5 - Viral Hepatitis Flashcards
What is Hepatitis?
Inflammation of the liver
Almost always implies elevation in liver enzymes
Key liver enzymes
AST and ALT
Other liver enzymes of consequence in hepatitis
Bilirubin
Albumin
Alkaline Phosphatase
GGT
Causes of Acute Hepatitis
Viruses A through E (hepatotrophic) CMV & EBV (non-hepatotrophic) Other infectious etiologies (TB, MAI, Fungus) Alcoholic hepatitis Drug hepatitis Ischemic hepatitis Biliary disease (Choledocholithiasis)
Human Hepatitis Viruses
HAV HBV HCV HDV HEV
RNA Hepatitis Viruses
HAV
HCV
HDV
HEV
Double Stranded DNA Hepatitis Viruses
HBV
Hepatitis A
ssRNA
7.5 kb Genome
No Envelope
Picornaviridae Hepatovirus
One Serotype
Multiple Genotypes
Acid/Heat Stable
Hepatitis B
dsDNA
3.2 kb Genome
Envelope
Hepadnaviridae
Multiple serotypes and genotypes (A - F)
Hepatitis C
ssRNA
9.6 kb Genome
Envelope
Flaviviridae Hepacivirus
Genotypes - 1 to 6
Hepatitis D
ssRNA
1.7 kb Genome
Envelope
Unclassified (viroid) delta virus
Hepatitis E
ssRNA
7.5 kb Genome
No Envelope
Unclassified togavirus and alpha virus-like
Other infectious etiologies of Acute Hepatitis
CMV - Immunocompromised Host
EBV - Mononucleosis, lymphadenopathy, splenomegaly
TB & M. Avium Intracellurare
Symptoms of Acute Viral Hepatitis
Complaint: Intense Fatigue, Nausea, Anorexia
Yellow Eyes/Skin, Dark Urine
Low Grade fever, Abdominal Pain
Arthralgia, myalgia, headache
Signs of Acute Viral Hepatitis
Jaundice
Hepatomegaly w/ RUQ tenderness
Fever - Low Grade
Splenomegaly - infrequent
Liver Blood Test Abnormalities - Acute Viral Hepatitis
AST & ALT: 500 - 5000 IU
Bilirubin: Generally elevated, both conjugated and unconjugated
Alkaline Phosphatase: Minimally elevated
Bilirubin and Urobilinogen in Urine: Increased (Coca cola color)
Normal AST/ALT
40 +/- 5 or 10
What is Alkaline Phosphatase elevation associated with?
Biliary Disease
Infiltrative Disease
Not so much viral
Outcomes of Acute Viral Hepatitis
Chronic Hepatitis
OR
Cure
OR
Fulminant Hepatitis
Fulminant Hepatitis
Overwhelming inflammatory response directed by the immune system against the body
Patient gets very sick
75% - 85% Mortality
Seen with HAV, HBV, HCV
Hepatitis A Virus - In Vitro
Monkey & Human Cell Cultures
Hepatitis A Virus - In Vivo Replication
In Cytoplasm of Hepatocyte
Human and other primates
Hepatitis A - Transmission
Oral Fecal Excreted in stool 2 weeks PRIOR to clinical illness Therefore it spreads in the military 1 month incubation period Children often asymptomatic NEVER causes chronic hepatitis
Serologic Course
1st Month - Fecal excretion
2nd Month - Symptoms & Increase in ALT
2nd - 6th month IgM Antibody spikes
3rd - 4th month, symptoms resolve
Marker for acute HAV infection
IgM anti-HAV spike
Hepatitis A - Prevention and Treatment
No treatment available
Passive immunity with Gamma Globulin can ameliorate disease in early stages of the infections
Gamma Globulin can prevent disease pre-exposure
Vaccine available to induce active immunity
Hepatitis B - In Vitro
Primary hepatocyte culture and transfection of cloned HBV DNA
Hepatitis B - In Vivo Replication
In cytoplasm, cccDNA in nucleus
Hepatocyte and other tissues
(Human and other primates)
Diagnosing Hepatitis B - Useful
E Antigen
Hepatitis C - Replicates in
Cytplasm
Hepatitis B - Viral Replication
Viral Entry Uncoating (in Cytoplasm) DNA Repair (in Nucleus) Transcription (in Nucleus) Export to Cytoplasm Priming, Translation via Reverse Transcriptase You can treat with NRTIs
Hepatitis B Virus - Immunopathogenesis
Typical B Cell and T Cell response
Results in hepatocyte apoptosis
Hepatitis B - Transmission
Horizontal - Parenteral, secretions, sexual
Vertical - Mother to child
6 - 8 week incubation
20% of patients have “serum sickness” prodrome
4% of adult patients develop chronic hepatitis
Treatment and vaccine available
NO CURE!!!!!!!!!!!!!!!
