Note:  According to the American Family Physician, “The Hepatitis B Carrier State”, April 1986, volume 33, number 4, “In 95 percent of patients with acute hepatitis B, HbsAg disappears from the serum within one year.”  They go on to say, “Chronic hepatitis B is a well-recognized cause of hepatocellular carcinoma.  In the United States, alcoholic cirrhosis more commonly leads to primary hepatic cancer than does chronic hepatitis B infection…..Hepatitis B carriers with cirrhosis are at highest risk for primary hepatic carcinoma.  Studies have shown that cancer of the liver develops in approximately 12% of carriers with cirrhosis, as compared with 1 percent without cirrhosis.”

 

In other words, if you have hepatitis B, but do not have cirrhosis of the liver, your chances of getting cancer, according to the AFP article,  are slim – 1% of the 5% who are chronic carriers.  (Remember the 5% is among hepatitis B positive people, not the general population.)  Also remember that there are only around 10,000 reported cases of Hepatitis B each year, and that the number bandied about, 140,000 to 300,00 new cases each year, is based on sampling.  These cases were apparently asymptomatic, or they would have been reported. 

 

According to Vaccine in “Hepatitis B prevention in Europe: a preliminary economic evaluation”, 1995; 13 Suppl 1S54-7 approximately 1 out of 10 asymptomatic infections become chronic.

 

Also remember that hepatitis B is generally a “life style” disease, meaning most cases occur among those who are sexually promiscuous or intravenous drug users. - SM

 

http://www.fccc.edu/research/reports/current/london.reportframe.html

 

EPIDEMIOLOGY, PATHOGENESIS, AND PREVENTION OF HEPATITIS B VIRUS INFECTION AND LIVER CANCER

W. THOMAS LONDON, M.D., Senior Member; Adjunct Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA
ANNA P. O'CONNELL, A.B., Staff Scientist
MANETTE FINE, D.O., Research Physician
ABOUBAKRY DIALLO, M.D., Visiting Scientist, Army Health Service, Dakar, Senegal (until January 1998)
MALICK DIENE, M.D., Visiting Scientist, Army Health Service, Dakar, Senegal (from November 1998)
MAMADOU N'DIAYE, B.S., Visiting Scientist, Army Health Service, Dakar, Senegal (from June to October 1998)
GANG CHEN, M.D., Ph.D., Postdoctoral Associate
LONG-LONG GAO, M.D., Research Data Coordinator
JAMES JOHNSTON, B.A., Research Data Coordinator
(until March 1998)
JOYCE ATLESON, R.N., B.F.A., Nurse Coordinator
GAIL DUNCAN, B.S., Technical Specialist
LORA PASTERNAK, B.S., Research Specialist
KATHLEEN GILLESPIE, Data Technician
DIANE FAISON, Scientific Technician
MARLINE HERCEG, B.A., Scientific Technician (until December 1998)
KIMBERLY NEWMAN-McCOWN, Scientific Technician (from November 1998)
JEFFRY SAPUTELLI, Scientific Technician
MAUREEN CLIMALDI, Administrative Assistant
BARBARA HAMELL, Secretary (until March 1998)
LUCILLE SIMPKINS, Secretary (from April 1998)

Hepatocellular carcinoma (HCC) causes 300,000 to one million deaths per year worldwide, including 10,000 in the United States. The major etiological factors are chronic infection with hepatitis B virus (HBV), chronic infection with hepatitis C virus (HCV), and exposure to the Aspergillus mycotoxin, aflatoxin-B1 (AFB1). Globally, about 80% of HCC cases are associated with chronic HBV infection, and 15 to 20% with HCV infection. In the United States, HCV infection alone, or in combination with HBV infection or alcohol consumption, is the major risk factor for HCC.

Our research is concerned with identifying and quantitating specific environmental, viral, and genetic factors that affect the risk of HCC and learning how such factors influence risk. To accomplish these goals, seven years ago we initiated two large prospective studies of HCC. One study was in Haimen City, Jiangsu Province, People's Republic of China, and the other in Senegal, West Africa. At the same time, we started a randomized trial of the efficacy of early detection methods for the secondary prevention of HCC. These studies involve multiple collaborative efforts at Fox Chase (see EVANS, MASON, SEEGER, LITWIN, KRUGER, and TESTA reports).

