Increased Cancer Rates in Patients With Chronic Hepatitis C

Anders H. Nyberg; Ekaterina Sadikova; Craig Cheetham; Kevin M. Chiang; Jiaxiao X. Shi; Susan Caparosa; Zobair M. Younossi; Lisa M. Nyberg


Liver International. 2020;40(3):685-693. 

In This Article

Abstract and Introduction


Aims: As previous reports show an association of chronic hepatitis C (HCV) with hepatocellular carcinoma (HCC) and non-liver cancers, we examine the association of HCV with liver cancer and non-liver cancers.

Methods: Retrospective cross-sectional study at Kaiser Permanente Southern California (KPSC) evaluating HCV and non-HCV patients from 1 January 2008 to 12 December 2012. Cancer diagnoses were obtained from the KPSC-SEER-affiliated registry. Logistic regression analyses were used for rate ratios and time-to-event analyses were performed using Cox proportional hazards models, adjusted for age, gender, race, smoking and cirrhosis. Cancer rate ratios were stratified by tobacco, alcohol abuse, diabetes and body mass index (BMI).

Results: The initial population and final population of multivariable analysis were N = 5 332 903 and N = 2 080 335 respectively. Cancer burden (all sites) was significantly higher in HCV than in non-HCV patients and HCV patients had a high rate of liver cancer. When liver cancer was excluded, cancer rates remained significantly increased in HCV. Unadjusted cancer rates were significantly higher in HCV compared to non-HCV for oesophageal, stomach, colorectal, pancreas, myeloma, non-Hodgkin's lymphoma, head/neck, lung, renal and prostate cancer. After stratification for alcohol abuse, tobacco, diabetes and BMI, increased cancer rates remained significant for all cancer sites, liver cancer and non-Hodgkin's lymphoma. Multivariable analyses demonstrated a strong correlation between cirrhosis and cancer. Tobacco use and diabetes were also associated with cancer. In the absence of cirrhosis, HCV, tobacco use and diabetes significantly increased the cancer risk. Mediation analyses showed that cirrhosis was responsible for a large proportion on the effect of HCV on cancer risk.

Conclusion: This study supports the concept of HCV as a systemic illness and treating HCV regardless of disease severity and prior to progression to cirrhosis.


The estimated global prevalence of chronic Hepatitis C (HCV) is 70–170 million.[1] Further, HCV is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC).[2] The incidence of HCC is rising rapidly and is now the second leading cause of cancer death worldwide with 20%-25% of HCC cases attributed to HCV.[3] In the USA, 3–7 million people have been infected with HCV and approximately 2.7 million are actively viraemic.[4,5]

The Hepatitis C virus is a single-stranded RNA virus that replicates in the plasma, but is not integrated in the genome. It was classified by the International Agency for Research on Cancer (IARC) in 1994 as an oncogenic virus.[6] There is a strong association between HCV and primary liver cancer.[7,8] The cause of the increased risk of liver cancer with HCV is unclear. Proposed mechanisms include indirect effects because of chronic inflammation, effects of cirrhosis (if present) and direct effects of HCV proteins on oncogenesis and on tumour suppression genes.[6,9]

There is also a well-established association of HCV and B-cell non-Hodgkin lymphoma (NHL) and the association is likely related to interactions between HCV and the host immune system.[10] For example, in a large retrospective study of US Veterans, Glordano et al found that HCV infection conferred a 20% to 30% increased risk of non-Hodgkin lymphoma overall.[11] Further, Lee et al, found higher mortality rates from oesophagus cancer, prostate cancer and thyroid cancer among anti-HCV seropositive persons than anti-HCV seronegative individuals.[12] Additionally, recent studies demonstrate higher rates of certain non-liver cancers in individuals with HCV compared to the general population.[13–18] These non-liver cancers include many histological types. In particular, cancers of the pancreas, kidney, prostate, lung, rectum and oral cavity are seen with greater frequency in HCV-infected individuals. However, these studies did not control for smoking, alcohol use or other behavioural risk factors that may be related to cancer risk. In the present study, we examine the association of HCV with liver cancers and non-liver cancers stratifying for behavioural risk factors which may be related to the cancer incidence.