Hepatocellular carcinoma is the most common form of liver cancer, affecting thousands of people worldwide each year. Understanding this serious condition, its risk factors, and how it develops is essential for those at high risk and their families.

Epidemiology: How Common Is Hepatocellular Carcinoma?

Hepatocellular carcinoma, often shortened to HCC, represents a significant global health challenge. It is the most common type of primary liver cancer, accounting for approximately 85% to 90% of all liver cancers^[2]. The term “primary” means that the cancer originates in the liver itself, rather than spreading there from another part of the body. Worldwide, HCC has become the sixth most frequently diagnosed cancer and ranks as the third leading cause of cancer-related deaths^[2].

The burden of this disease continues to grow. Current estimates suggest that more than one million new cases of liver cancer will be diagnosed globally by 2025^[6]. In the United States alone, approximately 41,000 people received a liver cancer diagnosis in 2022, with the majority of these cases being hepatocellular carcinoma^[4]. In Australia, around 3,000 people are diagnosed with HCC each year, and the rates are increasing^[7].

Certain demographic patterns are clear when examining who gets hepatocellular carcinoma. The disease is two to three times more common in men than in women^[2]. Age also plays a significant role. Most people diagnosed with HCC are 60 years old or older, with the highest rates occurring in people aged 60 to 64^[7]. HCC is one of the few cancers with an incidence-to-mortality ratio near one, meaning that nearly as many people die from this disease as are diagnosed with it each year^[3]. This sobering statistic reflects both the aggressive nature of the cancer and the challenges in detecting it early.

The five-year survival rate for HCC remains below 20%, making it one of the most serious cancer diagnoses^[14]. This low survival rate is primarily driven by late-stage diagnosis, where the cancer has already advanced significantly. When HCC is caught in its early stages, the median survival can reach 10 years. However, when diagnosis occurs at an advanced stage, median survival drops dramatically to just one to three years^[14].

Causes: What Leads to Hepatocellular Carcinoma?

Hepatocellular carcinoma does not develop in a vacuum. In the vast majority of cases—approximately 80% to 90%—HCC occurs in people who already have cirrhosis, which is severe scarring of the liver^[2]. Cirrhosis develops over time as the liver becomes damaged and inflamed, eventually leading to permanent scarring that affects how the liver functions. Once cirrhosis is present, the annual risk of developing HCC ranges from 2% to 4%^[3].

The process that leads to HCC typically begins with chronic liver damage. When the liver is repeatedly injured by infections, toxins, or other factors, it tries to repair itself. Over time, this constant repair process can lead to mistakes in how liver cells grow and divide. These abnormal cells can multiply out of control, forming tumors. The tumor can then damage healthy liver tissue, grow into nearby blood vessels, and eventually spread to other parts of the body^[1].

Several specific conditions are known to cause the chronic liver damage that can progress to cirrhosis and ultimately to HCC. Viral hepatitis infections, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV), are major culprits. Together, these two viruses account for more than 70% of all HCC cases worldwide^[3]. Hepatitis B alone is responsible for about 56% of global HCC cases, while hepatitis C accounts for approximately 20%^[3].

What makes hepatitis B particularly concerning is that it can lead to HCC even without first causing cirrhosis. While more than 80% of HBV-related HCC cases do involve underlying cirrhosis, some people develop liver cancer directly from the virus^[3]. The virus integrates its genetic material into human liver cells, causing mutations that can trigger cancer development. One important marker of risk is having elevated levels of hepatitis B virus in the blood—specifically, levels equal to or greater than 10,000 copies per milliliter^[3].

Another increasingly important cause of HCC is metabolic dysfunction-associated steatotic liver disease, or MASLD. This condition was formerly known as non-alcoholic fatty liver disease. MASLD occurs when excess fat builds up in the liver, causing inflammation and damage over time^[2]. People with obesity, inherited metabolic syndrome, or type 2 diabetes are more likely to develop MASLD. In Western countries, MASLD is becoming a more frequent risk factor for HCC^[6].

Heavy alcohol consumption is another well-established cause of liver damage leading to HCC. Alcohol is difficult for the liver to process, and drinking too much over many years can eventually lead to cirrhosis and liver cancer^[2]. The liver is responsible for breaking down and removing alcohol from the body, but chronic heavy drinking overwhelms this capacity and causes repeated injury to liver cells.

Risk Factors: Who Is Most at Risk?

