Inclusion Criteria:

Cases

• Males and females, ages 18 years or older.
• Treatment-naïve HCC as defined by LI-RADS (Liver Imaging Reporting and Data System) LR-5 or OPTN (Organ Procurement and Transplantation Network) 5 CT or MRI criteria (all lesions must exhibit arterial phase hyper-enhancement), or histologic evidence. 
• Early-stage HCC defined by single lesion < 5 cm or ≤ 3 lesions < 3 cm determined at enrollment or within 3 months prior. 
• Cirrhosis based on the following:
  • For viral hepatitis, serum biomarkers (FibroSure®/FibroTest > 0.74, APRI (AST to Platelet Ratio Index) > 2 or FIB-4 (Fibrosis-4) > 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease;
  • For non-viral hepatitis, histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease.
• Child-Pugh score A-B8.
• Subject must be able to understand and provide informed consent.

Controls

• Males and females ages 18 or older. 
• Cirrhosis based on the following: 
  • For viral hepatitis, serum biomarkers (FibroSure®/FibroTest > 0.74, APRI > 2, or FIB-4 > 3.25), histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease. 
  • For non-viral hepatitis, histology, imaging, elastography, or clinical evidence of portal hypertension in the setting of known chronic liver disease. 
• Evidence of the absence of a solid hepatic mass, suspicious for HCC, at enrollment or within 3 months prior based on one of the following:
  • Negative multiphase CT scan or MRI at screening/baseline visit; OR
  • Negative abdominal US at both screening/baseline visit AND 6-month follow-up visit; OR
  • Negative abdominal US at screening/baseline visit AND negative multiphase CT scan or MRI at 6-month follow-up visit.
• Child-Pugh score A-B8.
• Subject must be able to understand and provide informed consent.

Exclusion Criteria:

Cases

• Uncontrolled ascites.
• Uncontrolled encephalopathy.
• Diagnosis of active malignancy or history of active malignancy with 5 years prior to enrollment, including mixed HCC-CCA.
• Prior treatment of tumor.
• Any significant non-liver-related medical condition in which expected survival is less than 1 year.

Controls

• Imaging evidence of solid hepatic mass, suspicious for HCC.
• Uncontrolled ascites.
• Uncontrolled encephalopathy.
• Diagnosis of active malignancy or history of active malignancy with 5 years prior to enrollment, including mixed HCC-CCA.
• Any significant non-liver-related medical condition in which expected survival is less than 1 year.
• Pregnancy.