STATISTICAL MODELING OF HEPATO-CELLULAR CARCINOMA MORTALITY DATA FROM HAIMEN CITY. ROSS,^§ LONDON, GAO, CHEN, in collaboration with EVANS^§

The goals of this analysis of the cohort data from Haimen City were to identify significant risk factors for death due to HCC, and to develop a statistical model to estimate an individual's risk of death from HCC over a specified time interval. The outcome measure for this analysis is age at death from HCC. In this cohort, HB surface antigen (HBsAg) measurements were made on each member at recruitment by the Haimen City Anti-epidemic Station (HCAS). A subsample of these blood specimens was subsequently sent to Fox Chase where validation HBsAg tests were performed. Comparisons of these paired results revealed that the Fox Chase and HCAS HBsAg measurements were discordant in approximately 6% of the samples. Assuming that the Fox Chase HBsAg test is the "gold standard," direct estimation of the risk associated with being HBsAg(+) from the entire cohort was prevented by the measurement error in the HCAS results. Failure to account for the covariate measurement error could result in a biased estimate of the risk associated with being HBsAg (+).

The age at onset analysis was conducted using a modification to Cox's proportional hazards model. The counting process approach to partial likelihood methods was used to accommodate the fact that both right censoring, and left truncation can be observed in these data. Let HBsAg_F = 1 when the Fox Chase HBsAg result is positive and 0 when the Fox Chase result is negative. Define HBsAg_H in an analogous fashion using the HCAS HBsAg results. Finally, for the i-th cohort member, let HBsAgi = HBsAg_F when the Fox Chase HBsAg measurement is available and HBsAgi = HBsAg_H, otherwise. The following hazard function model was used to statistically account for the measurement error identified in the HCAS HBsAg results:

if Fox Chase HBsAg result is available:

	l(t;xi, HBsAgi) = l0 (t)(exp{x'ib+ HBsAgi q})

otherwise:

	l(t;xi, HBsAgi) =	l 0 (t)	(	exp{x'ib + q}Pr(HBsAg_F  = 1| HBsAgi) +	)
				exp{x'i b}Pr(HBsAg_F  = 0| HBsAgi)

Where x_i is a vector of covariate values (excluding HBsAg_i) for the i-th cohort member; b and q are parameters to be estimated; l₀(t) is the baseline hazard at time t; and l(t; x_i, HBsAg_i) is the hazard at time t for a cohort member with covariate data x_i and HBsAg_i. In essence, the information from the validation data set was used to improve the risk estimate of HCC associated with being HBsAg (+) by reducing the bias resulting from the measurement error in the surface antigen data available for the majority of the cohort.

The data used for this analysis included HCC deaths that were observed in the cohort through January 1, 1998. A stepwise elimination procedure was used to find the most parsimonious model. The resulting model included six significant risk factors for HCC death (see Table 1). Using this statistical model, we estimate that the 5-year probability of death from HCC for a 50-year-old individual from the lowest risk subset of the population is 0.08%. In contrast, an individual of the same age in the highest risk subset has an estimated 5-year risk of mortality from HCC of over 20%. This corresponds to a risk ratio of over 300. Additional research into the statistical issues concerning covariate measurement error and validation of this model remain to be done.

RELATIONSHIP OF VITAMINS TO HEPATOCELLULAR CARCINOMA RISK. LONDON, CHEN, JOHNSTON, in collaboration with McGLYNN,^f BUETOW,^g O'BROIN,^h FALL,^d NIOUKY,^d SHEN,^a CHEN,^c LIN,^b M'BOUP^e

In experimental animals exposed to AFB1, insufficiency of certain dietary components including choline, methionine, folate and vitamin B₁₂, increase the risk of HCC. We tested the hypothesis that lower serum levels of folate and/or vitamin B₁₂ would be associated with an increased risk of HCC. Because homocysteine levels are elevated in response to folate deficiency, we predicted that folate and B₁₂ levels would be higher and homocysteine levels lower in Senegalese men; HCC risk is lower in Senegal than in Haimen City despite very high exposures to aflatoxin. Twenty members of the Senegalese Army cohort and 42 men from Haimen City donated a blood sample and completed a dietary questionnaire. Blood samples were assayed for plasma homocysteine, plasma folate, plasma vitamin B₁₂ and red blood cell folate levels (performed by S. O'Broin at the Folate Laboratory of St. James Hospital, Dublin). Contrary to our predictions, the Senegalese participants had lower plasma folate levels (2.2 versus 10.8 ng/ml, p<0.0001) and higher homocysteine (18.6versus 7.4 mg/l, p<0.0001) and higher vitamin B₁₂ levels (776 versus 357 pg/ml, p<0.0001) than the Chinese. To determine whether these factors were related to HBV infection, we evaluated associations of the plasma concentrations of folate, B₁₂, and homocysteine with HBsAg and HB e antigen (HBeAg) positivity. In both locations, HBsAg negative men had somewhat higher homocysteine and lower folate levels than HBsAg positive men. These differences were only statistically significant when the subjects from the two locations were combined. There were no differences with respect to HBeAg positivity. In Haimen, but not in Senegal, HBsAg negative men had higher B₁₂ levels than HBsAg positive men.

These interrelationships are complex and require further study to clarify. At this stage however, it is apparent that folate levels in Senegal are very low and homocysteine levels are very high, a range that is thought to predispose to cardiovascular disease. Whether there is an increased risk of heart disease in Senegal is unknown.

