Immunohistochemical detection of proliferating cell nuclear antigen in hepatocellular carcinoma

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Localization of HCV RNA and capsid protein in human hepatocellular carcinoma

INTRODUCTION The relation of HCV to hepatocytic carcinoma (HCC) has been emphasized recently in low HBV infection countries and regions. The distribution patterns of HCV in liver tissues are not well understood although studies on HCV infection in blood and hepatocytes have been conducted by PCR. In this study, 42 liver cancers and surrounding liver tissues were detected for HCV RNA and HCAg using photosensitive biotin-labeled HCV Cdna probe and Immuno-gold-silver stain (IGSS) method.     

丙型肝炎病毒感染与脂肪性肝病

HCV除引起肝脏损害外,还与肝细胞癌(HCC)以及某些肝外组织的损害表现密切相关.大量研究报道,HCV慢性感染与2型糖尿病、脂肪肝等代谢性疾病的发生,发展密切相关[1].     

HCV genotypes in patients with liver disease of different stages and severity

Aims/Material: Hepatitis C virus (HCV) genotyping was performed in 213 anti-HCV-positive patients with chronic liver disease ranging from minimal histological changes to hepatocellular carcinoma. One hundred and twenty-two patients had non-cirrhotic chronic active or persistent hepatitis (including 29 who were asymptomatic with persistently normal ALT levels) (chronic liver disease group). The other 91 had hepatocellular carcinoma and, in all but three cases, cirrhosis (hepatocellular carcinoma group).Results: The overall prevalence of HCV variants was: 54.9% type 1b, 37.8% type 2, 2.5% type 1a, 2.0% type 3a, 2.0% type 4a. The genotype distribution showed no relation to the stage (chronic liver disease vs. hepatocellular carcinoma) or severity (chronic active vs. chronic persistent hepatitis) of the liver disease, or to the duration of the disease (<10 years vs. >10 years). Within the hepatocellular carcinoma group, the duration of type-1b disease was similar to that of type-2 infections. Ages at the time of infection and genotype were both independently associated with progression to cirrhosis and hepatocellular carcinoma, but multivariate analysis revealed that the effect of age was much stronger than that of genotype 1b.Conclusions: The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our findings indicate that infections caused by each HCV genotype are capable of progressing to hepatocellular carcinoma.     

肝硬变肝癌的细菌感染

目的进行肝硬变肝癌患者细菌感染的流行病学研究。方法回顾性地研究了719例肝硬变肝癌患者各种细菌感染的发生率。结果全组细菌感染发生率为15.4%,当肝硬变程度按 Child-Pugh 分级时,A 级感染率为2.3%,B 级为8.0%,C 级为26.4%,随着肝硬变程度的加剧,细菌感染率越高,严重的细菌感染发生在 B 级和 C 级肝硬变肝癌患者。结论肝癌患者对细菌的易感性主要与肝硬变有关,而与肝癌本身无关。     

Hepatitis C virus infection in chronic liver disease and hepatocellular carcinoma in Saudi Arabia

The prevalence of antibody to hepatitis C virus (HCV) was determined in 139 patients with chronic liver disease (CLD) and 42 patients with hepatocellular carcinoma (HCC) during one year at the Riyadh Military Hospital, Saudi Arabia. The anti-HCV was detected in 36 of 96 (37.5%) HBsAg-negative patients with chronic liver disease and six of 43 (13.9%) HBsAg-positive patients with chronic liver disease. In addition, 11 (42.3%) HBsAg-negative hepatocellular carcinoma patients and two of 16 (12.5%) HBsAg-positive hepatocellular patients had antibody to HCV. The anti-HCV prevalence was 1.5% in 4818 healthy blood donors and 1% in 385 antenatal patients. The overall HCV seropositivity of 30.4% in 181 liver disease patients (CLD and HCC) in Saudi Arabia is lower than that reported from European countries.     

肝硬变和原发性肝癌患者HCV与HBV标志物分析

目的探讨肝硬变（ＬＣ），原发性肝癌（ＨＣＣ）发生和发展与ＨＣＶ及ＨＢＶ感染的关系．方法ＨＣＣ２８例，ＬＣ４８例和对照组５０例，用ＥＬＩＳＡ法同步检测ＨＢＶ及ＨＣＶ的６项血清标志物（Ｍ）．结果ＨＣＣ，ＬＣ及对照组ＨＢＶ＿Ｍ的阳性率分别为７５０％，８１３％和４００％；ＨＣＶ＿Ｍ的阳性率分别为７１％，２０８％和２０％．ＨＣＣ，ＬＣ中ＨＢＶ＿Ｍ阴性患者ＨＣＶ＿Ｍ阳性率为１２５％．ＨＣＶ与ＨＢＶ重叠感染者占ＨＣＣ和ＬＣ全部患者的１３２％．结论ＨＣＣ，ＬＣ发生和发展与ＨＢＶ及ＨＣＶ病毒感染密切相关，重叠感染者肝功能损害及临床失代偿程度更严重．     

