HEPATITIS C

AYAN SANTRA

• It is the inflammation of liver caused by Hepatitis C virus.

• It is the most common cause of non A non B hepatitis.

• It is a major cause of chronic liver disease in the world.

Hepatitis C virus• Part of Flaviviridae family of viruses– Associated with both human and animal disease– 3 genera: pestiviruses (cattle, pigs), flaviviruses (dengue,

yellow fever), hepaciviruses (HCV)• It is an enveloped, icosahedral virus having single

stranded positive sense RNA.• 6 genotypes worldwide, many subtypes and isolates

based on nucleotide diversity• Quasispecies within individual• In vivo replication in liver and lymphocytes

HCV Genome

• 9.6 kb positive strand RNA genome• Open reading frame encoding polyprotein of

~3010 amino acids• 3 highly conserved areas:–5’ UTR: initiating translation–Core: codes for capsid protein monomer–3’ UTR: essential for RNA synthesis &

packaging

Life cycle

Mode of Transmission

6015

10

4 11

Injecting drug useSexual trnsmissionTransfusion before screen-ingOccupationalOthers

Incubation period: 2 to 26 weeks; Mean 6-12 weeks

Immune response

• Patterns of viraemia1. Drop after peak successful control2. Drop followed by rebound chronic

infection3. Consistent HCV chronic infection

Innate immune response

Viral resistance

• NS 5A & E2 can interfere with PKR• The core protein can inhibit the JAK-STAT

pathway by which IFN signals• NS3/4A can block the accumulation of

phosphorylated IRF3 which inhibitrs expression of type 1 interferons and IFN stimulated genes.

Cell mediated immunity

• More vigorous CD8+ and CD4+ T cell responses in all individuals that controlled infection

• Chronic infections occur when–unable to mount HCV-specific T cell

responses– strong response that results in viral RNA

clearance, followed by contraction in CD8+/CD4+ and rebound in viremia

Antibodies

• Role of antibodies unclear and poorly studied• Virus can be cleared in absence of detectable

antibody responses• Neutralizing antibodies target E2, which is

highly variable and able to evade

Immune-mediated liver injury

• Host immune response and not viral replication

• HCV infects only 1-10% of hepatocytes• IFN-γ and TNF-α from CD8+ destroy nearby

non-infected hepatocytes (“bystander killing”)• HCC occurs mainly

due to high turnover rate in hepatocytes

Clinical features

Acute

• Usually asymptomatic

• Constitutional symptoms

• Jaundice• Right upper quadrant

pain

Chronic• When there is persistent

RNA for more than 6 months

• Fatigue is the most common symptom

• Jaundice is rare• Immune complex

mediated diseases

Immune complex mediated diseases

• Essential mixed cryoglobulinaemia• Membranoproliferative glomerulonephritis• B cell lymphoma• Unexplained monoclonal gamopathy• Extrahepatic complications unrelated to

immune complexc:Sjogren syndrome,Lichen planus, Type 2 diabetes melitus

Course

Patients with risk to progression to chronic hepatitis

• Older age• Longer duration of

infection• Advanced histologic

stage and grade• Genotype 1• More complex

quasispecies variety• Increased hepatic iron

• Concominant other liver disease

Alcoholic liver diseaseHemochromatosisα₁ antitrypsin

deficiencySteatohepatitis• HIV Infection• Obesity

DiagnosisLiver function test

Parameters Acute ChronicBilirubin (both conj & unconj)

Raised Raised

ALT/AST Increased (400-1000 IU/L)

Episodic rise

Alkaline phosphatase

Normal to ˂3 times normal elevation

Normal to ˂3 times normal elevation

Albumin Normal DecreasedProthrombin time Usually normal Increased

Anti HCV antibody

First generation

Against C100-3 (NS4)

Appear 1-3 weeks after infection

Second generation

Against C200 & C33c (NS3)

Appear 9-10 weeks After infection

Third generation

Against C22-3 (core) & NS5

Appear 7-9 weeks after infection

HCV RNA

• In acute infection detected within 2 weeks.• Decreases after antibody production.• Detected by1. PCR2. Branched DNA technique.• HCV antigen: an EIA for hcv antigen is

available but less sensitive than HCV RNA.

Prognostic test

• 1.Genotyping: Detected by : DNA sequencing, PCR

hybridizationGenotype 1&4 have worst prognosis.Genotype 2&3 have better prognosis.• 2. Viral load: high viral load→ poor response

to therapy.

Liver biopsy

• It is done in chronic hepatitisTo know the etiology ,For grading and staging of the diseaseTo monitor the treatment.

Liver biopsy finding in chronic hepatitis C

• 1.Portal tracts: Inflammation may confine to portal tracts or may spill into adjacent parenchyma, with necrosis of hepatocytes (interface hepatitis);there may be bridging inflammation and necrosis. The portal infiltrate is rich in lymphocytes, often forming lymphoid aggregates and even a follicle with prominent germinal centres.

• 2. Bile duct lesion: swelling and polystratifications of bile duct lining cell, infiltration by lymphocytes and larger macrophages and preservation of the basement membrane of the bile duct.

Liver biopsy finding in chronic hepatitis C

• 3. Lobular lesion: • There may be loss of architecture. Hepatocytes show

balloning degeneration and necrosis.There may be bridging necrosis.

May comprise a striking number of acidophil bodies Cholestasis may be there.(canalicular bile plugs) Mild to moderate steatosis, usually macrovesicular

type( more common in genotype 3). Increased amount of hepatic iron even in absence of

blood transfusion.

Liver biopsy finding in chronic hepatitis C

Periportal hepatocytes may contain Mallory Denk body like coarse clumps of eosinophilic cytoplasm.

The lymphocytic infiltration in the lobules form rows along the sinusoids.

Fibrosis is progressive in chronic hepatitis C. Portal deposition→ Portal and periportal deposition→ Formation of bridging fibrous septa.

Angiogenesis occurs in CHC in the portal tract, fibrous septa and periportal zone.

Continued loss of hepatocytes and fibrosis results in cirrhosis,with fibrous septae and hepatocyte regenerative nodule.

HCV RNA can be detected by in-situ hybridization.

Chronic hepatitis Cshowing portal tract expansion with inflammatory cells and fibrous tissue and interface hepatitis with spillover of inflammation into the adjacent parenchyma. A lymphoid aggregate is present.

Scheuer system of grading and stagingGrading

Grade 1 no or minimal inflammation

Grade 2 Portal inflammation or lobular inflammation, no necrosis.

Grade 3 Mild piecemeal necrosis or focal hepatocellular necrosis.

Grade 4 Moderate piecemeal necrosis or severe focal damage.

Grade 5 Severe piecemeal necrosis or bridging necrosis.

StagingStage 0 No fibrosis.Stage 1 Enlarged fibrotic

portal tract.Stage 2 Periportal or

occasional portal to portal septa.

Stage 3 Bridging necrosis with architectural distortion, no obvious cirrhosis.

Stage 4 cirrhosis

Prevention

• Never share drug equipments • Practice safer sex• Always use new sterilized

equipments• Don’t touch dirty needles