Hepatitis and Its Types: An In-depth Study of Hepatitis C from Lifecycle to Treatment

Hepatitis is a term that signifies an inflammatory state of the liver. While viral infections are the most common cause, other factors can also lead to this condition. These include autoimmune hepatitis, where the body’s immune system targets liver tissue, and secondary hepatitis, which is a consequence of certain medications, drugs, toxins, and alcohol consumption.

Types of Hepatitis

There are five primary forms of hepatitis, each attributed to a distinct virus:

1. Hepatitis A: This type, caused by the Hepatitis A virus (HAV), is an acute or short-term disease.
2. Hepatitis B: The Hepatitis B virus (HBV) leads to this form, which is often chronic and long-lasting.
3. Hepatitis C: This form stems from the Hepatitis C virus (HCV). It is one of the most prevalent bloodborne viral infections in the United States and is typically a long-term condition.
4. Hepatitis D: This rare variant of hepatitis only occurs alongside a hepatitis B infection. The Hepatitis D virus (HDV) causes liver inflammation similar to other types, but HDV cannot be contracted without an existing hepatitis B infection.
5. Hepatitis E: This is a waterborne disease caused by the Hepatitis E virus (HEV). Hepatitis E is primarily found in regions with poor sanitation and is usually a result of consuming water contaminated with fecal matter.

The transmission methods vary for each type of hepatitis. Hepatitis A and E are generally contracted through exposure to the virus in food or water. Hepatitis B, C, and D are typically transmitted through contact with infected bodily fluids, such as blood, vaginal secretions, or semen.

While infections are the most common cause of hepatitis, other factors can also lead to this condition. These include the consumption of alcohol and exposure to other toxins.

Hepatitis C

Hepatitis C, similar to hepatitis B, represents a global health hazard. This longstanding disease is prevalent across all human populations. However, the incidence and risk factors are elevated among individuals residing in unsanitary environments, those with substance addiction, individuals with multiple sexual partners, and people engaged in certain professions. The hepatitis C virus (HCV) is the pathogen responsible for hepatitis C. It reaches the liver through the bloodstream, where it triggers an infection in the liver cells, known as hepatocytes. The disease is characterized by a notably high mortality rate.

Hepatitis C is a liver disease instigated by the hepatitis C virus (HCV). Initially, this disease was classified as non-A, non-B (NANB) hepatitis, following the exclusion of hepatitis A, hepatitis B, and an array of other viral and bacterial infections. Despite rigorous efforts and relentless investigations, the causative agent of this disease remained elusive to virologists. Various viral particles were identified in the serum, urine, hepatocytes, and Kupffer cells, yet a causal relationship with NANB hepatitis could not be established. However, a persistent observation by a few researchers revealed a virus associated with the majority of NANB hepatitis cases. This virus eventually garnered the attention of virologists who cloned it in three distinct laboratories using recombinant DNA techniques. Upon thorough examination, the clones were found to be identical in all respects. Consequently, the virus was designated as the hepatitis C virus, and the disease was termed hepatitis C. In 1989, a serological test was devised to detect HCV-specific antibodies. This test proved instrumental in the serological diagnosis of acute and chronic hepatitis C. Repeated application of this test confirmed the involvement of HCV in NANB hepatitis cases.

Viral Structure

HCV is a spherical, enveloped, single-stranded RNA virus that belongs to the Flaviviridae family. The virus measures approximately 50 nm in diameter. The envelope’s surface is adorned with protein spikes. The RNA, a linear structure comprising 9379 nucleotides, serves as the virus’s genome. The 5’ terminal of the genome encodes the structural capsid and envelope proteins. Conversely, the 3’ terminal, the functional region, encodes viral proteases, RNA polymerase, and regulatory proteins. The RNA genome is a positive strand that codes for a polyprotein of 3010 to 3030 amino acids. This protein undergoes proteolytic post-translational cleavage. The capsid is composed of phosphorylated protein.

Lifecycle of Hepatitis C

The lifecycle of the Hepatitis C virus (HCV) is a multifaceted process that predominantly takes place in the liver’s hepatocytes. The lifecycle can be divided into four primary stages within a host liver cell, as outlined below.

