Last updated May 2, 2022

Screening for Development of Hepatocellular Cancer in Patients with Hepatitis B and C

Recommendations

  1. Patients with hemophilia and hepatitis C who have documented cirrhosis should be screened for the development of hepatocellular cancer (HCC).
  2. Patients with hemophilia who have hepatitis B infection and are not cirrhotic should be screened for the development of hepatocellular cancer (HCC) in specific cases based on age, gender, and ethnicity.
  3. Patients with hemophilia who have NASH and advanced fibrosis (F3 on the Metavir fibrosis scale) but are not cirrhotic should be screened for the development of hepatocellular cancer (HCC).
  4. Screening for HCC should be done using a high-quality ultrasound. A high-quality ultrasound is an ultrasound that is technically adequate based on overall radiologist impression of quality based on anatomic coverage (at least 2/3 of the liver visualized), visual clarity of the liver parenchyma (including heterogeneity and nodularity), depth of penetration, and other exam limitations such as obstruction from ribs, lungs, or bowel gas (Simmons et al, Ref. 4). In multivariable analysis in the latter study, inadequate ultrasound quality was directly associated with male gender, increasing BMI, in-patient status, alcohol-related cirrhosis and NASH-related cirrhosis.
  5. Screening for HCC should be done at 4 to 8-month intervals. There is no need to change the frequency of the screening examinations for patients with a higher risk of HCC.
  6. Patients with cirrhosis who have been treated and have cleared the hepatitis C virus should also continue to be screened to determine the amount of fibrosis with elastography and/or specialized blood tests annually until their liver fibrosis has improved to the point that they are no longer cirrhotic. This improvement in fibrosis is anticipated but does not always happen. Improvement in fibrosis may take years to reach the point where the risk of HCC is minimal and HCC screening is no longer warranted.

Whom to Screen for HCC

Based on guidelines from AASLD and the AGA (references below) these patients should be screened for HCC:
  • All patients with cirrhosis, regardless of the cause of their liver disease
  • Patients with NASH and stage 3 fibrosis (Metavir scale)
  • Patients with hepatitis B who meet certain age, gender and ethnicity characteristics:

How to Screen for HCC

  • The most widely used radiological test for surveillance for HCC is an ultrasound. Ultrasound has been reported to have a sensitivity of greater than 90% when used as a screening test. Screening should be done using a high-quality ultrasound, specifically an ultrasound that is technically adequate based on overall radiologist impression of quality based on anatomic coverage (at least 2/3 of the liver visualized), visual clarity of the liver parenchyma (including heterogeneity and nodularity), depth of penetration, and other exam limitations such as obstruction from ribs, lungs, or bowel gas (Simmons et al, Ref. 4). In multivariable analysis in the latter study, inadequate ultrasound quality was directly associated with male gender, increasing BMI, in-patient status, alcohol-related cirrhosis, and NASH-related cirrhosis.
  • The use of a CT scan as a screening tool for HCC has been studied; however, its performance characteristics are not known. The theoretical disadvantage of contrast use and high levels of radiation involved in a 4-phase CT scan have limited its use as a screening test for HCC. Strategies for alternating testing modalities (e.g. ultrasound alternating with CT scan or MRI) have no basis.

How to Follow-up Abnormal Screening Results

  • Patients with a high risk for HCC who enter a surveillance system need to be notified of an abnormal result. An abnormal result is a nodule not seen on a prior study but now noted to be present, regardless of the size of the nodule. An enlarging mass or nodule is always considered abnormal and should lead to further characterization. Most liver centers use an MRI or 4-phase CT to follow-up on an abnormal ultrasound. Individual centers may prefer one modality over the other.

Additional Information

Statement of Problem
  • Patients with viral hepatitis due to hepatitis B (HBV) and C (HCV) infection have been shown to have a significantly increased risk of end-stage liver disease, hepatocellular cancer (HCC), and death due to these two complications of infection. The incidence of hepatocellular cancer (HCC) is rising in many countries, including the United States. Cirrhosis due to hepatitis B (HBV) and hepatitis C (HCV) infection is a major driving force behind the increased incidence in the US. Non-alcoholic fatty liver disease (NAFLD) and its more severe form (non-alcoholic steatohepatitis, NASH) are also rising in incidence with NASH-induced cirrhosis becoming the most common cause of cirrhosis in the United States. All causes of cirrhosis lead to an increased risk of developing hepatocellular cancer (HCC).

Surveillance
  • Surveillance for HCC involves determining who is at risk for the development of HCC and deciding how to screen, how frequently to screen, and what the process should be to follow up on abnormal results.

Definition of the At Risk Population
  • The incidence of HCC in a particular population of patients is used to determine if screening is appropriate for that population. Current guidelines published by the American Association for the Study of Liver Disease (AASLD) and the American Gastroenterology Association (AGA) (Loomba et al, Ref. 3) are based on a decades-old tenet of cost effectiveness being achieved if an intervention can be done at a cost of about $50,000 per year of life gained. There are published decision analysis/cost effectiveness models for HCC surveillance in chronic HBV/HCV infection and NASH. The risk of HCC is highest in patients who have cirrhosis, with an incidence of between 2-8% per year. Patients who are infected with HBV/HCV who do not have cirrhosis, or patients with NASH who do not have cirrhosis also have a higher risk of developing HCC so that screening may be indicated.

Patients who have Been Successfully Treated for their Chronic Hepatitis C Infection
  • Patients with cirrhosis from HCV infection who are successfully treated and clear the HCV virus are likely to have a reduced risk of developing HCC; however, data quantifying this reduced risk are not clear. It is likely that continued surveillance will become cost-ineffective with time as the liver fibrosis improves and the risk of HCC diminishes. The current guidelines of the AASLD suggest that treated patients with cirrhosis should continue to undergo surveillance for HCC every 4-8 months until there is evidence that their cirrhosis and advanced fibrosis has resolved. The timeline for this improvement in fibrosis is unknown.

Patients who are Co-infected with HCV and HIV
  • Patients with HCV and HIV (HCV-HIV) co-infection are likely to have advanced liver disease. When these patients develop cirrhosis, they are at increased risk of HCC and at higher risk for more aggressive HCC. Therefore, these co-infected patients should undergo HCC surveillance. The criteria for screening are the same as for mono-infected patients.

Recommendation Grading

Overview

Title

Screening for Development of Hepatocellular Cancer in Patients with Hepatitis B and C

Authoring Organization

Publication Month/Year

April 27, 2022

Document Type

Guideline

Country of Publication

US

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Laboratory services

Scope

Diagnosis, Assessment and screening

Diseases/Conditions (MeSH)

D006509 - Hepatitis B, D006526 - Hepatitis C

Keywords

hepatitis C, hepatitis B, hepatocellular carcinoma, liver cancer