Ryan/Nair - Hepatitis Flashcards
1
Q
HAV structural basics
A
- Picronaviridae family, genus enterovirus
- Non-enveloped icosahedral capsid
- < 7 kb ss RNA (+)
- Single serotype
- Human reservoir
2
Q
HEV
A
- Family Caliciviridae, genus Hepevirus
- Non-enveloped icosahedral capsid
- 7.5 kb ss RNA (+)
- Single serotype
- Possible swine or other animal reservoir
- Mostly prevalent in developing countries
- 1 in 5 fatality rate in pregnant F (3rd trimester: don’t see this with any of the other hep viruses)
3
Q
What is the pathogenesis of HAV?
A
- Fecal-oral route, and replication in GI tract
- Early childhood disease is most common and often asymptomatic (kids) -> common source of community outbreaks
- 33% of annual US acute hepatitis cases, and 1/3rd of US population has had this
-
Weeks of symptoms in adults with viral shedding before symptoms
1. Anorexia, malaise, fever, headache, perhaps jaundice - Vaccination has reduced this by >90% (no longer 33% of annual acute cases): still see community outbreaks
4
Q
What groups are at-risk for HAV?
A
- Household or sexual contacts
- Travelers to endemic areas
- Inhabitants of American Indian reservations
- During outbreaks:
1. Diners
2. Day care center workers: kids are a prominent target, but usually asymptomatic
3. Gay men
4. IV drug users: not typically contracted parenterally, but possible during an outbreak
5
Q
How is HAV diagnosed and controlled?
A
- DIAGNOSIS: presumptive based on appearance and history
1. Detection of anti-HAV IgM - PREVENTION: hand-washing for 10-20 seconds
1. Passive immunization w/gamma globulin (IgG)
2. Inactivated vaccine (Havrix): >2-y/o
3. Combo vaccine for HAV and HBV (Twinrix): 18 years or older
4. Vaccine or IgG recommended for travelers to endemic areas (vaccine for kids too) - CASE: 28, lives in Cooper Young. 2-yo child. Confirmed presence of anti-HAV IgM. Risk factors: child in daycare, bars and restaurants, denies IVDU (making C and B less likely)
6
Q
How did the HAV vaccine affect the Memphis outbreak?
A
- Predicted decline rate shown here: actual decline rate MUCH faster
- Vaccine had a tremendous affect on the clearance of the infection in the Memphis outbreak
- Good candidate for eradication: 1 serotype, HUMANS ARE ONLY RESERVOIR
1. Why not eradicate: self-resolves, incidence dropping dramatically after intro of vaccine, bigger worries in underdeveloped countries
7
Q
Hep B structural basics
A
- Hepadnavirus: enveloped (aka, Dane particle)
- Partially dsDNA genome, 3200 bp: one strand shorter than the other
- 5 major proteins:
1. _DNA poly_merase (reverse transcriptase)
2. HBsAg: surface antigen, attachment protein mostly found in 20 nm particles and filaments
3. HBcAg: core antigen, capsid protein
4. HBeAg: derivative of HBcAg, important serologic marker
5. X antigen: influences gene expression
8
Q
How does HBV create a “smoke screen?”
A
- Phospholipid blebs from infected cell floating around in blood that act as “smoke screen,” and distract immune system from surface antigen
- So many that first vaccine was blood-derived, and made up of these things purified from blood (people get weird about these blood-derived vaccines, so not used anymore)
- NOTE: serology is very important -> can’t detect core antigen in lab, but can detect e antigen
9
Q
Describe HBV replication. What is unique about it?
A
- Genome length RNA used as template for reverse transcription
- DNA can integrate into genome (probably not linked to cancer risk), but mostly maintained extra-chromosomally in chronic infections
- Completion of dsDNA during uncoating: now looks like a “plasmid” -> mRNA and (+) strand copy from host RNA polymerase that is pre-genomic RNA (virus has its own reverse transcriptase to now make strands of DNA: one is unfinished)
1. Opposite of HIV in this way: DNA virus with RNA intermediate rather than RNA virus with DNA intermediate -> both require reverse transcriptase
2. This is why some HIV drugs can be used to tx HBV too, opening up a lot of antivirals for use - NOTE: don’t necessarily need to know all of this, but know that the REVERSE TRANSCRIPTASE is important due to this RNA intermediate
10
Q
What is the epi of HBV?
A
- Endemic to China and sub-Saharan Africa
1. Early infection: 10-20% population rate - Late infection in US and Europe: <1% population rate
11
Q
How is HBV transmitted?
A
- Virus is present in blood, semen, and vaginal secretions
- Transmission by parenteral route:
1. Injection drug use
2. Sexual intercourse
3. Perinatal at delivery
12
Q
What are the phases of Hep B infection? How do these correlate to serum markers?
