HCC Risk Factors & High Risk Populations

What are the risk factors for HCC?

Hepatitis B Infection

It is well established that Hepatitis B infection can cause HCC. The vast majority of HCC that is associated with hepatitis B virus (HBV) occurs in patients who have had hepatitis B infection for most of their lives, also called chronic Hepatitis B. In patients with chronic HBV and HCC, the genetic material of HBV is frequently found to be part of the genetic material of the cancer cells. The HBV genetic material enters the normal liver cells and disrupts their function, causing these normal cells to turn into cancerous cells. Because of this genetic mutation caused by HBV, a patient who has the HBV infection may develop HCC with or without liver cirrhosis (scarring of the liver).

Hepatitis C Infection

The development of HCC is also associated with chronic Hepatitis C virus (HCV). The majority of patients who develop HCC as a result of HCV will have liver cirrhosis. The average time to develop HCC after initial exposure to HCV is about 28 years, and usually about 8-10 years after the development of liver cirrhosis. The way in which HCV causes HCC is not well understood, unlike with the HBV infection. HCV can cause cirrhosis, and cirrhosis can be a cause of HCC. It is possible to develop HCC if an individual has HCV but no cirrhosis. It is thought that the core protein of the virus may impede the natural process of cell death or interfere with the function of normal tumor suppressor genes within the body.

In patients with HCV, risk factors for the development of HCC include the presence of cirrhosis, older age, male gender, elevated baseline alpha feto-protein levels (a blood test used in determining liver cancer), alcohol use, and co-infection with HBV.

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 (a disorder that causes the body to accumulate excessive amounts of iron). 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 biliary cirrhosis (PBC) as well. Recent studies, however, show that the frequency of HCC in PBC is comparable to that in other forms of cirrhosis.

High Risk Populations for HCC

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The frequency of HCC is greater in certain geographic areas than others. For example, the incidence in Southeast Asia and sub-Saharan Africa is much higher than in North America and Western Europe. However, recent data suggests that the frequency of HCC in the United States is overall rising, primarily due to the increase in the amount of patients with viral hepatitis, one of the risk factors for HCC.