Understanding who is most at risk for hepatocellular carcinoma helps identify people who would benefit from regular screening. The most significant risk factors all involve conditions that cause long-term liver inflammation and damage.

Chronic hepatitis B infection is a major risk factor. This viral infection spreads through bodily fluids, including blood, semen, and other fluids. Importantly, hepatitis B can lead to HCC even before cirrhosis develops or without cirrhosis ever occurring^[2]. The virus affects more than 250 million people worldwide and is the most common cause of chronic hepatitis globally^[3].

Chronic hepatitis C infection, which spreads through contact with infected blood, is another major risk factor. People who inject drugs, received blood transfusions before widespread screening began, or had certain medical procedures with inadequately sterilized equipment face higher risk of hepatitis C infection.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing risk factor, particularly in developed countries. People with obesity, type 2 diabetes, or metabolic syndrome are more likely to develop this condition^[2]. The fat accumulation in the liver can progress from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), where inflammation and cell damage occur. MASH can eventually lead to cirrhosis and increase the risk of HCC.

Alcohol use disorder significantly raises the risk of HCC. The definition of heavy drinking varies, but chronic excessive alcohol consumption over many years damages the liver and can lead to alcoholic cirrhosis. When combined with other risk factors, such as viral hepatitis, alcohol consumption leads to an even greater risk of developing liver cancer^[20].

Several other factors can increase risk. Tobacco use has been linked to higher rates of HCC^[4]. Certain inherited disorders, such as hemochromatosis (where the body stores too much iron) and Wilson disease (where copper accumulates), can damage the liver over time. Being male and older age also increase risk, as HCC occurs more frequently in men and in people over 60.

Symptoms: What Does Hepatocellular Carcinoma Feel Like?

One of the most challenging aspects of hepatocellular carcinoma is that it often causes no symptoms in its early stages. This is why many people are not diagnosed until the cancer has already advanced significantly. When symptoms do eventually appear, they usually indicate that the cancer is in a more advanced stage^[7].

As HCC progresses, people may begin to notice a feeling of fullness or discover a hard lump under their ribs on the right side of their body. This occurs because the liver, which sits on the right side of the abdomen just below the rib cage, becomes enlarged as tumors grow^[2]. Some people also experience fullness under the ribs on the left side, which happens when the spleen becomes enlarged.

Another common symptom is the development of jaundice, where the skin and the whites of the eyes turn yellow. Jaundice occurs when the liver can no longer effectively process bilirubin, a yellow pigment produced when red blood cells break down. When bilirubin builds up in the body, it causes this characteristic yellowing^[2]. Along with yellow skin and eyes, people may notice that their urine becomes dark, almost tea-colored, while their stools turn pale.

Many people with HCC experience a swollen or bloated stomach. This occurs when fluid accumulates in the abdominal cavity, a condition called ascites. The abdomen may feel tight and uncomfortable, as if it is filling up with liquid^[2]. This symptom often develops as liver function declines.

Changes in appetite and weight are also common. People may lose their appetite or feel full after eating only a small amount of food. Unexplained weight loss frequently accompanies HCC^[2]. Nausea and vomiting can occur as the cancer affects normal digestion and liver function. Some people also develop persistent itching that can be difficult to relieve.

General symptoms such as extreme tiredness and weakness are frequently reported. Pain in the upper right part of the trunk or in the right shoulder can develop as the tumor grows and affects surrounding tissues^[7].

It is important to remember that many other conditions can cause these same symptoms, most of which are far less serious than liver cancer. However, if symptoms last longer than two weeks, it is important to see a healthcare provider for evaluation^[2]. Early detection significantly improves treatment outcomes and survival rates.

Prevention: Can Hepatocellular Carcinoma Be Prevented?

While not all cases of hepatocellular carcinoma can be prevented, there are several important steps people can take to reduce their risk. Because most HCC develops in people with chronic liver disease, protecting the liver from damage is the key to prevention.

Vaccination against hepatitis B virus is one of the most effective preventive measures available. The hepatitis B vaccine is safe and highly effective at preventing infection. Since hepatitis B is a major cause of HCC worldwide, widespread vaccination programs have the potential to significantly reduce liver cancer rates. People who have not been vaccinated should speak with their healthcare provider about receiving the vaccine.

For hepatitis C, while there is no vaccine currently available, the infection can be cured with antiviral medications. People at risk for hepatitis C should be tested, and those who test positive should receive treatment. Curing hepatitis C reduces the risk of cirrhosis and liver cancer.

