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HEPATITIS C VIRUS

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					HEPATITIS C VIRUS
    Structure of presentation
HCV epidemiology,viral
 dynamics,immunopathogenesis,diagnosis
HCV renal disease, management
HCV in CKD,CKD5D,CKD5T
KDIGO guidelines
• by the late 1970s it was apparent that HBV
  was not the only cause of "serum"
  hepatitis,
• and that other "non-A-non-B" hepatitis
  viruses existed , which
• could be transmitted by blood products to
  humans and chimpanzees
• Houghton and colleagues cloned and
  expressed portions of a RNA virus from
  the plasma of an infected chimpanzee in
  1989
• This virus, designated hepatitis C virus
  (HCV), is now known to be a major
• cause of both transfusion-associated and
  sporadic non-A-non-B hepatitis
• The persistent and indolent nature of HCV
  infection often
• results in prolonged viremia in spite of a
  strong humoral immune response
• To date, around 170–200 million
  individuals worldwide are estimated by the
  WHO to be chronically infected with HCV.
          THE VIRUS……
• Flavi virus
• 50 nm particles
• Nucleocapsid
• RNA
• Envelope
• Circulates…. a. lipo-viro-particles
                 b. Ig bound
                 c. free virions
THE GENOME
   RNA with 9600 nucleotides,encoding 3010 aminoacid
    polyprotein
   Single polypeptide
   Structural and non-structural
      1. core – steatosis , IFN resistance
      2. E1,E2 – cell entry
      3. p7 – viral maturation & release
      4. NS2 – autoprotease
      5. NS3 – serine protease & helicase
      6. NS4a – cofactor for 5
      7. NS4b – membranous web for replication
      8. NS5a – RNA binding , steatosis ,
      9. NS5b – RNA dep. RNA polymerase
      10. IRES – internal ribosome entry site
 Significant nucleotide and amino acid
  heterogeneity is present throughout the HCV
  genome, with a well characterized
 hypervariable region in the E2 envelope
  glycoprotein domain .
 This has led to the recognition of at least six HCV
  subtypes based on differences in the nucleotide
  sequence for NS5 .
 Infection is followed by an incubation period of 6
  to 12 weeks prior to the development of clinical
  hepatitis.
 In the majority of cases the hepatitis is mild and
  anicteric. Persistent viremia despite resolution of
  the acute hepatitis is seen in the majority of
  cases.
 many of these patients have persistent viremia
  despite minimal liver pathology, suggesting the
  presence of a "healthy― carrier state,
 at least 50% of patients develop chronic hepatitis,
  of which 20% progress to cirrhosis or chronic
  active hepatitis
GENOTYPE…
   Genetically distinct groups of HCV isolates arisen during viral replication
   35% variation esp. E1 E2
      Distribution
      1 --- 40 – 80% worldwide
             1a – USA ; 1b – Europe
       2 --- 10-40% worldwide
       3 ---- India , Australia
       4 --- Middle East , Africa
       5 --- South Africa
       6 --- Hongkong
   Do not influence severity
   Treatment response
   Genotype 3 – steatosis
   Genotype 1b – progressive post transplant disease
QUASISPECIES…
 Closely related heterogeneous sequences in HCV
  in single infected person
 Mutation on replication

 E1E2 HVR

 Escape host immunity

 Resistance to treatment
EPIDEMIOLOGY

   Seroprevelance
             Worldwide : 3% (Range 0.1 – 26%).Highest – Egypt
             India : 5% (Intermediate)
             Voluntary blood donor 0.6 – 0.8 %
             Gen.Population 1.8%
             Sex M: F 2.5 : 1.2
EPIDEMIOLOGY
   Epidemiology patterns
     Peak prevalence (Age) 30-50 yrs
        Recent source 1980-1990 IDU
     Peak prevalence > 50 yrs
        Remote acquisition 30 yrs ago
           Unsafe injections

           Folk medicine
TRANSMISSION
   Percutaneous
       Blood transfusion
       Needle stick


