Viral Hepatitis Flashcards
aOf the Hep. viruses, which one is the only one with a DNA genome?
Hep B
Which of the Hep. viruses are transmitted via fecal-oral route? Blood route?
Which Hep virus has the greatest transmission during sexual encounters?
Fecal oral: AE
blood: BCD
greatest transmission: Hep B, followed by Hep D.
Of the hep. viruses, which ones increases one’s risk of hepatocellular carcinoma?
BCD (also the same ones that are transmitted via fecal oral route)
What type of viruses are Hep. A, B, C, D, and E?
A = picoRNAvirus
B = HepaDNAvirus
C = Flavivirus
D = satellite
E = Calcivirus
What is the incubation periods for Hep. A, B, C, D, and E?
Hep A, D, E: 2 wks - 7/9 wks
Hep B: 6 wks - 6 mo. (avg 120d)
Hep C: 2 wks - 6 mo (avg 45d)
What are the main symptoms of chronic hepatitis? (7)
Fatigue
Decreased Exercise Tolerance
Anorexia
Arthralgias
Malaise
Weakness
Depression
Hep A
What is the international age-related prevalence?
How is it spread?
Risk factors?
developing countries = greater prevalence in the young
developed countries = “ ” adults
Spread via fecal oral route
Risk factors
- areas of decreased sanitation (low socioeconmic areas, inadequate hygiene)
- international travel (Mexico, Central/South America)
- Household contact
- Homosexual contact
- Food
- Daycare
- IV
Hep A
What type of virus is it?
What is the genome?
Does it have an envelope?
PicoRNAvirus
+RNA
no envelope
Hep A Life Cycle
What is the incubation period?
What is the disease progression after one is infected?
Are adults or children more likely to be symptomatic of the disease?
2-7 weeks (avg 30d)
- prodromal period (1 wk), followed by:
- increase in liver enzymes (>1000)
- concurrent development of jandice, fever, bausea, vomiting, abdominal pain
- development of antibodies (HAV-IgM - active infection; HAV-IgG - recovery)
- majority recover (no carrier state, no chronic hepatitis, no chronic phase)
Adults
Why do the majority of patients recover without development of chronic hepatitis?
Why would some patients get better but then become jaundiced again?
it’s an RNA virus. Once the infected cells are destroyed, the person is usually clear of the disease.
Relapsing: either due to a new infection or relapse
What two serologic studies would you perform on a HepA patient?
HAV-IgM
HAV-IgG (previous exposure or vaccination)
T/F 24 year old female develops acute Hepatitis 3 months after going to India. You tell her she likely has HAV.
False. HepA does not take that long to develop
T/F 32 year old with acute hepatitis have serologies anti-sAg+ and anti-HAV IgM+ has HAV
True
T/F: 50 year old Dart prof with HCV ab (+) anti-HAV ab (-) wants to go to Central America. You strongly recommend vaccination.
True
When does fecal shedding occur in HepA patients?
before patients become symptomatic
Hep B
Where is it most common? least common?
How is it acquired in these areas?
What are the risk factors of HepB?
most common in Asia and Africa (acquired perinatally, during childhood)
less common in the US (acquired via sex, IVDA, immigrants from high prevalence areas)
Risk Factors:
- Birth in high/intermediate prevalence HBV area
- Household or sexual contacts of HBsAg(+) persons
- History IVDA
- History of multiple sexual partners, STD
- Men who have sex with men
- Inmates of correctional facilities
- Chronic elevation of ALT or AST
- HCV or HIV infectionPatients undergoing renal dialysis
- All pregnant women
Hep B
What family is it?
What is the genome?
What are the 4 major genes and what proteins does they encode? (yep this is actually relevant)
DNA virus
hepaDNAviridae family
genome: relaxed, circular, partially ds-DNA, where the + strand is NOT complete and the – strand is complete
Encodes for
- pre-S1, preS2 and S - encodes for viral envelope/surface antigens
-
pre-Core and Core - encodes for HBeAg and HBcAg, respectively
- these can self-assemble into capsid-like structuresHBeAg is felt to be an immune tolerogen (an antigen that induces tolerance)
- DNA Polymerase - multifunctional (reverse transcriptase, DNA polymerase, ribonuclease)
- X protein - pleiotropic activities, among which is its ability to interfere with cell viability and stimulate HBV replication
What is unique about the Hep B polymerase?
multifunctional: reverse transcriptase, DNA polymerase, ribonuclease)
What is the lifecycle of the hep B virus like?
