associated with HGV infection, old age and low educational attainment were associated with HCV infection, and female gender was associated with HGV clearance. Alanine aminotransferase (ALT) values were significantly higher for residents with HCV infection alone, HBV infection alone, and co-infection of HCV and HBV than for those without HBV, HCV, and HGV infection. There were no differences in ALT values between subjects with HGV infection alone and those without HBV, HCV, and HGV infections. Residents with co-infection of HGV and HBV, or HGV and HCV had ALT values similar to those with HBV or HCV infection alone. CONCLUSION: HGV infection is common in the HCV endemic village. The transmission of HGV is closely related to low educational attainment. HGV clearance is frequently encountered in females. Co-infection of HGV does not compound hepatocellular inflammation.
AIMS/BACKGROUND: Midkine (MK) is a novel heparin-binding growth factor whose gene was identified in embryonal carcinoma cells in the early stages of retinoic acid-induced differentiation. This study investigates the over...AIMS/BACKGROUND: Midkine (MK) is a novel heparin-binding growth factor whose gene was identified in embryonal carcinoma cells in the early stages of retinoic acid-induced differentiation. This study investigates the overexpression of MK in intrahepatic cholangiocarcinoma (CC). METHODS: Forty-five primary CC specimens from patients (aged 19-81 years, 24 males and 21 females) were examined. Histologically, 17 cases of CC were classified as the well-differentiated type, 19 as moderately-differentiated and 9 as poorly-differentiated. Immunohistochemical analysis was performed using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK. RESULTS: We successfully applied this monoclonal antibody against MK to analyze archival paraffin sections. The cancer tissues showed a positive reaction to this antibody, and there was an intense reaction in their cytoplasm. Approximately 40% of individuals with CC (17/45) had tumor cells that expressed MK, and these were classified into the following types: moderately-differentiated type (9/19), well-differentiated type (8/17) and poorly-differentiated type (0/ 9). In situ hybridization analysis revealed that signals of MK transcripts were found in the cytoplasm of the cancer cells; the distribution and localization of the MK-transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. CONCLUSIONS: These findings revealed that CC express increased MK at the messenger RNA and protein levels.
BACKGROUND/AIMS: The transcription of mdm2 gene is activated by p53 and this limits the growth-suppressing activity of p53 by direct binding. It has been reported that MDM2 protein is overexpressed in several types of ca...BACKGROUND/AIMS: The transcription of mdm2 gene is activated by p53 and this limits the growth-suppressing activity of p53 by direct binding. It has been reported that MDM2 protein is overexpressed in several types of cancers. However, there have been no immunohistochemical studies on MDM2 in human hepatocellular carcinoma (HCC). METHODS: We immunohistochemically examined the expression of MDM2 and the relationships between its expression and histological grade, clinicopathological parameters, p53 expression and patient survival in 107 patients with HCC. RESULTS: The frequency of MDM2 positivity in the nuclei of HCC cells was 28/107 (26%). There was no correlation between the MDM2 expression and HCC grade. However, positivity of MDM2 expression significantly correlated with small HCC size (p<0.05, chi2 test) and the absence of vascular invasion (p<0.01, chi2 test). No significant differences were noted between MDM2 expression and capsular invasion or satellite nodules. Expression of MDM2 showed a significantly positive correlation with expression of p53 (p<0.03, chi2 test). Patients with positive expression of MDM2 had poorer prognosis than patients with negative MDM2 expression. MDM2 expression was the most useful independent factor for overall survival (p=0.0001). CONCLUSIONS: MDM2 was expressed in 26% of HCC, and its expression correlated positively with p53 mutations. MDM2 over-expression is a useful predictor of poor prognosis in patients with HCC following hepatic resection.
AIMS/BACKGROUND: Rat liver perfused with an oxygenated buffered solution alone results in degenerative changes even when the perfusion flow is accelerated to give a sufficient oxygen supply. On the other hand, perfusion...AIMS/BACKGROUND: Rat liver perfused with an oxygenated buffered solution alone results in degenerative changes even when the perfusion flow is accelerated to give a sufficient oxygen supply. On the other hand, perfusion media supplemented with red blood cells (RBCs) preserve the viability of the liver. The present study was conducted to clarify how RBCs protect the isolated perfused liver. METHODS: The liver was perfused with and without RBCs in a perfusate equilibrated with supra-physiological oxygen tension at regulated inflow pressures, and controlled hepatic oxygen consumption. We examined alanine aminotransferase and purine nucleoside phosphorylase activity in the perfusate as specific markers of liver cells injury. Hydrogen peroxide (H2O2) production and morphological changes were determined using cerium electron microscopy. Apoptosis was detected by measuring CPP 32 protease activity and using TdT-mediated dUTP-digoxigenin nick end-labeling. RESULTS: When the liver was perfused with RBC-free buffer, H2O2 production and consequent injury progressing to apoptosis were initiated in the sinusoidal endothelial cells (SECs). After SECs were injured, H2O2 appeared in the hepatocytes. H2O2 production and associated degenerative changes were attenuated both morphologically and enzymatically by the addition of RBCs, a specific xanthine oxidase (XOD) inhibitor and the H2O2 radical scavenger, catalase. CONCLUSIONS: In the liver perfused with RBC-free buffer, H2O2 production and consequent injury were initiated in SECs. RBCs attenuate liver injury by scavenging XOD-dependent H2O2.
The liver has long been known to respond to exposure to certain chemicals with hyperplasia and proliferation of the peroxisomal compartment. This response is now known to be mediated by specific receptors. The peroxisome...The liver has long been known to respond to exposure to certain chemicals with hyperplasia and proliferation of the peroxisomal compartment. This response is now known to be mediated by specific receptors. The peroxisome proliferator-activated receptors (PPARs) were cloned 10 years ago, and in that interval, have been found to serve as receptors for a number of endogenous lipid compounds, in addition to the peroxisome proliferators that originally led to their study. Three receptors, designated the alpha, delta, and gamma receptors, have been found in mammals. PPARalpha: is the most abundant form found in the liver, with smaller amounts of the delta and gamma forms also expressed there. Kupffer cells, like other macrophages, appear to express the alpha and gamma isoforms. Hepatic stellate cells are reported to express the gamma isoform. PPARalpha knock-out mice fail to undergo peroxisome proliferation when challenged with the proliferators. Moreover, they have severe derangements of lipid metabolism, particularly during fasting, indicating that normal function of the alpha receptors is needed for lipid homeostasis. This in turn suggests that inadequate PPAR-mediated responses may contribute to abnormal fatty acid metabolism in alcoholic and non-alcoholic steatohepatitis. Recent information suggests that PPARgamma receptors may be important in control of the activation state of the stellate cells, and their repression or inactivation may predispose to hepatic fibrosis. The first approved drug that specifically activates PPARgamma, troglitazone, has rarely been found to cause serious liver injury. Although this is likely to represent an idiosyncratic reaction, the medical community will need to be alert to the possibility that activation or blockade of these receptors may cause hepatic dysfunction.