An expert consensus for the management of chronic hepatitis B in Asian Americans.

BACKGROUND: Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM: To generate recommendations for the management of Asian Americans infected with HBV. METHODS: These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS: Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS: Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.

Antiviral prophylaxis and recurrence of hepatocellular carcinoma following liver transplantation in patients with hepatitis B.

BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.

A systems comparison of once- versus twice-daily milking of pastured dairy cows.

The objective of this study was to compare the effect of milking frequency (once vs. twice-daily milking) and breed (Holstein-Friesians vs. Jerseys) on milk and milk solids (MS; milk fat + milk protein), yield per cow, milk composition, somatic cell count and lactation length; cow body weight, body condition score, and reproductive performance over a 4-yr period. Total cow numbers in each herd were 30, 35, 36, and 42 for Holstein-Friesians milked once or twice daily, and Jerseys milked once or twice daily, respectively. Forty hectares of pasture were subdivided into 4 smaller pastures of 10 ha each. Stocking rates for the once-daily herds were 16.7% greater than the twice-daily herd in their respective breed. An increased stocking rate was chosen to achieve equal milk and MS per ha from the 2 milking frequencies. Annual milk, fat, protein, and lactose yields per cow were less for once-daily than for twice-daily milking. Interactions were detected between milking frequency and breed for annual milk, fat, protein, and lactose yields per cow, because Jerseys were relatively less affected by once-daily than by twice-daily milking than Holstein-Friesians. Holstein-Friesian cows milked once daily produced 31.2% less milk and 29.4% less MS per cow than their twice-daily counterparts. In contrast, Jersey cows milked once daily produced 22.1% less milk and 19.9% less MS per cow than their twice-daily counterparts. Milk per ha was 17.7 and 9% less for the once-daily Holstein-Friesians and once-daily Jersey herds, respectively, compared with their twice-daily counterparts, because the greater stocking rate for the once-daily herds did not fully compensate for the milk loss per cow. Milking once daily increased somatic cell count throughout the year in both breeds. Cows milked once daily conceived 3 d earlier, took 5 d less from calving to conception, and needed 11% fewer controlled internal drug release devices than those milked twice daily. Milking once daily is a viable milking option for New Zealand farmers who are prepared to trade-off loss of MS income for increased time to accomplish other non-milking activities.

Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California.

We conducted interviews on 74 patients with histologically confirmed hepatocellular carcinoma. These patients, aged 18-74 years, were black or white residents of Los Angeles County. We also interviewed 162 population control subjects who were comparable to the case patients by age, sex, and race. Cigarette smoking was a significant risk factor for hepatocellular carcinoma [relative risk (RR) = 2.1; 95% confidence limits (CL) = 1.1, 4.0]; the effects were similar in men and in women. Heavy alcohol consumption was another risk factor for hepatocellular carcinoma in men; men who consumed 80 g or more of ethanol per day had an RR of 4.7 (95% CL = 1.4, 15.4) relative to those who had never drunk alcohol on a weekly basis. The level of alcohol intake was relatively low in women, and no significant effect on risk of hepatocellular carcinoma was observed. Use of oral contraceptives was significantly related to risk of hepatocellular carcinoma in women (RR = 3.0; 95% CL = 1.0, 8.8); those who were exposed for more than 5 years exhibited a 5.5-fold increased risk (95% CL = 1.2, 24.8). The effects of these three risk factors on hepatocellular carcinoma development were independent of each other and independent of serologically determined viral hepatitis. Our data suggest that cigarette smoking, alcohol consumption, and use of oral contraceptives are major risk factors for hepatocellular carcinoma among non-Asian residents of Los Angeles County. We also observed a significant association between a history of diabetes and hepatocellular carcinoma (RR = 3.3; 95% CL = 1.5, 7.2), especially among those who had received insulin treatment (RR = 18.5; 95% CL = 2.2, 156.0). This association may have etiological significance.

