Hepatitis and Its Implications on Liver Cancer

Introduction

Chronic hepatitis virus infection is the leading cause of hepatocellular carcinoma (HCC), the third most common cause of cancer death worldwide. Because of the increased likelihood of developing end-stage liver disease or hepatocellular carcinoma, chronic hepatitis B (CHB) is connected to a substantial mortality (death) rate. The incidence of symptoms in the presence of an acute infection varies with age. The majority of childhood infections are clinically silent. Approximately 70 percent of adults have subclinical hepatitis with a rise in transaminases (an enzyme), and up to 30 percent have transient jaundice and a flu-like prodromal stage.

Acute HBV infection can cause sudden onset of hepatitis with liver failure, but acute symptoms are commonly temporary and self-limiting. The clinical course of chronic hepatitis B is usually impossible to distinguish until the late stage of liver disease. High hygiene standards, blood product screening, and the introduction of a prophylactic vaccine significantly reduced the risk of acquiring HBV infection. To reduce perinatal infection in endemic areas, highly viremic (virus present in the bloodstream) mothers may require nucleoside or nucleotide analog treatment in addition to postnatal hepatitis B immunoglobulin and HBV vaccination. Lamivudine, Telbivudine, and Tenofovir are safe and reduce the risk of HBV transmission during pregnancy and the first year of life.

What Is Hepatitis B Virus Infection?

• HBV is a virus with partially double-stranded DNA that replicates (multiplies) through reverse transcription. HBV is distinguished by its limited host range and hepatocyte-specific replication (liver cell).

• The virus survives using an episomal transcription template (DNA fragments not contained within a chromosome) defined as covalently closed circular DNA inside the nucleus of infected hepatocytes.

• The viral genome contains four overlapping open reading frames that encode the structural core (HBc) and envelope proteins; the viral polymerase or reverse transcriptase and the oncoprotein regulatory X protein (HBx) are all components of the viral genome.

• Three envelope proteins of various sizes (small (S), medium (M), and large (L), are encoded with M and L carrying N-terminal endings of the same open reading frames.

• A small number of HBV virions (viral particles of about one to ten) are required to cause infection, and the virus is transferred through sexual contact with blood or body fluids and vertically from mother to child.

What Is Hepatitis C Virus Infection?

• HCV is transmitted through parenteral routes, occurs in industrialized countries due to intravenous drug abuse or invasive (spreads quickly) sexual practices, and is rarely passed down from mother to child. In addition, improved hygienic standards have helped to limit transmission.

• Most cases of acute HCV infection are asymptomatic (showing no symptoms), and only 15 percent of the patients experience fatigue, nausea, pain in the joint, or signs of liver damage.

• Chronic hepatitis C is a slowly progressive disease characterized by chronic hepatic inflammation, which leads to liver fibrosis (formation of scar tissues) and cirrhosis (fibrous thickening of the tissue).

• However, only a tiny proportion of HCV-infected individuals develop cancer, indicating a complex relationship between the expression of the viral genes and host and environmental factors to promote hepatocyte transformation and carcinogenesis.

• HCV is a positive-sense, single-stranded RNA virus that encodes a single polyprotein cleaved (broken down) post-translationally into structural (S) and non-structural (NS) proteins.

• The viral particle comprises structural proteins such as core protein, envelope E1, E2 glycoproteins, and p7 protein. In addition, non-structural proteins (NS1, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) help to replicate (multiply) viral genomes and assemble particles.

• HCV replicates in hepatocyte cytoplasm and is distinctive among cancer-causing viruses in that it does not encode oncoproteins (is encoded by oncogenes and is responsible for uncontrolled cell division) or integrate (combine) its genome into the host chromosomal DNA.

What Is the Mechanism Underlying HCV - Associated Carcinogenesis?

The mechanisms underlying HCV-associated carcinogenesis are primarily indirect effects of virus deregulation of host cellular processes, such as:

• Enhanced proliferation and steatosis of hepatocytes (too much fat in the liver).

• Virus-induced inflammation and oxidative stress-inducing genomic (genetic) mutations and genome instability.

• Damage of mitochondria and induction of reactive oxygen species (ROS).

• Effects of virus-induced host immune responses.

What Is Hepatitis Delta Virus Infection?

• Hepatitis delta virus (HDV) is a satellite virus dependent on HBV for virus formation and spread. The HDV genome is made of circular single-stranded RNA.

• The only viral protein encoded by the antigenomic open reading frame is hepatitis delta antigen (HDAg), which occurs in two forms, small-HDAg, and large-HDAg, and HDV particle assembly is entirely dependent on the HBV envelope glycoprotein.

• Thus, HDV infection can occur only in HBV co-infection. Chronic HDV co-infection causes more severe inflammation and liver disease than HBV mono-infection.

