W. Thomas London

The Global Epidemiology of Hepatocellular Carcinoma: Present and Future

The global risk of hepatocellular carcinoma (HCC) has been largely driven by hepatitis B virus (HBV) infection for the past century, along with hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, and obesity/diabetes. The dominant effect of HBV on global HCC risk should decline as the population vaccinated against HBV grows older. Infection with HCV is also expected to decline. Projections of HCV-related HCC rates remaining high for another 30 years may be overly pessimistic. Alcohol may be less of a factor in HCC in coming years. However, obesity and diabetes may become even more important risk factors for HCC.

Past HBV Viral Load as Predictor of Mortality and Morbidity from HCC and Chronic Liver Disease in a Prospective Study

BACKGROUND AND AIMS:In a prospective cohort study with 11 yr of follow-up, we assessed the relationship between past hepatitis B virus (HBV) viral load and mortality. Surviving cohort members were evaluated for current liver disease.METHODS:We measured HBV viral load by real-time polymerase chain reaction on stored samples from cohort entry (1992–1993) in 2,763 hepatitis B surface antigen (HBsAg)-positive adults. Major end points were death from hepatocellular carcinoma (HCC) or chronic liver disease (CLD). There were 447 deaths. In the 1,683 survivors, we assessed severity of liver disease on a return visit in 2003. Viral load was divided into three categories: undetected (<1.6 × 103 copies/mL); low titer (<105 copies/mL); and high titer (≥105 copies/mL).RESULTS:For HCC, there was a significant increase in mortality across viral load categories (ptrend < 0.001). Compared to the HBV undetected category, the relative risk (RR) for HCC mortality in the low viral load group was 1.7 (95% confidence interval [CI] 0.5–5.7) and 11.2 (3.6–35.0) in the high viral load group. For CLD mortality, the RRs were 1.5 (0.2–12.1) and 15.2 (2.1–109.8), respectively (ptrend < 0.001). The RR associated with high viral load did not change with increased follow-up time. In surviving cohort members evaluated for liver disease in 2003, there was also a significant association of viral load with disease severity.CONCLUSION:In this prospective study, viral load is associated with increased mortality from HCC and CLD in HBV-infected subjects. Viral load may be a useful prognostic tool in HBV infection, and interventions aimed at its reduction should be explored.

An epidemic of hepatitis in a chronic-hemodialysis unit. Australia antigen and differences in host response.

Abstract In a chronic-hemodialysis unit all nine patients and six of 15 staff members, within one year, had evidence of viral hepatitis. Australia antigen (Au[1]), a virus-like particle associated with acute and chronic viral hepatitis but not other liver diseases was found in the blood of eight of the nine patients and in the two staff members with hepatitis tested. Clinical and laboratory features of hepatitis in the staff and the patients in dialysis were different. In the former an acute disease characterized by serum bilirubin over 3 mg per 100 ml, SGPT over 1000 units and duration of SGPT elevations of less than 10 weeks developed. The patients on dialysis manifested a chronic anicteric disease, with SGPTs under 1000 units but SGPT elevations lasting for 20 weeks or more; the cases were detected only because of frequent testing for Au(1) and SGPT. Susceptibility of patients with chronic renal disease to chronic Au(1) hepatitis is probably related to impaired immunologic responsiveness.

Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability

Liver cancer is the second leading cause of global cancer mortality. The major risk factors for hepatocellular carcinoma (HCC) are being addressed with success by prevention efforts. Vaccination against hepatitis B virus has reduced incidence of HCC in Taiwan and is partly responsible for lower rates in China. New infections with hepatitis C virus are low in developed countries because of prevention of posttransfusion infections and reduced exposure to HCV by drug users. Aflatoxin exposure has been reduced by better grain storage and dietary changes. Obesity, metabolic syndrome, and diabetes are increasing in developed and developing countries and will lead to more cases of HCC.

Treatment of children with chronic hepatitis B virus infection in the United States: Patient selection and therapeutic options

Chronic hepatitis B virus (HBV) infection in children presents a therapeutic challenge for the practitioner. Decisions regarding selection of patients who may benefit from treatment, appropriate timing of treatment, and the choice of antiviral therapy are complex and are compounded by the limited number of drugs that have been studied in children. An expert panel of nationally recognized pediatric liver specialists was convened by the Hepatitis B Foundation on August 11, 2009, to consider clinical practice relative to the therapeutic options available for children. A detailed account of these discussions is provided, and the opinions expressed are based on consensus of the experts, as well as on published evidence when available. The panel concludes that, at this time, there is no established benefit of treatment of children in the immune tolerant phase, and there is a very high risk of development of drug resistance. In addition, there is no indication for treatment of children in the inactive carrier state. For children in the immune active or reactivation phases, liver histology can help guide treatment decisions, and family history of liver disease, especially hepatocellular carcinoma, may argue for early treatment in some cases. Outside of clinical trials, interferon is the agent of choice in most cases. Nucleos(t)ide analogues are secondary therapies, and children who receive these agents require careful monitoring for development of resistance. There are a few situations when treatment is indicated regardless of HBV DNA or alanine aminotransferase levels. There is still much to be elucidated about the appropriate use of HBV therapy in children. Until more clinical data and therapeutic options are available, a conservative approach is warranted. (HEPATOLOGY 2010.)

