Hepatitis C

Etiology

HCV is a spherical, enveloped, positive-strand ribonucleic acid (RNA) virus that is approximately 55 nm in diameter. It is a member of the family Flaviviridae, yet distinct to be classified as a separate genus, Hepacivirus. The genome is approximately 9.6 kb in length. It encodes a polyprotein that then gets processed into at least ten proteins. These include three “structural” proteins, the nucleocapsid protein, core (C), and two envelope proteins (E1 and E2); two proteins that are essential for virion production (p7 and NS2); and five nonstructural proteins that are essential part of the viral replication complex (NS3, NS4A, NS4B, NS5A, and NS5B). There is a very high level of virion turnover by the NS5B RNA polymerase with an absence of proofreading, resulting in the generation of viral mutants, also known as "quasispecies."[4][5][6]

Epidemiology

Globally, it is estimated that more than 58 million people are living with HCV. In developed nations, the HCV prevalence is typically 1 to 2%. The number of acute cases of HCV reported in the United States increased each year from 2009 to 2013. After adjusting, an estimated 29,718 acute HCV cases occurred in 2013. Of the three types of viral hepatitis (hepatitis A, B, and C), HCV accounted for the greatest number of deaths and the highest mortality rate, 5.0 deaths per 100,000 population in 2013. HCV transmission requires that infectious virions contact susceptible cells that allow replication. HCV RNA can be detected in blood (including serum and plasma), saliva, tears, seminal fluid, ascitic fluid, and cerebrospinal fluid. Available data suggest that HCV may get transmitted during sexual intercourse, but this rarely occurs. Perinatal transmission frequency ranges from 0% to 4% in more extensive studies. But for most patients with HCV in the United States and Europe, the infection is acquired via intravenous drug abuse or poor medical practices in resource-limited areas of the world.[7]

As per the most updated classification, there are seven genotypes of HCV based on their nucleotide variability in HCV sequences recovered from multiple geographic regions. 

• Genotype 1: the most widely dispersed worldwide, 60% to 70% of isolates from the United States are subtype 1a or 1b
• Genotype 2: widely dispersed but most diverse in central and west Africa
• Genotype 3: widely distributed but most diverse in Asia, linked to illicit drug use
• Genotype 4: Northern Africa and the Middle East. 
• Genotype 5: South Africa
• Genotype 6: Southeast Asia. 
• Genotype 7: Central Africa (Congo)

Pathophysiology

The hepatitis C RNA virus enters the hepatocyte via endocytosis mediated by at least four co-receptor molecules. Following internalization in the cytoplasm, its positive-stranded RNA is uncoated and translated into ten mature peptides. These are then cleaved by both host proteases and virally encoded proteases known as NS3-4a serine proteases. These mature peptides then go on to reside on the endoplasmic reticulum, forming a replication complex that contains an important enzyme, the NS5B RNA dependent RNA polymerase. This enzyme catalyzes the positive RNA strand into its negative-strand intermediate, which in turn serves as the template for new positive-strand synthesis. These are then packaged with core and envelop glycoprotein into mature virions, which then exit the cell via exocytosis. HCV cannot integrate into the host's genome.

Over the years, many genotypes of HCV have been identified. The dominant genotype globally is genotype 1, which is also associated with more severe liver disease and a much greater risk of developing liver cancer. In the US, genotype 1 accounts for about 60% of cases of HCV. Genotypes 2a, 3b, and 2c account for about 10% of cases in the USA and are most responsive to antiviral medications.

The virus is detectable in plasma within days of exposure, often 1 to 4 weeks. Viremia peaks in the first 8 to 12 weeks of infection and then plateaus or drops to undetectable levels (viral clearance); in the majority, 50% to 85%, it persists. Persistent infection appears to be due to weak CD4+ and CD8+ T-cell responses, which fail to control viral replication. When a chronic infection is established, HCV does not appear to be cytopathic; it is the local inflammatory response that triggers fibrogenesis. Multiple external factors, including alcohol consumption, HIV/HBV coinfections, Genotype 3 infection, insulin resistance, obesity, and non-alcoholic fatty liver disease, have links with accelerated fibrosis progression and cirrhosis. The severity of liver fibrosis tightly correlates with the increased risk of hepatocellular carcinoma via facilitating genetic aberrations and promoting neoplastic clones.[8]

History and Physical

Although usually not associated with symptoms, acute HCV infection may cause malaise, nausea, and right upper quadrant pain, followed by dark urine and jaundice. This is clinically indistinguishable from any other acute viral hepatitis. Persistently infected individuals tend to be asymptomatic for the most part. Symptoms are nonspecific and include fatigue or malaise, intermittent right upper quadrant pain, and joint pain as well as a general feeling of being unwell with overall reduced quality of life. It is challenging to relate these symptoms to HCV alone, as there could be a potential psychological basis due to the knowledge of having an underlying chronic disease.

Ten percent to 20% of HCV-infected persons with cirrhosis will decompensate clinically within five years, as evidenced by the development of portal hypertension, esophageal varices, ascites, coagulopathy, encephalopathy, or hepatocellular carcinoma. At this stage, they could have physical signs indicating stigmata of chronic liver disease with caput-medusae, spider angiomas, palmar erythema, asterixis, anasarca, and fluid thrill. Moreover, they may have signs and symptoms of other extrahepatic manifestations like mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, neurocognitive changes, insulin resistance, and B cell lymphoproliferative disorders. 