Long interval between HCV infection and development of hepatocellular carcinoma

Abstract: A high prevalence of HCV infection has been reported in patients with hepatocellular carcinoma. The progression from acute transfusion-associated hepatitis to hepatic cirrhosis and hepatocellular carcinoma has been suggested in several studies to be very long. We have investigated the prevalence of anti-HCV and the interval between HCV infection and hepatocellular carcinoma among 191 consecutive patients with cirrhosis and liver-cell carcinoma. Serum samples from 191 patients with cirrhosis and hepatocellular carcinoma, consecutively diagnosed in our hospital between 1988 and 1993, were tested for serological markers of HBV and HCV infection. One hundred and forty-eight patients (77.5%; 95% confidence interval (c.i): 76% to 80%) were anti-HCV positive by 2nd generation enzyme immunoassay (confirmed by 2nd generation recombinant immunoblot assay) and 152 patients (79.5%; 95% c.i: 76% to 80%) were anti-HCV positive by 3rd generation enzyme immunoassay, while only 14 (7.4%; 95% c.i: 5% to 10%) were HBsAg positive. Of the 29 anti-HCV positive patients with previous transfusion, the interval between the date of blood transfusion and the diagnosis of hepatic cirrhosis was 24±12.5 years and that of hepatocellular carcinoma was 26.8±12.4 years. These results confirm the high prevalence of HCV infection in patients with hepatocellular carcinoma and the slow sequential progression from HCV infection through cirrhosis and hepatocellular carcinoma.     

肝癌、肝硬化患者淋巴细胞染色体着丝粒点结构的变化

目的 探讨染色体着丝粒点结构（Ｃｄ）的变化在肝癌发生过程的意义。方法 采用染色体Ｃｄ带技术检测２８例肝癌、２５例肝硬化及２６例正常人染色体Ｃｄ结构丢 失频率。结果 肝癌组Ｃｄ结构在总消失率、Ａ和Ｃ组染色体中明显高于肝硬化和正常对组（Ｐ〈０．０１）,在Ｄ、Ｅ组染色体中亦高于正常组（Ｐ〈０．０５）。结论 肝癌患者外周血细胞染色体Ｃｄ结构丢失在增高趋势,提示Ｃｄ结构消失率增加是引起肝癌细胞染色体非整倍性     

丙型肝炎病毒核心抗原转位表达抑制肝(癌)细胞

目的探讨丙型肝炎病毒核心抗原的转位表达与肝（癌）细胞凋亡的关系及其意义．方法采用免疫组织化学方法检测ＨＣＶ核心区抗原Ｃ２２在肝硬变（ＬＣ）、肝细胞肝癌（ＨＣＣ）组织中的分布;同时对连续切片进行原位凋亡检测并计算凋亡指数．结果ＨＣＶ核心区抗原定位于肝细胞或肝癌细胞的胞质或胞核中,在ＬＣ组织中,Ｃ２２呈弥漫或灶状分布于肝细胞胞质,偶见胞核阳性的肝细胞,阳性率为６０７％;Ｃ２２抗原在ＨＣＣ细胞中以核阳性分布为主,阳性率为３７６％,癌旁肝组织以胞质阳性为多见．ＨＣＣ中ＨＣＶ核心抗原的核阳性率（７５０％,１５例／２０例）和阳性细胞数明显高于其在ＬＣ（１７７％,６例／３４例）及癌旁肝组织（１１８％,２例／１７例）中的阳性率（Ｐ＜００５）和阳性细胞数．在ＨＣＣ中,ＨＣＶ核心抗原核转位表达的癌组织的ＡＰＯＰＬＩ凋亡指数值（０１７４±００９３）显著低于胞质阳性的癌组织（０５１２±０１１３,Ｐ＜００１）．结论ＨＣＶ感染与我国ＬＣ,ＨＣＣ的发生关系密切,ＨＣＶ核心抗原在肝癌组织中常发生核转位表达,这种核转位表达使肿瘤细胞凋亡受到抑制,从而促进肿瘤组织的恶性生长．     

High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis

Abstract

Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (<80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years always ≥80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always <80 IU; n=48; Group B) (p<0.005) during an observation period of 7.9±3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.     

SEN virus infection in patients with chronic liver disease and hepatocellular carcinoma in Thailand

