HBV, the Silent Killer Among Us

(Howard Liu M.D.)

Recently, a very famous Hong Kong singer, Luo Wen, was diagnosed with inoperable liver cancer (hepatoma or hepatic cellular carcinoma). Liver cancer in Chinese is mostly associated with Hepatitis B. Recent survey showed that among Chinese living in New York City, 13% of them are hepatitis B virus (HBV) carrier. Another survey conducted recently by American Chinese Medical Association showed approximate 15% HBV carrier rate among Chinese living in Boston area. This article will address how HBV transmission, symptoms of HBV carrier state, diagnosis and treatment of HBV, relationship between HBV infection and liver cancer and hopefully it will shed light on the reason why HBV is the number one silent killer among Chinese.

The Quiet Passenger

The way HBV is transmitted helps explain why HBV is so prevalent among Chinese.

Right now, 5% of the world's population is infected with HBV. Of those, 75% are Asian (majority of them are Chinese). Infection rate differs among different parts of the World. High prevalence area includes China, Southeastern Asia, and Sub-Saharan Africa, with infection rate ranging from 10 to 20%. Japan, central Asia, Middle East, Mediterranean area, and Latin America have infection rate from 3 to 5%. Low prevalence area such as the United States, Canada, and Western Europe has infection rate of 0.1-2%.

In high prevalence area like China vertical transmission from mother to child is the major mode of transmission. Contrary to common belief that HBV is transmitted from mother to fetus via the placenta, the majority of transmission occurs during delivery where the newborn is exposed to maternal blood. This is why giving child born of infected mother immunloglobulin against HBV is so effective against maternal-fetal transmission (together with giving the newborn HBV vaccines). Chinese females of reproductive age have as high as 50% HBV carrier rate, according to one survey. That helps explain the high prevalence of HBV infection among Chinese children. They are the unwilling recipients from their infected mothers. Even though HBsAg (surface antigen on HBV particles) can be found in all body fluid examined, oral ingestion of saliva or milk is not a effective way to transmit HBV. Another mode of transmission is horizontal transmission among children through minor skin break, mucosal break or close bodily contact. HBV is also a tough virus that can survive outside the body for long period of time, contaminating toothbrushes, razor, and toys. That may explain why family members of infected individual are at particularly high risk for HBV infection. Sexually transmission and intravenous drug use can also transmit HBV. This is the usual mode how adults acquire HBV. Blood products in the US and China are routinely screened for HBV and poses minimal risk of transmission, but there are reports of illegal sale of contaminated blood causing HIV and HBV infection.

Like a quiet passenger who travels from city to city, HBV is quietly passed from mother to child, from one child to another, from one sexual partner to another, and from one family member to another. But that also sets up deadly consequence down the road.　

Silence of the Lamb

Contrary to most other diseases, HBV infection is a silent disease, causing substantial damage to the liver before it becomes symptomatic. The two deadly consequences are cirrhosis and liver cancer.

Liver is an organ situated in the right upper part of the abdomen, protected by the rib cage on the right side of the body, and works as a factory of decontamination and detoxification of all kinds of toxins a human body produces every day. The majority of the liver tissue, except the outside capsule, has minimal pain innervation. So except for the case of enlargement of the liver, which causes stretching of the liver capsule and thus pain, inflammation and damage to the liver has little pain and other symptoms. So HBV infecting the liver cells causes smothering inflammation of the liver cells, fibrosis and damage of liver tissue without any warning signs.

Eventually the majority of the liver tissue is replaced by fibrosis and that leads to shrinkage and hardening of the liver, which is called cirrhosis. That can lead to catastrophic bleeding from the gastrointestinal tract, jaundice (yellow skin), swelling of the abdomen, confused mental state, coma, or death. When the damaged liver cells try to repair themselves, some of the repair process goes unregulated and the cell becomes cancer cell. Cancer cells proliferate and cause little symptoms until the cell mass reaches more than several centimeters in size. When the patient notices pain or discomfort at the liver area, constant nausea or vomiting, anorexia, weight loss, fatigue, the cancer usually has spread to other part of the body and thus inoperable. We will talk about liver cancer, its symptoms, diagnosis, treatment, and prevention on our next article.