Prevalence of hepatitis B and C viral markers in black and white patients with hepatocellular carcinoma in the United States.

The recent cloning of the genome of a non-A, non-B hepatitis agent, designated the hepatitis C virus (HCV), has led to the development of an immunoassay for circulating HCV antibodies (anti-HCV). We used this immunoassay to investigate the possible association between HCV infection and hepatocellular carcinoma in black and white residents of Los Angeles County, California. Serum samples from 51 patients (12 black and 39 white) in Los Angeles County with hepatocellular carcinoma and 128 control subjects (1 black and 127 white) were tested for the presence of anti-HCV. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). Our results indicate that the presence of anti-HCV was a significant risk factor for hepatocellular carcinoma; the relative risk was 10.5 (95% confidence limits = 3.5, 31.3). Hepatocellular carcinoma risk was also significantly related to the presence of one or more of the hepatitis B virus (HBV) markers, primarily HBsAg and anti-HBc, and the relative risk was 7.0 (95% confidence limits = 3.1, 16.1). HCV and HBV independently contributed to hepatocellular carcinoma development. Significantly increased risk of hepatocellular carcinoma was demonstrated in individuals with HCV (relative risk = 4.8) or HBV (relative risk = 4.4) serologic markers alone. A synergistic effect on risk was observed when both hepatitis B and C viral markers were present in peripheral blood (10 cases vs. no controls). We estimate that approximately 47% of hepatocellular carcinoma occurring in black and white residents of Los Angeles County could be attributed to prior HCV and/or HBV infections: 9% were related to HCV alone, 20% to HBV alone, and 18% to occurrence of both HCV and HBV infections.

Hepatitis B viral markers in patients with primary hepatocellular carcinoma in Taiwan.

The presence of hepatitis B viral markers in patients with primary hepatocellular carcinoma (PHC) was studied retrospectively at the Taiwan Veterans General Hospital in Taipei, Taiwan. Serum samples from 102 PHC patients and from 100 control individuals were tested for hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), hepatitis Be antigen (HBeAg), and antibody to HBeAg (anti-HBe). Of the 102 PHC patients, 72 (71%) were positive for HBsAg. Nine (9%) additional patients were positive for anti-HBc alone in high titer, 19 (19%) had both anti-HBc and anti-HBs, and 9 (9%) had HBsAg, anti-HBc, and anti-HBs. In the 100 controls, 12 (12%) were HBsAg-positive, whereas 22 (22%) had anti-HBc alone and 50 (50%) had both anti-HBc and anti-HBs. Only 4 (4%) controls and no PHC patients had anti-HBs alone. Of the HBsAg-positive patients with PHC, 17 (29%) had HBeAg and 36 (61%) had anti-HBe. The alpha-fetoprotein (AFP) levels above 400 ng/ml were found in 44% of the PHC patients. Values of AFP above 1 x 10(5) ng/ml were more frequently detected in PHC patients who were HBsAg-positive. Categorization of the geographic origins of the families whose members had PHC revealed that most families had originated from southern China. This study confirms that hepatitis B viral markers are frequently present in Chinese patients with PHC.

A serological case-control study of primary hepatocellular carcinoma in Guangxi, China.

Guangxi is a very high-risk area for primary hepatocellular carcinoma (PHC); the age-standardized (world population) rates for males and females in that Chinese Autonomous Region were 32.5 and 8.5, respectively. Blood specimens from 50 PHC patients and 50 age- and sex-matched controls in Guangxi were analyzed for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. Eighty-six % of cases were hepatitis B surface antigen positive, compared to 22% of controls (relative risk, 17.0). We estimate from the data that persistent hepatitis B virus infection can account for at least 80% of all PHC cases occurring in Guangxi. The consistency of our findings with those from Hong Kong and Taiwan strongly suggests that hepatitis B virus infection is also an important risk factor for PHC in other parts of southern China.

Relationship between cell membrane potential and natural killer cell cytolysis in human hepatocellular carcinoma cells.