   Non percutaneous
       Sexual
       Perinatal
TRANSFUSION
 Initial Post Transfusion hepatitis : 85% Hep C
 Transfusion Hep C – 4% of Acute HCV
 Decreased after anti-HCV introduced in May
  1990
 Present risk - 0.01 – 0.001 %
 At risk
        Patient Requiring multiple transfusions
            Hemophilia
            Thallasemia
 Apollo chennai -
       HCV in blood donors : 3-5/ year
                                    (14,000
  donations)
 HCV RNA screening
IDU & OTHERS…
 Prevalence : 48 – 90%
 More than HIV & HBV

 Positive in 6 months

 Tattooing – 2- 24%

 Acupuncture
HEMODIALYSIS
 Anti   HCV prevalence: 10- 20%

 Underestimate       (4-15%)

 Duration    on HD

 Annual    Risk : 0.15% (HD) & 0.03%
 (CAPD)

 Chr.HCV    : 70-90%
        At Apollo
       HCV+ve on HD – 11/140
 HCV in CKD on HD


         Prevalence –
              1. Developed nations – 7 – 40%
              2. Developing nations– 16 – 80%
              3. India – 12 – 40% ( Saha etal 2001)
              4. Apollo – 12%
         Risk factors –
              1. Duration on HD
              2. Local prevalence
              3. Blood transfusions
              4. Nosocomial transmission




November 11, 2011                                     HCV and Renal Disease
 Nosocomial Transmission…

           Breach of standard infection control precautions
            1. Hand wash , glove change
              Okuda et al ; Arenas et al
            2. Multi-dose vials
            3. Spillage
           Dialysis internal circuits minor contributor
           DOPPS – Isolation does not protect
           CDC – 1. No isolation
                     2. No dedicated machines
           Belgian study – 0% transmission by standard
                               precautions only
           Slow seroconversion ( 5 months)
           Regular EIA / NAT , ALT / AST




November 11, 2011                                              HCV and Renal Disease
NOSOCOMIAL
 Health workers
 Needle stick : 0-4% by anti-HCV
                  10% by PCR
 Overall seroprevelance is as
  gen.population
 Risks of transmission < HBV,HIV

 HCW  patient
     0.014%

 Patient       HCW
      2- 10%
NON-PERCUTANEOUS
 Sexual – controversial
 More common in male homosexuals

 Associated risk factors

 RNA levels in semen low

 HCV in spouse 3%
PERINATAL TRANSMISSION
 Risk upto 10%
 No difference in CS vs. vaginal
 Increased risk 
            RNA +ve
            Increased RNA levels
            HIV-HCV
              decreased with HAART
 Not transmitted by breast feed
 Passive transfusion of Anti HCV
 Anti HCV upto 18 months
SPORADIC HCV
 Upto 30- 40% of cases
 Occult / unidentified percutaneous

 Sharing of hygiene items

 Forgotten risks, Transfusion

 Multi-dose vials

 Cocaine snorting
PATHOGENESIS
 Viral
 Human

 Environmental

Main sites : Hepatocyte
Other : Mononuclear
        : Dendritic cells
IMMUNE MEDIATED MECHANISM
 Humoral Response
 CMI
     CD4
     CD8 - liver infiltrating

     NK
CMI RESPONSE

   •   CD4,CD8, NK
   •   Protective and Destructive
   •   More in Acute cases
   •   Activated by antigen presentation
   •   CD4+ (polyclonal)        TH1
                                  TH2
   •   TH1 IFN + IL2        NK cells & CTLs
   •   TH2 IL4 + IL10        decrease TH1
   •   TH1 viral clearance
VIRAL PERSISTENCE
 Quasi-species nature
 Immune evasion

 Inadequate innate immunity

 Insufficient adaptive response

 Re-infection with different strain
PATHOGENESIS..
   Pathogenesis - Viral
                - Host
                - Environmental
VIRAL
   Direct cytopathic effect
          Viral Protein
          Viral particles


   Steatosis  30 – 70%
                C, NS5a viral proteins
                Genotype 3
                Activation of lipid peroxidation
                Increased RNA  Increased Steatosis
                Contribution of fibrosis
                     - Oxidative stress
                     - Hyperinsulinemia
CMI IN PATHOGENESIS……
 CD8+
 Polyclonal activation

