Liver Cancer (cont.)
What are the population characteristics (epidemiology) of
liver cancer?
In the U.S. the highest frequency of liver cancer occurs in immigrants from Asian
countries, where liver cancer is common. The frequency of liver cancer among Caucasians is the
lowest, whereas among African-Americans and Hispanics, it is intermediate. The
frequency of liver cancer is high among Asians because liver cancer is closely linked to chronic
hepatitis B infection. This is especially so in individuals who have been
infected with chronic hepatitis B for most of their lives. If you take a world
map depicting the frequency of chronic hepatitis B infection, you can easily
superimpose that map on a map showing the frequency of liver cancer.
The initial presentation (symptoms) of liver cancer in patients in areas of high
liver cancer
frequency is quite different from that seen in low frequency areas. Patients
from high frequency areas usually start developing liver cancer in their 40s, and the
cancer is usually more aggressive. That is, the liver cancer presents with severe
symptoms and is inoperable (too advanced for surgery) at the time of diagnosis.
Also, in these areas, the frequency of liver cancer is three to four times higher in men
than in women, and most of these patients are infected with chronic hepatitis B.
In contrast, liver cancer in lower risk areas occurs in patients in their 50s and 60s
and the predominance of men is less striking.
What are the risk factors for liver cancer?
Hepatitis B infection
The role of hepatitis B virus (HBV) infection in causing liver cancer is well
established. Several lines of evidence point to this strong association. As
noted earlier, the frequency of liver cancer relates to (correlates with) the frequency
of chronic hepatitis B virus infection. In addition, the patients with hepatitis
B virus who are at greatest
risk for liver cancer are men with hepatitis B virus cirrhosis (scarring of the liver) and a family
history of liver cancer. Perhaps the most convincing evidence, however, comes from a
prospective (looking forward in time) study done in the 1970's in Taiwan
involving male government employees over the age of 40. In this study, the
investigators found that the risk of developing liver cancer was 200 times higher among
employees who had chronic hepatitis B virus as compared to employees without chronic
hepatitis B virus!
Studies in animals also have provided evidence that hepatitis B virus can cause liver
cancer. For
example, we have learned that liver cancer develops in other mammals that are naturally
infected with hepatitis B virus-related viruses. Finally, by infecting transgenic mice with
certain parts of the hepatitis B virus, scientists caused liver cancer to develop in mice
that do not usually develop liver cancer. (Transgenic mice are mice that have
been injected with new or foreign genetic material.)
How does chronic hepatitis B virus cause liver cancer? In patients with both chronic
hepatitis B virus and
liver cancer,
the genetic material of hepatitis B virus is frequently found to be part of the genetic
material of the cancer cells. It is thought, therefore, that specific regions of
the hepatitis B virus genome (genetic code) enter the genetic material of the liver cells.
This hepatitis B virus genetic material may then disrupt the normal genetic material in the
liver cells, thereby causing the liver cells to become cancerous.
The vast majority of liver cancer that is associated with chronic hepatitis B
virus occurs in
individuals who have been infected most of their lives. In areas where hepatitis
B virus is
not always present (endemic) in the community (for example, the U.S.), liver cancer is relatively
uncommon. The reason for this is that most of the people with chronic hepatitis
B virus in
these areas acquired the infection as adults. However, liver cancer can develop in
individuals who acquired chronic hepatitis B virus in adulthood if there are other risk
factors, such as chronic alcohol use or co-infection with chronic hepatitis C
virus infection.
Hepatitis C infection
Hepatitis C virus (HCV) infection is also associated with the development of
liver cancer. In fact, in Japan, hepatitis C virus is present in up to 75% of cases of liver
cancer. As with
hepatitis B virus, the majority of hepatitis C virus patients with liver cancer have associated cirrhosis (liver
scarring). In several retrospective-prospective studies (looking backward and
forward in time) of the natural history of hepatitis C, the average time to
develop liver cancer after exposure to hepatitis C virus was about 28 years. The liver cancer occurred about eight
to 10 years after the development of cirrhosis in these patients with hepatitis
C. Several prospective European studies report that the annual incidence
(occurrence over time) of liver cancer in cirrhotic hepatitis C virus patients ranges from 1.4 to 2.5%
per year.
In hepatitis C virus patients, the risk factors for developing liver cancer include the presence of
cirrhosis, older age, male gender, elevated baseline alpha-fetoprotein level (a
blood tumor marker), alcohol use, and co-infection with hepatitis B virus. Some earlier
studies suggested that hepatitis C virus genotype 1b (a common genotype in the U.S.) may be a
risk factor, but more recent studies do not support this finding.
