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Flashcards in Hepatitis Viruses Deck (22)

The human hepatitis virus

-6 known to exist- A, B, C, D, E and G
-not phylogentically related, instead share a common host cell type: hepatocyte
-all cause an initial bout of acute hepatitis on first infection, wide range of severity
-rule out pharmaceutical causes first
-vaccines for A, B, E, desperately need one for C


Rule out non-infectious hepatitis

-reactions to prescription meds
-med interactions
-acetaminophen OD


Hep A virology

-human restricted picornavirus
-fecal-oral transmission, similar replication cycle to other enteroviruses
-if sanitation level is low, contaminated stool reaches drinking water
-highly environmentally stable
-single serotype, no reinfection, vaccine
-neutralizing antibodies recognize virion proteins 1 and 3


Hep A Disease

-US is a low-endemic area
-CDC rec for routine childhood vaccination in 2006
-viral replication often asymptomatic, but alternatively can keep an adult out of work for a month
-predominantly portal and periportal lymphocytic infiltrate and a varying degree of necrosis
-not very hepatotoxic, symptoms largely immunogenic
->99% of patients recover completely: no chronic infection
-rare patients develop fulminant hepatitis- 40% mortality
-risk factors: elderly, preexisting liver disease. Transplant is an option, though most patients eventually recover without


Hep A Diagnosis

-Enzyme Immunoassay (EIA) for Anti-HepA IgM -> acute infection
-EIA for Anti-Hep A IgG -> past infection, vacccination
-alanine aminotransferase (ALT) level: high-> ongoing liver damage


Hep A time course of infection

-viraemia- 2-5 weeks after infection
-virus in faeces- 2-7 weeks after infection
-elevated transaminases- 3-9 weeks after infection
-symptoms/jaundice- 4-7 weeks


Hep A Treatment

-prevention is best: Handwashing, sanitation, water treatment, Hep A vaccine (Twinrix: HAV+HBV)

-prophylaxis is second best: immune serum globulin (Gammagard)
-treatment is symptomatic: best rest, hydration, careful w/ Tylenol
-trace contacts, alert local public health authorities


Hep B Virus Virology

-human-restricted Hepadnavirus
-small enveloped, DNA virus, partly double stranded
-a very messy virus: 1000X more HBsAg decoys than virions
-unusually stable for an enveloped virus
-only one serotype, HBsAb protective against reinfection -> effective vaccine available
-despite DNA genome, carries a reverse transcriptase and replicates through an RNA intermediate
-replicates in hepatocytes and leaves behind integrated copies of viral DNA


Hep B Virus Pathogenesis

-transmitted efficiently by injection of contaminated blood, less efficiently by sexual or birth contact
-~1/3 human pop seropositive worldwide
-in US, 200k new cases annually, 5000 deaths, causes 5-10% of end stage liver failure and 10-15% of hepatocellular carcinoma
-90% clear the virus
-10% go fulminant or establish chronic infection


Time course of HBV infection

-surface antigen appears early, ceases being detectable as surface antibody is produced, resumes being detectable in chronic (incubation period- 1-3 months)
-surface antibody becomes detectable as surface antigen levels fall
-core antibody arises a little later, stays: IgM for acute, IgG for resolved or chronic
-E Antigen detectable when virus most transmissible


Four stages of Hep B/ immune interaction

1) Immune tolerance- virus replicates w/o symptoms. Lasts 2-4 weeks in adults, decades in newborns. Hep B DNA and antigens in serum, but little antibody
2) Immunogenic symptoms- ALT increases, HepB DNA declines. Coincides w/ 3-4 week symptomatic period (acute) or lasts for years leading to cirrhosis
3) Clearing the virus- viral replication shuts down, HBeAb detected, Hep B DNA not detected, ALT declines, HBsAg remains
4) Virus cleared. No viral antigens, permanent HBsAb IgG


