Liver Cancer: Signs, Risk Factors, and Who Needs Screening

Research-informed explainer — last updated April 12, 2026

Liver cancer — specifically hepatocellular carcinoma (HCC), the most common type — almost never causes symptoms in its early stages. By the time most people feel sick, the cancer has often grown to a size or stage where treatment options are limited. That's what makes screening so important: it's the only reliable way to find liver cancer when it's still curable.

This explainer draws on research from five liver cancer specialists in the Convene directory. Amit Singal at UT Southwestern Medical Center has published the most widely used overview of HCC epidemiology and treatment, led a meta-analysis on surveillance tools, and directed the Liver Tumor Program. Laura Kulik at Northwestern Memorial Hospital co-authored the 2018 AASLD Practice Guidance on HCC and the AASLD treatment guidelines. Ju Dong Yang at Cedars-Sinai Medical Center contributed the global view of HCC trends and prevention. Renumathy Dhanasekaran at Stanford provided comprehensive genomic characterization of HCC that shapes how targeted treatments are selected. Ramsey Cheung at Stanford published research establishing that fatty liver disease has overtaken hepatitis C as the fastest-growing driver of liver cancer requiring transplant.

What is hepatocellular carcinoma

Hepatocellular carcinoma is cancer that originates in the liver cells (hepatocytes). It is distinct from cancers that spread to the liver from other organs, which are called metastatic liver cancer. HCC accounts for roughly 75-85% of all primary liver cancers.

HCC is the sixth most common cancer worldwide and the third leading cause of cancer death globally [8]. In the United States, rates have been rising steadily for decades, driven first by hepatitis C infection and more recently by the epidemic of fatty liver disease related to obesity and type 2 diabetes.

How it is diagnosed

When HCC is detected through surveillance (discussed below), it is usually found on imaging — either ultrasound, CT, or MRI — before symptoms develop. A characteristic appearance on contrast-enhanced CT or MRI, called arterial phase enhancement with washout, is sufficient to diagnose HCC without a biopsy in most cases. This is unlike most other cancers.

If imaging is uncertain, a liver biopsy may be performed. A blood test called alpha-fetoprotein (AFP) is often elevated in HCC, but it is not a reliable screening test on its own — many HCCs don't produce AFP, and many conditions other than cancer can raise AFP levels.

Staging follows the BCLC system (Barcelona Clinic Liver Cancer staging), which accounts for both tumor characteristics and liver function, since HCC almost always arises in the context of liver disease [2]. BCLC staging guides treatment decisions: early-stage HCC can be cured; advanced HCC can be managed with systemic therapy but rarely cured.

Warning signs — and why they are late

Most people with early HCC have no symptoms. When symptoms do appear, they often reflect either the underlying liver disease or a tumor that has grown large enough to cause local effects.

Symptoms that should prompt evaluation if you have known liver disease:

• Pain or discomfort in the upper right abdomen (where the liver sits)
• Unexplained weight loss
• Loss of appetite or early satiety
• Worsening jaundice (yellowing of skin or eyes) in someone with liver disease
• Sudden worsening of abdominal fluid (ascites) after previously being stable
• A new mass felt in the right upper abdomen

These symptoms are late-stage warning signs. None of them is specific to liver cancer — they can all be caused by worsening cirrhosis or other liver conditions. But if you have known liver disease and experience any of these, see your hepatologist promptly rather than waiting for a scheduled appointment.

Who should be screened and how often

Current guidelines from AASLD, based in part on research by Amit Singal and colleagues, recommend screening every six months for patients at significant risk of HCC [7].

The standard surveillance protocol is abdominal ultrasound with or without AFP blood test, every 6 months. Adding AFP to ultrasound improves sensitivity, though AFP alone is insufficient.

Who qualifies for screening:

All patients with cirrhosis from any cause — including cirrhosis due to:

• Hepatitis B
• Hepatitis C (even if previously treated and cured — cured patients with cirrhosis still need surveillance)
• Alcoholic liver disease
• Fatty liver disease (MASH/NASH-related cirrhosis)
• Autoimmune hepatitis
• Primary biliary cholangitis

Patients with chronic hepatitis B infection, even without cirrhosis, if they are high-risk — including men over 40 with active viral replication, individuals from high-incidence regions (sub-Saharan Africa, Asia), or those with a family history of HCC.

