- File Under liver cancer
How Liver Cancer Develops
A healthy liver is made up of cells. Normally, these cells maintain specialized functions as they grow and divide. Eventually these cells become old and die. The body replaces them with new, healthy cells. A balance maintained between cell birth and cell death. Cells that are part of a bigger structure--like the liver--can communicate and influence each other.
In patients with cirrhosis, healthy liver tissue is replaced by scar tissue. Cirrhosis is most often due to inflammation within the liver. This scar tissue disrupts the normal organization and function of the liver. Cirrhosis, in some individuals, can be a cause of liver cancer
Liver tumors can be benign or malignant. Benign tumors are masses of tissue but they are not cancer. They are usually not harmful and do not spread to other parts of the body. Malignant tumors are considered cancers. Malignant tumors of liver tissue localized in the liver, or metastatic to other organs, can be life threatening
More commonly, cancers may metastasize, or spread, to the liver from other organs. Secondary liver cancers may develop in tissues distant from the liver. Cancer cells from the breast, lung, colon and pancreas can reach be carried to the liver by the blood or lymph systems. Some cancers will "invade" the liver by direct extension from adjacent organs (gallbladder, stomach).
Many patients with HCC have no symptoms in the early stages.
Some, with more advanced tumors, have symptoms such as:
Pain in the upper right portion of the abdomen.
Worsening liver function, as noted by increasing jaundice (yellowing of the whites of the eyes and skin and/ or increasing abdominal fluid (ascites).
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.
On physical examination, an enlarged, sometimes tender, liver is the most common sign. 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.
A very common sign 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.
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.
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.
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 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.
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.
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.