Hepatitis C Virus

Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C infection is diagnosed by testing for the presence of HCV antibodies and HCV RNA. Management is supportive but includes direct antiviral agents (DAAs) if infection does not resolve spontaneously.

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Classification

Rna viruses flowchart classification

Flowchart RNA viruses

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Structure

  • Taxonomy:
    • Family: Flaviviridae
    • Genus: Hepacivirus 
  • Positive-sense ssRNA 
  • Genome is made up of a single open reading frame that is 9600 nucleotide bases long.
  • Small (55–65 nm)
  • Spherical
  • Enveloped: lipid membrane with 2 glycoproteins (E1 and E2) embedded → play a role in the attachment of the virus to the host cell
Structure of hepatitis c virus

Structure of hepatitis C virus:
Note the positive-sense ssRNA and the glycoproteins embedded in the virus’s lipid envelope, which mediate cell entry.

Image by Lecturio.

Features

  • Incubation period: 2 weeks–6 months (median incubation period: 8 weeks)
  • Can cause both acute and chronic hepatitis 
  • Most common reason for liver transplantation

Epidemiology

  • Prevalence:
    • About 70 million people globally have chronic hepatitis C.
    • Only about 20% of individuals infected with hepatitis C virus (HCV) know their diagnosis.
    • Only about 60% with chronic infection receive appropriate treatment.
    • Regions with highest prevalence: 
      • Eastern Mediterranean
      • South East Asia
      • Western Pacific
      • Sub-Saharan Africa
  • About 290,000 fatalities each year
  • HCV is the most common cause of chronic hepatitis in the United States. 
  • Genotypes cluster by location:
    • Genotype 1: United States and Northern Europe (45%–55%)
    • Genotype 2: Mediterranean countries (80%–90%)
    • Genotype 3: Indian subcontinent (70%–85%)
    • Genotype 4: Egypt and North Africa (50%–60%)

Pathogenesis

Transmission

Humans are the only reservoir for the virus. Modes of transmission include:

  • Parenteral
  • Sexual
  • Perinatal
  • Tattooing, sharing razors, and reusing acupuncture needles

Host risk factors

  • People who inject drugs (PWID) → nonsterile needles and needle sharing pose the highest risk for HCV infection
  • Men who have sex with men (MSM)
  • Screening donated blood for HCV antibody sharply ↓ the risk of transfusion-associated HCV infection.
  • Health care workers or other occupational exposures (needlestick injuries)

Pathophysiology

  • Entry into host cells occurs via glycoproteins on virion surfaces
  • Protein–receptor interactions lead to endocytosis of the viral particle (aided by clathrin proteins)
  • Enter endosome → endosome and viral envelope fuse → RNA is allowed into the cytoplasm
  • HCV controls the intracellular machinery of the host cell to replicate itself → HCV genome translated
  • RNA replication takes place via the viral RNA–dependent RNA polymerase
  • Negative-strand RNA acts like a template for new positive-strand viral genome production
  • Nascent RNA can then be translated, further replicated, or packaged within new virus particles.

Clinical Presentation

Acute infection

  • Often asymptomatic
  • If present, symptoms may include:
    • Icterus and jaundice
    • Fatigue
    • Arthralgias, myalgias
    • Abdominal pain
    • Fever
    • Nausea, vomiting, diarrhea
    • Very rare: severe disease with acute liver failure

Chronic infection

  • 60%–85% of all infected individuals develop chronic HCV infection.
  • About 1 in 5 infections results in cirrhosis within 20 years.
  • Symptoms: mostly nonspecific symptoms similar to acute infection
  • Liver cirrhosis
  • Extrahepatic manifestations:
    • Hematologic:
      • Cryoglobulinemia
      • Lymphoma
    • Endocrine:
      • Diabetes mellitus
      • Autoimmune thyroiditis 
    • Renal: glomerulonephritis
    • Dermatologic:
      • Erythema nodosum
      • Porphyria cutanea tarda
      • Lichen planus

Diagnosis

Viral markers

  • HCV antibodies:
    • Initial test
    • Positive results cannot differentiate between acute, chronic, and previous HCV infection.
    • Can be detected 7–8 weeks after initial infection
    • Positive result → confirm current infection by HCV RNA test
    • Negative HCV antibody test but clinical suspicion → test for HCV RNA or repeat HCV antibody testing 
  • HCV RNA:
    • Performed after a positive HCV antibody result
    • Indicates active infection (acute or chronic)
    • Always test for HCV RNA instead of HCV antibodies in the following cases:
      • Immunosuppression
      • HIV infection
      • Individuals on dialysis

