Liver cancer (hepatocellular carcinoma) is a cancer arising from the liver. It is also known as primary liver cancer or hepatoma. The liver is made up of different cell types (for example, bile ducts, blood vessels, and fat-storing cells).
However, liver cells (hepatocytes) make up 80% of the liver tissue. Thus, the majority of primary liver cancers (over 90%-95%) arises from liver cells and is called hepatocellular cancer or carcinoma.
When patients or physicians speak of liver cancer, however, they are often referring to cancer that has spread to the liver, having originated in other organs (such as the colon, stomach, pancreas, breast, and lung). More specifically, this type of liver cancer is called metastatic liver disease (cancer) or secondary liver cancer.
This is a much more common problem around the world than primary liver cancer and frequently leads toconfusion, because the term liver cancer actually can refer to either metastatic liver cancer or hepatocellular cancer. The subject of this article is hepatocellular carcinoma, which I will refer to as liver cancer.
What is the scope of the liver cancer problem?
Liver cancer is the third most common cancer in the world. A deadly cancer, liver cancer will kill almost all patients who have it within a year. In 2000, it was estimated that there were about 564,000 new cases of liver cancer worldwide, and a similar number of patients died as a result of this disease. About three-quarters of the cases of liver cancer are found in Southeast Asia (China, Hong Kong, Taiwan, Korea, and Japan). Liver cancer is also very common in sub-Saharan Africa (Mozambique and South Africa).
The frequency of liver cancer in Southeast Asia and sub-Saharan Africa is greater than 100 cases per 100,000 population. In contrast, the frequency of liver cancer in North America and Western Europe is much lower, less than five per 100,000 population. However, the frequency of liver cancer among native Alaskans is comparable to that seen in Southeast Asia.
This reflects the prevalence of hepatitis B infection, which is the most common cause of this cancer worldwide. Recent data show, however, that the frequency of liver cancer in the U.S. overall is rising. This increase is due primarily to rising obesity and diabetes rates, and to chronic hepatitis C, another infection of the liver that causes liver cancer.
The initial symptoms (the clinical presentations) of liver cancer are variable. It is becoming much more common for patients to be identified by screening people at high risk for the cancer and finding the cancer before there are any symptoms at all.
In countries where liver cancer is very common, the cancer generally is discovered at a very advanced stage of disease for several reasons. For one thing, areas where there is a high frequency of liver cancer are generally developing countries where access to health care is limited.
For another, screening examinations for patients at risk for developing liver cancer are not available in these areas. In addition, patients from these regions may actually have more aggressive liver cancer disease. In other words, the tumor usually reaches an advanced stage and causes symptoms more rapidly. In contrast, patients in areas of low liver cancer frequency tend to have liver cancer tumors that progress more slowly and, therefore, remain without symptoms longer.
There are no specific symptoms of liver cancer, and in fact, the earliest signs are usually subtle and can be mistaken for simple worsening of cirrhosis and liver function. Abdominal pain is uncommon with liver cancer and usually signifies a very large tumor or widespread involvement of the liver. Additionally, unexplained weight loss or unexplained fevers are warning signs of liver cancer in patients with cirrhosis.
These symptoms are less common in individuals with liver cancer in the U.S. because these patients are usually diagnosed at an earlier stage. However, whenever the overall health of a patient with cirrhosis deteriorates, every effort should be made to look for liver cancer.
A common initial presentation of liver cancer in a patient with compensated cirrhosis (meaning that there are no complications of liver disease) is the sudden onset of a complication. For example, the sudden appearance ofascites (abdominal fluid and swelling), jaundice (yellow color of the skin), or muscle wasting without causative (precipitating) factors (for example, alcohol consumption) suggests the possibility of liver cancer.
What's more, the cancer can invade and block the portal vein (a large vein that brings blood to the liver from the intestine and spleen). When this happens, the blood will travel paths of less resistance, such as through esophageal veins.
This causes increased pressure in these veins, which results in dilated (widened) veins called esophageal varices. The patient then is at risk for hemorrhage from the rupture of the varices into the gastrointestinal tract. Rarely, the cancer itself can rupture and bleed into the abdominal cavity, resulting in bloody ascites.
On physical examination, an enlarged, sometimes tender, liver is the most common finding. Liver cancers are very vascular (containing many blood vessels) tumors. Thus, increased amounts of blood feed into the hepatic artery (artery to the liver) and cause turbulent blood flow in the artery. The turbulence results in a distinct sound in the liver (hepatic bruit) that can be heard with a stethoscope in about one-quarter to one-half of patients with liver cancer.
Any sign of advanced liver disease (for example, ascites, jaundice, or muscle wasting) means a poor prognosis. Rarely, a patient with liver cancer can become suddenly jaundiced when the tumor erodes into the bile duct. The jaundice occurs in this situation because both sloughing of the tumor into the duct and bleeding that clots in the duct can block the duct.
In advanced liver cancer, the tumor can spread locally to neighboring tissues or, through the blood vessels, elsewhere in the body (distant metastasis). Locally, liver cancer can invade the veins that drain the liver (hepatic veins).