Primary hepatocellular carcinoma—etiology, pathogenesis, and prevention

Worldwide, primary hepatocellular carcinoma may be the most common cancer in men. Usually it occurs in association with cirrhosis or chronic hepatitis. In this article I present evidence that the majority of these cases are associated with, and probably caused by, persistent infection with hepatitis B virus. I also propose a model that describes the role of the hepatitis B virus in the pathogenesis of primary hepatocellular carcinoma. If persistent infection with hepatitis B virus is required for the development of most cases of primary hepatocellular carcinoma, prevention of such infections should prevent most cases of primary hepatocellular carcinoma. A vaccine against hepatitis B virus, prepared from surface antigen particles (HBsAg) harvested from the blood of hepatitis B virus carriers, has been safe and effective in preventing acute infection with hepatitis B virus in adult homosexual men. If it is equally safe and effective in young children, it will be administered widely to populations living in areas endemic for hepatitis B virus infections. Thereafter it may be possible to learn within five to 10 years whether the vaccine prevents chronic liver disease. If it does, it will be reasonable to conclude that it will also prevent primary hepatocellular carcinoma.

ANTIBODY TO HEPATITIS-B CORE ANTIGEN IN PATIENTS WITH PRIMARY HEPATIC CARCINOMA

Antibody to hepatitis-B core antigen (anti-HBc) was assayed in the serum of patients with primary hepatic carcinoma (P.H.C.) and controls from Hong Kong, West Africa, and the United States. In each region the prevalence of anti-HBc was higher in P.H.C. patients than in controls, ranging from 70 to 95% in the patients and from 20 to 68% in the controls from Asia and Africa; 24% of P.H.C. patients and 4% of controls from the U.S. had anti-HBc. These data support the hypothesis that chronic infection with hepatitis-B virus is aetiologically related to P.H.C., especially in Asia and Africa, although other factors must also be involved.

Lack of perinatal transmission of hepatitis B virus infection in senegal, West Africa

Between 1977 and 1980, 1442 pregnant women in Thies, Senegal, were tested for serologic markers of hepatitis B virus (HBV) infection. Of these, 9.8% were HBsAg(+), 59.9% were anti-HBs(+), and 15.6% had anti-HBc alone. Of 116 HBsAg(+) pregnant women, only 19.8% were HBeAg(+), a much lower proportion of infectious carriers than seen in Asian populations. Cord blood from 1353 babies was HBsAg(-), implying that the babies were not infected prior to birth. Four hundred sixty-two babies, including 88 born to HBsAg(+) mothers, were observed for 2 weeks to 38 months after birth. In contrast to observations in Asia, none of the babies became HBsAg(+) before 5 months of age, and only three of the 16 born to HBeAg(+) mothers became HBsAg(+) within the first year of life; all three developed chronic infections (i.e., HBsAg(+) for greater than or equal to 6 months. In the second year of life, six of 34 babies born to HBsAg(+), HBeAg(-)/anti-HBe(-) mothers became infected with HBV, and four of the six developed chronic infections. During the first 3 years of life, infections occurred at a higher rate in infants born to HBsAg(+) (17%) than to HBsAg(-) (4%) women. The latter group of infants included 4.0% of those born to anti-HBs(+) mothers, 4.6% born to anti-HBcAg(+), and 3.2% born to uninfected women. These observations indicate that HBV infections in Senegal usually do not occur perinatally, but do occur at high incidence later in infancy and childhood. Such infections can be prevented by the use of hepatitis B vaccine alone; administration of hepatitis B immune globulin should not be needed.

Hepatitis B Virus and the Prevention of Primary Hepatocellular Carcinoma

Primary hepatocellular carcinoma (PHC or hepatoma) is one of the most lethal and most common cancers in the world. Before 1950, several pathologists noted that PHC usually occurred in livers that w...

Spontaneous Seroconversion in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Implications for Interferon Therapy

This study compared rates of spontaneous hepatitis B e antigen (HBeAg)-positive to -negative seroconversion in chronic carriers of hepatitis B virus (HBV) with rates reported during interferon-alpha therapy. Four hundred fifty-four Asian-American HBeAg-positive HBV carriers, followed for 1-10 years, were tested approximately every 6 months for HBeAg. Patients with alanine aminotransferase levels > or = 50 IU/mL at entry had 1067.3 seroconversions/10(5) person-months in the 5- to 19-year age group, 1753.3 in the 20- to 34-year group, and 1257.2 in the 35- to 50-year group. Published data indicate that 30% of children and 33% of adults seroconvert during interferon-alpha treatment and follow-up. In our study population, spontaneous seroconversion occurred in 15% of children (95% confidence interval [CI], 8%-27%), 23% of adults 20-34 years (95% CI, 15%-34%), and 17% of adults 35-50 years (95% CI, 10%-28%) during the same interval. The high rate of spontaneous seroconversion should be weighed in decisions to treat HBV carriers with interferon-alpha.