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Flashcards in Ryan/Nair - Hepatitis Deck (69)
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1

HAV structural basics

- Picronaviridae family, genus enterovirus 

- Non-enveloped icosahedral capsid 

- < 7 kb ss RNA (+)

- Single serotype

- Human reservoir

2

HEV

- 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

What is the pathogenesis of HAV?

- 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

What groups are at-risk for HAV?

- 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

How is HAV diagnosed and controlled?

- 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

How did the HAV vaccine affect the Memphis outbreak?

- 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

Hep B structural basics

- Hepadnavirus: enveloped (aka, Dane particle)

- Partially dsDNA genome, 3200 bp: one strand shorter than the other

- 5 major proteins: 

1. DNA polymerase (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

How does HBV create a "smoke screen?"

- 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

Describe HBV replication. What is unique about it?

- 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

What is the epi of HBV?

- Endemic to China and sub-Saharan Africa

1. Early infection: 10-20% population rate

- Late infection in US and Europe: <1% population rate

11

How is HBV transmitted?

- 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

What are the phases of Hep B infection? How do these correlate to serum markers?

- 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

What are the diagnostic HBV markers?

- 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

HDV

- 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

Structural basics of HCV

- 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

What is the epi of HCV? Risk factors?

- 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

What is the pathogenesis of HCV?

- 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

What is the role of the immune response in HCV?

- Hepatitis viruses are not cytolytic

- Immune destruction (cytotoxic T cells) of infected hepatocytes leads to liver disease

19

What are the viral causes of chronic hepatitis?

- 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

Chronic HBV

- 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

Chronic HCV

- 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

How can you diagnose viral hepatitis?

- 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

How is HBV controlled?

- 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

What is the goal of HBV antivirals? General criteria?

- 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

How is HCV controlled? Antivirals?

- 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

Why does it take so long to devo HCC and cirrhosis in chronic HBV and HCV pts?

Because liver can regenerate itself at first; virus is not what is destroying the liver, but the immune response 

27

What are the 3 clinical presentations of viral hepatitis?

- 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 

28

What is the "clinical picture" of acute hepatitis?

- Usually caused by HAV and HBV in the US 

1. Acute HEV (zoonosis; India) and HCV (IVDU) are rare in clinical practice in US 

- LABS: high AST/ALT: 1000- 5000 IU/L 

1. High bilirubin, prothrombin time (INR)

a. Liver makes all clotting factors except Factor VIII (made in endothelium)

2. Very high INR may indicate progression to fulminant failure (serious disease)

a. Acute Hep and INR >4, worried about fulminant liver failure 

- NOTE: jaundice with high AST/ALT, think Hep

29

What is the Ddx for acute hepatitis?

- Autoimmune disease 

- Ischemic hepatitis (in ICU setting): shock -> no blood flow -> necrosis -> high ALT/AST + jaundice

- Alcohol/drug induced, Tylenol OD (esp. + alcohol)

- Wilson Disease 

-NOTE: AST of 1,000 and jaundice = acute viral hepatitis, ischemic liver, or drug toxicity 

1. High IgM + high ALT = acute viral hepatitis

30

HAV: dx and viral shedding

- 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