This discussion deals only with adult primary liver cancer. Primary liver cancer is cancer that begins in the liver. Adult primary liver cancer is rare in the United States. Usually, when the liver is affected by cancer, it is because cancer that started in a different part of the body—the pancreas, colon, stomach, breast, or lung, for example—has spread (metastasized) to the liver. These cancers are not primary liver cancer but, rather, are named for the part of the body in which they originated. For example, breast cancer that has metastasized to the liver is called "metastatic breast cancer" or "secondary liver cancer."

The liver is the largest organ in the body, and its functions are vital to the digestion of food. No one can survive without a liver. The liver does the following:

* Collects and filters blood from the intestine.
* Processes and stores needed nutrients absorbed from the intestines.
* Chemically changes (metabolizes) some nutrients before they can be used by the rest of the body for energy or to repair and build tissue.
* Produces some of the clotting factors needed in the blood stream.
* Removes toxic wastes from the body.
* Helps maintain the proper sugar level in the body.

As we well know, there are many kinds of cancer; unfortunately they all come about because of the out-of-control growth of abnormal cells.

What is hepatocellular carcinoma (HCC)?

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 (e.g., 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 to 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. Thus, 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 HCC.

What is the scope of the HCC problem?

HCC is the fifth most common cancer in the world. A deadly cancer, HCC will kill almost all patients who have it within a year. In 1990, the World Health Organization estimated that there were about 430,000 new cases of HCC worldwide, and a similar number of patients died as a result of this disease. About three quarters of the cases of HCC are found in Southeast Asia (China, Hong Kong, Taiwan, Korea, and Japan). HCC is also very common in sub-Saharan Africa (Mozambique and South Africa).

The frequency of HCC in Southeast Asia and sub-Saharan Africa is greater than 20 cases per 100,000 population. In contrast, the frequency of HCC in North America and Western Europe is much lower, less than 5 per 100,000 population. However, the frequency of HCC among native Alaskans is comparable to that seen in Southeast Asia. Moreover, recent data show that the frequency of HCC in the U.S. overall is rising. This increase is due primarily to chronic hepatitis C, an infection of the liver that causes HCC.

What are the population characteristics (epidemiology) of HCC?

In the U.S. the highest frequency of HCC occurs in immigrants from Asian countries, where HCC is common. The frequency of HCC among Caucasians is the lowest, whereas among African-Americans and Hispanics, it is intermediate. The frequency of HCC is high among Asians because HCC 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 HCC.

The initial presentation (symptoms) of HCC in patients in areas of high HCC frequency is quite different from that seen in low frequency areas. Patients from high frequency areas usually start developing HCC in their 40's, and the cancer is usually more aggressive. That is, the HCC presents with severe symptoms and is inoperable (too advanced for surgery) at the time of diagnosis. Also, in these areas, the frequency of HCC is three to four times higher in men than in women, and most of these patients are infected with chronic hepatitis B. In contrast, HCC in lower risk areas occurs in patients in their 50's and 60's and the predominance of men is less striking.

What are the risk factors for HCC?

Hepatitis B infection

The role of hepatitis B virus (HBV) infection in causing HCC is well established. Several lines of evidence point to this strong association. As noted earlier, the frequency of HCC relates to (correlates with) the frequency of chronic HBV infection. In addition, the patients with HBV who are at greatest risk for HCC are men with HBV cirrhosis (scarring of the liver) and a family history of HCC. 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 HCC was 200 times higher among employees who had chronic HBV as compared to employees without chronic HBV!

Studies in animals also have provided evidence that HBV can cause HCC. For example, we have learned that HCC develops in other mammals that are naturally infected with HBV-related viruses. Finally, by infecting transgenic mice with certain parts of the hepatitis B virus, scientists caused HCC 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 HBV cause HCC? In patients with both chronic HBV and HCC, the genetic material of HBV is frequently found to be part of the genetic material of the cancer cells. It is thought, therefore, that specific regions of the HBV genome (genetic code) enter the genetic material of the liver cells. This HBV 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 HCC that is associated with chronic HBV occurs in individuals who have been infected most of their lives. In areas where HBV is not always present (endemic) in the community (e.g., the U.S.), HCC is relatively uncommon. The reason for this is that most of the people with chronic HBV in these areas acquired the infection as adults. However, HCC can develop in individuals who acquired chronic HBV in adulthood if there are other risk factors, such as chronic alcohol use or co-infection with chronic HCV infection.