Stage 1: Viral Entry

1. HCV Virion: This stage involves a Hepatitis C virion, a spherical entity with a protein shell that encases its single-stranded RNA genome.
2. Attachment: The virion attaches to specific receptor molecules present on the liver cell’s surface.
3. Endocytosis: The liver cell membrane engulfs the virion, forming an internal vesicle.

Stage 2: Genome Translation and Polyprotein Processing

1. Endosomal Vesicle: This stage showcases the vesicle, which houses the virion within the liver cell's cytoplasm.
2. RNA Release: The virion’s RNA genome is discharged into the cytoplasm.
3. Polyprotein Translation: Ribosomes located on the rough endoplasmic reticulum (RER) translate the viral RNA into a singular, large polyprotein.
4. Protease Cleavage: Cellular and viral proteases dissect the polyprotein into individual functional proteins.

Stage 3: Genome Replication

1. Non-structural Proteins: Several of the cleaved proteins are non-structural proteins that assist in viral RNA replication.
2. Negative Strand Synthesis: These proteins generate a negative strand intermediate from the positive-sense RNA genome.
3. Positive Strand Synthesis: New positive-sense RNA strands are produced using the negative strand as a template.

Stage 4: Particle Assembly and Release

1. Viral Assembly: The newly synthesized RNA strands associate with viral proteins and assemble into new virions within the RER.
2. Maturation: The virions mature as they traverse through the cellular secretory pathway.

Release: Mature virions are released from the host liver cell, primed to infect other cells.

Viral Replication

HCV replicates in the cytoplasm of hepatocytes. Upon penetration, the positive RNA strand is initially translated to synthesize various structural and functional proteins, including RNA-dependent RNA polymerase. The RNA polymerase creates a complementary copy, or the negative strand, using the positive strand as a template. The negative strand serves as a replicative intermediate. The RNA-dependent RNA polymerase uses this structure as a template and synthesizes positive strands. The virus is then assembled and released through a process of budding.

Genetic Variation

HCV exhibits a propensity for genetic variation during replication. This characteristic is attributed to the absence of a proofreading mechanism for newly synthesized RNA, resulting in highly heterogeneous HCV populations. This enduring diversity has, over centuries, culminated in the evolution of several distinct viral groups, now classified into six primary HCV genotypes, each with several subtypes. The role these genotypes or their subtypes play in disease severity remains to be determined. HCV’s ability to alter its genotypic character over time also manifests within the infected individual, leading to the formation of a family of closely related viruses with minor differences, known as quasispecies. These minor variations benefit the virus by enabling it to evade host immune surveillance, as antibodies produced against one quasispecies often fail to defend against another.

Pathogenesis

Hepatitis C is a global disease affecting all population segments. HCV is present in the blood of patients and carriers, with an estimated 10 to 105 infectious doses potentially present in one microliter of blood. Until recently, transmission was thought to occur primarily through blood transfusion, needle sharing, and promiscuous sexual activities. However, transmission patterns have evolved in recent years. While direct percutaneous exposure through blood or blood product transfusion remains an efficient transmission method, most current HCV infections are acquired outside transfusion settings. Modern blood bank practices, including viral disease screening tests, have nearly eradicated the risk of HCV infection for blood recipients in most parts of the world. Consequently, injection-drug use has become the most common cause of HCV infection. According to one medical survey, over 75% of all new injection-drug users become HCV seropositive within one year of initiating drug use. In Pakistan, however, the situation remains unchanged, as transfusion practices are not as safe as in many other countries, making blood transfusion the primary cause of HCV transmission. Today, the most commonly identified risk factors include injection-drug use, hemodialysis, exposure to an infected contact through sexual or household contact, multiple sexual partners, perinatal exposure, healthcare employment, and low socioeconomic status. The transmission of HCV to the host marks the onset of infection. The virus is transported to the liver via the bloodstream, where it initiates replication in hepatocytes.

