Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and incidence in the US has tripled in the last four decades. Chronic viral hepatitis is the leading pathway to HCC in the US, followed by noninfectious causes such as obesity, Type-2 Diabetes, Non-alcoholic fatty liver disease (NAFLD), and Non-alcoholic steatohepatitis (NASH) which have been growing rapidly. We will describe viral hepatitis (HCV and HBV) pathways in this blog, and the prevention, diagnosis, and treatment options for these pathways.


In a previous blog on HCC care considerations, we described four leading risk factors and causal pathways for the development of HCC. This blog will describe the leading pathway and one that can develop quietly and insidiously and is on the rise. We will provide you with some tools and resources to help you to identify HCC, ways to link your patient to suitable specialists and to help you find appropriate studies and trials for your patient.

Four leading HCC risk factors:

  1. Hepatitis B (HBV)
  2. Hepatitis C (HCV)
  3. Excessive alcohol consumption
  4. Nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH)

Hepatocellular Carcinoma Pathways

Figure 1 HCC Pathways (c) @Creativemeddose

While the overall HBV infection rate has dropped nationally since 1991, it remains of concern for the African American population and has shown resurgence in some states. In 2017, non-Hispanic African Americans were 1.5x as likely to die as a result of viral hepatitis than whites, and almost twice as likely to die as a result of HCV. (HHS-OMH “Hepatitis and African Americans”) HBV is a DNA virus and remains the main causative infectious agent of HCC. It is responsible for most liver cancer patients in Asia and Africa. HCV is an RNA virus and sadly a major contributor to liver cancer in Egypt, Africa, Japan, and most of the Western Hemisphere.

The pathway from HBV to HCC is both indirect and direct

    1. Indirect: Necro-inflammation and regeneration injury
    2. Direct: Integration of HBV DNA in the host genome pathways

The most effective means to prevent HBV-related HCC is vaccination, and there are interferon-based approaches for those already infected. (Michielsen & Ho, 2011)

The pathway from HCV to HCC is a multistep process. It is thought that a combination of pathway alterations are caused directly by viral factors or chronic liver inflammation. HCV is more variable than HAV and HBV, and there are some 60 subtypes, complicating the development of a vaccine, and there is currently no approved HCV vaccine, but there are several HCV vaccine trials underway and some show long-term promise. The good news is that direct-acting antivirals can reduce the rate of HCC in HCV patients (Vescovo, Refolo, Vitagliano, Fimia, & Piacentini, 2016), and most people can receive treatment for HCV that will cure them in 8 to 12 weeks.


Figure 2 Viral HCC Pathways (c) @Creativemeddose

Encountering Hepatitis B and Hepatitis C in Patients

Approximately 78% of people with HCC also have HBV and/or HCV. The HHS reports that up to 2.2 million people in the United States have hepatitis B, while as many as 4.7 million people in the United States may be living with hepatitis C. 67% of those infected with HBV and 51% of those infected with HCV were unaware that they were living with the disease, and were at risk of cancer, as well as passing the virus on to others.

In contrast to the national decrease in HBV infections, some states continue along a path of increased HBV infection, and predictable increase in HCC deaths.

Incidence of acute hepatitis B virus infection by year in the United States and Kentucky, Tennessee, and West Virginia from 2006 to 2013

Figure 3 Incidence of acute hepatitis B virus infection by year in the United States and Kentucky, Tennessee, and West Virginia from 2006 to 2013. (HHS.gov)

The HHS further reports that the incidence of HCV infections in 2018 was four times higher than it was in 2010, and especially in the 20-40 age group, due to injected drug use.


Reported Acute Hepatitis C Cases 2000-2014

Figure 4 Reported Acute HCV cases 2000-2014 (HHS – 2022)

Starting in 2012, HCV-related deaths have surpassed those of other pre-COVID nationally notifiable infection conditions, and there have been more deaths due to HCV than all 60 of the other non-COVID reportable infectious diseases combined.