- Viral DNA polymerase synthesizes the partially ds DNA -> cccDNA (covalently closed circular DNA)
- cccDNA transcribed by host RNA polymerase into RNA, which enters the cytoplasm to be transcribed into:
- sAg envelope proteins in the ER -> can be packaged with polymerase/genome or self-assemble into 3 HBV particle types: spheres, filaments, and intact virions found in high abundance within the serum of an acutely infected individual
- intact virions “Dane particle” – infectious; contains nucleocapsid encasing genome and polymerase that is covered with sAg
- filament and sphere – consists only of sAg; non-infectious
- sAg envelope proteins in the ER -> can be packaged with polymerase/genome or self-assemble into 3 HBV particle types: spheres, filaments, and intact virions found in high abundance within the serum of an acutely infected individual
- Polymerase
- Pol-RT produces (-) DNA from RNA template
- Pol-Rnase degrades RNA, resulting in a single strand of (-) DNA
- Pol-DNA produces (+) DNA g dsDNA and circularizes it
- core proteins
- surrounds the Pol-DNA + dsDNA to form a nucleocapsid, which is transported to the ER to pick up sAg envelope proteins, golgi, and subsequent exit from the cellthe nucleus to increase cccDNA -> amplification
Hep B
Incubation time?
What is the natural progression of the disease once someone is infected?
- 50-65% have no symptoms
- 1% goes on to develop acute fulminant hepatitis
- recovery in 90% of immunocompement patients; 1-2% develop chronic hepatitis
natural progression and effects on liver
- perinatal transmission
- Immune tolerant
- Active
- Seroconversion
- inactive-> clearance, OR inactive -> active
- latter due to to mutation in HBeAg. this results in a virus that is much less efficient in replication, resulting in lower viral loads, but you can still see inflammation and fibrosis in the liver
What does this patient have? How do you know?
Hep B infection
cells rich in HBsAg have a ground-glass appearance (arrow)
What is HBsAg?
When does it appear?
What does its presence indicate?
Surface antigen
- First marker of active infection
- Precedes ALT and clinical symptoms
- Presence indicates HBV infection (no sAg = no HepB infection)
- presence for >6 months defines chronic HBV infection
What is Anti-HBs?
When does it appear?
What does its presence indicate?
Antibody against surface antigen
- appears after HBsAg declines (indicates decline in viral load)
- indicates active immunity (protective antibody), passive immunity (vaccination) or exogenous administration** **(exogenous anti-HBs)
What is Anti-HBc?
When does it appear?
What does its presence indicate?
antibodies against core antigens
- IgM class: remains positive in acute infections and persists during the window phase (aka serologic gap) or reactivation of infection
- IgG class: indicates a history of HBV infection
What is the window phase (aka serologic gap)?
What infection do you normally see this in?
*high yield point*
Hep B infection
phase where HBsAg and anti-HBs are absent
What is HBeAg?
When does it appear?
What does its presence indicate?
e antigen
- Appears concurrent with or soon after HBsAg
- Loss = nonreplicative phase or replicative mutant
- indicator of replicative HBV
What is Anti-HBe?
When does it appear?
What does its presence indicate?
Antibody aganist E antigen
- appears after the loss of active replication
- indicates seroconversion
What is HBV DNA?
When does it appear?
What does its presence indicate?
- Found in serum in active infection; but may be present after pt is “immune”
- indicator of replicative stage
How is chronic hepatitis B defined by?
What are the two carrier states of CHB?
Of the people who acquire HBV, who are at greatest of developing chronic hepatitis?
What is the prognosis of chronic hepatitis?
- HBsAg >6 months
- Healthy chronic carrier – still contagious but at a much lower risk; defined by presence of HBsAg and anti-HBc IgG
- Infective chronic carrier – increased risk for post-necrotic cirrhosis and HCC; defined by presence of HBsAg, anti-HBc IgG, and infective particles (DNA and e antigen)
- greatest risk: neonates (opposite that of HepA!!) immune compromised patients
- Prognosis: BAD. VERY AGGRESSIVE DISEASE.
- Can result in cirrhosis in 5 years!! Once it reaches to cirrhosis, the 5 year survival rate is dismal (5 year survival is 55%)
T/F chronic hep B infection is a benign state
FALSE.
Chronic Hep B is a very aggressive disease.