 Increased in infected liver

 IFN gamma

 Hepatocyte cytolysis

 Inhibit multiplication
HUMORAL IMMUNITY……
 Ig to viral proteins
 Non neutralising
 4 – 8 weeks of infection
 Marker of infection
 Lymphoid aggregates
 Extra hepatic manifestations
      B cell ++     polyclonal Ig auto Ig
 CD5 ++       rheumatoid factor
                cryoglobulinemia ( Ig + RF )
SUMMARY OF PATHOGENESIS
 Viralreplication & persistence
 Inhibition of innate immunity
 Balance between CD4 & CD8


      hepatocyte damage
 Poor response in chronic disease
 Viral cytopathic effect
 Antibodies --- 1. diagnostic
                 2. extra hepatic
  manifestations
EXTRAHEPATIC MANIFESTATIONS
   Mixed Cryoglobulinemia
   MPGN
   Porphyria cutanea tarda
   NHL
   Leucocytoclastic vasculitis
   Focal lymphocytic sialadenitis
   Lichen planus
   DM
   Rheumatoid arthritis
   Thyroid disease
   Non specific antibodies
         ANA – 20% , ASMA -20% , anti LKM – 5% ,
    cryoglobulins-40%
MIXED CRYOGLOBULINEMIA
•   Circulating Igs precipitating at < 37c
•   Vasculitis by deposition of cryoprecipitate in
    small vessels
•   IgG, IgM RF, anti HCV, HCV RNA , LDL
•   IgM RF from liver
•   B cell activation by E1 E2 – CD81 interaction
•   50 -90% EMC – HCV +
•   60% HCV pts. - MC (30%asymptomatic)
•   Purpurae, arthralgias , weakness
•   Peripheral neuropathy
•   Raynaud’s phenomenon
•   MPGN – nephrotic syndrome
        liver disease occult
•   Antiviral therapy
EXTRAHEPATIC MANIFESTATIONS….
 B cell NHL –
       HCV 15%
       lymphotropism & clonal expansion
 Sialadenitis – 10% patients

 Diabetes Mellitus –

         steatosis , insulin resistance,
IN A NUTSHELL….
•   A RNA virus with hepatotropism
•   Widely distributed with distinct genotypes
•   Evades immune system
•   Pathogenesis by steatosis fibrogenesis & host
    immunity
•   Transmission by parenteral route
•   Acute hepatitis rarely recognised
•   High rate of chronicity
•   Multiple influences
•   Extrahepatic manifestations
•   HCC
 Mesangio proliferative gn
 igA

 Fibrillary and immunotactoid gn

 Diffuse endocapillary proliferative gn

 MGN

 MPGN

 Renal vasculitis cryoglobulinemic
 HCV induced renal disease

      EMC type II ( 50% of HCV ; 1% symptomatic)
      MPGN type I ( with or without MC)
      Membranous glomerulonephritis
      Pathology - Deposition of HCV RNA – Ig complexes
      OLT – intraop renal biopsy – 25 – 30% GN
      Proteinuria , Microscopic hematuria
      Liver disese may be occult
      Melzer Franklin triad (EMC)
            Weakness , Arthralgia , Purpurae
      Elevated Cryocrit ,Rheumatoid factor ; Decreased C4
      Test annually 1. hematuria
                         2. proteinuria
                         3. GFR
      Renal biopsy




November 11, 2011                                           HCV and Renal Disease
Diagnostic tools…
 Serological
  1. Enzyme Immunoassay (EIA)
  2. Recombinant Antigen Immunoblot Assay (RIBA)
 HCV RNA detection
   a. Qualitative
   b. Quantitative
  Methods
   1. PCR
   2. TMA (Transcription mediated amplification)
 HCV Genotyping
 Liver biopsy
Serological……
 Detect  Igs against viral proteins
 EIA 3rd generation
 NS3 , NS4 , NS5
 Positive at 7 – 8 weeks
 Sensitivity – 97%
 RIBA for clarifying false positives
 Negative anti- HCV in HCV infection
        1. immunosuppressed
        2. CKD , on HD
        3. Acute HCV
   The original first generation enzyme
    immunoassay (EIA-l), which measured antibodies
    to the nonstructural Cl00-3 antigen (coded by the
    NS4 domain), lacked sensitivity and specificity,
    and was undetectable in 10 to 25% of patients
    with chronic HCV viremia and falsely present in
    both healthy individuals and patients with
    chronic autoimmune hepatitis
   The second generation enzyme immunoassay
    (EIA-2) measures antibodies to recombinant core
    and NS3 antigens in addition to that coded by
    NS4, and has greatly improved sensitivity (—
    95%) and specificity.

