Liver cancer and cirrhosis

Cirrhosis and Liver Cancer

More than 70 percent of patients in the United States who develop liver cancer do so because they have cirrhosis of the liver.

Cirrhosis is a form of internal scarring of the liver, says George Y. Wu, MD, PhD, a professor of medicine and chief of the hepatology section at the University of Connecticut Medical Center in Farmington. “It usually occurs when the liver is damaged over an extended period of time. When liver cells are damaged and die due to chronic disease of the liver, fibrous scar tissue can be deposited in place of the missing cells,” says Dr. Wu.

And normal cells can become cancer cells when they’ve been extensively damaged.

Liver Cancer: Causes of Cirrhosis

In the United States, the main causes of cirrhosis are alcohol abuse and chronic viral hepatitis.

While everyone needs a functioning liver to survive, once enough liver cells are replaced by scar tissue, cirrhosis becomes irreversible.

“Cirrhosis increases the risk of developing liver cancer by at least 40 times over the risk of an average person,” says Wu. “Of all people with cirrhosis, 3 percent will develop liver cancer every year. So, it is not surprising that 70 to 90 percent of all cases of liver cancer in the United States occur in livers that are cirrhotic.”

Liver Cancer: Cirrhosis Risk Factors

Chronic hepatitis can be caused by the hepatitis C and hepatitis B viruses. These viruses are spread by contact with infected body fluids. The best way to avoid hepatitis B and C is to avoid intravenous drug abuse and unsafe sex.

And then there’s alcohol: A good percentage of alcoholics will eventually develop cirrhosis. The amount of alcohol you need to drink to cause cirrhosis varies from person to person. If you are a woman, drinking two to three drinks a day over several years puts you at risk. For a man, three to four drinks a day puts you at risk for cirrhosis.

Another increasingly important cirrhosis risk factor is non-alcoholic fatty liver disease (NAFLD). Why? The obesity epidemic. This disease causes liver cells to be replaced with fat cells. NAFLD is common in people with poorly controlled diabetes and obesity.

Liver Cancer: Cirrhosis Signs and Symptoms

In the early stages of cirrhosis, there may not be any symptoms. But, as cirrhosis gets worse, symptoms can be caused by the liver’s failure to perform its many essential functions, and by scar tissue that decreases blood flow through the liver.

Many of the symptoms of cirrhosis are also the first symptoms of liver cancer. The most common symptoms of liver cancer and cirrhosis include:

  • Fatigue
  • Right-side abdominal pain
  • Loss of appetite and nausea
  • Weight loss
  • Yellow discoloration of the eyes and the skin
  • Fluid collection in the legs and abdomen
  • Increased bruising and bleeding
  • Decrease in mental function

Liver Cancer and Cirrhosis

It is not well understood how cirrhosis increases cancer risk, says Wu. “But it may be related to the increased opportunity for DNA changes to develop as the liver cells reproduce in response to the damage that leads to cirrhosis.”

Another factor, he continues, can be that the presence of cirrhosis “reflects a long duration of damage. The longer the duration of damage, the greater the chance that cancer-causing changes in DNA will occur.”

Research shows that as liver cells are damaged and need to be rapidly replaced over and over again the chance of mutations — changes in the DNA — in the liver cell’s DNA increases. As these mutations build up over time and are passed along, liver cells may eventually lose their ability to control their own growth. When cells start to grow uncontrollably, liver cancer can develop.

Although it’s possible to treat cirrhosis with a liver transplant, the best way to avoid liver cancer is to know the risk factors.

Liver cancer

While the exact cause of liver cancer may not be known, several factors may increase the risk of developing the disease. Because no widely recommended routine screening tests have been developed for liver cancer, people with a family history of the disease or other risk factors should talk with their doctor about steps they can take to monitor or reduce their risk. The National Comprehensive Cancer Center recommends alpha-fetoprotein blood tests and ultrasounds every six to 12 months for people with a high risk of developing liver cancer.

Risk factors for liver cancer include:

General

Age: In the United States, the average age at onset of liver cancer is 63 years.

Gender: Men are more likely to develop liver cancer than women, by a ratio of 2 to 1.

Race and ethnicity: In the United States, liver cancer rates are highest in Asian Americans and Pacific Islanders. White Americans have the lowest risk for liver cancer. Chronic infection with hepatitis B virus or hepatitis C virus is the most common liver cancer risk factor. These infections lead to cirrhosis of the liver. Both hepatitis B and C viruses may spread from person to person through sharing of contaminated needles (such as in drug use), unprotected sex or childbirth. The viruses may also be passed on through blood transfusion, though this risk has been greatly reduced in the United States since the start of blood testing for these viruses.

