State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases.

Abstract

Using the Southern blot technique and cloned hepatitis B virus (HBV) DNA as a probe, we studied the state of HBV DNA in the liver of 13 patients with hepatocellular carcinoma, 17 patients with chronic hepatitis, and 2 patients with acute hepatitis. The hybridization results were compared with the serological and immunohistological data. Integration of HBV DNA in cellular DNA of the liver from patients with hepatocellular carcinoma was demonstrated. In two patients from which tumorous and nontumorous liver tissue samples were available the integration patterns were different. In one patient with hepatitis B e antigen (HBeAg)-positive early hepatocellular carcinoma, free viral DNA was present in the liver. In some patients with HBeAg-negative chronic hepatitis, without tumor, integration of HBV DNA in cellular DNA was also demonstrated. This suggests that HBV is not the only factor involved in the development of a tumor. In patients with HBeAg-positive chronic hepatitis, free viral DNA was detected in the liver. In the two acute hepatitis patients analyzed, the restriction endonuclease patterns strongly suggested HBV DNA integration. Therefore, viral DNA integration seems to occur early in infection. Whatever the form of the disease, discrete bands were observed, suggesting the existence oflimited and specific integration sites in host cellular DNA. The presence of integrated or free DNA sequences has implications for antiviral therapy. In addition, detection ofHBV DNA in the liver is another sensitive viral marker that could be useful for diagnostic purposes.Exposure to hepatitis B virus (HBV) can be followed by acute and chronic hepatitis (1). In addition, human HBV chronic carriers have a significantly increased risk of developing hepatocellular carcinoma (2). The Southern blot technique (3) using cloned HBV DNA as a probe (4) provides another approach to investigating the relationship between HBV and these pathological conditions. Presence and integration of HBV DNA sequences in the cellular DNA of hepatocellular carcinomas and of a hepatoma cell line (5-8) have been demonstrated. This observation is an additional argument for HBV as a factor in this human cancer. Thus, it is important to investigate the state of the viral DNA in chronic hepatitis and acute hepatitis. Additionally, the results of the hybridization technique should be compared to the serological and histological tests of HBV infection to evaluate its diagnostic usefulness. In this report, we present evidence for integration of HBV DNA in tumorous and nontumorous parts of the liver of patients with hepatocellular carcinoma and in the liver of patients with chronic and acute hepatitis B.

Virologic and Clinical Expressions of Reciprocal Inhibitory Effect of Hepatitis B, C, and Delta Viruses in Patients With Chronic Hepatitis

“…34 In the second study, HBV sequences were detected in the liver or serum of anti-HCVpositive/HBsAg-negative patients with a prevalence significantly higher in patients with serum anti-HBc as the only marker of HBV infection than in those with no evidence of serum HBV markers; in this study liver cirrhosis was significantly more frequent in patients with HBV-DNA sequences than in those without. 35 We should also consider that an appreciable number of HBsAg-negative patients with chronic hepatitis or HCC showed clonally integrated HBV-DNA sequences in their liver or tumor tissues [36][37][38][39][40] and that a much higher prevalence of anti-HBc was described in HCV-infected chronic hepatitis patients with HCC than in those without. 41 Our data, which are supported by the observations of other investigators mentioned earlier, allow us to hypothesize that HCV infection blocks all circulating viral expression of HBV replication, but anti-HBc remains in serum and HBV DNA persists in the hepatocytes, resulting in an increased severity of liver disease and a higher risk of developing HCC.…”

Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: Clinically significant or purely “occult”?

“…As shown in Tables 2 and 3, despite initial controversies, the identification of HBV genome in the HCC tumors of HBsAg-negative patients has now also been reported in most, although not all, studies conducted in several geographic areas, including Japan. Some studies using Southern blots with an optimized sensitivity 77,78 and PCR 2 have revealed patterns consistent with limited clonal proliferation of the cells containing HBV genomes. 79 HBV-related cis-activation has also been recently reported in an HBsAg-negative, anti-HBc-positive individual with HCC without cirrhosis.…”

A study on sequence variations in pre‐S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non‐B, non‐C hepatocellular carcinoma patients in Taiwan

“…[6][7][8] Since the early 1980s, several studies have reported the detection of HBV DNA in both tumorous and non-tumorous liver tissue of HBsAg-negative HCC patients. 9,10 However, whether occult HBV infection also contributes to the pathogenesis of HCC remains unclear. Previous studies have demonstrated that the incidence of occult HBV infection varies significantly in HCC patients (12-61%).…”