Lecture 16: Viruses - Hepatitis

Slide 1-4: Introduction

• Dark urine (bilirubinuria)
• Clay-colored (pale) stools (absence of bile pigments in stool)

Slides 5-9: Hepatitis A Virus (HAV)

Classification

• Order: Picornavirales
• Family: Picornaviridae
• Genus: Hepatovirus

Transmission & Pathogenesis

• Transmitted by the fecal-oral route (contaminated food/water)
• Humans are the only reservoir
• The virus replicates in the GI tract and spreads to the liver via the bloodstream
• Key point: The virus appears in feces ~2 weeks BEFORE symptoms - so quarantine is largely ineffective
• Children are the most frequently infected group

Clinical Manifestations

• Incubation period: 14-28 days
• Symptoms include: fever, malaise, loss of appetite, diarrhea, nausea, abdominal discomfort, dark urine, and jaundice
• Children under 6 usually show no noticeable symptoms; only 10% develop jaundice
• In adults: jaundice occurs in >70% of cases; severity increases with age
• The disease can occasionally relapse but is followed by full recovery
• HAV does NOT cause chronic hepatitis

Diagnosis, Treatment & Prevention

• Diagnosis: Detection of HAV-specific IgM antibodies in the blood
• RT-PCR can detect HAV RNA (specialized labs needed)
• No antiviral therapy is available
• Prevention: Inactivated HAV vaccine - 2 doses (initial + booster at 6-12 months)

Slides 10-14: Hepatitis E Virus (HEV)

Classification & Epidemiology

• Small virus with a positive-sense, single-stranded RNA genome
• At least 4 genotypes: genotypes 1 & 2 found only in humans; genotypes 3 & 4 also found in animals
• Found worldwide; highest prevalence in East and South Asia
• Estimated 20 million HEV infections/year, ~3.3 million symptomatic, ~56,000 deaths annually

Transmission

• Primarily fecal-oral through contaminated drinking water
• Other routes: foodborne (infected animal products), zoonotic, blood transfusion, and vertical (mother to fetus)

Pathogenesis & Clinical Features

• Incubation period: 2-10 weeks (average 5-6 weeks)
• Usually self-limiting, resolving in 2-6 weeks
• Symptoms: mild fever, reduced appetite, nausea/vomiting, abdominal pain, itching, skin rash, jaundice, dark urine, pale stools, hepatomegaly
• Special danger in pregnancy: Pregnant women (especially 2nd and 3rd trimester) can develop fulminant hepatitis with 20-25% fatality rate, increased risk of acute liver failure and fetal loss

Diagnosis & Treatment

• Diagnosis: Detection of HEV-specific IgM antibodies; RT-PCR for HEV RNA in blood/stool
• No specific treatment for acute HEV (self-limiting, hospitalization usually not needed)
• Immunosuppressed patients with chronic HEV: ribavirin (antiviral); sometimes interferon
• A vaccine exists but is licensed only in China, not available elsewhere

Slides 15-23: Hepatitis B Virus (HBV)

Classification & Structure

• Major member of the Hepadnaviruses
• Small, enveloped DNA virus
• Very resilient: can survive outside the body for at least 7 days

Epidemiology

• Caused ~887,000 deaths in 2015 (mostly from cirrhosis and hepatocellular carcinoma)
• Important occupational hazard for healthcare workers

Transmission & Pathogenesis

• Transmitted through blood, body fluids, and sexual contact
• Incubation period: average 75 days (range: 30-180 days)
• After entering blood, HBV infects hepatocytes; viral antigens are displayed on cell surfaces
• Cytotoxic T cells attack the infected hepatocytes, causing inflammation and necrosis (immune-mediated damage)

Chronicity Rates (Very Important!)

Clinical Manifestations

• Many have no symptoms during acute phase
• When symptomatic: jaundice, dark urine, extreme fatigue, nausea, vomiting, abdominal pain
• Small subset can develop acute liver failure (can be fatal)
• Chronic infection can lead to cirrhosis or hepatocellular carcinoma (HCC)
• Lifelong immunity follows natural infection (mediated by antibody against HBsAg)

Diagnosis

• Serology panel using HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc (IgM and IgG)
• Many infections detected only by anti-HBsAg antibody (asymptomatic)

Treatment & Prevention

• Tenofovir or Entecavir - most potent antivirals; once daily, low resistance profile, few side effects
• Prevention: HBV vaccine and/or hyperimmune globulin
• All unvaccinated children/adolescents under 18 should receive the vaccine (in low/intermediate endemic countries)

Slides 24-26: Hepatitis D Virus (HDV)

Key Concept: Defective Virus

• HDV is a defective (satellite) virus - it CANNOT replicate on its own
• It lacks the gene for its own envelope protein
• It uses HBsAg (surface antigen of HBV) as its envelope - so it can ONLY replicate in cells co-infected with HBV

Infection Patterns

1. Co-infection: HBV and HDV acquired simultaneously - usually mild to severe acute hepatitis, but mostly complete recovery; chronic hepatitis D is rare
2. Superinfection: HDV infects someone already chronically infected with HBV - accelerates to severe disease in 70-90% of cases; cirrhosis develops almost a decade earlier than with HBV alone

Transmission

• Same routes as HBV: sexual contact, blood

Diagnosis & Treatment

• Diagnosis: Detection of delta antigen or IgM anti-delta antibody in serum
• No specific antiviral therapy
• No separate HDV vaccine - but HBV vaccination protects against HDV too (since HDV depends on HBV)

Slides 27-33: Hepatitis C Virus (HCV)

Classification & Structure

• Only member of Hepacivirus genus, family Flaviviridae
• 30-60 nm in diameter
• Positive-sense RNA genome (~9,100 nucleotides), enveloped
• Encodes 10 proteins including two glycoproteins (E1, E2)

Epidemiology

• ~71 million people have chronic HCV infection globally
• Humans are the only reservoir

Transmission

• Blood-borne virus - injection drug use, unsafe injections, unsafe healthcare, unscreened blood transfusions
• Less commonly: sexual transmission

Clinical Features

• Incubation: 2 weeks to 6 months
• ~80% of acutely infected people show NO symptoms
• High rate of chronicity (unlike HAV/HEV)

Clinical Outcome

• Acute infection → 15-45% clear spontaneously
• The remaining ~55-85% develop chronic HCV
• Chronic HCV → can progress to cirrhosis and hepatocellular carcinoma

Diagnosis

• ELISA to detect anti-HCV antibodies (initial test)
• False positives possible - confirm with RIBA (Recombinant Immunoblot Assay)
• If RIBA positive, use PCR to confirm active infection and viral load

Treatment & Prevention

• Acute HCV: Peginterferon alfa
• Chronic HCV (older regimen): Peginterferon alfa-2a + ribavirin + protease inhibitor
• Modern regimen (current standard of care):
  • Sofosbuvir (Sovaldi) - FDA approved 2013 for genotypes 1, 2, 3, 4
  • Sofosbuvir/ledipasvir combination and daclatasvir in WHO preferred regimens
  • Cure rates above 95%
• No vaccine exists for HCV; no hyperimmune globulins available

Summary Comparison Table