Obesity: Being obese may increase the chances of developing liver cancer, probably through development of non-alcoholic steatohepatitis (NASH) and eventually, cirrhosis.

Lifestyle

Heavy use of alcohol: Alcohol abuse is a common cause of cirrhosis of the liver, which increases a person’s liver cancer risks.

Smoking: Tobacco use may increase the risk of developing liver cancer.

Anabolic steroids: Used by athletes to increase strength and muscle mass, the long-term use of anabolic steroids (male hormones) may slightly increase the risk of developing liver cancer. Cortisone-like steroids such as hydrocortisone, dexamethasone and prednisone do not carry the same risk.

Arsenic: Chronic exposure to naturally occurring arsenic through drinking water (contaminations in some wells) increases the risk of developing some forms of liver cancer.

Aflatoxins: These are cancer-causing substances made by a fungus that contaminates wheat, corn, soybeans, rice and some types of nuts. Contamination usually occurs due to storage of the food stuff in a moist, warm environment, more common in warmer and tropical countries. Long-term exposure to aflatoxins is a major liver cancer risk factor, especially in people with hepatitis B or C infections. Regular testing by the federal government regulates the content of aflatoxins in foods in the United States.

Exposure to certain chemicals: Exposure to vinyl chloride (a chemical used in the making of some plastics) and thorium dioxide (a chemical previously used for X-ray testing) may increase the risk of angiosarcoma of the liver. In recent years, strict regulation on exposure to these chemicals has been imposed in the United States.

Other conditions

Cirrhosis of the liver: Cirrhosis occurs when liver cells become damaged and are replaced by scar tissue. People with cirrhosis have an increased risk of liver cancer. In most cases (up to 90 percent of the cases in the United States), people who develop HCC have underlying cirrhosis. Cirrhosis is caused by several factors. Besides alcohol abuse and chronic hepatitis B or C infections, non-alcoholic steatohepatitis (NASH, a fatty liver disease often seen in obese people who consume little or no alcohol), certain types of inherited metabolic diseases and autoimmune diseases may cause cirrhosis.

Metabolic diseases: Certain types of inherited metabolic diseases may cause cirrhosis and increase the chances of developing liver cancer. Genetic hemochromatosis (an iron-overload disorder that builds up iron stores throughout the body including the liver), tyrosinemia (elevated levels of the amino acid tyrosine), alpha-1-antitrypsin deficiency, porphyria cutanea tarda (deficiency in heme synthesis), glycogen storage disease, and Wilson disease (elevated levels of copper in the liver) are rare diseases that may damage the liver and increase a person’s liver cancer risks.

Diabetes: Having diabetes may also increase the risk of developing liver cancer.

Learn more about diagnostic procedures for liver cancer

Next topic: What are the symptoms of liver cancer?

Curative Options in Liver Cancer and Cirrhosis

Richard Finn, MD: The question becomes, can this patient be cured? He has a solitary lesion in the liver, but the only way to cure this disease is really with surgery, and that means either a resection or a liver transplant. In regards to surgical resection, the challenge is that this patient has some decompensation in his liver disease. If we calculate his Child-Pugh score, we can see that he has a Child-Pugh score of 7 points, which is just at the entryway into B-class cirrhosis. That by itself probably precludes surgical resection. In addition, we would look at his platelet count as a marker of portal hypertension. In this case, his platelet count is 98,000, and, for many surgeons, a platelet count under 100,000 would indicate a degree of portal hypertension that would preclude a surgical resection.