One of the body's natural defense mechanisms against tumor cells is lysis of the invading cell by cytotoxic T-cells and natural killer (NK) cells. Five human hepatocellular carcinoma cell lines were found to have different sensitivities to killing by peripheral blood monocytes in a 51Cr release assay. This killing was demonstrated to be due to NK cell lysis. Electrical recording measurements of the membrane potentials of these five cell lines showed different values for each line, all below values reported for normal hepatocytes. Correlation between mean cell membrane potential, and sensitivity to NK lysis, revealed an inverse relationship. In this study we demonstrate that the lower the mean membrane potential of a human hepatocellular carcinoma cell line, the more sensitive it is to NK cell cytolysis. Cell surface positive potential did not correlate with NK cytolysis and only a weak correlation was found between cell membrane negative potential and cell surface positive potential between cell lines.

Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangxi, China.

We examined the roles of the hepatitis B virus and aflatoxin B1 in the development of primary hepatocellular carcinoma (PHC) in a cohort of 7917 men aged 25 to 64 yr old in southern Guangxi, China, where the incidence of PHC is among the highest in the world. After accumulating 30,188 man-yr of observation, 149 deaths were observed, 76 (51%) of which were due to PHC. Ninety-one% (69 of 76) of PHC deaths were hepatitis B surface antigen (HBsAg) positive at enrollment into the study in contrast to 23% of all members of the cohort (RR = 38.6). Three of the four patients who died of liver cirrhosis also were HBsAg positive at enrollment. There was no association between HBsAg positivity state and other causes of death. Within the cohort, there was a 3.5-fold difference in PHC mortality by place of residence. When estimated aflatoxin B1 levels in the subpopulations were plotted against the corresponding mortality rates of PHC, a positive and almost perfectly linear relationship was observed. On the other hand, no significant association was observed when the prevalence of HBsAg positivity in the subpopulations was compared with their corresponding rates of PHC mortality.

Liver involvement in sickle cell disease.

In an effort to clarify the features of hepatic dysfunction in sickle cell disease, we obtained serial tests of liver function in 100 consecutive patients with sickle cell anemia and in 30 consecutive patients with hemoglobinopathy SC during a five-year period. There were 32 patients with chronic abnormalities in tests of liver function. These abnormal tests were explained by a variety of lesions in 30 cases, and the liver disease remained unexplained in only 2 patients who declined liver biopsy. The diagnoses in these 30 patients included hepatitis, chronic passive congestion, common duct obstruction, alcoholic liver disease, pregnancy, collagen-vascular disease, and sarcoidosis. Evidence for hepatitis B infection was present in 19 of those with sickle cell anemia and in 6 of those with hemoglobinopathy SC. The bilirubin levels in sickle cell anemia appeared to have a trimodal distribution, with six patients exhibiting markedly elevated levels of indirect bilirubin suggesting a difference in bilirubin metabolism. There was no evidence of liver disease in 72 patients with sickle cell anemia, nor in 24 patients with hemoglobinopathy SC, as these patients exhibited only mild elevation of their serum indirect bilirubin levels owing to chronic hemolysis. Intrasinusoidal sickling and Kupffer cell erythrophagocytosis were nearly universal findings at liver biopsy, irrespective of the clinical disorder, and were not related to the degree of liver test abnormalities. Liver and biliary tract dysfunction in sickle cell disease have been attributed to anoxia secondary to sinusoidal obstruction by sickled erythrocytes and Kupffer cell erythrophagocytosis. However, some causes of liver disease in sickle cell patients can be explained by clinical disorders other than the hemoglobinopathy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Discordance between serum alanine aminotransferase (ALT) and virologic response to IFN-alpha2b in chronic hepatitis C patients with high and low pretreatment serum hepatitis C virus RNA titers.