• Chronic HDV co-infection causes more severe inflammation and liver disease than HBV mono-infection. Furthermore, HDV accelerates the progression of fibrosis and cirrhosis and increases the risk of HCC development and early cirrhosis decompensation.

• Although HDV infection is not cytotoxic and HDAg is not directly oncogenic, high levels of HDV infection expression and nuclear translocation can activate the nuclear factor-B (NFB), and STAT3-induced inflammatory response and oxidative stress, both of these enhance HBV oncogenesis.

• Compared to HBV mono-infection, HDV infection is characterized by significantly increased inflammatory liver disease with necro-inflammation and increased hepatocyte turnover, resulting in active hepatitis.

What Are the Risk Factors of Hepatocellular Carcinoma?

• Cirrhosis of the liver is the most visible risk factor for HCC.

• Risk factors: Age above 49 years, duration of infection, male gender, alcohol consumption, smoking, previous exposure to Aflatoxin B1, and infection with HIV, Hepatitis B, and C virus.

• The risk of HCC in chronic hepatitis B and C is closely associated with ongoing infection-induced liver inflammation. Both viruses are non-cytopathic, and liver damage is thought to be caused by viral-specific CD8+ T- and natural killer (NK) cells rather than the viruses themselves.

What Are the Clinical Features of HBV - Associated Hepatocellular Carcinoma?

• Liver inflammation and necroinflammatory tissue damage.

• HBV viremia increases the risk of HCC. In multivariate Cox regression analyses, increasing HBV-DNA levels were identified as the most significant independent indicator of death from chronic liver disease and cirrhosis. It was second only to cirrhosis in predicting death from HCC.

How Is Hepatocellular Carcinoma Caused by HBV Diagnosed?

• Most (70 to 90 percent) of HBV patients who develop Hepatocellular carcinoma (HCC) have cirrhosis, and the yearly prevalence rate is around 2.5 percent. As a result, each patient with HBV-related cirrhosis should be screened -bi-annually. Moreover, HCC can occur in HBV individuals who do not have cirrhosis.

• The most often used imaging technique for HCC screening is ultrasonography (u/s), which has been demonstrated to have excellent diagnostic accuracy for HCC identification with a sensitivity of 65 to 80 percent and specificity of more than 90 percent.

• The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver Diseases (EASL) propose a six-month gap between ultrasonography screening as the most cost-effective screening method.

• When ultrasound results are unsatisfactory or inconclusive, multi-phase computed tomography (CT) or magnetic resonance imaging (MRI) should be conducted to improve diagnostic accuracy for HCC diagnosis.

• Screening for alpha-fetoprotein (AFP) with serological testing is not advised due to low sensitivity and specificity. However, the National Comprehensive Cancer Network (NCCN) says that AFP may be useful when paired with ultrasonography for at-risk patients.

How Is Hepatocellular Carcinoma Caused by HBV Managed?

• There are currently no treatments available to eradicate HBV infection. IFN (interferons) can treat chronic hepatitis B (CHB) in three to fifteen percent of patients, but it has severe adverse effects and is only used in rare cases.

• In more than 95 percent of treated individuals, nucleotide analogs (NAs) block reverse transcription and reduce HBV replication, reducing liver inflammation, disease progression, and HCC risk.

• However, these medications have little effect on viral cccDNA (covalently closed circular DNA) or integrated copies of DNA and must be taken for an extended period. Despite antiviral therapy, individuals with chronic hepatitis B (CHB) are at risk for developing HCC. HBV integration and proliferation of clonal hepatocytes have previously been reported early in the course of infection, and they may be a source of part of the persisting HCC risk after treatment commencement.

• Treatment alternatives for HCV have evolved substantially over the last five years. With the emergence of the nucleotide NS5B polymerase inhibitor Sofosbuvir in 2013, which demonstrated sustained virological response (SVR) rates of more than 95 percent when combined with IFN.

• Since then, new direct-acting antiviral (DAA) medications with significantly few adverse effects are currently available, with exceptional SVR rates of better than 90 percent following eight to twelve weeks of therapy for practically all HCV genotypes.

• However, it has become obvious that even effective direct-acting antiviral (DAA) therapy for chronic hepatitis C will not remove the risk of hepatocellular carcinoma once high-grade fibrosis or cirrhosis has been established.

• DAA- and IFN-based regimens demonstrated a significantly decreased but still present risk (0.33 percent per year) for HCC following HCV cure, emphasizing the significance of monitoring after liver cirrhosis has formed regardless of therapeutic response.

Conclusion

Both chronic HBV and HCV are linked to the development of HCC. HCC rates are reduced when chronic HBV is treated with oral antiviral therapy. Patients with chronic HCV who receive a virologic cure have a lower risk of HCC. Still, the risk is not eliminated, and patients with advanced cirrhosis should remain monitored.