Lecture 81_82: Hepatitis Flashcards
Hepatitis – General:
what is it?
Acute vs Chronic
Cirrhosis vs Decompensated Cirrhosis ?
Symptoms of acute hepatitis ?
labs?
Hepatitis – inflammation of the liver which can lead to dysfunction over time
Acute – more symptomatic; can progress to chronic if virus is not cleared
Chronic – usually asymptomatic until onset of cirrhosis
Cirrhosis – scarring of the liver; but not necessarily dysfunction
Decompensated cirrhosis – enough scarring of normal tissue; significant hepatic dysfunction. Requires liver transplant
Symptoms; Jaundince, Icterus, Labs to check: ATLs, AST Bilirubin Prothrombin Time INR
Hepatitis B
- what viral family?
- virion is aka?
- describe the nucleic acid content
Viral Family; HepaDNAvirus
Virion is aka Dane Particle
Nucleic Acid – partially ds DNA; incompletely circular
Describe the structure of HBV
What are some important antigens ?
What are spheres and filaments
What is E antigen
- Smallest DNA virus
- Enveloped – surface antigens comprise the viral component of the lipoprotein coat
Partially dsDNA
Surrounded by HB Core antigen
Spheres and filaments – 22nm secretions from the virus with DNA material; circulate in the blood
E Antigen – not well characterized functuon; indicator of transmissibility in high viral loads
Important Antigens-
Surface antigen
Core antigen
E Antigen
Describe the Lifecylce of HBV?
what is unique about DNA replication?
What is unique about the genome?
how is this overcome ?
Enters host cell and is uncoated
DNA is “incompletely closed” and enters the nucleus
Host polymerases make the DNA —> cccDNA
cccDNA is supercoiled and fully dsDNA
Persists in the host nucleus indefinitely
cccDNA is transcribed and translated, leading to virion assembly.
DNA replication goes through RNA intermediate and therefore requires Reverse Trasncriptase
Therefore can use RT inhibitors as treatment
The genome – smallest DNA viruses; uses overlapping reading frames
HBV Epi and Transmission
1 million with chronic HBV in the US
2/3s unaware
400 million people world wide with chronic HBV
Highest burden in west africa
transmission: Low infectious dose
- Sexually transmitted
- Parenteral – eg IVDU; stable on fomites for 7 days
- Perinatal – 70-90% of transmission is mother to child
pathogenesis and progression of EBV:
Pathogenesis –
Host immune responses mediates the tissue damage
Most Damage is done by CTLs
Adative and immune response necessary to clear the virus
Chronic infection can cause immune dysregulation
In general:
The better the immune response to an acute infection, the more symptomatic, and the more likely the virus will be cleared
Therefore:
90% Children infected (such as perinatal): Asymptomatic, but do not clear the virus and develop disease
Only 5% of adults do not clear the disease
95% are symptomatic to acute infection; clear infection
25% of chronic infections lead to cirrhosis
25% of these will have decompensated cirrhosis
(HBV is the 6th most common cause for liver transplant)
5-10% of chronic HBV infections —> Hepatocellular carcinoma
Describe the patterns of diagnositc HBV markers for an acute HBV infection which resolves ?
what is the window period?
whats a marker for acute HBV infection?
what about the HBV DNA ?
HBV Surface Antigen – first to appear
Anti-core IgM and IgG — next to appera
Surface antigen begins to be cleared;
Window period passes before Anti-surface antigen begins to appear and persist
Anti core IgM will dissappear but anti-core IgG will persist
Therefore IgM anti-core is good marker for acute HBV infection
HBV DNA – marker for replication and moves in parallel with the HBV surface antigen
Describe the patters of diagnositic HBV markers for chronic HBV Infection ?
HBV Surface Antigen and HBV DNA – never cleared and persist
HBV Surface Antibody – Never develops; no immune response was mounted
Viral Load will remain positive
Core IgG will be positive for life
Treatment of HBV –
who to treat? what are the treatments?
Prevention
Who to treat? __ based on viral burden and ALT levels
Treatments:
Entecavir — guanosine analog
Tenofovir – adenosine analog
Prevention:
HBV Vaccine – all children in the US – course of 3 injections
Uses surface antigen
vaccinated persons will not have IgG -core antigen
HBV IG – temporary passive protection; given to children born to infected mothers; unvaccinated persons exposed to blood or body fluids. VERY EXPENSIVE
Hepatitis D Virus -- whats unique about this virus? antigens? Genome? co infection vs superinfection
when add to ddx?
Diagnosis ?
Virus that cannot cause harm without HBV infection
single stranded RNA Genome
Only unique antigen is the Delta Antigen
Co-infection: HBV and HDV acquired together
Superfinction: HBV first followed by HDV infection later
Add to DDx when someone with chronic HBV infection all of sudden has changes in the transaminases (ALT)
Hepatitis C Virus
family? genus?