So, now we’re thinking of a liver transplant. He is within Milan criteria. He has 1 tumor less than 5 cm, the other part of Milan criteria being up to 3 tumors that are all less than 3 cm. With that in mind, the patient can be considered for a liver transplant, but in the United States, that’s not a procedure that’s going to happen very quickly. There’s going to be a fair amount of wait time on the waiting list. So, how do we manage this patient? Well, treatments that are aimed at the liver are very effective at treating cancer. We know that chemoembolization, which is a local regional therapy that goes through the femoral artery up into the liver, can be very effective at managing liver cancer. It can be a definitive treatment for liver cancer. It has been shown to help people live longer.
Also, for some patients, radiofrequency ablation (RFA) is another appropriate liver-directed therapy. Unlike chemoembolization, which goes through the vasculature, radiofrequency ablation goes percutaneously through the liver. But we know the best results with RFA typically occur with a tumor that’s less than 3 cm.
So, we have a patient who has a 4-cm tumor, some liver dysfunction, but otherwise a good ECOG performance status of about 1. We’re trying to figure out what the best management for this patient is, and certainly chemoembolization would be very appropriate. It would be appropriate whether he’s going for a transplant or not. Now, since patients have a long wait time for transplant, we have the sense that we don’t want their tumor to get bigger. Should it get bigger, they may fall out of the wait list or drop out. And so, in practice, it is very common for patients like this to receive a chemoembolization procedure while they wait for transplant. The data that this improves outcomes for transplant do not exist; however, the sense is that we get some time to observe the biologic behavior of this tumor.
Patients who have newly diagnosed liver cancer—even though it’s within Milan criteria—some of them may have aggressive tumors, and to take them to transplant, even if it was feasible right away, might not be in their best interest. And so, local regional therapy plays an important role in managing these patients who are on the liver transplant list—or even if they’re not, just as a definitive treatment. If this patient has a bad heart and could not get a transplant for that reason, chemoembolization would be an important part of their management.
Transcript edited for clarity.

Overview


Liver cancer

Causes of liver cancer

The exact cause of liver cancer is unknown, but most cases are associated with damage and scarring of the liver known as cirrhosis.

Cirrhosis can have a number of different causes, including:

  • drinking excessive amounts of alcohol over many years – read more about alcohol misuse
  • having a long-term hepatitis B or hepatitis C viral infection
  • haemochromatosis – an inherited disorder in which iron levels in the body slowly build up over many years
  • primary biliary cirrhosis – a long-term liver disease in which the bile ducts in the liver become damaged

It’s also believed obesity and an unhealthy diet can increase the risk of liver cancer because this can lead to non-alcoholic fatty liver disease.

You may be able to significantly reduce your chances of developing liver cancer by:

  • avoiding or cutting down on alcohol
  • eating healthily
  • exercising regularly
  • taking steps to reduce your risk of becoming infected with hepatitis B and C

Although liver cancer is relatively uncommon in the UK, the chances of developing the condition are high for people with risk factors for the condition.

Over the past few decades, rates of liver cancer in the UK have risen considerably, possibly as a result of increased levels of alcohol consumption and obesity.

Liver Cancer Risk Factors

A risk factor is anything that increases your chance of getting a disease, such as cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be changed. Others, like a person’s age or family history, can’t be changed.

But having a risk factor, or even several risk factors, does not mean that you will get the disease. And some people who get the disease may have few or no known risk factors.

Factors that can increase your risk of liver cancer

Several factors can increase a person’s chance of getting a hepatocellular carcinoma (HCC).

Gender

Hepatocellular carcinoma is much more common in men than in women. Much of this is probably because of behaviors affecting some of the risk factors described below. The fibrolamellar subtype of HCC is more common in women.

Race/ethnicity

In the United States, Asian Americans and Pacific Islanders have the highest rates of liver cancer, followed by Hispanics/Latinos, American Indians/Alaska Natives, African Americans, and whites.

Chronic viral hepatitis

Worldwide, the most common risk factor for liver cancer is chronic (long-term) infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). These infections lead to cirrhosis of the liver and are responsible for making liver cancer the most common cancer in many parts of the world.

In the US, infection with hepatitis C is the more common cause of HCC, while in Asia and developing countries, hepatitis B is more common. People infected with both viruses have a high risk of developing chronic hepatitis, cirrhosis, and liver cancer. The risk is even higher if they are heavy drinkers (at least 6 alcoholic drinks a day).

HBV and HCV can spread from person to person through sharing contaminated needles (such as in drug use), unprotected sex, or childbirth. They can also be passed on through blood transfusions, although this is very rare in the United States since blood products are tested for these viruses. In developing countries, children sometimes contract hepatitis B infection from prolonged contact with family members who are infected.

HBV is more likely to cause symptoms, such as a flu-like illness and jaundice (a yellowing of the eyes and skin). But most people recover completely from HBV infection within a few months. Only a very small percentage of adults become chronic carriers (and have a higher risk for liver cancer). Infants and small children who become infected have a higher risk of becoming chronic carriers.

