Many studies have suggested that occult HBV infection has a substantial clinical relevance to hepatocellular carcinoma (HCC). Occult HBV infection is an important risk factor for the development of cirrhosis and HCC in patients without HBsAg. As a matter of fact, occult HBV infection is one of the most common causes of crytogenic HCC in endemic areas of HBV. However, there still are controversial issues about the association between occult HBV infection and HCC according to the underlying liver disease. In alcoholic cirrhosis, occult HBV infection may exert synergistic effect on the development of HCC. However, there is insufficient evidence to relate occult HBV infection to hepatocarcinogenesis in non-alcoholic fatty liver disease. In cryptogenic HCC, occult HBV infection may play a direct role in the development of HCC. In order to elucidate the assocciation between occult HBV infection and HCC, underlying liver disease must be specified and larger number of cases must be included in future studies.
Carcinoma, Hepatocellular/*complications/*diagnosis/epidemiology ; DNA, Viral/analysis ; Hepatitis/complications ; Hepatitis B/*complications/*diagnosis/epidemiology ; Hepatitis B virus/genetics ; Humans ; Liver Cirrhosis, Alcoholic/complications ; Liver Neoplasms/*complications/*diagnosis/epidemiology ; Risk Factors

Occult HBV infection is defined as the presence of HBV DNA in the liver (with or without detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg. Studies on occult HBV infection in hepatitis C patients have reported highly variable prevalence, because the prevalence of occult HBV infection varies depending on the hepatitis B risk factors and methodological approaches. The most reliable diagnostic approach for detecting occult HBV detection is through examination of liver DNA extracts. HCV has been suspected to strongly suppress HBV replication up to the point where it may be directly responsible for occult HBV infection development. However, more data are needed to arrive at a definitive conclusion regarding the role of HCV in inducing occult HBV infection. Occult HBV infection in chronic hepatitis C patients is a complex biological entity with possible relevant clinical implications. Influence of occult HBV infection on the clinical outcomes of chronic hepatitis C may be considered negative. However, recent studies have shown that occult HBV infection could be associated with the development of hepatocellular carcinoma and contribute to the worsening of the course of chronic liver disease over time in chronic hepatitis C patients. Nevertheless, the possible role of occult HBV infection in chronic hepatitis C is still unresolved and no firm conclusion has been made up until now. It still remains unclear how occult HBV infection affects the treatment of chronic hepatitis C. Therefore, in order to resolve current controversies and understand the pathogenic role and clinical impacts of occult HBV infection in chronic hepatitis C patients, well-designed clinical studies are needed.
Carcinoma, Hepatocellular/complications ; DNA, Viral/analysis ; Hepacivirus/genetics ; Hepatitis B/*complications/*diagnosis/drug therapy ; Hepatitis B virus/genetics ; Hepatitis C, Chronic/*complications/*diagnosis/drug therapy ; Humans ; Interferon-alpha/therapeutic use ; Liver/virology ; Liver Neoplasms/complications

Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
Biological Markers ; Carcinoma, Hepatocellular/diagnosis/*epidemiology/*genetics ; Genetic Predisposition to Disease ; Hepatitis B, Chronic/*complications/diagnosis/epidemiology ; Humans ; Liver Neoplasms/diagnosis/*epidemiology/*genetics ; *Polymorphism, Single Nucleotide

