Chronic hepatitis B infection significantly raises the risk of developing liver cancer, especially in older adults, through a complex interplay of viral, cellular, and immune mechanisms that progressively damage the liver and promote malignant transformation.
Hepatitis B virus (HBV) infects liver cells and can persist in the body for decades, often without symptoms. When the infection becomes chronic, meaning the virus remains active in the liver over a long period, it causes ongoing inflammation and liver cell injury. This chronic inflammation triggers cycles of liver cell death and regeneration, which increase the chance of genetic mutations and abnormalities in liver cells. Over time, these changes can lead to the development of hepatocellular carcinoma (HCC), the most common form of liver cancer.
One key way chronic HBV raises cancer risk is through **viral DNA integration** into the host liver cell genome. HBV can insert its DNA into the DNA of liver cells, disrupting normal genes that control cell growth and division. This disruption can inactivate tumor suppressor genes that normally prevent cancer and activate oncogenes that promote uncontrolled cell proliferation. The viral protein HBx, produced by HBV, also plays a direct role by interfering with cellular pathways that regulate cell cycle, apoptosis (programmed cell death), and DNA repair. This interference promotes abnormal cell growth and survival, setting the stage for cancer development.
Chronic HBV infection also causes **persistent liver inflammation**. The immune system’s attempt to clear the virus leads to the release of inflammatory molecules and reactive oxygen species, which cause oxidative stress and DNA damage in liver cells. This environment of chronic injury and repair fosters fibrosis (scarring) and eventually cirrhosis, a condition where normal liver tissue is replaced by scar tissue. Cirrhosis itself is a major risk factor for liver cancer because the altered tissue architecture and ongoing cell turnover increase the likelihood of malignant transformation.
In older adults, the cumulative effects of decades of chronic HBV infection and liver damage become more pronounced. The longer the infection persists, the greater the chance for genetic mutations and epigenetic changes—alterations in gene expression without changes in the DNA sequence—that promote cancer. Aging also weakens the immune system’s ability to control viral replication and clear damaged cells, allowing cancerous cells to evade immune surveillance more easily.
Another important factor is the role of **extracellular vesicles (EVs)** released by HBV-infected liver cells. These small particles carry viral components and signaling molecules that can influence the tumor microenvironment. EVs promote cancer progression by enhancing blood vessel formation (angiogenesis), supporting cancer cell migration and invasion, suppressing immune responses, and helping cancer cells resist chemotherapy. This communication network between infected cells and their surroundings accelerates tumor growth and metastasis.
Chronic HBV infection also leads to **immune dysfunction**. The virus induces T cell exhaustion, where immune cells become less effective at attacking infected or abnormal cells. This immune suppression allows cancer cells to escape detection and destruction. In addition, HBV infection increases regulatory T cells and inhibitory receptors that dampen immune responses, further weakening the body’s natural defenses against cancer.
In summary, chronic hepatitis B raises cancer risk in older adults by:
– Integrating viral DNA into liver cell genomes, disrupting normal gene function.
– Producing viral proteins that promote abnormal cell growth and survival.
– Causing persistent liver inflammation, oxidative stress, fibrosis, and cirrhosis.
– Inducing genetic and epigenetic changes that accumulate over time.
– Releasing extracellular vesicles that modify the tumor environment and promote cancer progression.
– Impairing immune surveillance through T cell exhaustion and immune suppression.
The combination of these factors creates a high-risk environment for liver cells to become cancerous, especially as the infection and liver damage accumulate with age. This is why older adults with chronic hepatitis B are at significantly increased risk for developing hepatocellular carcinoma compared to uninfected individuals or those with resolved infection. Early detection, monitoring