HCV, on the other hand, is less likely to cause symptoms. But most people with HCV develop chronic infections, which are more likely to lead to liver damage or even cancer.

Other viruses, such as the hepatitis A virus and hepatitis E virus, can also cause hepatitis. But people infected with these viruses do not develop chronic hepatitis or cirrhosis, and do not have an increased risk of liver cancer.

Cirrhosis

Cirrhosis is a disease in which liver cells become damaged and are replaced by scar tissue. People with cirrhosis have an increased risk of liver cancer. Most (but not all) people who develop liver cancer already have some evidence of cirrhosis.

There are several possible causes of cirrhosis. Most cases in the United States occur in people who abuse alcohol or have chronic HBV or HCV infections.

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is a common condition in obese people. People with a subtype of this disease, known as non-alcoholic steatohepatitis (NASH), might go on to develop cirrhosis.

Primary biliary cirrhosis

Some types of autoimmune diseases that affect the liver can also cause cirrhosis. For example, in primary biliary cirrhosis (PBC) the bile ducts in the liver are damaged and even destroyed which can lead to cirrhosis. People with advanced PBC have a high risk of liver cancer.

Inherited metabolic diseases

Certain inherited metabolic diseases can lead to cirrhosis.

People with hereditary hemochromatosis absorb too much iron from their food. The iron settles in tissues throughout the body, including the liver. If enough iron builds up in the liver, it can lead to cirrhosis and liver cancer.

Heavy alcohol use

Alcohol abuse is a leading cause of cirrhosis in the US, which in turn is linked with an increased risk of liver cancer.

Tobacco use

Smoking increases the risk of liver cancer. Former smokers have a lower risk than current smokers, but both groups have a higher risk than those who never smoked.

Obesity

Being obese (very overweight) increases the risk of developing liver cancer. This is probably because it can result in fatty liver disease and cirrhosis.

Type 2 diabetes

Type 2 diabetes has been linked with an increased risk of liver cancer, usually in patients who also have other risk factors such as heavy alcohol use and/or chronic viral hepatitis. This risk may also be increased because people with type 2 diabetes tend to be overweight or obese, which in turn can cause liver problems.

Certain rare diseases

Diseases that increase the risk of liver cancer include:

  • Tyrosinemia
  • Alpha1-antitrypsin deficiency
  • Porphyria cutanea tarda
  • Glycogen storage diseases
  • Wilson disease

Aflatoxins

These cancer-causing substances are made by a fungus that contaminates peanuts, wheat, soybeans, ground nuts, corn, and rice. Storage in a moist, warm environment can lead to the growth of this fungus. Although this can occur almost anywhere in the world, it is more common in warmer and tropical countries. Developed countries, such as the US and those in Europe, test foods for levels of aflatoxins.

Long-term exposure to these substances is a major risk factor for liver cancer. The risk is increased even more in people with hepatitis B or C infections.

Vinyl chloride and thorium dioxide (Thorotrast)

Exposure to these chemicals raises the risk of angiosarcoma of the liver (see What is liver cancer?). It also increases the risk of developing cholangiocarcinoma and hepatocellular cancer, but to a far lesser degree. Vinyl chloride is a chemical used in making some kinds of plastics. Thorotrast is a chemical that in the past was injected into some patients as part of certain x-ray tests. When the cancer-causing properties of these chemicals were recognized, steps were taken to eliminate them or minimize exposure to them. Thorotrast is no longer used, and exposure of workers to vinyl chloride is strictly regulated.

Anabolic steroids

Anabolic steroids are male hormones used by some athletes to increase their strength and muscle mass. Long-term anabolic steroid use can slightly increase the risk of hepatocellular cancer. Cortisone-like steroids, such as hydrocortisone, prednisone, and dexamethasone, do not carry this same risk.

Factors that may lower your risk of liver cancer

Hepatitis B vaccine

Since chronic hepatitis B infection can lead to cirrhosis and then liver cancer, getting vaccinated against the hepatitis B virus may protect people from liver cancer caused by the hepatitis B virus.

Treatment of viral hepatitis

It is known that chronic infections with hepatitis B or even hepatitis C can lead to cirrhosis and liver cancer. Getting treatment for either infection can lower one’s risk of liver cancer.

Factors with unclear effects on liver cancer risk

Aspirin

Aspirin has been shown to reduce the risk of a few cancers. Some studies have shown a reduced risk of liver cancer with regular use of aspirin, but more research is needed.

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