Although serum alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA concentrations are primary markers used to assess the clinical benefit of interferon (IFN) therapy in patients with chronic HCV infection, discrepancies between these two variables exist. In this study, 103 patients with chronic hepatitis C were treated with 3 MIU IFN-alpha2b three times weekly for 24 weeks, followed by 24 weeks of observation. ALT and virologic responses were compared in patients with high pretreatment HCV RNA titers (defined as pretreatment HCV RNA concentrations at or above the 75th percentile of the distribution or >5,000,000 copies/ml) and low pretreatment HCV RNA titers (defined as pretreatment concentrations below the 75th percentile or < or =5,000,000 copies/ml). Analysis of the virologic response for the high-titer and low-titer groups demonstrated a significantly greater HCV RNA sustained response in the low-titer group (21%) compared with the high-titer group (7%) (p < 0.05). In contrast, the ALT sustained response was not significantly different between the low-titer group (21%) and the high-titer group (18%). Analysis of the correspondence between biochemical and virologic responses showed that only 38% of patients with high pretreatment HCV RNA titers had both a sustained ALT response and a sustained loss of HCV RNA compared with 75% of patients with low pretreatment HCV RNA titers. The level of agreement between the ALT and HCV RNA responses was greater for the low-titer group compared with the high-titer group (kappa = .6848 and kappa = .4966, respectively). Our results indicate that chronic HCV patients with high pretreatment HCV RNA titers showed greater discordance between sustained ALT and HCV RNA responses compared with patients with low pretreatment HCV RNA titers and that measurement of HCV RNA should be included in the assessment of response to IFN therapy in chronic hepatitis C patients.

Treatment of chronic hepatitis C virus infection with recombinant consensus interferon.

To assess the safety and efficacy of consensus interferon (IFN-Con-1), 55 patients with chronic hepatitis C infection were treated with either 3, 6, 9, 12, or 15 microg IFN-Con-1 s.c. three times a week for 24 weeks, followed by 24 weeks of observation. There was a dose-response relationship with respect to the number of patients with normalized ALT concentrations or undetectable HCV RNA. At the end of the 24-week treatment period, the serum ALT had normalized in 18% of patients given the 3 microg dose and 42% of patients given the 12 microg or 15 microg doses of IFN-Con-1. At the end of the posttreatment observation period, the serum ALT was still normal in 10% of patients given the 3 microg, 6 microg, or 9 microg doses and in 50% of patients given the 15 microg dose. Also, at the end of the 24-week treatment period, 27% of patients given the 3 microg dose and 75% given the 15 microg dose had undetectable serum HCV RNA. At the end of the posttreatment observation period, the proportion of patients with undetectable HCV RNA ranged from 9% of those given the 3 microg dose to 50% of those given the 15 microg dose. Our study indicates that treatment with IFN-Con-1 appears to be safe and effective. In addition, use of 15 microg of IFN-Con-1 resulted in significantly more patients with sustained ALT normalization and absence of HCV RNA 6 months after cessation of therapy compared with treatment with lower doses of IFN-Con-1. Additional trials are underway to confirm these findings.

Hepatitis B vaccination of neonates and children.

Perinatal transmission of the hepatitis B virus (HBV) occurs in a high percentage of infants born to mothers who are acutely infected with the virus at the time of delivery or who are chronic carriers of the hepatitis B surface antigen (HBsAg). The majority of infants who acquire the virus during the perinatal period and become HBV carriers have no clinical symptoms. However, there are reports of acute and fulminant hepatitis and even primary liver cancer occurring in a few HBsAg-positive infants. Immunoprophylaxis given to infants born to HBsAg-positive mothers at birth with a combination of hepatitis B immunoglobulin and hepatitis B vaccine is the most effective means of preventing the chronic HBV carrier state and its potential complications. In a multicenter trial in the United States, 85 to 90 percent of the children of HBsAg-positive mothers remained HBsAg-negative when treated with this combination regimen. Studies conducted outside the United States have yielded similar results. Other investigations indicate that the hepatitis B vaccine alone may be of value in preventing perinatal transmission of HBV in developing countries that are unable to afford hepatitis B immunoglobulin.

