Epidemiology of Hepatitis B: From Carrier to Cancer

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When R. Palmer Beasley suggested in the 1970s that the hepatitis B virus caused liver cancer, scientists all across the country said "definitely not."

"People were saying I was crazy," recollects Beasley. But despite the skepticism of his peers, working grueling hours overseas, at times lonely and isolated, Beasley developed a breakthrough in the prevention of hepatitis B infection in infants, and carried out studies that demonstrated a link between hepatitis B (serum hepatitis) and liver cancer. Liver cancer thus became one of the earliest human cancers demonstrated to have a viral cause, and the first one to have a definitive prevention.

Beasley served on the faculty of the UW School of Public Health (formerly Department of Preventive Medicine) from 1967 to 1986. Before becoming interested in hepatitis, he had worked on rubella (German measles) in Taiwan with Professor Thomas Grayston, who was the first dean and founder of the UW School of Public Health at the UW and later UW Vice President. Beasley accompanied Grayston to Taiwan in 1969 to begin a two-year project studying the efficacy of now widely-used rubella vaccine. While working on that project, Beasley became interested in hepatitis as "the infectious disease problem least understood and seemingly most important among those that remained unconquered after polio, smallpox, and measles had been brought under control." At that time, no hepatitis B vaccine existed; the virus had not even been cultured.

Baruch Blumberg of Fox Chase Institute in Philadelphia succeeded in detecting the hepatitis B antigen in the circulation of chronic carriers by using serum from hemophiliacs who, through multiple transfusions, had been repeatedly exposed from other carriers and therefore had antibodies to the virus. That work was later awarded the Nobel Prize. Blumberg's discovery led to a more sensitive and specific radioimmunoassay technique developed by Abbott Labs, which provided Beasley with the tool he needed to study the epidemiology of hepatitis B.

While at the UW, Beasley tested the Abbott method on an outbreak of the virus that occurred in a dialysis unit at the Veterans Administration Hospital in Seattle during 1971-72. "Prior to Blumberg's discovery, there was no way to detect the carrier state, and so there was a lot of transfusion-associated and dialysis-associated hepatitis in those days," notes Beasley. He explains that people infected with hepatitis B may come down with an acute infection, with or without illness, resulting in formation of antibodies that are subsequently protective, allowing the person to recover completely; or, they may enter the carrier state, in which the antibodies are not protective, for many years or for life, making their blood capable of spreading the disease. "There are about 300 million carriers world-wide, equally divided among males and females," notes Beasley. "About 75% of them are found in Asia, most of those in China. Of males, about 40% are going to die from liver cancer. Females have a lower cancer rate, about 15%."

Hepatitis B was known to be transmitted only from blood--by transfusions, injections, blood products, inadvertent needle sticks. But it occurred to Beasley to pose a very simple, but crucial question: How was the virus transferred prior to the advent of modern technology?

"Since transfusions are relatively recent in human history, how was this agent transmitted in nature before that?" he asked. Beasley says he "got a lot of puzzled looks" but no answers. "I suggested we ought to look to see if it isn't transmitted from mothers to babies, since that's the commonest way in nature that blood is shared between people. With that hypothesis I went to Taiwan and, with the Abbott test, began screening and detecting carrier pregnant women in the obstetric clinics at the hospitals in Taipei. After some months of doing this, we had determined that almost 20% of the mothers in Taiwan were hepatitis B carriers, which is a phenomenally high rate." That figure contrasts sharply to a rate of less than 1% in the U.S. "About 40% of the babies of those carrier-mothers became infected," he adds. Beasley's findings were published in the New England Journal of Medicine in 1975. "That was really the beginning of it all," he reflects.

Those babies all remained carriers but were clinically well, as were their mothers. The mothers that had higher levels of surface antigen in their blood were more infectious. Using results and methods developed by a group in Sweden, Beasley was able to show that the presence of something called the "E" antigen was an almost perfect predictor of which mothers would infect their babies. The E antigen is very closely associated with hepatitis B DNA circulating in the blood.

These new observations led to clinical trials to test the efficacy of hepatitis B immune globulin (HBIG) to protect newborn infants. He showed that babies receiving HBIG within a few hours of birth were protected, and those receiving it after 24 hours had no protection at all. So he refined the treatment to give the immune globulin to all babies within minutes after birth. In that study, there was a dramatic protective effect, and the incidence of infection was reduced by about 75%. "That was the first breakthrough in any protection against hepatitis B infections at all," he notes.

About that time, Beasley had started studies of chronic liver disease in the carriers. A series of tests on those individuals showed they had high levels of hepatitis B surface antigen; specifically, 70% of chronic hepatitis B cases, 80% of cirrhosis cases, and 90% of liver cancer cases had high levels, compared to only 20% of the general population.

Beasley designed a series of studies to test the hypothesis that the virus caused liver cancer, but he "ran into enormous skepticism by almost everybody. The world was not in any mood whatsoever to hear such a notion. The War on Cancer had begun in 1975, and the focus was substantially on environmental causes. The viral causes of cancer in animals had been acknowledged for a long time; but in humans, the link remained elusive. We're back to viruses now, but in the seventies, the world was all geared up to look at chemical causes," he explains.

"The world already thought it knew what caused liver cancer: aflatoxins," he continues. They are chemicals found in foodstuffs, like peanuts and corn, made by molds; they are widely distributed in nature, and cause demonstrable liver cancer in animals of almost every sort (see Ecogenetics). "Epidemiology studies going on around the world at the time showed that the geographic distribution of liver cancer in humans supported that ideait occurred in places like Africa where moldy food was likely to be found."

Somewhat discouraged, Beasley nevertheless proceeded and designed a large prospective study that became the basis for the later prizes he received.

He studied a sample of more than 22,000 government employees in Taiwan who were identified by screening for the hepatitis B surface antigen and other markers. Beasley tracked these participants to follow rates of chronic liver disease, cirrhosis, and liver cancer. The study was begun in late 1974, and has been ongoing ever since. Results were evident within the first several years: The liver cancers were occurring almost exclusively in hepatitis B carriers.

The study is showing that people with hepatitis B surface antigen are at least 60 times more likely to develop liver cancer than those without it. That relative risk is much larger than even that for smoking and lung cancer (20-25 times). "It's one of the highest relative risks that anyone has ever seen," says Beasley. "That might seem like overwhelming evidence of a causal relationship. But skepticism remained," he notes, "because many people feel that establishing causation requires elucidating a plausible mechanism by which the effect occurs."

Beaseley's efforts and subsequent work by other researchers eventually were enough to convince most people of the causal link between hepatitis and liver cancer. Beasley's work had firmly established that the mother-to-infant route is likely the fundamental route of transmission in sustaining the infections, in causing the high rates of infection, and in leading to chronic liver disease and cancer.

In honor of his achievements, Beasley was awarded the King Faisal International Prize in Medicine, given by King Faisal Foundation, Saudi Arabia, and the General Motors Charles S. Mott Prize in 1986 for research into the cause and prevention of cancer, a major American prize for cancer research. In 1987, Beasley became professor of epidemiology and dean of the School of Public Health at the University of Texas, Houston.

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