The way in which hepatitis C virus causes liver cancer is not well understood. Unlike
hepatitis B virus, the
genetic material of hepatitis C virus is not inserted directly into the genetic material of
the liver cells. It is known, however, that cirrhosis from any cause is a risk
factor for the development of liver cancer. It has been argued, therefore, that
hepatitis C virus,
which causes cirrhosis of the liver, is an indirect cause of
liver cancer.
On the other hand, there are some chronic hepatitis C virus infected individuals who have
liver cancer without cirrhosis. So, it has been suggested that the core (central) protein
of hepatitis C virus is the culprit in the development of liver cancer. The core protein itself (a part
of the hepatitis C virus) is thought to impede the natural process of cell death
or interfere with the function of a normal tumor suppressor (inhibitor) gene
(the p53 gene). The result of these actions is that the liver cells go on living
and reproducing without the normal restraints, which is what happens in cancer.
Alcohol
Cirrhosis caused by chronic alcohol consumption is the most common
association of liver cancer in the developed world. Actually, we now understand that many
of these cases are also infected with chronic hepatitis C virus. The usual setting is an
individual with alcoholic cirrhosis who has stopped drinking for ten years, and
then develops liver cancer. It is somewhat unusual for an actively drinking alcoholic to
develop liver cancer. What happens is that when the drinking is stopped, the liver cells
try to heal by regenerating (reproducing). It is during this active regeneration
that a cancer-producing genetic change (mutation) can occur, which explains the
occurrence of liver cancer after the drinking has been stopped.
Patients who are actively drinking are more likely to die from non-cancer
related complications of alcoholic liver disease (for example, liver failure). Indeed,
patients with alcoholic cirrhosis who die of liver cancer are about 10 years older than
patients who die of non-cancer causes. Finally, as noted above, alcohol adds to
the risk of developing liver cancer in patients with chronic hepatitis C virus or
hepatitis B virus infections.
Aflatoxin B1
Aflatoxin B1 is the most potent liver cancer-forming chemical known. It is a
product of a mold called Aspergillus flavus, which is found in food that has
been stored in a hot and humid environment. This mold is found in such foods as
peanuts, rice, soybeans, corn, and wheat. Aflatoxin B1 has been implicated in
the development of liver cancer in Southern China and Sub-Saharan Africa. It is thought
to cause cancer by producing changes (mutations) in the p53 gene. These
mutations work by interfering with the gene's important tumor suppressing
(inhibiting) functions.
Drugs, medications, and chemicals
There are no medications that cause liver cancer, but female hormones (estrogens) and
protein-building (anabolic) steroids are associated with the development of
hepatic adenomas. These are benign liver tumors that may have the potential to
become malignant (cancerous). Thus, in some individuals, hepatic adenoma can
evolve into cancer.
Certain chemicals are associated with other types of cancers found in the
liver. For example, thorotrast, a previously used contrast agent for imaging,
caused a cancer of the blood vessels in the liver called hepatic angiosarcoma.
Also, vinyl chloride, a compound used in the plastics industry, can cause
hepatic angiosarcomas that appear many years after the exposure.
Hemochromatosis
Liver cancer will develop in up to 30% of
patients with hereditary hemochromatosis.
Patients at the greatest risk are those who develop cirrhosis with their
hemochromatosis. Unfortunately, once cirrhosis is established, effective removal
of excess iron (the treatment for hemochromatosis) will not reduce the risk of
developing liver cancer.
Cirrhosis
Individuals with most types of cirrhosis of the liver are at an increased
risk of developing liver cancer. In addition to the conditions described above (hepatitis
B, hepatitis C, alcohol, and hemochromatosis), alpha 1 anti-trypsin deficiency,
a hereditary condition that can cause emphysema and cirrhosis, may lead to liver
cancer.
Liver cancer is also strongly associated with hereditary tyrosinemia, a
childhood biochemical abnormality that results in early cirrhosis.
Certain causes of cirrhosis are less frequently associated with liver cancer than are
other causes. For example, liver cancer is rarely seen with the cirrhosis in Wilson's
disease (abnormal copper metabolism) or primary sclerosing cholangitis (chronic
scarring and narrowing of the bile ducts). It used to be thought that liver
cancer is
rarely found in primary biliary cirrhosis (PBC) as well. Recent studies,
however, show that the frequency of liver cancer in PBC is comparable to that in other
forms of cirrhosis.
Next: What are the symptoms of liver cancer? »
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