The tumor can then block these veins, which results in congestion of the liver. The congestion occurs because the blocked veins cannot drain the blood out of the liver. Normally, the blood in the hepatic veins leaving the liver flows through the inferior vena cava, which is the largest vein that drains into the heart.
In African patients, the tumor frequently blocks the inferior vena cava. Blockage of either the hepatic veins or the inferior vena cava results in a very swollen liver and massive formation of ascites. In some patients, as previously mentioned, the tumor can invade the portal vein and lead to the rupture of esophageal varices.
Regarding distant metastases, liver cancer frequently spreads to the lungs, presumably by way of the bloodstream. Usually, patients do not have symptoms from the lung metastases, which are diagnosed by radiologic (X-ray) studies. Rarely, in very advanced cases, liver cancer can spread to the bone or brain. These are an infrequent problem in many patients who do not live long enough to develop these complications.
Hepatitis B infection
Hepatitis B can be caught from contaminated blood products or used needles or sexual contact but is frequent among Asian children from contamination at birth or even biting among children at play. 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 1970s 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 infection.
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 viruses related to the hepatitis B virus. 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, and very few develop an ongoing (chronic active) infection, which happens as often as 15% of the time in Asia.
Hepatitis C infection
Hepatitis C virus (HCV) infection is more difficult to get than hepatitis B. It usually requires direct contact with infected blood, either from contaminated blood products or needles. HCV 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%-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. Therefore, it has been argued 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.
Cirrhosis caused by chronic alcohol consumption is the most common association of liver cancer in the developed world. In fact, at autopsy, as many as half of alcoholics previously unsuspected to have cancer will have early evidence of cancer hidden within the liver. Many of these people are also infected with chronic hepatitis C virus.
The usual setting is an individual with alcoholic cirrhosis who has stopped drinking for 10 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.
More importantly, if an alcoholic does not stop drinking, he or she is unlikely to live long enough to develop the cancer. Alcoholics 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 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 diagnostic imaging studies, 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.
Liver cancer will develop in up to 30% of patients with hereditary hemochromatosis (a disorder in which there is too much iron stored in the body, including in the liver). 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.
Diabetes and obesity
Over the past decade, the incidence of liver cancer in the United States has risen significantly, paralleling the rise in obesity. Although it is hard to separate the effects of diabetes from obesity on the liver, both conditions can cause chronic damage and accumulation of fat within the liver. This is a disease called NASH (non-alcoholic steatohepatitis), which is present in up to 5% of North Americans.
Fatty liver disease like this causes damage to the individual liver cells and may lead to cirrhosis in some people, thereby increasing the risk of liver cancer. Not only is the chance of developing the cancer enhanced, but patients with diabetes who undergo surgical removal of liver cancer have a higher chance of the cancer returning than do those without diabetes.
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.
The treatment options are dictated by the stage of liver cancer and the overall condition of the patient. The only proven cure for liver cancer is liver transplantation for a solitary, small (<3cm) tumor. Now, many physicians may dispute this statement.
They would argue that a small tumor can be surgically removed (partial hepatic resection) without the need for a liver transplantation. Moreover, they may claim that the one- and three-year survival rates for resection are perhaps comparable to those for liver transplantation.
However, most patients with liver cancer also have cirrhosis of the liver and would not tolerate liver resection surgery. In fact, in the United States, only 8% of people with liver cancer are able to undergo surgery. But, they probably could tolerate the transplantation operation, which involves removal of the patient's entire diseased liver just prior to transplanting a donor liver.
Furthermore, many patients who undergo hepatic resections will develop a recurrence of liver cancer elsewhere in the liver within several years. In fact, some experts believe that once a liver develops liver cancer, there is a tendency for that liver to develop other tumors at the same time (synchronous multicentric occurrence) or at a later time (metachronous multicentric occurrence).
This makes sense, since whatever in the liver caused the cancer to develop in the first place is still there. Realistically, though, donor livers are a very limited resource, so many patients who need a transplantation will never receive one.
The results of the various medical treatments available (see below; chemotherapy, chemoembolization, ablation, and proton beam therapy) remain disappointing. Moreover, for reasons noted earlier (primarily the variability in natural history), there have been no systematic study comparisons of the different treatments.
As a result, individual patients will find that the various treatment options available to them depend largely on the local expertise.
How do we know if a particular treatment worked for a particular patient? Well, hopefully, the patient will feel better. However, a clinical response to treatment is usually defined more objectively. Thus, a response is defined as a decrease in the size of the tumor on imaging studies along with a reduction of the alpha-fetoprotein in the blood if the level was elevated prior to treatment.
One thing to keep in mind is that in a relatively healthy patient there is never just one answer to this question. Usually, people go through multiple different treatments sequentially. Something is chosen as the best place to start, and then other treatments are tried once the previous one stops working. The idea is to make sure someone is healthy enough to be able to try another therapy if they still desire it.