Those infected as a young child have about 90% chance of developing cirrhosis. Of those developing cirrhosis, one in four will develop liver cancer. There was one study conducting in Taiwan following more than 23 thousand patients, of whom 15% are HBV carriers, if patient is positive for HBeAg, which is an indicator for active HBV infection, he/she has a 223 fold increase chance of developing liver cancer when comparing to non carrier. If a patient is a HBV carrier who also develops cirrhosis, his/her chance of developing liver cancer is as high as 3% per year. That is a 60% chance of having a deadly cancer over a twenty-year period! Talk about the roar of the tiger after a long silence!

Diagnosis of A Killer

There are two reasons to diagnose HBV. One is to find out whether one is infected with the virus. The other is diagnosis made for prevention or treatment of infection.

To find out whether one has been infected with HBV, a simple blood test requiring 2 to 3cc of blood is sufficient. It is a common belief in Chinese culture that blood is precious and blood drawn, however small in quantity, can be detrimental to health. This fear factor definitely can prevent (*) one from getting tested not only for deadly viruses like HBV or HIV, but also for anemia, cholesterol, liver function or kidney function. The truth is one has more blood than one can handle (*). The human body produces about 50cc of fresh blood every day from bone marrow. Because of volume of blood remains the same, otherwise the human body will explode as a result, about 50cc of old blood is being destroyed by the spleen (an organ located on the left upper part of the abdomen). So taking 2-3cc of blood that would otherwise be destroyed by the spleen is not a big deal for the body.

To test for HBV infection, a single test of HBsAg is sufficient. If HBsAg is negative, you are pretty much sure that you do not have the virus. One can be vaccinated against future infection if one has not been immuned, which we will talk about on our next section when we talk about prevention of HBV infection. If the test is positive, subsequent blood tests are necessary to decide whether one is very infectious to people around him/her and whether he/she is a candidate for treatment.

Those tests include HBeAg, HBeAb, HBV DNA, ALT, and alpha-fetal protein. Please see the table explaining those tests. If HBeAg is positive, that person is very infectious and definitely should seriously consider treatment and vaccinating family members against HBV. We will next talk about treatment candidate on our next section, which depends on HbeAg, HBV DNA, ALT status.

Treatment of HBV

It is estimated that one in four HBV carrier will die of HBV related disease, including cirrhosis and liver cancer. So treatment is critical.

There are now two FDA approved treatments for HBV. First treatment is Interferon (IFN). After 3 to 6 months of treatment, one can expect 33% chance of losing HBeAg and HBV DNA six to twelve months post treatment. The most important determining factor is ALT. Candidates for IFN include those with elevated ALT and positive HBV DNA. Status of HbeAg is important because those with negative HbeAg tends to have higher relapse rate and thus need longer treatment. The higher the ALT, the better is the response to IFN. If ALT is normal, whether or not one is positive for HbeAg or HBV DNA, response to IFN is poor (<10%). If ALT, HbeAg, DNA are all negative, that is indication that there is no active HBV replication and thus no treatment is necessary.

The second treatment is Lamivudin (3TC). In contrast to Interferon, which is a strong stimulator of the immune system but a mild antiviral medication, Lamivudin is a potent antiviral pill. It decreases viral load by 2-3 log after one month of treatment. Similar to Interferon, the higher the ALT, the better is the response. If ALT is normal, 1-2x normal, 2-5x normal, or >5x normal, the seroconversion rate is 2%, 9%, 21%, and 47% respectively.