Can result in cirrhosis in 5 years!! Once it reaches to cirrhosis, the 5 year survival rate is dismal (5 year survival is 55%)
What are the primary adverse outcome of chronic hep B infection?
liver cirrhosis and hepatocellular carcinoma
If a person has hep B, what would you focus your lab tests on?
early:
- HBeAg
- HBV DNA
- HBsAg
- IgM anti-HBc
- IgG anti-HBc
Later
- Anti-HBe
- HBsAg
- IgG anti-HBc
- HBV DNA (maybe
What are some extrahepatic manifestations of Hep B infection?
What causes it?
immune complex formation of (HBeAg + Anti-HBe and HBsAg and Anti-HBs)
- Variable fever
- Profound malaise
- Painful hepatometagly
- Serum sickness prodrome
- Immune complex disease (HBsAg + antibody)
- Vasculitis
- Urticaria
- Polyarthritis
- Membranous glomerulopathy (renal)
Recommended screening for HCC in patients with HBV?
recommended every 6-12 months
patients with specific risk factors may need to increase more (ie Asian, patients with cirrhosis who are seropositive for HBsAg, family hx of HCC, Africans, high serum levels of HV DNA and ongoing hepatic injury)
Two best treatments for Hep B infection?
What are the indications for treatment?
Etencavir
Tenofovir
Indications
- Acute and active HBV infections
- active HBe+ (mutated form) infection
T/F Hep B is a preventable disease.
True
Who is the Hep B vaccination recommended for?
Are boosters needed?
US: all newborn infants, kids before sex/IVDA
- note that 2-5% may not respond, even after multiple attempts. Stop after the 6th attempt
boosters are not needed!
What are some recommended practices to minimize spread of HepB?
- Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune
- Have sexual contacts vaccinated
- Don’t share toothbrushes or razors
- Cover open cuts and scratches
- Clean blood spills with detergent or bleach
- Don’t donate blood, organs or sperms
T/F Children and adults who are HBsAg (+) should minimize all contact from healthy persons in general.
False.
These patients can:
- participate in all activities including contact sports
- should not be excluded from daycare or school participation
- should not be isolate from other children
- share food, utensils or kiss others
Hep D
What type of virus is it?
What is the genome?
Does it have an envelope?
What is unique about this virus?
- satellite family
- RNA virus
- No envelope
- Defective RNA virus that requires HBsAg (ie coinfection with HBV) to replicate
Where is Hep D most common?
Rare in the US, but common in Mediterranean and parts South America
What are the two modes of acquiring Hep D virus?
What is the prognosis of each mode?
coinfection (HBV and HDV exposure at the same time)
- results in a more severe acute hepatitis
- higher mortality rate than HBV alonerarely leads to chronic infection
superinfection (HBV carrier exposed to blood containing HDV)
- Flare or worsening of stable HBV
- Higher rates of chronic infection of both viruses
- Higher cirrhosis, decompensation, HCC than HBV alone
What tests can be used to detect Hep D infection?
- HDV RNA
- IHC for HDV Ag
- Anti-HDV (Hep D)
- IgM - Coinfection
- IgG - superinfection
How is Hep D treated?
IFN (conventional or PEG) only treatment
HDV RNA is measured at 24 wks
Hep E
What type of virus is it?
What is the genome?
Where is its reservoir?
- Calcivirus
- +ssRNA
- reservoir in pigs and domestic animals
*
Hep E
Where is it most common?
What ist he prognosis of an Hep E infection?
- endemic in developing countries (most epidemics related to consumption of fecal-contaminated water, usually after heavy rainfall and floods)
- sporadic in developed countries (most related to exposures to Pigs, poorly cooked wild boar, deer, pork, effluent from pig farm)
- mortality is 1%, but up to **20% in pregnancy **
Why should pregnant women be wary of a Hep E infection?
- mortality is 1%, but up to 20% in pregnancy
- Hep E is common in pregnant women, esp in the third trimester; can result in vertical transmission to neonates
- pregnant women may develop **fulminant hepatitis **
When is Hep E viruses transmissible?
shed in stool weeks before the symptoms and increase in ALT occur
What markers are present in the acute phase of Hep E infection? past exposure?
Acute exposure: HEV IgM, or HEV DNA
Past exposure: HEV IgG
Hep C
What type of virus is it?
What is the genome?
Why is it so good at evading the immune system?
What is unique to this virus?