Structure?
unique morphology
Flavivirus – Hepacivirus
Enveloped
RNA
Glycoproteins in lioid envelope
Nucleopcapsid with Core antigens
Pleomorphic characteristics — lipo particles in the blood stick to the glycoprotein
Describe the life cycle of HCV?
tropism
whats unique about the translation of the genome
infects the Hepatocyte
Viral Entry —> uncoating
processes occur in association with the Endoplasmic Reticulum
Replication of RNA
9.4K Nucleotides are translated into 3000 amino acid long chain. Which is then cleaved by proteases (host and virus)
Proteins form a menbraneous web with the ER
To exit the cell – Hijacks the lipid secretions pathways
budding
The virus never integrates; takes place outside of the nucleus
Targets for Treatment of HCV
The nonstructural Protiens –
proteases,
polymerase, and
NS5A (unknown enzymatic activity, but effective target for treatment)
Why is it difficult to ammount a host immune response to HCV?
RNA Dependent RNA Polymerase – lacks proof-reading fuction – high mutation rate
Different Genotypes and Subtypes
Viral Proteins – can also inhibit the innate immune response –
eg NS4A – cleaves translated proteins for packaging but acts nonspecifically and cleaves host proteins involved in immune response
Pathogenesis and Progression of HCV
Acute infection:
15% mount immune response and clear disease
80% devleop chronic Hepatits
Host CTL Response leads to collateral damage of the liver
20% of chronic cases lead to Cirrhosis
25% of cirrhosis cases become decompensated cirrhosis
HCC is only prevelant in HCV Cirrhosis –
It is thought that the cirrhosis leads to the cancer; not the extra-nuclear HCV RNA
Epi and Trasmission of HCV
what country has the highest rate
what genotype is most prevelent in the US and europe ?
what genotype is easiest to treat clinically?
Epi – 185 million cases world wide. 130 million chronic cases
3-5 million cases in the US
Genotype 1 – most difficult to treat
Leading cause for liver transplants
cause of 27% of cirrhosis; 25% of all HCC
Highest in Egypt
Transmission:
60% via IVDU, body piercings
Transfusions - 1 in 10,000
10% unknown
Genotype 2 is easiest to treat
HCV
what co-morbiditis are associated with disease progressin?
which features are not associated with disease progression ?
Alcoholism
DM, Iron Overlaod
Not associated: Viral load, genotype
Diagnosis of HCV
○ ELISA Screening Test for HCV Antibodies
§ — 98% sensitivity
If positive, confirm with HCV viral load
Treatment of HCV
what metric is used to
goals of therapy
treatment based on liver damage – assessed bt histology
Interferon Therapy – prior to 2011
Toxicities and side effects
Not very effective
Direct Acting Anti-virals (protease inhibitors)
Very expensive
§ Virus does not integrate -- therefore it is curable § Sustained virological response --- Undectable viral load 3-6 months after therapy
With cure – patients are NOT immune to new infecti
what is the appropriate combination therapy treatment for HCV?
Sofosbuvir RNA Polymerase Inhibitor (NS5B) + Ledipasvir (NS5A Inhibitor)
NS5A – no enzymatic activity; but associated with replication and assembly
Hepatitis A
RNA or DNA ?
What family of virus?
How is transmitted?
whats unique?
Picornavirus
SS Linear RNA
fecal-oral transmission – raw oysters and uncooked shellfish
THE VIRUS NEVER BECOMES CHRONIC
Hepatitis A -
Pathogenesis
Clinical Features
Pathogenesis – virus replicates in hepatocytes; released into bile and stool. Infectious prior to clinical symptoms
Clinical Features: due to mounting immune response
30 day incubation
Sx: fatgue, abd, loss of appetite, nausea, vomiting, diarrhea; jaundice, elevated LFTs, dark urine, light stool;
Adults are more symptomatic
Clears in 2-4 weeks
immune for ever
THE VIRUS NEVER BECOMES CHRONIC
Hep A
Treatment
Prevention
Supportive –
Lifelong immunity after infection or vaccination
Prevention Hygiene, sanitation Vaccine -- Pre exposure § 0 month, and booster at 6 months ○Who gets the vaccination --- newborns, travelers, MSM, IDU, Patients with HBV, HCV;
Passive Immunization – immune globulin therapy – pre and post exposure
○ Given to travelrers; exposure risks
Hep E
Family –
RNA or DNA ?
Transmission
Hepevirus
Single Stranded Linear RNA
Fecal oral transmission –
THIS DISEASE CAN BECOME CHRONIC
How is hep E similar to hep A?
how is it different?
Different:
Hep E can become chronic disease –but rare
Pregnant women – higher mortality rate
Same:
Replicates
Sheds into stool
infectious prior to symptoms
Hep E – epi
Dx
treatment
Uncommon in the US
Dx: Serology,
Treatment: Symptomatic