The choice of one treatment versus another depends on side effect profile and duration of treatment effects. Lamivudin is usually well tolerated and is easy to take as a pill a day. Interferon is subcutanous injection three times a week and is associated with flu-like symptoms and depression. But Interferon has long lasting effects beyond two years post treatment. Lamivudin clears HbeAg in 33% of cases after three year of treatment but is associated with a as high as 49% HBV mutation rate. How long the virus remains responsive to Lamivudin remains an unanswered question.

The obvious question then is whether the combination of the two, one potent immune stimulator, one potent antiviral, will have additive effect. Unfortunately, clinical trials combining the two have been disappointing. Combination is no more effective than either one alone.

Even when there is no seroconvertion, treatment against HBV may be beneficial in the long run. There are examples of patients getting off the liver transplant list after treatment despite the lack of seroconvertion. Questions remain whether there is survival benefit in patients who only had their ALT lowered or those having relapse after cessation of treatment (when comparing with patients who had never been treated).

Herbal medicine has been touted as alternative and inexpensive way to treat HBV. The authors had conversations with an herbal expert from Mainland China who specializes in HBV treatment. Even he acknowledged that herbal treatment is used in China because Interferon is too expensive. When questioning regarding the rate of seroconvertion, he said that he had no data but he knew of examples of lowering ALT after treatment. One patient told us his story of spending large sum of money buying herbal medicine, only to find out the side effects are intolerable after just a few days of treatment. Because of the lack of data, the clinical efficacy remains unproven.

Relationship between HBV and liver cancer

Liver cancer is a much-feared diagnosis because most of the cancers are not operable by the time of diagnosis. Radiation treatment or chemotherapy is not effective against liver cancer. Median survival is between 6 to 12 months. So prevention is the key.

Liver cancer in Chinese is mainly associated with two risk factors. One is HBV infection, the other is Afla-toxin (which commonly contaminates corn,

soybeans, and peanuts). As we mention above, HBV carrier has a much higher chance of developing liver cancer than non-carrier. Clinical trials have been conducted trying to determine if screening for alpha-fetoprotein every 6 months can find liver cancer at its early stage and thus more operable. Experience from both Alaska and Hong Kong both showed promising results. Comparing with cancer found when patients are symptomatic, cancers tend to be smaller and more operable when they are found after Alpha-protein screen is positive. During HBV screening in Chinatown one patient told his successful story of detecting his liver cancer at 1cm stage after screening for alpha-fetoprotein, which would have been totally asymptomatic and undetectable.

Please read our next article for details regarding liver cancer.

Prevention Is Much Better than Treatment

Obviously, prevention is a much better strategy than treating a disease once it has developed. All children born in the US now are required to have HBV vaccinated. The New England Journal of Medicine published an article in 1997 reported a dramatic decrease in Childhood hepatocelluar carcinoma (liver cancer). First five years after the nationwide hepatitis B vaccination program, rate of liver cancer in children dropped 20%, and in 10 years the rate dropped 50%! Surgeons in the past were frequently infected by HBV because of frequent skin break and exposure to patient’s blood. After vaccination against HBV become part of the job requirement, infection rate drops dramatically. So vaccination is a very effective mean to prevent future infection in oneself and in family members of those infected with HBV. Vaccination can also prevent development of liver cancer.

Because 10 to 20% of Chinese are infected with HBV, we recommend that every Chinese check his/her own HBV status. If one is positive, then one can seek appropriate treatment and monitor for early development of liver cancer. Their family members should also be vaccinated against HBV because of high incidence of cross-infection among family members. If one is negative, vaccination against HBV would provide life-long protection against a deadly virus.

One elderly Chinese female from Mainland China was tested during ACMA sponsored free HBV screening and was found to be HBV carrier for the first time in her life. Subsequently, the two grandchildren she takes care of were tested for HBV immediately. Fortunately, they have not been infected and they quickly received HBV vaccines. Her son and daughter in law were also tested and vaccinated against HBV. She is currently undergoing further testing and monitored for early signs of liver cancer.

Please take care of yourself, so you can take care of the ones you love.