Background: SEN virus (SENV) has been recently identified as a candidate agent of non-A-E hepatitis virus. However, the exact role of this novel virus in the pathogenesis of chronic liver disease, including chronic hepatitis and cirrhosis, and the development of hepatocellular carcinoma (HCC) remains to be established. Methods: Using seminested polymerase chain reaction (PCR) amplification to detect SENV-D and SENV-H strains in serum, we investigated SENV infection in voluntary blood donors and in patients with chronic liver disease and HCC. Results: SENV was detected in 5 of 100 blood donors (5%), in 15 of 60 patients with chronic liver disease (25%), and in 25 of 60 patients with HCC (42%). The prevalence of SENV in patients with HCC was higher than that in patients with chronic liver disease (P = 0.05) and in blood donors (P < 0.001). An age-specific prevalence of SENV was found at high levels among individuals aged 21–40 years, but was not detected among individuals in the lower age group. No differences between SENV-infected and non-infected patients were demonstrated with respect to demographic data, assumed source of infection, biochemical abnormalities, and severity of chronic liver disease and HCC. Moreover, SENV infection had no apparent effect on the survival of patients with HCC. Conclusions: Our data suggest that SENV infection is frequent among patients with chronic liver disease and HCC. However, pathogenic effects associated with SENV infection in chronic liver disease and HCC need further investigation. Received: April 4, 2002 / Accepted: July 26, 2002 Acknowledgments. We would like to express our gratitude to the entire staff of the Viral Hepatitis Research Unit, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, for their tireless effort in this research project. We also would like to thank the Center of Excellence Fund, Rachadaphisek Somphot Endowment, Chulalongkorn University, and the Thailand Research Fund, Senior Research Scholar, for supporting this research. Reprint requests to: Y. Poovorawan     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.     

Plasma and urine levels of urinary trypsin inhibitor in patients with chronic liver diseases and hepatocellular carcinoma

BACKGROUND AND AIM: Because urinary trypsin inhibitor (UTI) is synthesized by hepatocytes and excreted into the urine, plasma and urine levels of UTI may alter in liver diseases. However, there are few reports on the changes in these levels in chronic liver diseases and hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationships between plasma and urine UTI levels and the severity of liver damage or progression of HCC in patients with chronic liver diseases and HCC. METHODS: Plasma and urine UTI levels were measured by a newly developed enzyme-linked immunosorbent assay in 16 patients with chronic hepatitis (CH), 19 patients with liver cirrhosis (LC) and 39 patients with HCC. RESULTS: Plasma UTI level exhibited a significant positive correlation with the urine UTI level. Plasma and urine UTI levels significantly decreased in LC patients compared with those of normal controls. In contrast, the plasma UTI level in HCC patients was higher than that in LC patients, but there was no difference between the groups in the urine UTI level. Plasma and urine UTI levels in LC and HCC patients were significantly correlated with the degree of liver damage according to the Child-Pugh classification. Although neither the plasma nor urine level of UTI in HCC patients were related to the clinical stage of HCC, both levels were closely associated with the level of protein induced by vitamin K absence or antagonist-II. CONCLUSIONS: The present findings indicate that the levels of plasma and urine UTI in patients with LC reflect the severity of liver damage. In HCC patients, these levels may also reflect progression of HCC, although further study is required.     

原发性肝细胞癌组织中Cyclin D1的表达及意义

目的探讨Cyclin D1在原发性肝细胞癌（HCC）组织中的表达及其在HCC发病中的作用。方法采用免疫组化法检测50例HCC、20例正常肝组织中的Cyclin D1。结果HCC中Cyclin D1阳性表达率为44.0％（22／50）,正常肝组织组均为阴性表达,两者相比P〈0.001;Cyclin D1的阳性表达率与HCC的肝内转移和肝癌的分化程度有关（P均〈0.05）,与患者术后3a生存期相关（P〈0.05）。结论Cyclin D1在HCC的发生发展过程发挥作用,检测Cyclin D1有助于HCC的预后判断。     

Hierarchical and selective roles of galectins in hepatocarcinogenesis,liver fibrosis and inflammation of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)represents a global health problem.Infections with hepatitis B or C virus,non-alcoholic steatohepatitis disease,alcohol abuse,or dietary exposure to aflatoxin are the major risk factors to the development of this tumor.Regardless of the carcinogenic insult,HCC usually develops in a context of cirrhosis due to chronic inflammation and advanced fibrosis.Galectins are a family of evolutionarily-conserved proteins defined by at least one carbohydrate recognition domain with affinity forβ-galactosides and conserved sequence motifs.Here,we summarize the current literature implicating galectins in the pathogenesis of HCC.Expression of"proto-type"galectin-1,"chimera-type"galectin-3 and"tandem repeat-type"galectin-4 is up-regulated in HCC cells compared to their normal counterparts.On the other hand,the"tandemrepeat-type"lectins galectin-8 and galectin-9 are downregulated in tumor hepatocytes.The abnormal expression of these galectins correlates with tumor growth,HCC cell migration and invasion,tumor aggressiveness,metastasis,postoperative recurrence and poor prognosis.Moreover,these galectins have important roles in other pathological conditions of the liver,where chronic inflammation and/or fibrosis take place.Galectin-based therapies have been proposed to attenuate liver pathologies.Further functional studies are required to delineate the precise molecular mechanisms through which galectins contribute to HCC.     

非酒精性脂肪性肝病与肝细胞癌关系的研究进展

非酒精性脂肪性肝病(NAFLD)作为一种与机体代谢紊乱相关的疾病,其发病率呈逐年上升趋势,随之引起肝脏代谢功能失调及相关病程进展,最终发展为脂肪性肝炎、隐源性肝硬化,甚至有可能发展为肝细胞癌(HCC).本文就NAFLD相关HCC的发病机制、危险因素、诊断等作一综述.