Lifestyle modifications play a crucial role in prevention. Maintaining a healthy weight is important, as obesity increases the risk of MASLD, which can progress to cirrhosis and HCC. A balanced diet rich in vegetables, fruits, whole grains, and healthy proteins supports liver health. Research suggests that consuming omega-3 fatty acids found in fish, as well as eating plenty of vegetables and fiber, may be protective against HCC. In contrast, high consumption of red meat, saturated fat, cholesterol, and sugar has been associated with increased risk^[20].

Regular physical activity appears to have a beneficial effect in reducing HCC risk, although the optimal duration, type, and intensity of exercise are still being studied^[20]. Exercise helps maintain a healthy weight, reduces fat accumulation in the liver, and has anti-inflammatory effects.

Avoiding or limiting alcohol consumption is critical for liver health. Even moderate alcohol use can be harmful to people with existing liver disease. For those without liver disease, staying within recommended limits or abstaining entirely is advisable. People with alcohol use disorder should seek help and support to reduce or stop drinking.

Tobacco cessation is also important. Smoking has been linked to increased HCC risk and can compound the damage caused by other risk factors^[20]. Combined with alcohol use, smoking leads to even greater risk.

For people with existing liver disease or cirrhosis, regular screening is a form of secondary prevention. While screening does not prevent HCC from developing, it can detect the cancer at an early, more treatable stage. Most guidelines recommend that people with cirrhosis or high-risk hepatitis B infection undergo liver ultrasound screening every six months. This may be combined with a blood test for alpha-fetoprotein (AFP), a protein that can be elevated in people with HCC^[7].

Pathophysiology: How Does HCC Change the Liver?

Understanding the pathophysiology of hepatocellular carcinoma means looking at the changes that occur in the liver at the cellular, biochemical, and physical levels. These changes explain why HCC is such a serious and complex disease.

In a healthy liver, cells called hepatocytes perform essential functions. They help break down nutrients from food, produce proteins needed for blood clotting, remove toxins and waste products from the blood, and store energy in the form of glycogen. The liver also produces bile, which helps digest fats^[4]. A well-functioning liver is essential for survival.

HCC begins when something—usually chronic inflammation and damage—causes changes in the genetic material of hepatocytes. These changes, or mutations, disrupt the normal controls that regulate how cells grow, divide, and die. Instead of following orderly patterns of growth and repair, the affected hepatocytes begin to multiply uncontrollably. They form masses of abnormal cells called tumors.

The integration of hepatitis B virus genetic material into human DNA is one well-understood mechanism. The viral DNA inserts itself into critical areas of the human genome, such as the telomerase reverse transcriptase (TERT) promoter region, causing mutations that account for about 60% of HCC cases related to hepatitis B^[3]. Other genetic changes involve mutations in genes that control the cell cycle, cell growth signals, and DNA repair mechanisms.

As tumors grow, they disrupt normal liver architecture. The tumors can compress or invade blood vessels within the liver. The liver receives blood from two sources: the hepatic artery, which brings oxygen-rich blood, and the hepatic portal vein, which brings blood from the intestines containing nutrients. When HCC tumors grow into these vessels, they can block blood flow and cause further liver damage. Tumors predominantly receive their blood supply from the hepatic artery, while healthy liver tissue is supplied mainly by the portal vein^[15].

In advanced stages, cancer cells can break away from the primary tumor and spread through the bloodstream or lymphatic system to other parts of the body. This process, called metastasis, most commonly affects the lungs, bones, and other areas of the liver^[1].

The presence of cirrhosis adds another layer of complexity. In cirrhosis, the normal smooth liver tissue is replaced by bands of scar tissue, creating a nodular, hardened organ. This scarring interferes with blood flow through the liver and reduces its ability to perform its vital functions. The combination of cirrhosis and cancer creates a double burden: the liver is already damaged and struggling to function, and now tumors are growing that further impair liver function.

As HCC progresses and liver function declines, several serious complications can develop. Portal hypertension occurs when blood flow through the liver is blocked, causing increased pressure in the portal vein. This can lead to enlarged veins in the esophagus and stomach called varices, which can bleed dangerously. Ascites develops as fluid leaks from blood vessels into the abdominal cavity. Hepatic encephalopathy occurs when the damaged liver can no longer remove toxins from the blood effectively, and these toxins affect brain function, causing confusion and altered consciousness.

Eventually, in advanced cases, HCC can lead to complete liver failure. The liver becomes unable to perform any of its essential functions. This stage is often fatal without liver transplantation^[2].