- Flavivirus
- RNA
- RNA dependent RNA polymerase – NO proofreading capability; prone to making mutations (esp. in the envelope proteins), which means that it’s good at evading the immune systemreplicates in the cytoplasm
- multiple genotypes (major types 1-6, but there is no clear evidence of increased virulence of a particular genotype)
Hep C is the most common blood borne infection in the US; only 25% of patients are aware that they have the infection. Why is it only 25%??
- Symptoms are non specific (fatigue most common)
- ALT normal in 25%
- Risk factors frequently not volunteered and must be ascertained.
- Patients unaware of diagnosis or afraid to find out: stigma and “No good treatment”
What is the paradox of Hep C infection?
prevalence has been falling, but complications (cirrhosis, HCC, deaths) are on the rise
What is the leading cause of liver cancer and leading indication for liver transplantation in the US?
Hep C
Link to CT/MS lecture:
Who is best at clearing a Hep C infection?
Why is this considered to be a double edged sword?
HLA-B27 genotype have high rates of HepC clearance, but unfortunately, molecular mimicry may predispose one to diseases like Ankylosing Spondylitis or reactive arthritis
Why must you repeat HCV RNA testing 4-6 months if the initial RNA test was negative for HCV? (2 reasons)
1) the RNA levels may oscillate and return to a positive
2) there is spontaneous resolution of the HCV infection later on, requiring no treatment
What is the natural progression of HCV infection?
~15-30% spontaneously resolves on its own after an acute HCV infection, but cure rate for HCV is drops if viral load is high
cure can result in regression of fibrosis and improved clinical outcomes
~70% go on to develop a chronic infection, of which a subset develops chronic hepatitis/cirrhosis, and ultimately HCC or death
What are factors that increase rate of progression to HCC (hepatocellular carcinoma) in HepC infection? (6)
- NASH (Nonalcoholic Steatohepatitis aka fatty liver)
- insulin resistance/DM
- smoking
- ALCOHOL
- older age
- HIV/HBV infections
What are some extrahepatic manifestations of HepC infection?
Hematologic
-
Cryoglobulinemia - results in
- dermatitis
- Porphyria Cutanea Tarda – photosensitivity due to increase in circulating porphyrins. Results in fragile skin, blisters in sun-exposed area
- Lichen planus – inflammatory dz of skin/mucous membranes; pruritic, purple polygonal papules with Wickman’s striae
- leukocytoclastic vasculitis
- myalgias and arthralgias (RA and/or ANA positive)
- membranoproliferative glomerulonephritis (nephrotic syndrome)
- neuropathy
- dermatitis
- Aplastic anemia
- Thrombocytopenia
- B-cell lymphoma
Vascular
- Polyarteritis nodosa
Endocrine
- Glucose intolerance
How do you screen for Hep C infection?
What are interpretations of each?
ELISA
Who is Hep C screening indicated for?
- Needles: IV Drugs, unsterile tattoos, needle-stick injury
- Blood: transfusions or organ transplant before July 1992, hemodialysis, or hemophilia receiving clotting factor concentrates prior to 1987
- Mucosal contact: IN cocaine use, intimate/sexual contact with HCV-infected persons, children born to HCV-infected mothers
- Viral infections with same risks, HIV, HBV
- Unexplained abnormalAST levels
- patients born 1945 to 1965
Why are all patients born 1945 to 1965 screened for Hep C (even if there are no risk factors)?
75% with Chronic HCV were born between 1945–1965; with prevalence in older/former IDVUs
What is Sofosbuvir used to treat??
What therapy regmine is it usually added to?
Hep C infection
added to Peg-IFN + WB Ribavirin
What is SVR?
What is it used to measure?
What factors influence SVR? (5)
Sustained viral response
- measure of efficacy of hepatitis C treatment
- defined as the absence of detectable HepC RNA in blood for at least 6 months after discontinuing the treatment
Factors
- Black/Race = lower SVR
- Cirrhosis = lower SVR
- Viral load
- Genotype (1/4 have worse SVR even with a longer treatment)
- IL28 gene - asians have a good response to IFN due to increased IL28 production; provides natural immunity to the virus – compared to africans who have low level
T/F If patients are virus negative, then they are cured of hepC.
True.
If patients are Hep C virus negative, then they are cured of hepC. What is the only problem with this?
even if someone is cured of hepC, if they have developed cirrhosis, they are still at risk of developing HCC!!