BACKGROUND/AIMS: Epigenetic silencing of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT), hMLH1 and hMSH3, by promoter hypermethylation have been observed in various cancers. However, the relationship between hypermethylation of DNA mismatch repair genes and microsatellite instability (MSI) has not been studied in hepatocellular carcinoma (HCC) associated with cirrhosis. METHODS: We investigated the methylation pattern of CpG islands of 3 genes using methylation-specific PCR (MSP) and MSI in 40 patients with paired hepatocellular carcinoma and associated cirrhosis. RESULTS: hMSH3 and MGMT were the most methylated genes in both cirrhosis (70% and 68%, respectively) and HCC (75% and 73%, respectively). The methylation of hMLH1 was rarely found in both cirrhosis (8%) and HCC (5%). Gene promoters methylated in cirrhosis were also methylated in HCC with the exception of 9 cases found to be methylated either in cirrhosis or HCC. Of 40 cases of HCC associated with cirrhosis, three had MSI-positive phenotype in which two were MSI-low and one was MSI-high. One MSI-positive phenotype was present both in cirrhosis and in HCC, while two were only in HCC. There was no significant correlation between aberrant DNA methylation of mismatch repair genes and MSI status in HCC associated with cirrhosis. Immunohistochemical expressions of hMLH1, MGMT, and hMSH3 proteins were present in 16 (40%), 6 (15%), and 11 (28%) of 40 cases of HCC respectively. There was no significant correlaton between the aberrant DNA methylation of mismatch repair genes and clinical characteristics such as histological differentiation, postoperative recurrence and mortality. CONCLUSIONS: The methylation of MGMT and hMSH3 among DNA repair genes are frequent, but those of hMLH1 and MSI is very rare in both cirrhosis and HCC. There is no significant correlation between the methylation of DNA repair genes and clinical characteristics of HCC.
Adaptor Proteins, Signal Transducing/genetics ; Adult ; Aged ; Carcinoma, Hepatocellular/complications/diagnosis/*genetics ; *DNA Methylation ; DNA Modification Methylases/genetics ; *DNA Repair ; DNA Repair Enzymes/*genetics ; DNA-Binding Proteins/genetics ; Female ; Humans ; Liver Cirrhosis/complications/diagnosis/*genetics ; Liver Neoplasms/complications/diagnosis/*genetics ; Male ; *Microsatellite Instability ; Middle Aged ; Nuclear Proteins/genetics ; Tumor Suppressor Proteins/genetics

BACKGROUND/AIMS: Alcohol and the hepatitis B virus (HBV) exert synergistic effects in hepatocelluar carcinogenesis. We aimed to elucidate the clinical significance of the antibody to hepatitis B core antigen (anti-HBc) and occult HBV infection on the development of hepatocellular carcinoma (HCC) in patients with alcoholic liver cirrhosis (LC). METHODS: Patients with alcoholic LC alone (n=193) or combined with HCC (n=36), who did not have HBsAg or antibody to hepatitis C virus were enrolled. Clinical data and laboratory data including anti-HBc were investigated at enrollment. The polymerase chain reaction was applied to HBV DNA using sera of patients with HCC or LC after age and sex matching. RESULTS: Patients with HCC were older (60+/-11 years vs. 53+/-10 years, mean+/-SD, P<0.001), more likely to be male (100% vs. 89%, P=0.03), and had a higher positive rate of anti-HBc (91.2% vs. 77.3%, P=0.067), and a higher alcohol intake (739+/-448 kg vs. 603+/-409 kg, P=0.076) than those with LC. Age was the only significant risk factor for HCC revealed by multiple logistic regression analysis (odds ratio, 1.056; P=0.003). The positive rate of anti-HBc and alcohol intake did not differ in age- and sex-matched subjects between the LC (n=32) and HCC (n=31) groups. However, the detection rate of serum HBV DNA was higher in the HCC group (48.4%) than in the LC group (0%, P<0.001). CONCLUSIONS: Anti-HBc positivity is not a risk factor for HCC. However, occult HBV infection may be a risk factor for HCC in patients with alcoholic LC.
Adult ; Aged ; Antibodies, Viral/blood ; Carcinoma, Hepatocellular/diagnosis/epidemiology/*etiology ; DNA, Viral/analysis ; Female ; Hepatitis B/*complications/diagnosis ; Hepatitis B Core Antigens/*immunology ; Hepatitis B Surface Antigens/immunology ; Hepatitis B virus/genetics/immunology/isolation & purification ; Hepatitis C/complications/diagnosis ; Humans ; Liver Cirrhosis, Alcoholic/*complications/diagnosis/epidemiology ; Liver Neoplasms/diagnosis/epidemiology/*etiology ; Male ; Middle Aged ; Risk Factors