A
- If not resolved in 6 months, considered chronic
- Chronic patients often remain asymptomatic until cirrhosis or HCC appears
- Scale for symptoms larger than for HAV: more insidious infection
1. Viral shedding before symptoms (like HAV) - Graph shows acute resolved
13
Q
What are the diagnostic HBV markers?
A
-
HBsAg: ID of carriers or acutely infected persons
1. Anti-HBs: ID of persons who have had HBV infection or received vaccine -
HBeAg: ID of those at INC risk of transmission (active marker) -> means capsid protein being made
1. Anti-HBe: ID of HBsAg carriers with low risk of transmission -> immune response starting to contain the infection -
Anti-HBc: ID of persons with past infection
1. IgM Anti-HBc: ID of acute or recent infection
2. Can detect anti-HBc, but not HBcAg - High-risk carrier: HBeAg + anti-HBc
14
Q
HDV
A
- Encodes delta antigen, its core (capsid) protein
- Enveloped, circular ssRNA genome of 1.7 kb, and must incorporate HBsAg to infect hepatocytes (source of attachment to proteins)
- Uses host RNA polymerase
- Good anti-HBs = resolution of infection
- CO-INFECTION: primary acute infection can be more severe, but no increased risk of chronicity
- SUPER-INFECTION: HDV will trigger spike in ALT, and levels will never drop down to baseline -> makes chronic infection worse
15
Q
Structural basics of HCV
A
- First described in 1989: Flaviviridae Hepacivirus
- Enveloped icosahedral capsid with 9.4 kb ss RNA (+) genome
- 6 major genotypes, divided into subtypes: 1a, 1b, 2a, 2b are worldwide -> 1a and 1b most comm in US
1. Pts also contain quasi-species (antigenic variants from E2 region) - Translates one big polyprotein first:
1. 2 envelope proteins: E1 and E2 -> E2 is a prime source for antigenic variation (30 AA’s that can change, allowing virus to escape immune response)
2. PROTEASE: major target for antivirals - CASE: contaminated blood transfusion -> Hep C (pre-1992 = tip-off that Hep C because prior to screening for it)
16
Q
What is the epi of HCV? Risk factors?
A
- Highest incidence world-wide in Asia, Middle East, and North Africa
- New case incidence in US has dropped A LOT since the 80s -> general population rate is 2%, but estimates of 16-41% in prison population
- RISK FACTORS: born b/t 1945-65 (80% of chronic cases)
1. Illicit (injection) drug use
2. Perinatal infection at birth
17
Q
What is the pathogenesis of HCV?
A
- Acute infections milder than HBV: resolved, acute infection lasts 2-3 wks
- CHRONIC pts have multiple bouts: immune response, but not sufficient to keep everything in check -> this may be where the antigenic variants come into play (some could also be reinfection with other serotypes): spikes in ALT every 2 years or so
- Reinfection
- Emergence of quasi-species
18
Q
What is the role of the immune response in HCV?
A
- Hepatitis viruses are not cytolytic
- Immune destruction (cytotoxic T cells) of infected hepatocytes leads to liver disease
19
Q
What are the viral causes of chronic hepatitis?
A
- 40% of cases are due to HCV and 20% HBV (5% contain HDV)
1. Immunize HBV and HCV chronic pts against HAV and discourage alcohol use
2. HBV/HCV liver disease is leading reason for liver transplants
3. Despite HBV vaccine, HBV-related cancers and deaths have doubled in the past decade - Remainder of unknown origin
20
Q
Chronic HBV
A
- Devo depends on age of infection:
1. < 1 yo: 90% chronicity rate -> endemic in certain areas of the world due to EARLY infection
2. 1-5 yo: 30% rate
3. > 5 yo: 2% rate - 1 in 4 chronic patients will die of liver disease, mostly in 6th decade
- 3 stages:
1. Immune tolerance phase
2. Immune clearance phase: eAg (+) to eAb (+)
3. Residual phase - NOTE THE ATTACHED FIGURE
21
Q
Chronic HCV
A
- 85% of untreated infections will lead to chronic infection
- 1 in 25 people will devo cancer from this infection: this is a very significant thing
- NOTE THE ATTACHED FIGURE
22
Q
How can you diagnose viral hepatitis?
A
- Acute forms of ET- and PT-hepatitis can be similar
-
Source of infection and ELISA:
1. HBV: HBsAg, anti-HBc IgM; HBeAg, HBe antibody, HBV DNA
2. HCV: anti-HCV antibodies, HCV RNA - Determine HCV genotype
23
Q
How is HBV controlled?