Perinatal transmitted acute icteric hepatitis B in infants born to hepatitis B surface antigen-positive and anti-hepatitis Be-positive carrier mothers.

Three infants born to mothers who were hepatitis B surface antigen (HBsAg) positive and had antibody to hepatitis Be antigen (anti-HBe), developed acute icteric hepatitis B within three months of birth. All three infants clinically recovered and developed circulating anti-HBs. Contrary to previous studies, these three cases indicate that mother-infant transmission of the hepatitis B virus (HBV) does occur in infants born to HBsAg-positive, HBe-Ag-negative carrier mothers, and these infants may develop severe acute icteric hepatitis. Therefore, immunoprophylaxis in such newborns may be indicated.

Histologic and clinicopathologic features of Chinese patients with HBsAg-positive chronic active hepatitis.

Needle biopsies of both the right and left lobes of the liver were performed during peritoneoscopy in 20 male patients with chronic active hepatitis B in Taiwan. Microscopic study of these biopsy specimens led to the recognition of three groups: 1) five patients in whom the lobular architecture was easily recognizable but in whom necrosis and early intralobular fibrosis were present, along with severe chronic inflammation of the portal tracts; 2) seven patients in whom the livers were characterized by early septal formation and a good regenerative response, but few recognizable lobules with normal architecture; and 3) eight patients in whom the disease had progressed to severe fibrosis with septal formation and tiny pseudolobules, indicative of early cirrhosis. The left lobe was the more severely damaged in 16 of the 20 patients.

A cost comparison analysis for screening and vaccination of hospital personnel with high- and low-prevalence hepatitis B virus antibodies in California.

We compared the cost of antibody screening and the projected cost for hepatitis B vaccination of antibody-negative individuals at hospitals with "high prevalence" and "low prevalence" rates for hepatitis B virus antibodies among their employees. The use of hepatitis B core antibody for screening and subsequent hepatitis B vaccination of antibody-negative personnel was most cost-effective for hospitals considered to have high prevalence for hepatitis B virus antibodies among its staff, although use of hepatitis B surface antibody in this setting only increased costs by 1.4%. In a hospital with low prevalence for hepatitis B virus antibodies among its staff, use of hepatitis B surface antibody and subsequent vaccination of antibody-negative individuals was the most cost-effective approach, while use of hepatitis B core antibody for the above purposes would have increased costs by 3.4%. The use of both hepatitis B surface antibody and core antibody in either setting followed by immunization was least economical, as costs were increased by 13% and 13.5% respectively. We concluded that hepatitis B core antibody should be used for screening in hospitals with high prevalence for hepatitis B virus antibodies among employees while hepatitis B surface antibody be used for screening in hospitals with low prevalence for hepatitis B virus antibodies among employees. A prediction of high and low prevalence for hepatitis B virus antibodies in hospital personnel may be made by knowledge of the distribution in ethnicity of staff.

Risk factors for hepatitis C virus infection among health care personnel in a community hospital.

OBJECTIVE: To determine the prevalence of and risk factors for antibody to the hepatitis C virus in hospital employees. METHODS: Retrospective testing of serum samples obtained from 1677 hospital employees during a prehepatitis B vaccination program in a private teaching community hospital. RESULTS: Twenty-three employees (1.4%) were found to have antibody to hepatitis C virus. The prevalence of antibody to hepatitis C virus was higher in blacks (3.4%) than in whites (1.1%, p = 0.03) and Hispanics (2.6%, p = 0.88). In a logistic regression model, factors significantly associated with antibody to hepatitis C virus seropositivity included antibody to hepatitis B core antigen (p = 0.002), a history of blood transfusion (p = 0.03), and needlestick injuries (p = 0.04). CONCLUSION: Although the prevalence of antibody to hepatitis C virus in health care workers was not high, needlestick injuries were associated with an increased risk for acquiring hepatitis C virus infection.