Hepatitis C virus (HCV) is one of the main viral causes of hepatocellular carcinoma (HCC) and is associated with lymphoproliferative disorder such as non-Hodgkin's lymphoma (NHL). However, there are only few case reports on concomitantly induced NHL and HCC by HCV. Herein, we report a case of synchronous NHL and HCC in a patient with chronic hepatitis C which was unexpectedly diagnosed during liver transplantation surgery. This case suggests that although intrahepatic lymph node enlargements are often considered as reactive or metastatic lymphadenopathy in chronic hepatitis C patients with HCC, NHL should also be considered as a differential diagnosis.
Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/complications/*diagnosis/radiotherapy ; Drug Therapy, Combination ; Embolization, Therapeutic ; Fluorodeoxyglucose F18 ; Gadolinium DTPA ; Genotype ; Hepatitis B virus/genetics ; Hepatitis C, Chronic/complications/*diagnosis/*virology ; Humans ; Liver Neoplasms/complications/*diagnosis/radiotherapy ; Lymph Nodes/pathology ; Lymphoma, Non-Hodgkin/complications/*diagnosis/drug therapy ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Positron-Emission Tomography ; Tomography, X-Ray Computed

OBJECTIVETo investigate the infection of Helicobacter pylori (Hp) in the liver tissue of patients with chronic liver disease and the association between Hp and chronic liver disease.

METHODSLiver tissue samples were obtained by liver biopsy and surgical resection from 30 healthy subjects, 30 patients with chronic hepatitis, 30 with cirrhosis and 30 with liver cancer. All the samples were confirmed by pathological examination. The gene fragment coding for 16SrRNA were amplified by PCR with sequence analysis.

RESULTSThe PCR product of the 16SrRNA gene was 109 bp in length. Hp 16SrRNA was detected in 18 out of 30 liver biopsy samples from patients with primary cancer (60.0%), in 14 samples from patients with liver cirrhosis (47.0%), and in none of the samples from normal subjects or patients with chronic hepatitis. Sequencing analysis of Hp 16SrRNA gene in the liver tissue showed a 98.8% homology with the gene fragment encoding Hp 16SrRNA.

CONCLUSIONHp is identified in the liver tissue of patients with chronic liver disease, suggesting the possible correlation between Hp infection and hepatocellular carcinoma.

Adult ; Aged ; Base Sequence ; Female ; Helicobacter Infections ; complications ; diagnosis ; microbiology ; Helicobacter pylori ; genetics ; isolation & purification ; Hepatitis, Chronic ; complications ; microbiology ; Humans ; Liver Cirrhosis ; complications ; microbiology ; Liver Neoplasms ; complications ; microbiology ; Male ; Middle Aged ; Molecular Sequence Data ; RNA, Bacterial ; analysis ; RNA, Ribosomal, 16S ; analysis ; Young Adult

Parvovirus B19 infection is known to cause chronic anemia in immunocompromised hosts, including organ transplant recipients. We report the first case of liver transplant recipient with parvovirus B19-induced pure red cell aplasia in Korea. A 57-yr-old female patient with hepatocellular carcinoma due to hepatitis C virus received a liver transplantation. Two months later, anemia developed and she received periodic red blood cell transfusions. However, chronic anemia persisted and bone marrow examination was performed 8 months after transplantation. Bone marrow aspiration smears showed markedly reduced erythroid precursors with atypical giant pronormoblasts and nuclear remnants with viral inclusions, and characteristic lantern cells were observed in biopsy sections. In addition, parvovirus B19 DNA PCR was positive. She was diagnosed as parvovirus B19-induced pure red cell aplasia and her anemia was improved following intravenous immunoglobulin therapy.
Blood Transfusion ; Bone Marrow/pathology ; Carcinoma, Hepatocellular/etiology/therapy ; DNA, Viral/analysis ; Female ; Hepatitis C/complications/diagnosis ; Humans ; Immunocompromised Host ; Immunoglobulins/therapeutic use ; Liver Neoplasms/etiology/therapy ; Liver Transplantation ; Middle Aged ; Parvoviridae Infections/complications/*diagnosis ; *Parvovirus B19, Human/genetics ; Red-Cell Aplasia, Pure/*diagnosis/therapy/virology