A
- Screen blood supplies for HBsAg, HBc antibodies, HBV DNA
-
Vaccines: yeast expressed HBsAg
1. Twinrix: HAV + HBV -> NOT labeled for anyone under age 18
2. Childhood immunization recommended
3. NOTE: plasma-derived HBsAg not used anymore - HBIg for exposed individuals: newborns, and can be used prophylactically for travelers
24
Q
What is the goal of HBV antivirals? General criteria?
A
- GOAL: to reduce risk of progressive chronic disease, transmission, and complications (cirrhosis, HCC)
- General criteria:
1. >2000 units/mL HBV DNA
2. >2x upper normal limit of serum ALT
25
Q
How is HCV controlled? Antivirals?
A
- Screen blood supplies for antibodies to core antigen, HCV RNA
- No vaccine in US yet, no passive immunization
- “HCV is relatively easily treated and can be eliminated in almost all patients,” so the goal of therapy is to eliminate HCV RNA
1. Treatment varies by genotype - ANTIVIRALS: Entecavir and Tenofovir target reverse transcriptase
1. Entecavir: directly INH polymerase molecule itself vs. Tenofovir, which is a chain terminator -> work 2 different ways to exploit reverse transcriptase
26
Q
Why does it take so long to devo HCC and cirrhosis in chronic HBV and HCV pts?
A
Because liver can regenerate itself at first; virus is not what is destroying the liver, but the immune response
27
Q
What are the 3 clinical presentations of viral hepatitis?
A
- Acute
- Fulminant hepatic failure: really bad acute hep
- Chronic -> 20-30 yrs before cirrhosis with the following long-term complications:
1. Cirrhosis
2. Liver failure: ascites, jaundice, confusion, encephalopathy, bleeding
3. Hepatocellular carcinoma - NOTE: while Hep C can cause acute hep, it most often presents as chronic
30
Q
HAV: dx and viral shedding
A
- DX: IgM anti-HAV in acute/early convalescent; generally present 5-10d before onset of symptoms, and no longer detectable in most pts 6 mos later
1. IgG anti-HAV appears early, and remains detectable for lifetime, conferring lifelong protection
2. Commercial tests available for IgM, and total (IgM + IgG) - SHEDDING: HAV replicates in liver, is excreted in bile, and is shed in stool
1. Peak infectivity (concentration in stool highest) in 2-wk period before onset of jaundice or elevation of liver enzymes, and declines after jaundice appears
2. Children and infants can shed HAV in stool longer than adults, up to several mos after onset - HAV RNA can be detected in blood/stool of most pts in acute phase with PCR -> not generally used for diagnostic purposes
35
Q
What factors can accelerate fibrosis in chronic HBV/HCV?
A
- Accelerated = progression to cirrhosis in 15-20y:
1. Obesity: fatty liver
2. HIV
3. Post-liver transplant
4. Alcohol consumption: def want <2 cups/d - Tx algorithm recommend consideration of liver biopsy for monitoring -> useful in making tx decisions and assessing degree of damage
- IMAGE: progression of hepatic histology from normal through fibrosis to cirrhosis; also present on the far right, one can see cords of neoplastic hepatocytes in a patient with HCC
36
Q
What US ethnic pop is disproportionately affected by HBV?
A
- Foreign-born Asian Americans and their kids
- Growing population in the US (8% of pop): 68.9% foreign-born -> many of the countries of origin are regions of high/intermediate HBV endemicity
- 2.7x more likely to devo hepatocellular carcinoma (HCC) and 2.4x more likely to die from HCC than their white counterparts
37
Q
What are the CDC recommendations for routine HBV testing?
A
- Chronic Hep B: no symptoms, so SCREEN for it in high-risk pts
- While health care workers are not specifically mentioned by the CDC as a pop at risk, those with reasonably-anticipated occupational exposures to infectious body fluids should also be vaccinated
- NOTE: stars next to HIV+ ppl, and those who are immunosuppressed (b/c reactivation possible)
1. Other high-risk pops are those at high-risk for all parenterally transmitted infections
38
Q
Describe the HBV serological markers.
A
- (+) HBsAg: active infection (acute or chronic)
- Anti-HBs Ab: resolved infection or prior exposure, vaccination
- Anti-HB core Ab: definite exposure (not seen in vaccination -> IgM: acute HBV, Ig G resolved or chronic infection)
- HBe Ag and high DNA: active replication & high risk of transmission
39
Q
What is the course of chronic HBV infection (4 phases)?
