Hepatitis c virus
Download
1 / 67

HEPATITIS C VIRUS - PowerPoint PPT Presentation


  • 106 Views
  • Uploaded on

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,

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' HEPATITIS C VIRUS' - sharon-snyder


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

Structure of presentation
Structure of presentation

HCV epidemiology,viral dynamics,immunopathogenesis,diagnosis

HCV renal disease, management

HCV in CKD,CKD5D,CKD5T

KDIGO guidelines






The virus
THE VIRUS…… estimated by the WHO to be chronically infected with HCV.

  • Flavi virus

  • 50 nm particles

  • Nucleocapsid

  • RNA

  • Envelope

  • Circulates…. a. lipo-viro-particles

    b. Ig bound

    c. free virions


The genome
The genome estimated by the WHO to be chronically infected with HCV.

  • 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
Genotype… weeks prior to the development of clinical hepatitis.

  • 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
Quasispecies… weeks prior to the development of clinical hepatitis.

Closely related heterogeneous sequences in HCV in single infected person

Mutation on replication

E1E2 HVR

Escape host immunity

Resistance to treatment


Epidemiology
EPIDEMIOLOGY weeks prior to the development of clinical hepatitis.

  • 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


Epidemiology1
Epidemiology weeks prior to the development of clinical hepatitis.

  • 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
Transmission weeks prior to the development of clinical hepatitis.

  • Percutaneous

    • Blood transfusion

    • Needle stick

  • Non percutaneous

    • Sexual

    • Perinatal


  • Transfusion
    Transfusion weeks prior to the development of clinical hepatitis.

    • 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
    IDU & others… weeks prior to the development of clinical hepatitis.

    Prevalence : 48 – 90%

    More than HIV & HBV

    Positive in 6 months

    Tattooing – 2- 24%

    Acupuncture


    Hemodialysis
    Hemodialysis weeks prior to the development of clinical hepatitis.

    • 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
    HCV in CKD on HD weeks prior to the development of clinical hepatitis.

    • 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 17, 2014

    HCV and Renal Disease


    Nosocomial transmission
    Nosocomial Transmission… weeks prior to the development of clinical hepatitis.

    • 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 17, 2014

    HCV and Renal Disease


    Nosocomial
    Nosocomial weeks prior to the development of clinical hepatitis.

    • 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
    Non-percutaneous weeks prior to the development of clinical hepatitis.

    Sexual – controversial

    More common in male homosexuals

    Associated risk factors

    RNA levels in semen low

    HCV in spouse 3%


    Perinatal transmission
    Perinatal Transmission weeks prior to the development of clinical hepatitis.

    • 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
    Sporadic HCV weeks prior to the development of clinical hepatitis.

    Upto 30- 40% of cases

    Occult / unidentified percutaneous

    Sharing of hygiene items

    Forgotten risks, Transfusion

    Multi-dose vials

    Cocaine snorting


    Pathogenesis
    Pathogenesis weeks prior to the development of clinical hepatitis.

    • Viral

    • Human

    • Environmental

      Main sites : Hepatocyte

      Other : Mononuclear

      : Dendritic cells


    Immune mediated mechanism
    Immune Mediated Mechanism weeks prior to the development of clinical hepatitis.

    • Humoral Response

    • CMI

      • CD4

      • CD8 - liver infiltrating

      • NK


    Cmi response
    CMI Response weeks prior to the development of clinical hepatitis.

    • 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
    Viral persistence weeks prior to the development of clinical hepatitis.

    • Quasi-species nature

    • Immune evasion

    • Inadequate innate immunity

    • Insufficient adaptive response

    • Re-infection with different strain


    Pathogenesis1
    Pathogenesis.. weeks prior to the development of clinical hepatitis.

    • Pathogenesis - Viral

      - Host

      - Environmental


    Viral
    Viral weeks prior to the development of clinical hepatitis.

    • 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
    CMI in pathogenesis…… weeks prior to the development of clinical hepatitis.

    CD8+

    Polyclonal activation

    Increased in infected liver

    IFN gamma

    Hepatocyte cytolysis

    Inhibit multiplication


    Humoral immunity
    Humoral immunity…… weeks prior to the development of clinical hepatitis.

    • 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
    Summary of Pathogenesis weeks prior to the development of clinical hepatitis.

    • Viral replication & 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
    Extrahepatic manifestations weeks prior to the development of clinical hepatitis.

    • 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
    Mixed cryoglobulinemia weeks prior to the development of clinical hepatitis.

    • 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 manifestations1
    Extrahepatic manifestations…. weeks prior to the development of clinical hepatitis.

    B cell NHL –

    HCV 15%

    lymphotropism & clonal expansion

    Sialadenitis – 10% patients

    Diabetes Mellitus –

    steatosis , insulin resistance,


    In a nutshell
    In a nutshell…. weeks prior to the development of clinical hepatitis.

    • 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 weeks prior to the development of clinical hepatitis.

    • igA

    • Fibrillary and immunotactoid gn

    • Diffuse endocapillary proliferative gn

    • MGN

    • MPGN

    • Renal vasculitis cryoglobulinemic


    Hcv induced renal disease
    HCV induced renal disease weeks prior to the development of clinical hepatitis.

    • 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 17, 2014

    HCV and Renal Disease


    Diagnostic tools
    Diagnostic tools… weeks prior to the development of clinical hepatitis.

    • 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
    Serological…… weeks prior to the development of clinical hepatitis.

    • 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 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.



    Rna testing
    RNA testing varied from 53 to 100% and the specificity from 85 to 100%,

    • 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
    RNA analysis… varied from 53 to 100% and the specificity from 85 to 100%,

    • Genotyping….

      1. reverse hybridisation by line probe assay

      2. failure – 0.3%

      3. duration of treatment

      4. response to treatment


    Histopathology
    Histopathology varied from 53 to 100% and the specificity from 85 to 100%,

    • 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
    Liver biopsy - problems….. varied from 53 to 100% and the specificity from 85 to 100%,

    • 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
    Noninvasive staging undergoing laparoscopic liver biopsy with direct visualization

    • FIBROSCAN

      transient elastography

      assess liver stiffness

      evaluates larger liver volume

      better correlate with higher stage

      problems –

      1. obese

      2. cannot differentiate steatosis


    Other markers
    Other markers undergoing laparoscopic liver biopsy with direct visualization

    • 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
    ALT levels undergoing laparoscopic liver biopsy with direct visualization

    • 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
    THANK U…. undergoing laparoscopic liver biopsy with direct visualizationMORE TO FOLLOW………….


    ad