BACKGROUND/AIMS: There is some controversy regarding whether or not hepatitis C virus (HCV) subtype 1b is more influential than non-1b subtypes on the progression of chronic hepatitis (CH) C to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 823 patients with chronic HCV infection, including 443 CH patients, 264 LC patients, and 116 HCC patients, who were HCV RNA positive and HBsAg negative. These patients had not received any prior treatment with either interferon alone or a combination of interferon and ribavirin. RESULTS: HCV subtypes 1b (51.6%) and 2a/2c (39.5%) were the two most common genotypes. The proportions of genotypes 2 (2a/2c, 2b, and 2) and 3 were 45.8% and 1.1%, respectively. One case of genotype 4 was found. HCV subtype 1b (47.3%) was less common than the non-1b subtypes (52.7%) in non-LC patients, but its proportion (56.9%) was higher than that of non-1b subtypes (43.1%) in LC patients (P=0.006). The proportions of patients with HCV subtype 1b did not differ significantly between the LC (55.3%) and HCC (60.3%) groups. Older age, male gender, and the relative progression of liver damage (non-LC vs. compensated LC vs. decompensated LC) were significant risk factors for HCC, with odds ratios of 1.081 (95% confidence interval [CI], 1.056-1.106), 5.749 (95% CI, 3.329-9.930), and 2.895 (95% CI, 2.183-3.840), respectively. HCV subtype 1b was not a significant risk factor for HCC (odds ratio, 1.423; 95% CI, 0.895-2.262). CONCLUSIONS: HCV subtypes 1b and 2a/2c were the two most common HCV genotypes. HCV subtype 1b seemed to be more influential than non-1b subtypes on the progression of CH to LC, but not on the development of HCC from LC.
Adult ; Age Factors ; Aged ; Carcinoma, Hepatocellular/diagnosis/etiology ; Female ; Genotype ; Hepacivirus/genetics ; Hepatitis C, Chronic/complications/*diagnosis/pathology ; Humans ; Liver Cirrhosis/diagnosis/etiology ; Liver Neoplasms/diagnosis/etiology ; Male ; Middle Aged ; Odds Ratio ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Severity of Illness Index ; Sex Factors

BACKGROUND/AIMS: Human hepatocellular carcinoma (HCC) is a hypervascular tumor, and vascular endothelial growth factor (VEGF) plays a key role in the regulation of tumor-associated angiogenesis. In this study, we analyzed the significance of the expression of VEGF family members on the prognosis and clinicopathologic progress of HCC. METHODS: Surgically resected specimens of HCC and noncancerous liver tissue were obtained from 323 patients with HCC, and VEGF mRNA was examined by quantitative reverse transcriptase-polymerase chain reactions (RT-PCRs). Patients who were seropositive for hepatitis B surface antigen were selected for the analysis (n=208). The VEGF(tumor)/GAPDH (glyceraldehyde-3-phosphate dehydrogenase)(tumor)/VEGF(nontumor)/GAPDH(nontumor) ratio was calculated using a quantitative RT-PCR assay, and the relationships between the expressions of VEGF family members and clinicopathologic parameters were analyzed to evaluate their significance in the prognosis of HCC. RESULTS: The disease-free survival was significantly worse in the high-VEGF-A group than in the low-VEGF-A group (P=0.035), whereas VEGF-A expression was not significantly related to overall survival (P=0.172). The factors significantly related to poor prognosis in univariate analysis were tumor size, portal vein invasion, microvascular thrombi, intrahepatic metastasis, tumor capsule invasion, liver capsule invasion, preoperative serum albumin level, and VEGF-A ratio. Multivariate analysis showed that a poor prognosis in HCC patients was significantly related to portal vein invasion (hazard ratio=3.381, P<0.001), intrahepatic metastasis (hazard ratio=2.379, P<0.001), tumor size (hazard ratio=1.834, P=0.003), and preoperative serum albumin level (hazard ratio=2.050, P=0.006). CONCLUSIONS: Our study showed that the expression of VEGF-A is positively correlated with the recurrence rate of HCC after curative resection. Therefore, a high expression of VEGF-A might be predictive of HCC recurrence after curative resection.
Adult ; Aged ; Base Sequence ; Carcinoma, Hepatocellular/*diagnosis/*surgery/virology ; Female ; Hepatitis B/complications ; Hepatitis B Surface Antigens/blood ; Humans ; Liver Neoplasms/*diagnosis/*surgery/virology ; Male ; Middle Aged ; Molecular Sequence Data ; Multivariate Analysis ; Neoplasm Invasiveness ; Neoplasm Staging ; Predictive Value of Tests ; Prognosis ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Survival Analysis ; Vascular Endothelial Growth Factors/genetics/*metabolism