A
- 4 PHASES:
1. Immune tolerant: little hepatic inflam despite high serum level of HBV DNA, & (+) HBeAg
2. Immune clearance: hepatic inflam, DEC in serum HBV DNA, and ultimate loss of HBeAg; known as the HBeAg+ phase
3. Inactive carrier: low level HBV DNA, (-) HBeAg, and normal LFT’s
4. Reactivation: high levels of HBV DNA in serum + hepatic inflam; many pts HBeAg (-), but some may revert to HBeAg (+); HBeAg- CHB (some never enter this phase) - 50+ pt w/chronic HBV probably in inactive carrier state, whereas teen who comes in w/chronic HBV more likely to be in immune tolerant stage
- Not all pts go through all 4 phases:
1. Immune clearance phase most common in young Asian pts with perinatally acquired HBV infection
2. Immune clearance phase and reactivation phases may be prolonged with recurrent exacerbations of hepatitis and fluctuations in serum HBV DNA levels
40
Q
When do you treat chronic HBV?
A
- When there is evidence of liver injury (high ALT )
- Liver biopsy showing advanced fibrosis
- STARS: associated with liver injury
46
Q
What is the liver-related burden of chronic HCV in the US?
A
- Rise in HCV-related cirrhosis and HCC due to manifestation of disease in aging baby boomers
1. Prevalence of HCV infection in HCC pts from 20-90%, and risk of HCC in HCV-related cirrhosis from 1-7% - HCC rates projected to peak in 2019
47
Q
What are the HCV screening guidelines for at-risk pts?
A
- All screening guidelines recommend screening BABY BOOMER population (1945-65 birth cohort)
- Guidelines also incl. screening recommendations based on risk factors and other medical conditions
48
Q
How does HCV affect mortality?
A
- INC risk of:
1. Non-liver related cancers
2. Strokes, circulatory diseases
3. Heart attacks
4. Diabetes
5. Kidney failure: nephritis, nephrotic syndromes, nephrosis - INC risk of dying from extra-hepatic disease
49
Q
How does HCV progress (flow chart)?
A
- Image shows the natural history of hepatitis C virus (HCV) infection from acute infection to devo of disease complications
50
Q
What are the recommended lab tests for chronic HCV?
A
- Screening test = Hep C Ab via EIA
- Positive results are to confirmed using PCR for HCV RNA
51
Q
How do you interpret HCV assay test results?
A
- Hep C can be cured, but Ab persists
- HCV Ab’s with no HCV RNA could indicate either resolution of prior infection or acute HCV infection in setting of intermittent or low-level viremia.
- HCV RNA w/no HCV antibody could indicate either early acute HCV infection or chronic HCV infection in those with immunosuppression or false-positive HCV RNA tests
- HCV Ab’s and HCV RNA implies either acute OR chronic infection, depending on the clinical setting
- No HCV antibodies and no HCV RNA indicated the absence of HCV infection
52
Q
What are the HCV genotypes? Where are they prevalent?
A
- Prevalence depends on geographic location
- Most common type in US is T1, then T2 and T3
1. 75% of HCV in US T1, but as high as 90-95% in African-Americans in the US
53
Q
What is the HCV life cycle (image)?
A
54
Q
What is the tx for HCV?
A
- HCV is curable w/tx (unlike HBV or HIV), but ACCESS TO CARE is the biggest issue
- Multiple direct-acting agents target HCV replication and prevent resistance: 90-95% cured
1. Shorter duration 3- 6 months
2. Less side effects
3. Less Drug Interaction - SOFOBSUVIR: no major side effects, and no food interaction
1. Limited drug interaction
2. $1000/pill - NOTE: choose drug based on cost, and what insurance will accept
57
Q
How is HCV different than HBV and HIV, making it curable?
A
- Hep C does not have archived resistance
- High replication and mut rate of HCV (due to error-prone RNA poly that lacks proofreading func)
- Unlike HBV and HIV, which have been shown to archive resistance (as stable, covalently closed circular DNA persisting in nucleus or as integration in host genome, respectively), there is no known mechanism for HCV to be archived in the host
58
Q
Why is curing HCV important?
A
- Achieving sustained virologic response assoc with DEC:
1. HCC incidence
2. Liver-related or transplantation mortality
3. All-cause mortality
59
Q
What are the potential barriers to curing HCV?
A
- POOR ADHERENCE is the result of factors spanning several dimensions and issues related to:
1. Socioeconomic conditions
2. Therapy admin
3. Healthcare system - Patient adherence is critical to good pt outcomes
64
Q
What are the extra-hepatic manifestations in viral hepatitis?
A
- Membranoproliferative glomerulonephritis
- Porphyria cutanea tarda
- Mixed cryoglobulinemia (vasculitis,neuropathy)
- Lymphoproliferative conditions
- Extra hepatic manifestations may correlate with Viral RNA/DNA levels
- Treatment is indicated and can be successful if viral replication can be reduced
66
Q
What is this?
A
- CMV hepatitis: fever diarrhea (involvement of GI tract)
- DX: CMV DNA or tissue biopsy –> liver or GI tract
- TX: Ganciclovir
1. Prophylaxis is recommended w/Valcyclovir for organ transplant recipients
2. Long-term tx needed for some people