Hep B Chronic Infection

-ongoing cytotoxic T cell response against infected hepatocytes cause permanent cirrhosis- virus itself is not hepatotoxic
-acculumation of Hep antigen-antibody complexes leads to kidney damage and arthritis (membranous glomerulonephritis, mostly peds)
-virus genome integration, expression of viral transciptional transactivators, and chronic inflammation can lead to cancer (primary hepatocellular carcinoma


Hep B Lab Diagnosis

-if infection appears active chronic, perform liver biopsy:
-inflammation around portal tracts
-ground glass cytopathology
-positive staining for Hep B antigens


Hep B Treatment

-Best option: vaccinatin (recombivax, twinrix)- recommended for children and all at risk adults. Recombinant HbsAg produced in yeast- raises neutralizing antibody, blocks virus entry
-second best: antibody prophylaxis (HBIG= HBsAb). Immune globulin administered shortly prior to exposure
-combination of both given for needle sticks and newborns of HBV+ mothers
-provide supportive care for acute hepatitis
-drug treatment for chronic active infection (cure rate is low)- 1 year of polymerase inhibitors and 4 months of PEG-Intron (significantly toxic)- crazy full body alpha interferon
-can be sexually transmitted- condoms!


Hep C Virus Virology

-human-restricted flavivirus: 30-60 nm enveloped +RNA genome
-transmitted by blood, sometimes sex
-discovered in 1989- get blood before that at risk
-~3 million carriers in US- many unaware
-much high potential for chronic infection, and stronger association with primary hepatocellular carinoma (11-19%)
-no vaccine


Hep C Pathogenesis

-HCV infects hepatocytes (50% in chronic) and possibly B lymphocytes (both carry CD81 receptor)
-highly mutagenic (rdRNAP has no proofreading) generates quasispecies
-can produce 10 trillion new particles/ day
-less than half of infectees clear it, requires strong cytotoxic T response
-15% of infections clear after acute hepatitis
-85% establish chronic infection- liver failure, cirrhosis, hepatocellular carcinoma, 100K deaths/yr worldwide


Hep C Diagnosis

-acute symptoms similar to HBV, milder
-red falg: travel to Egypt (22% HCV+)
-new infections in US usually from IV drugs but many old ones still being uncovered
-liver function tests- ALT levels, autoantibodies, cyroglobulin
-EIA followed by RIBA- if positive HCV genotyping
-judge severity by liver biopsy
-screen for HIV, HepB, drug abuse


Recombinant Immunoblot Assay (RIBA) for HCV

-used as a follow up to confrim HCV exposure
-vendor provides recombinant HCV antigens, which are run out on a gel and blotted onto a membrane
-patient serum sample is laid over blot, so that any anti-HCV antibodies that are present find the HCV antigens
-patient serum is washed off and replaced with a tagged secondary antibody. If abs are present, some bands will develop a bright color


Hep C Treatment of Acute infection

-judgment call:
-short course of peg-alpha-IFN treatment reduces rate of chronic infection
-infection may spontaneously clear w/o treatment


Hep C Treatment of Chronic infection with ongoing damage

-proceed with drug treatment
-ribavirin- antiviral (chain terminator), also immunomodulatory. Can cause birth defects

-pegylated alpha inferon: antiviral, side effects

-if serotype 1:
HCV protease inhibitors- boceprevir and telaprevir- increases SVR rates by 20-45% by also increases discontinued treatment rates: additional side effects


Hep C multiple serotypes

-serotypes 2 and 3 have >50% SVR rate with 6 months pegylated-alpha interferon +ribavirin therapy
-serotypes 1 and 4 require 1-2 years therapy and still have lower recoverty rates
-new polymerase inhibitors developed for serotype 1 are less effective against 2 and 3 and have their own side effects


Living-Donor Liver Transplant (LDLT) for Hep C

-many HepC patients cannot tolerate a long enough course of drugs to clear their infection and enter terminal liver failure
-as many as 1/6 of patient have a matched family member willing to donate part of his/her liver
-living-donor transplant can take place on a medical schedule (instead of whenenver an organ is available)