Be aware of all factors related to HCC risk, not just HCV
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Hepatitis C virus infection remains a strong driver of hepatocellular carcinoma with a high rate of progression to cirrhosis over an extended follow-up period, according to a study in International Journal of Molecular Sciences.
“Although the face of liver disease is changing and hepatitis C virus is certainly shrinking as a driver for decompensated liver disease, one place it’s going to continue to persist is liver cancer,” Nancy S. Reau, MD, FAASLD, AGAF, professor in the department of Internal Medicine, Division of Digestive Diseases and Nutrition at Rush Medical College at Rush University Medical Center, said in a Healio Gastroenterology and Liver Disease guest editorial. “When I talk about HCV and the risk for liver cancer, the most important message to providers is you should not withhold treating HCV in a patient with cirrhosis for fear of accelerating their risk for cancer.”
Cirrhosis prevalence
While individuals with hepatitis B and hepatitis C are at high risk for cirrhosis development and therefore progression to HCC, there remains a risk for cancer even in those without cirrhosis, Reau said in a recent interview.
“Globally, Hepatitis C has been and remains a common cause of cirrhosis,” she told Healio. “Given the demographics in the United States, HCV continues to be a common explanation for chronic liver disease. Many individuals with HCV are undiagnosed and thus at risk for disease progression to advanced fibrosis. Unfortunately, this also means we continue to see cases of hepatitis c that are complicated by liver cancer, many of which present when curative options are not available.”
Reau said that hepatologists can miss early cirrhosis because lab work may be underwhelming, and the patients may lack symptoms. There are many non-invasive tests to estimate how affected a person’s liver is, yet they may not be available to all clinicians (or inaccurate in some patients) leaving biopsy as the only modality to accurately diagnose cirrhosis in some scenarios. Clinicians may also be tempted to restage a patient after successful therapy, which may not accurately reflect future cancer risk.
In the guest editorial, she emphasized that all patients, irrespective of etiology of liver disease, should be staged, even if just with a simple tool like ARFI or APRI. This is the best way for clinicians to estimate risk for liver related morbidity and mortality. Some groups of patients, such as those with cirrhosis from fatty liver disease, may be frequently underdiagnosed. If a patient is not staged providers may miss advanced disease and miss the opportunity to screen them for HCC, Reau explained.
With the reliance on non-invasive markers which have overlap between degrees of fibrosis, “We often lump both stage III and stage IV or cirrhosis into ‘advanced fibrosis,’ thus treating stage III and stage IV liver disease essential the same,” Reau said. “Our guidelines typically recommend screening for cirrhosis or stage IV. However, as the non-invasive staging tests may not differentiate between these stages, many clinicians assume a stage III patient could still be at risk.”
Reau said providers do better at screening for cancer in someone with known cirrhosis, finding lesions at a time when curative options are still available. Prognosis is much worse if cancer is found after symptoms emerge.
Other HCC risk factors
Other additives that lead to liver cancer include drinking alcohol, fatty liver, age and diabetes. Reau noted these are also factors at play for many hepatitis C patients with cirrhosis or pre-cirrhosis.
Reau said that although curing hepatitis C substantially reduces the risk to develop liver cancer, some patients will still get hepatocellular carcinoma (HCC). Several observational studies show that many of these individuals have additional risk factors for HCC such as older age, male gender, obesity, alcohol use, and diabetes.
“Even after you cure hepatitis C, which monumentally decreased the risk for developing cancer, there is still a little residual risk for cancer,” Reau said. “Although we would love to think that as time goes by that risk gets smaller, that's not true. We know that as time goes by, that residual risk continues to be there and sometimes increases especially for patients who develop other co-risk factors like diabetes or obesity.”
Still, cancer screening focuses on fibrosis not the number of risk factors. “Without advanced fibrosis, the risk isn’t high enough for guidelines to advocate for screening all patients with any known risk for liver cancer,” she said.
Obesity is a stressful thing for the liver, according to Reau. Even if an individual does not have diabetes, insulin resistance and obesity can change gut permeability. This may increase the proinflammatory cytokines that go to the liver that act as stress signals and if there is fat in the liver stress signals are not handled well, she said.
Alcohol also causes liver disease, increase the risk for liver cancer and increases gut permeability, according to Reau.
“The more detrimental things that get added together, the higher the chance the liver will get damaged or develop cancer,” she said. “In those studies where they look back and see what additional risk factors other than etiology of liver disease lead to a person developing cancer, alcohol use is consistently an additive risk factor. Recognize, when you are screening patients for hepatitis C and fatty liver disease their overall risk is also impacted by other modifiable factors.”
HCC risk reduction
“Knowledge is powerful if you can reduce risk,” she said. “Someone has liver disease — from alcohol use, hepatitis C or obesity — there are things that you can do to reduce their risk: control someone’s hepatitis B, cure someone’s hepatitis C, encourage them to engage in a healthy lifestyle and abstain from alcohol. You’re going to work on risk reduction anyway possible.”
Reau explained it is important to not lose vigilance after treating a patient with hepatitis C or if they happen to lose weight.
“Most studies will demonstrate that a person never eliminates the risk for liver cancer,” Reau said. “Restaging them or reclassifying them might make you feel better and should, but it can’t change the interval for screening in a known cirrhotic yet. You should be able to tell someone you cured their hepatitis C and their rate for cancer is now much lower. We might stop screening someday when we have biomarkers that allows us to better characterize risk, but we aren’t there just yet.”
References:
Kanda,T et al. Int J Mol Sci. 2019; doi:10.3390/ijms20061358.
Gastroenterology. Available at: https://www.healio.com/gastroenterology/oncology/news/print/healio-gastroenterology/%7B7f3abd57-7d8e-44f7-819a-ab08e329b537%7D/managing-risk-reduction-in-the-changing-face-of-liver-cancer. Accessed: April 27, 2020.
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