Clinical Manifestations

The clinical symptoms of hepatitis C bear resemblance to those of hepatitis B. The average incubation period for the disease spans seven weeks, with a range between 3 to 20 weeks. The onset of the disease is typically insidious, commencing with symptoms such as anorexia, general discomfort, nausea, vomiting, muscle pain, and an enlarged liver. Hepatitis C is characterized by extended viremia and the development of a persistent carrier state. The disease is generally milder than hepatitis B, as evidenced by lower ALT levels and less severe jaundice. The acute phase of the illness typically lasts between 2 to 12 weeks. In approximately 15% of cases, the disease is self-limiting; symptoms resolve, HCV RNA becomes undetectable, and ALT levels return to normal.

Medical reports suggest that over 85% of patients with acute disease become chronically infected (HCV RNA positive), and between 65 to 85% develop chronic hepatitis (elevated ALT). Among chronically infected patients, approximately 30% maintain persistently normal ALT levels, while others experience occasional ALT elevation. Chronic hepatitis C is a progressive liver disease, characterized by mild, intermittent, and nonspecific symptoms such as fatigue, abdominal pain, fever, and joint pain. The progression of the disease typically spans decades and, in many patients, may be so gradual that it does not result in increased morbidity or mortality. Some patients develop cirrhosis, primarily during the first 20 years of the disease. Symptoms exhibited by a patient with cirrhosis include severe fatigue, significant muscle soreness and nerve pain, fluid retention, jaundice, darkening of urine, upper intestinal bleeding, and itching. In most cases, hepatitis C, when accompanied by cirrhosis, may lead to liver failure and death. There are a few serious extrahepatic manifestations of hepatitis C, including essential mixed cryoglobulinemia (EMC), arthritis, membranoproliferative glomerulonephritis, keratoconjunctivitis, and porphyria cutanea tarda. EMC is characterized by the presence of cryoglobulins in the serum, hypocomplementemia, and symptoms such as fatigue, muscle and joint pain, arthritis, dermatitis, and neuropathy.

Laboratory Diagnosis

ELISA-2

Hepatitis C is diagnosed in laboratories through serological methods. The most crucial method for detecting antibodies specific to HCV is the second-generation enzyme-linked immunoassay (ELISA-2). This test is gaining popularity due to its simplicity, automation, reproducibility, and cost-effectiveness. Its sensitivity and accuracy are extremely high, exceeding 90%, and a single positive test is reliably sufficient for diagnosis. Efforts are underway to develop a third-generation assay with a sensitivity and specificity rate higher than 95%.

Recombinant Immunoblot Assay

Another significant diagnostic test for hepatitis C is the recombinant immunoblot assay (RIBA). This test employs a recombinant viral antigen, named C100-3, in a ‘capture’ assay for circulating HCV antibodies. Anti-C100-3 antibodies, which appear to develop against nonstructural viral epitopes weeks or months after acute infection, also indicate chronic persistent viremia.

HCV RNA Assay

A recent advancement in the diagnosis of hepatitis C involves the detection of HCV RNA in the patient's blood. This method, known as the HCV RNA assay, is highly beneficial in identifying the HCV genome and quantifying the level of circulating virus in the infected individual. This test also plays a crucial role in monitoring the effectiveness of antiviral therapy.

Therapy

At present, interferons are the sole agents with demonstrated efficacy in treating hepatitis C. Three types of interferons are currently available on the market:

1. Interferon alpha-2b (introduced in 1991),
2. Interferon alpha-2a (introduced in 1996),
3. And a synthetic consensus interferon alphacon-1 (introduced in 1997).

Other interferons, including a leucocyte interferon, a lymphoblastoid interferon, and an interferon beta, are under investigation.

Prevention

The World Health Organization’s recommended measures for preventing hepatitis C align with those for hepatitis B. However, there is currently no available vaccine for hepatitis C. The primary challenge in developing an effective vaccine for HCV infection is the persistent genetic variation exhibited by the virus in its genome. Nevertheless, it is recommended that all patients with hepatitis C receive vaccinations against hepatitis A and hepatitis B, as these infections can lead to significant morbidity and mortality when they occur alongside preexisting liver disease.