SECONDARY PREVENTION OF HEPATOCELLULAR CARCINOMA IN HAIMEN CITY. GAO, LONDON, CHEN, PASTERNAK, in collaboration with EVANS,^§ ROSS,^§ BALSHEM,^§ CHEN,^c LIN,^b SHEN^a

The overall goal of this project was to determine whether early detection of HCC, using a-fetoprotein (AFP) screening followed by ultrasonography (US), reduces mortality from this otherwise lethal disease. A randomized trial of these modalities was conducted in Haimen City among 14,794 chronic carriers of HBV. The study population comprised 9630 men and 5164 women, ranging in age from 29 to 64 years, representing all 36 townships in Haimen. Two cohorts were studied for five years; one was monitored at six-month intervals, while the other remained unmonitored (receiving usual care). Randomization by village resulted in 7317 persons assigned to the monitored and 7477 assigned to the unmonitored cohort. The cohorts were well balanced by age and gender.

As reported previously, the major problem with this study was that persons diagnosed with HCC did not receive optimal therapy. Because of the high out-of-pocket cost of hepatic surgery and other invasive treatments in China, most patients with small (<3cm) HCCs did not have their tumors resected or have intralesional alcohol treatment. Nevertheless, the study does permit evaluation of the performance of AFP as a screening tool.

From January 1994 to February 1998, 27,032 AFP screening tests were performed. Six thousand eight hundred-nine subjects were tested; 6,102 subjects were tested more than once. Of the 704 subjects who had at least one AFP above the normal range (>20ng/ml), 21% were diagnosed with HCC during follow-up. Thirty-six percent of individuals who were diagnosed with HCC had no prior elevation of AFP detected. Elevated AFPs among those subjects who did not develop HCC were associated with elevated alanine amino-transferase, male gender, and history of acute hepatitis in adulthood. Only 22% of HCCs in the monitored group were of a size considered surgically resectable (<3cm in diameter) at diagnosis compared with 15% of HCCs in the unmonitored group.

Population screening of HBV carriers did not reduce HCC mortality, which was 698/100,000 in the unmonitored group and 750/100,000 in the monitored group. AFP was neither sufficiently sensitive nor specific to be an adequate screening method for the secondary prevention of HCC.

PUBLICATIONS

EVANS, A.A., FINE, M.K., LONDON, W.T. Do Asian HBV carriers differ from non-Asian carriers? Letter to the Editor. Lancet 351:1285-1286, 1998.

LONDON, W.T. Hepatocellular carcinoma: Etiology and pathogenesis. In American Society of Clinical Oncology Educational Book, edited by M.C. Perry. ASCO, Alexandria, VA, pp. 168-175, 1998.

Papers in press at time of previous report:

EVANS, A.A., LONDON, W.T. The epidemiology of hepatitis B virus. In Viral Hepatitis, edited by A. J. Zuckerman, H.C. Thomas. Harcourt Brace and Co., Ltd., pp. 107-114, 1998.

EVANS, A.A., O'CONNELL, A.P., PUGH, J.C., MASON, W.S., SHEN, F-M., CHEN, G-C., LIN, W-Y., DIA, A., M'BOUP, S., DRAMÉ, B. AND LONDON, W.T. Geographic variation in viral load among hepatitis B carriers with differing risks of hepatocellular carcinoma. Cancer Epidemiol. Biomarkers Prev. 7:559-565, 1998.

MASON, W.S., EVANS, A.A., LONDON, W.T. Hepatitis B virus replication, liver disease and hepatocellular carcinoma. In Human Tumor Viruses, edited by D. McCance. ASM Publications, Washington DC, pp. 253-281, 1998.

^§   Fox Chase researcher

^a   F-M. Shen: Department of Epidemiology, Shanghai Medical University, Shanghai, P.R. China

^b   W-Y. Lin: Medical Director, Haimen City Anti-Epidemic Station, Haimen, P.R. China

^c   G-C. Chen: Haimen City Anti-Epidemic Station, Haimen, P.R. China (until June 1, 1998)

^d   C. Fall, G. Niouky: Army Health Service, Camp Dial Diop, Dakar, Senegal

^e   S. M'Boup: Laboratory of Bacteriologie & Virologie, Hospital Le Dantec, Dakar, Senegal

^f   K. McGlynn: Environmental Epidemiology Branch, DCEG, NCI, Bethesda, MD 20892

^g   K. Buetow: Chief, Laboratory of Population Genetics, DCEG, NCI, Bethesda, MD 20892

^h   S. O'Broin: Department of Hematology, Central Pathology Laboratory, St. James Hospital, Dublin 8, Ireland

Illustrations or unpublished data in these reports should not be used without permission of the author.

ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.