Comparison of three different hybridization assays in the quantitative measurement of serum hepatitis B virus DNA.

The measurement of hepatitis B virus (HBV) DNA, is important for monitoring and evaluating the efficacy of anti-viral agents in the treatment of patients with chronic hepatitis B. Three different hybridization assays for quantitative measurement of HBV DNA: direct membrane (dot-blot) hybridization, liquid hybridization (Abbott HBV DNA assay) and branched DNA signal amplification assay (Quantiplex, Chiron), were applied to 114 serial serum samples obtained from 13 patients with chronic active hepatitis B who had received ribavirin 600 mg daily for four weeks. Among the three assays, the correlation was found to be highest between Quantiplex and Abbott HBV DNA assay (r = 0.71, p < 0.01), moderate between Quantiplex and dot-blot hybridization (r = 0.58, p < 0.01) and lowest between dot-blot hybridization and Abbott HBV DNA assay (r = 0.27, p < 0.01). Quantiplex detected 107 (94%) of 114 specimens and was the most sensitive assay. All specimens positive by dot-blot hybridization and Abbott HBV DNA assays were detected positive by Quantiplex. The Dot-blot hybridization assay detected all 89 (100%) specimens with a high HBV DNA level (> or = 10 million genome equivalent (Meq)/ml by Quantiplex), but detected only 7 (50%) of 14 specimens with a low HBV DNA level (< 10 Meq/ml). The Abbott HBV DNA assay detected 85 (95%) of 89 specimens with a high HBV DNA level, but detected only 3 (17%) of 18 specimens with a low HBV DNA level. Among 7 negative specimens in the Quantiplex assay, 2 were detected positive by polymerase chain reaction. In conclusion, Quantiplex assay was more sensitive than Abbott HBV DNA assay and dot-blot hybridization assay for quantitative measurement of serum HBV DNA and can be used in the evaluation of the therapeutic drug effect on chronic hepatitis B patients.

Papular acrodermatitis of childhood and hepatitis B infection.

A case of papular acrodermatitis (PAC) associated with acute anicteric type B hepatitis occurred in a 2-year-old child. Immunocytochemical studies failed to detect the presence of viral antigens in the involved skin lesion. Current knowledge of the hepatitis B viral antigens and of their possible role in PAC is discussed.

Correlation between hepatic hepatitis B core antigen and serum hepatitis B virus-DNA levels in patients with chronic hepatitis B virus infections in Taiwan.

Paired liver biopsy specimens and serum samples from 76 patients with chronic hepatitis B virus (HBV) infection were taken for staining of hepatitis B core antigen (HBcAg) by immunoperoxidase and testing of HBV-DNA by a spot hybridization technique, respectively. Thirty-two tissue specimens showed positive staining for HBcAg in their hepatocytes. The two patients with diffuse HBcAg expression in liver tissue also had high serum concentrations of HBV-DNA (greater than 10 pg/10 microL). Among 30 patients with focal HBcAg distribution, 28 patients (93.3%) had measurable levels of serum HBV-DNA and 17 patients (60.7%) had high levels of serum HBV-DNA. Of 44 patients without hepatic HBcAg expression, only 12 patients (27.3%) had detectable serum HBV-DNA, and most patients (93.1% [11/12]) had low concentrations (less than 10 pg/10 microL). Nineteen patients had superimposed hepatitis D virus infection, and, of these, three patients (15.8%) had detectable serum HBV-DNA in low concentrations, while one of the three patients had stainable HBcAg in his hepatocytes with focal distribution. Two of the three patients with hepatitis A virus superinfection who had focal HBcAg expression in their liver tissue had serum HBV-DNA levels that were high during the acute phase of hepatitis A virus infection, and in one patient his serum HBV-DNA levels further increased from 10 pg/10 microL to 40 pg/10 microL during the recovery phase. Thus, measurement of serum HBV-DNA levels in patients with chronic HBV infection correlated well with their hepatic HBcAg expression, and both represent the precise status of HBV replication.