Hepatitis C Deaths and Deaths from Other Nationally Notifiable Infectious Diseases, 2003-2013

Figure 5 HCV Deaths and Deaths from Other Nationally Notifiable Infectious Diseases, 2003-2013 (HHS.Gov)


Age Group Distribution of Hepatitis C

Figure 6 Age Group Distribution of HCV (2018)

With increases of HBV in some states, and the growth of HCV nationally, it is thus important to conduct regular screenings for at-risk patients, and be alert to HBV and HCV risk factors.

Note: Although atypical, HCC can be the result of maternal HBV or HCV infection passed on vertically to children. For example, read the medical memoir Better Off Bald: A Life in 147 Days.

HBV Risk Factors (Mayo Clinic)

  • Unprotected sex or multiple sex partners
  • Needle sharing
  • Men who have sex with other men
  • Live with someone with chronic HBV
  • Infants born to an infected mother
  • Work with exposure to human blood
  • Travel to regions with high infection rates of HBV, including Africa, Asia, Eastern Europe, Pacific Islands

HCV Risk Factors (Mayo Clinic)

  • Health care workers exposed to infected blood – Needle-stick, etc.
  • Ever injected or inhaled illicit drugs
  • HIV positive
  • Piercings or tattoos in an unclean environment (unsterile equipment)
  • Blood transfusion or organ transplant before 1992
  • Clotting factor concentrates before 1987
  • Hemodialysis treatments for a long period
  • Infants born to an infected mother
  • Ever in prison
  • Born between 1945 and 1965 (Highest incidence of HCV infection)


Hepatocellular Carcinoma Viral Outcomes Pathways

Figure 7 Viral Outcomes Pathways (c) @Creativemeddose


How to Discuss Hepatocellular Carcinoma Staging With the Patient

Discussing staging with patients can be difficult. The public literature available to patients often contains misleading information, while the most trustworthy and authoritative information is usually aimed at clinicians and often only available behind paywalls. Blue Faery provides clinically accurate materials that the patient will find understandable. These materials are designed to assist the physician in describing the staging and to help patients to understand where they are in the spectrum.

These materials include:

  • The HCC patient education brochures, written in layman’s terms and intended for patients to read.
  • The Blue Faery HCC staging discussion pad, which contains anatomical graphics and easily understood text. Each double-sided sheet has space for clinicians to add notes for their patients to use after an appointment.
  • The Patient Resource Guide for Liver Canceris a 20-page booklet with explanations and resources pertinent to patients with HCC and their caregivers.

Blue Faery will send these free materials to any requesting physician.


How to Find Hepatocellular Carcinoma Specialists, Treatment Options, Clinical Trials

The treatment of HCC is best approached with a multidisciplinary team coordinated by a primary care physician. The most effective approach will likely require the expertise of multiple medical professionals and may include an oncologist with experience in HCC, a gastroenterologist, hepatologist, interventional radiologist, radiation oncologist, surgical oncologist, and a transplant surgeon.

To find all clinical trials, the best option is clinicaltrials.gov, but this website can be confusing and difficult to navigate. To assist clinicians in guiding patients to relevant trials, Blue Faery provides a custom HCC clinical trial navigator.

Community Support for Patients With HCC

Patient communities help provide patients with practical tips for their care journey and are often a source of emotional support by people who understand the experience.

The Blue Faery Liver Cancer Community is a free, HIPAA-compliant online community where patients and caregivers are welcome to join and to seek or exchange information relevant to HCC care. Members ask questions, discuss concerns, and find common ground as they navigate their cancer journeys. The forum moderators include community ambassadors who were former caregivers of patients with HCC.

For one-on-one patient support, Blue Faery has partnered with Imerman Angels, a nonprofit organization that provides peer-to-peer support services for the liver cancer community. Blue Faery and Imerman Angels believe that no one should face cancer alone.


Combating the “Infodemic”

Considering the experience during COVID-19 of an infodemic of misinformation, it may be worthwhile to draw on resources to combat misinformation. Dash et al (2021) described a three level infodemic approach for low and middle income environments, and the WHO provides an Infodemic Management library. Mayo offered an infodemic CME course (until Oct 28, 2023).



With adequate screening, testing, and inoculation, the viral pathway to HCC can often be interrupted. To aid in the care of those who have developed HCC, Blue Faery provides free, patient-readable, and clinically accurate materials to assist clinicians in discussing their patients’ staging, options, and resources.