If you get hepatitis B early
You’re likely to get chronic hep B
You don’t have symptoms
If you get hep b late
You’re not likely to get chronic hep b
You do have symptoms
Hepatitis B Diagnosis
Antigens and Antibodies
Many specifics to know
Acute HBV Infection
IgM Anti-HBcore
Order Anti-Core IgM - Separates out ACUTE infection
HBV Prevention
HBV Infection can be prevented with both passive and active immunity
High titer immunoglobulins can be administered at birth or post exposure to prevent acute HBV
Recombinant vaccine available to induce active immunity
Hepatitis C Virus - In Vitro
Primary hepatocyte and T Cell cultures (Replicon system)
Hepatitis C Virus - In Vivo Replication
In Cytoplasm
Hepatocyte and lymphocyte
(Human and other primates)
Hep C Replication
Binds to hepatocyte, enters Uncoats Translates IN CYTOPLASM RNA translated Protein products synthesized in ER Progeny genome created New virus assembled
Hepatitis C Immunopathogenesis
Virus secreted in blood
B Cells aren’t neutralizing Ab - Only marks, doesn’t clear
ELISA screening Ab test for Ab produced by B cells
Hepatitis C Clinical
Most common cause of chronic hepatitis in USA 1.5% of population in USA carries the virus Parenteral transmission - blood, sexual 6 - 8 week incubation period Acute infection generally mild 80% develop chronic disease No vaccine available Treatment - 80 - 99% cure rate
Acute Hepatitis C Serologic Pattern
ALT goes up over the first 3 months
ALT goes down over the second 3 months
Anti HCV Ab goes up at about 6 months
Acute Hep C, 20% get better, 80% get chronic
Outcome following Hep C Infection
Acute Hep C 80% of those go to chronic infection 70% of those go to chronic hepatitis 20% of those get cirrhosis 1 - 4% of those/yr get HCC OR 4 - 5% get Decompensation
Hepatitis D
Known as Delta Agent
Uses the HBsAg protein coat
Hep B must be present (coinfection or preexisting)
Hepatitis E
Waterborne resembling Hepatitis A
Endemic in Asia, Northern Africa and MExico
Rarely seen in the USA
Antibody testing is not standardized
Chronic Hepatitis
Elevated AST and/or ALT for greater than 6 months
Characteristic path findings
Many different diseases cause chronic hepatitis
Liver biopsy frequently performed for definitive diagnosis
Chronic Hepatitis - Path
Portal Tracts, Peri-portal regions and lobules involved Liver biopsy: Chronic inflammation Increased inflammatory cells Many plasma cells and lymphocytes Inflammation > Fibrosis > Cirrhosis
Chronic Liver Enzyme Elevation - Etiology
Viral Infection - B & C
Autoimmune
Drugs
Metabolic - Wilson’s
Fatty Liver - Steatohepatitis
Alcohol
Others - CHF, hemochromatosis, ulcerative colitis, celiac disease, others
Chronic Hepatitis B & C
Cirrhosis in 20% of patients
Liver failure and hepatoma develop in 1/2 of cirrhotics
Treatment available with varying success rates
Diagnosis of Chronic Hepatitis B or C
Chronic AST or ALT elevations (though some patients have normal enzymes)
Positive serology - HBsAG or Anti HCV
Positive DNA or RNA in blood
Diagnostic Liver Biopsy
Difference between acute and chronic hep B serologically
Surface antigen NEVER disappears (chronic)
DNA is continuously present in the blood
E antigen is
HE WAS NOT CLEAR 9:45am
Chronic HBV - 4 Phases of Disease over Decades
Immune Tolerant
Immune Clearance (HBeAg positive, Chronic HBV)
Inactive Carrier (Chronic HBV, surface Ag positive, low DNA, low transaminase)
Reactivation (HBeAg negative, Chronic HBV, IT IS A MUTANT)
Serologic Events in HBV Infection
Surface Antigen - Acute Hep B or some form of Chronic
No Surface Antigen - Vaccine responder or immune
Anti HBs - Vaccine Responder (but no anti-core) or Exposed and cured (with anti-core)
The more HBV DNA in your body
The higher chance you have of getting cirrhosis
Therapeutic Options of Hepatitis B Treatment
Most often:
Tenofovir (Viread)
Entecavir (Baraclude)
Peg-Interferon (Pegasys or PegIntron)
Telbivudine (Tyzeka)
Lamivudine (Epivir)
Adefovir (Hepsera)
Emtricitabine (FTC)
These drugs don’t get rid of episomal DNA in the nucleus. When treatment stops, virus comes back!
Chronic HCV Infection
ALT goes up, ALT goes down
Chronic mild ALT elevations
HCV RNA measurable in the blood chronically
Ab measurable but doesn’t do anything to clear virus
Hepatitis C Treatments
90 - 100% CURE rates!!
Sofosbuvir Simeprevir Daclatasvir Ledipasvir Ombitasvir Paritaprevir Ritonavir Dasabuvir
Factors affecting response to HCV Rx
Virus - Genotype, Viral Load
Host - IL28B
IL28B
SNP Chromosome 19 Near IL28B Gene Encoding IFN - Lamda3 Associated with twofold changes in response to treatment