The physical exam may reveal signs of end-stage liver disease, which include:

• Temporal muscle wasting, cyanosis, icterus, enlarged parotid gland
• Palmar erythema, asterixis, clubbing, Dupuytren contracture
• Gynecomastia, small testes
• Fetor hepaticus
• Ankle edema, spider nevi, petechiae, scant body hair
• Caput medusae, paraumbilical hernia, hepatosplenomegaly

Evaluation

The diagnosis of HCV infection is based principally on the detection of antibodies to recombinant HCV polypeptides and by assays for HCV RNA. These are enzyme immunoassays that measure antibodies directed against NS4, core, NS3, and NS5 sequences. These cannot differentiate between past or current HCV infection. Direct testing for HCV RNA is necessary to distinguish between ongoing or prior infection in persons with HCV antibodies. HCV Rapid Antibody Test with rapid turnover can be an essential public health tool in nontraditional settings. There are three scenarios in which the HCV RNA test should be considered upfront: (1) exposure within the past six months, (2) an immunocompromised host, and (3) suspicion for reinfection.

Further evaluation consists of checking the viral genotype, which is still important in choosing the most optimal regimen and also for predicting the response to therapy. Other baseline evaluations include testing for HIV, hepatitis B surface antigen, susceptibility to hepatitis A and hepatitis B virus infections, and screening for other underlying causes of liver disease such as autoimmune liver disease, hemochromatosis, and Wilson disease. Before determining the HCV treatment strategy, the next step is to stage the disease, utilizing liver biopsy (gold standard) or approved imaging modalities with or without noninvasive biomarkers. Lastly, all of these patients should also undergo variceal screening and screening for hepatocellular carcinoma.[9][10][11]

Other studies include:

• INR, prothrombin time
• Complete blood count
• Liver function tests
• GFR
• Serology for other hepatic viruses
• Thyroid function
• Screening for drug abuse and alcohol
• Mental health assessment

A liver biopsy is not routine, but it may help determine the severity of the disease. Other indications for a liver biopsy include 1) uncertain diagnosis, 2) presence of another liver disorder, and 3) immunocompromised patient.

Treatment / Management

Acute HCV infection is self-limited, or it may lead to chronic infection. Treatment of chronic HCV infection is achieved by eradicating HCV RNA by the attainment of a sustained virologic response (SVR). SVR is achieved when HCV RNA is no longer detectable in the blood after 12 weeks of therapy, with a decline in antibody titers and improved liver pathology. Before the development of the all-oral DAAs, the mainstay of therapy was injectable pegylated interferon and ribavirin. In addition to only having a cure rate of 40% to 60%, this form of treatment led to numerous adverse effects, including flu-like illness, hematological effects like neutropenia, thrombocytopenia, severe anemia, and neurocognitive effects. With the advent of DAAs, immense progress has been seen toward shortening the duration of treatment from 48 weeks to 12 weeks, improving the adverse effects, increasing cure rates to 90% to 97%, and eliminating the need for injectable agents. Currently, three classes of DAAs include (1) second-generation protease inhibitors that inhibit the NS3/4 serine proteases, (2) the NS5A inhibitors which interfere with the structural protein NS5A, a crucial element in the formation of the replication complex, and (3) the NS5B polymerase inhibitor which inhibits the enzyme responsible for transcription of a negative-strand intermediate for future viral progeny. These three classes are used in different combinations to make a robust treatment regimen against the various genotypes of hepatitis C.[6][12][13]

The standard regimens are anywhere from 12 weeks to 24 weeks with or without ribavirin based on the genotype, treatment experience, and presence or absence of cirrhosis. With the current DAAs, it is the Genotype 3 infection, which is the least responsive, that is associated with rapid accelerated fibrosis progression and a higher incidence of hepatocellular carcinoma. Genotype 1, the most common genotype present in the United States, has four different treatments approved, two of which require only a single pill per day. For example, the combination of sofosbuvir and ledipasvir in a single pill and the combination of grazoprevir and elbasvir as a single pill. There are many more drugs in phase III and IV clinical trials that appear to have a pan-genotypic potential such that it will eliminate the need to check the hepatitis C genotype. Defining each regimen for the various genotypes is beyond the scope of this article.

Differential Diagnosis

• Autoimmune hepatitis

• Alcoholic liver disease

• Abdominal aneurysm

• Bowel obstruction

• Cholangitis

• Cholecystitis

• Cholelithiasis

• Drug-induced liver injury

• Gastritis

• Gastroenteritis

• Hepatocellular carcinoma

• Liver abscess

• Peptic ulcer disease

• Viral hepatitis

Prognosis

Only 10-15% of patients infected with HCV have a self-limited infection; in all others, the infection is progressive. About 20% will develop cirrhosis within two decades, and another 1 to 5% will develop liver cancer within three decades. The progression of the disease is more common in heavy users of alcohol, cirrhotics, and those with a coexisting HBV infection. Individuals who have an undetectable viral load generally have a decreased risk of developing cirrhosis and death.

Complications

End-stage liver disease

Liver cancer