   A supplemental serologic assay, the recombinant
    immunoblot assay (RIBA II test), measures
    antibody to four HCV antigens (the nonstructural
    antigens 5-1-1, C100-3, and C33, and the core
    antigen C22), and has comparable sensitivity and
    slightly more specificity than the EIA-2 test
   The most definitive test for diagnosing active
    HCV infection is the reverse transcription
    polymerase chain reaction (RT-PCR), which
    measures the presence of viral RNA in patient
    serum and hence determines potential infectivity
 The detection of anti-HCV antibodies is based on
  the use of third-generation EIA that detects
  antibodies directed against various HCV epitope
 RIBA has become obsolete because of this

 In the near future, fourth-generation tests will be
  available, allowing the simultaneous detection of
  HCV antibodies and HCV core protein.
 In the relevant published studies, the sensitivity
  of EIA varied from 53 to 100% and the specificity
  from 85 to 100%,
 with pooled sensitivity and specificity of 75 and
  95%, respectively
RNA testing
   Qualitative
      1. high sensitivity 96- 100%
      2. PCR / TMA
      3. lower limit – 50iu / 5iu
      4. confirm clearance
      5. special situations
   Quantitative
      1. RT - PCR / branched DNA
      2. closed tube systems
      3. Amplicor – PCR - 3 copies – 1 unit
      4. Versant – TMA – 5 copies = 1 unit
   Indications
      1. anti HCV positive
      2. antiviral treatment monitoring
      3. immunocompromised
RNA analysis…
   Genotyping….
      1. reverse hybridisation by line probe assay
      2. failure – 0.3%
      3. duration of treatment
      4. response to treatment
Histopathology
   Degree of inflammation – grade
   Extent of fibrosis – stage
   Characteristic features
      1. steatosis ( micro or macrovesicular)
      2. lymphoid aggregates
      3. bile ductular damage
   Metavir and Knodell Ishak staging systems
   Fibrosis – prognosis & treatment response
   Metavir – fibrosis 0 – 4
              grade – 0 -4
   Knodell Ishak – fibrosis 0 – 6
   Significant fibrosis - Metavir ≥2
                           Knodell Ishak ≥3
Liver biopsy - problems…..
 Inter observer variation – 60 – 90%
 Variability within liver
 Specimen size
 Complications –
    1. pain – 20%
    2. hemorrhage – 0.5%
    3. mortality – 0.1%
 Sampling error – 10 – 40%
    1. small size
    2. less than 11 portal tracts analysed
 Typically, a platelet count o50 000 and an INR
  >1.5 are regarded as contraindications to blind
  percutaneous liver biopsy
 However, there is a controversy in recent medical
  literature about whether any platelet count level
  or INR derangement truly separates out those
  patients with liver disease most likely to bleed
  after liver biopsy.
 A study performed in the early 1980s in 200
  patients undergoing laparoscopic liver biopsy
  with direct visualization
 of the site failed to establish any relationship
  between duration and extent of bleeding
 and prothrombin times,platelet count, or whole
  clot time.
 a systematic review of bleeding, including that
  associated with liverbiopsy, also failed to
  establish a relationship between risk and
  conventional tests of coagulation
Noninvasive staging
   FIBROSCAN
     transient elastography
     assess liver stiffness
     evaluates larger liver volume
     better correlate with higher stage
     problems –
        1. obese
        2. cannot differentiate steatosis
Other markers
 FIBROTEST-
   α2-macroglobulin , α2-globulin , gamma globulin ,
  GGTP , bilirubin
   sens. 75% & spec. 85% for Metavir >2
 improved with Fibroscan
 ACTITEST - Fibrotest + ALT
 APRI – AST – Platelet count ratio
 Ser. Hyaluronate levels
 Collagen based panels
ALT levels
 Mildly elevated only
 10 fold increase – sig. necrosis

 30% normal ALT

 17% - levels fluctuate to normal

 30 – 40% - occ. elevations only
THANK U….
MORE TO FOLLOW………….

				
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posted:11/10/2011
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