Hepatitis C infection

Hepatitis C virus (HCV) infection is also associated with the development of HCC. In fact, in Japan, HCV is present in up to 75% of cases of HCC. As with HBV, the majority of HCV patients with HCC 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 HCC after exposure to HCV was about 28 years. The HCC occurred about 8 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 HCC in cirrhotic HCV patients ranges from 1.4 to 2.5% per year.

In HCV patients, the risk factors for developing HCC include the presence of cirrhosis, older age, male gender, elevated baseline alpha-fetoprotein level (a blood tumor marker), alcohol use, and co-infection with HBV. Some earlier studies suggested that HCV 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 HCV causes HCC is not well understood. Unlike HBV, the genetic material of HCV 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 HCC. It has been argued, therefore, that HCV, which causes cirrhosis of the liver, is an indirect cause of HCC.

On the other hand, there are some chronic HCV infected individuals who have HCC without cirrhosis. So, it has been suggested that the core (central) protein of HCV is the culprit in the development of HCC. 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 HCC in the developed world. Actually, we now understand that many of these cases are also infected with chronic HCV. The usual setting is an individual with alcoholic cirrhosis who has stopped drinking for ten years, and then develops HCC. It is somewhat unusual for an actively drinking alcoholic to develop HCC. 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 HCC 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 (e.g., liver failure). Indeed, patients with alcoholic cirrhosis who die of HCC are about 10 years older than patients who die of non-cancer causes. Finally, as noted above, alcohol adds to the risk of developing HCC in patients with chronic HCV or HBV 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 HCC 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 HCC, 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

HCC 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 HCC.

Cirrhosis

Individuals with most types of cirrhosis of the liver are at an increased risk of developing HCC. 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 HCC. 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 HCC than are other causes. For example, HCC 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 HCC is rarely found in primary bilary cirrhosis (PBC) as well. Recent studies, however, show that the frequency of HCC in PBC is comparable to that in other forms of cirrhosis.

What are the symptoms of HCC?

The initial symptoms (the clinical presentations) of HCC are variable. In countries where HCC 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 HCC are generally developing countries where access to healthcare is limited. For another, screening examinations for patients at risk for developing HCC are not available in these areas. In addition, patients from these regions actually have more aggressive HCC disease. In other words, the tumor usually reaches an advanced stage and causes symptoms more rapidly. In contrast, patients in areas of low HCC frequency tend to have HCC tumors that progress more slowly and, therefore, remain without symptoms longer.

Abdominal pain is the most common symptom of HCC and usually signifies a very large tumor or widespread involvement of the liver. Additionally, unexplained weight loss or unexplained fevers are warning signs of HCC in patients with cirrhosis. These symptoms are less common in individuals with HCC 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 HCC.

A very common initial presentation of HCC in a patient with compensated cirrhosis (no complications of liver disease) is the sudden onset of a complication. For example, the sudden appearance of ascites (abdominal fluid and swelling), jaundice (yellow color of the skin), or muscle wasting without causative (precipitating) factors (e.g., alcohol consumption) suggests the possibility of HCC. 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. HCCs 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 HCC. Any sign of advanced liver disease (e.g., ascites, jaundice, or muscle wasting) means a poor prognosis. Rarely, a patient with HCC 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 HCC, the tumor can spread locally to neighboring tissues or, through the blood vessels, to elsewhere in the body (distant metastasis). Locally, HCC 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 the distant metastases, HCC frequently spreads to the lungs, presumably by way of the blood stream. Usually, patients do not have symptoms from the lung metastases, which are diagnosed by radiologic (x-ray) studies. Rarely, in very advanced cases, HCC can spread to the bone or brain.