Important note on fatty liver disease: Research by Ramsey Cheung at Stanford showed that NASH (now called MASH) became the most rapidly growing indication for liver transplantation in HCC patients in the United States, a finding with major implications for who needs screening [10]. Unlike hepatitis C-related HCC, a small proportion of HCC cases linked to fatty liver disease occur without cirrhosis, which creates challenges for defining who needs surveillance in that population.

Why standard ultrasound misses some early cancers

A meta-analysis by Amit Singal's group, published in Gastroenterology, found that surveillance with ultrasound plus AFP detected early HCC — defined as cancer meeting Milan criteria for transplant eligibility — in about 63% of cases [3]. The sensitivity of ultrasound alone for early-stage HCC was approximately 45%, meaning roughly half of early tumors were missed.

This detection gap is clinically important. Missing early HCC means finding it later, when curative treatment is no longer possible. It's part of why several academic centers are now studying enhanced surveillance protocols — including MRI-based screening for patients at highest risk — though ultrasound every 6 months remains the standard-of-care recommendation in most guidelines [7].

Treatment options and how stage determines them

Treatment choices follow BCLC staging closely [2].

Very early and early stage (BCLC 0 and A): Tumors that are small (under 2 cm for BCLC 0, or 2-3 cm/single up to 3 tumors under 3 cm for BCLC A). Treatment options include surgical resection (if liver function is adequate), liver transplantation, or local ablation (radiofrequency or microwave ablation). Five-year survival rates with curative treatment can exceed 70%.

Intermediate stage (BCLC B): Larger tumors or more tumor nodules but without vascular invasion or spread outside the liver. Treatment is transarterial chemoembolization (TACE) — a procedure that delivers chemotherapy directly to the liver arteries feeding the tumor. Median survival with TACE is roughly 26-40 months in clinical trials.

Advanced stage (BCLC C): Vascular invasion or spread to lymph nodes or other organs. Systemic therapy is the main treatment. Atezolizumab plus bevacizumab (an immunotherapy combination) is the current first-line recommendation after showing superior survival over sorafenib in the IMbrave150 trial. Median overall survival with first-line immunotherapy combinations in advanced HCC is now roughly 19-20 months.

Terminal stage (BCLC D): Severely impaired liver function. Best supportive care. Aggressive treatment is not appropriate.

The genomic research from Renumathy Dhanasekaran at Stanford — the comprehensive characterization of HCC molecular subtypes — is beginning to inform how patients are matched to systemic therapies, particularly which patients are most likely to respond to immunotherapy [9].

Hepatitis B and C: the most preventable HCC

Hepatitis B vaccination prevents the most common global cause of HCC. For people born before vaccination became routine, treating chronic hepatitis B with antiviral therapy (tenofovir or entecavir) significantly reduces HCC risk.

Hepatitis C treatment with direct-acting antivirals (DAAs) cures the infection in more than 95% of patients and substantially reduces HCC risk in those without cirrhosis. Patients with hepatitis C-related cirrhosis who are cured still need ongoing HCC surveillance — cure reduces risk but does not eliminate it in patients who already have scarring.

Fatty liver disease prevention — weight management, treating diabetes, avoiding alcohol — is the largest modifiable HCC risk factor going forward, given how rapidly MASH-related liver disease is growing as a driver of HCC [4].

Questions to ask your doctor

• Do I have cirrhosis, and am I on a six-month ultrasound surveillance schedule?
• I was treated and cured of hepatitis C — do I still need liver cancer screening?
• I have fatty liver disease but haven't been diagnosed with cirrhosis — is there any reason I should be screened?
• If my ultrasound shows something suspicious, what happens next?
• What is my BCLC stage, and which treatment option does that point to?
• Should I be seen at a specialized liver cancer center with a multidisciplinary tumor board?