Further testing

  • Transaminases (ALT/AST) may be ↑ 
  • Cholestasis parameters: γ-glutamyl transferase (γ-GT), alkaline phosphatase (AP), bilirubin, may be ↑
  • Albumin, cholinesterase may be
  • Liver sonography and elastography → assess for cirrhosis and hepatocellular carcinoma (HCC)

Management

Pharmacotherapy

  • Indication: any replicative HCV infection (= HCV RNA detectable)
  • Quantify HCV RNA before initiating antiviral therapy to obtain baseline viral load
  • About 30% of infected individuals spontaneously clear the infection because of a strong immune response → no need for treatment 
  • Treatment goals:
    • Eradication of HCV (defined as the persistent absence of HCV RNA in serum 12 weeks after completing antiviral treatment)
    • Prevention of progression to cirrhosis, HCC, and decompensated liver disease requiring liver transplantation
  • Combination of 2 direct-acting antiviral agents (DAAs) based on genotypes, e.g.:
    • Ledipasvir + sofosbuvir
    • Sofosbuvir + velpatasvir
    • Administered for 8–24 weeks, depending on presence and severity of cirrhosis
    • Interferon and ribavirin are now generally avoided owing to side effects.

Prevention

  • No vaccine available
  • No preexposure or postexposure prophylaxis available
  • Prevention focuses on reducing the risk of exposure:
    • Educating populations at high risk for infection (PWID, MSM, people infected with HIV)
    • Safe use of health care injections
    • Safe handling and disposal of sharps and waste
    • Testing of blood donations for HCV 

Hepatitis Viruses Comparative Table

Comparison table of hepatitis viruses

Anti-HBc: hepatitis B core antibody
Anti-HBs: hepatitis B surface antibody
HBcAg: hepatitis B core antigen
HBsAg: hepatitis B surface antigen
HBV: hepatitis B virus
HCC: hepatocellular carcinoma
HCV: hepatitis C virus
HDV: hepatitis D virus

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Alcoholic liver disease (ALD): liver pathology that occurs because of prolonged excessive alcohol consumption. The 1st stage is an asymptomatic fatty liver, which is reversible. The 2nd stage is alcoholic hepatitis, which most commonly presents with jaundice, fever, and RUQ pain. The 3rd stage is cirrhosis of the liver. Diagnosis is established by history, liver-function tests, and imaging studies. 
  • Drug-induced liver injury (DILI): occurs when drugs ingested cause injury to the hepatocytes directly in a predictable dose-dependent way or through idiosyncratic reactions. The presentation of DILI can be acute or chronic, with severe toxicity manifesting as fulminant liver failure. The diagnosis of DILI requires a thorough history and laboratory tests. Management consists of early diagnosis and discontinuing the drug, as well as supportive therapy.
  • Autoimmune hepatitis (AIH): liver inflammation that occurs when the body’s immune system attacks its own liver cells. Clinical presentation ranges from asymptomatic to symptoms of acute liver failure. Diagnosis is established via testing the blood for characteristic autoantibodies (especially, anti–smooth muscle antibodies) and liver biopsy. Management includes corticosteroids and azathioprine. 
  • Wilson disease: autosomal recessive disorder from a mutation in the ATP7B gene, which regulates copper transport within hepatocytes. Neuropsychiatric manifestations of Wilson disease help differentiate it from other causes of hepatitis. In early stages, Wilson disease may be confused with hepatic encephalopathy. Kayser-Fleischer rings, low ceruloplasmin levels help separate Wilson disease from other causes of hepatitis.
  • Nonalcoholic fatty liver disease (NAFLD): spectrum of liver pathology that arises due to accumulation of triglycerides in hepatocytes. Nonalcoholic fatty liver disease ranges from fatty liver or hepatic steatosis but can lead to nonalcoholic steatohepatitis which has fatty deposits and inflammation. Progressive liver injury and fibrosis irreversibly develop into cirrhosis and possibly, primary liver cancer. Management is with lifestyle modifications (diet and exercise).

References

  1. Chopra, S., Pockros, P. (2020). Overview of the management of chronic hepatitis C virus infection. UpToDate. Retrieved January 28, 2021, from https://www.uptodate.com/contents/overview-of-the-management-of-chronic-hepatitis-c-virus-infection
  2. Chopra, S., Flamm, S. (2020). Extrahepatic manifestations of hepatitis C virus infection. UptoDate. Retrieved January 28, 2021, from https://www.uptodate.com/contents/extrahepatic-manifestations-of-hepatitis-c-virus-infection
  3. World Health Organization (WHO). Fact sheet: hepatitis C. Retrieved September 29, 2021, from https://www.who.int/news-room/fact-sheets/detail/hepatitis-c 

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