JC57 - Hepatitis B Flashcards
Standard workup tests for hepatitis
WBC - normal or relative lymphocytosis LFT: Transaminase at 200-2000IU/L during acute infections PT: index for progress and prognosis Bilirubin Serology: → IgM anti-HAV → HBsAg and IgM anti-HBc → Anti-HCV and HCV RNA → IgM anti-HEV
Structure and genome of HBV
Structure: ‘double-shelled’
→ Nucleocapsid core formed by HBcAg
→ Envelope formed by HBsAg
overlapping open reading frames (ORFs) genome: S ORF (S gene): codes for polyalbumin binding sites, cell surface receptors, HBsAg C ORF (C gene): HBcAg and HBeAg P ORF (P gene): viral polymerase X ORF (X gene): HBX protein
HBV proteins that indicate active infection
Small/ Medium/ Large HBsAg: Presence in serum indicates active viral infection
C ORF Proteins:
HBeAg: Secreted in serum during replication, indicates active viral replication
HBcAg: Reside in virions and infected hepatocytes only, NOT detectable in serum
Pathogenesis of HBV infection
HBV NOT directly cytopathic
1) Proteolytic cleavage of viral proteins in infected hepatocytes
2) peptide presented to cell surface by MHC class I
3) triggers immune reaction via TNF-α and IL-1β
4) damage to liver through cytotoxic T cells and cytokines
Transmission of HBV
Vertical transmission at birth
→ Typically mother-to-child
Blood transfusion/ contaminated blood products
Close contact as toddlers
Needles
→ IVDU, acupuncture, tattoo
Sexual contact
Reason for higher risk of chronic HBV infection in neonates
1) Immature immunity»_space;> Failure of host to recognize infected hepatocytes
Eg. covering of viral Ag displayed by HLA by maternal anti-HBc
Viral factors:
Excessive production of HBsAg, acts as empty decoy against humoral and T cell response
HBx protein: inhibits degradation of viral protein, less APC
Polymerase protein: suppresses myeloid differentiation protein, less toll-like receptor (TLR) function
Precore/HBeAg:
- Down-regulates TLR-2 expression on Kupffer cells, hepatocytes and monocytes
- Down-regulates CD28 on T cells and CD86 on monocytes and Kupffer cells
HBV Serological markers and indications
HBsAg, antiHBs and anti-HBc informs on the disease status in acute/chronic hepatitis
- HBsAg indicates ongoing infection
- Anti-HBs indicates immunity, functional recovery
- Anti-HBc indicates previous exposure
HBeAg and HBV DNA informs on the disease activity of hepatitis
- HBeAg indicates active replication
- HBV DNA indicates viral load
In vaccinated individuals, anti-HBs is present but not anti-HBc (not included in vaccines)
Differentiate Combinations of HBsAg, Anti-HBs, Anti-HBc +/- results
Titer of different HBV serological markers with time
HBV serological markers to ddx chronic flares vs acute infection
Function of HBeAg
HBeAg indicates active replication
□ Acute infection:
→ Only present transiently at onset of illness
→ Followed by rapid seroconversion (before s-seroconversion)
□ Chronic infection: useful to inform on the phase of chronic hepatitis B infection
→ HBeAg seroconversion indicates immune clearance phase
→ Exception: HBeAg-negative chronic hepatitis in pre-core and core promoter mutants
(with high levels of HBV-DNA and liver damage despite HBeAg-)
Function of Anti-HBc
Anti-HBc indicates previous exposure
□ Acute infection:
→ Appears early during symptomatic phase
→ Initially IgM, later converted into IgG
□ Chronic infection:
→ Usually present
→ May be lost in late infection w/ HBV DNA integration into host genome
□ Presence of IgM anti-HBc indicates
→ Acute infection
→ Chronic reactivation of hepatitis B (with lower titres)
□ In vaccinated individuals, anti-HBs is present but not for anti-HBc
Functions of Anti-HBs
Anti-HBs indicates immunity
□ Acute infection:
→ Appears ~3-6mo after acute infection
→ Usually persists for many years or even permanently but may become undetectable
□ Chronic infection:
→ Seroconversion rarely occurs (~10%)
→ Presence indicates “functional recovery”
Treatment of acute HBV infection
Supportive (eg. avoid hepatotoxins)
Antivirals if severe or prolonged
- Tenofovir
- Aim for 2 log drop in HBV DNA in 2 weeks
3 phases of chronic Hep B
Causes of flares during chronic Hep B
HBV-related:
Spontaneous reactivation: with ↑IgM anti-HBc
- E-seroconversion in viral clearance phase, i.e. HBeAg+ → anti-HBe Ab+
- E-sero-reversion in late/residual phase, i.e. anti-HBe+ → HBeAg+
- Gaining resistance
- Steroid withdrawal
Superinfection by other viral agents, esp HAV, HEV, HDV
Drug-induced hepatic injury
Role of Anti-HBe
Presence of Anti-HBe = reach late INACTIVE phase, typically no more disease progression
Exceptions:
- Early HBV infection during birth/ toddler with life-long inflammatory destruction, leading to cirrhosis and HCC even with Anti-HBe +ve
- HBeAg-negative chronic hepatitis: pre-core or core promoter mutation lowers HBeAg production»_space; FALSE e-seroconversion, continued damage to liver even with Anti-HBe +ve
Complications of Chronic Hep B
Cirrhosis and HCC
RF for higher risk of cirrhosis: □ ↑age □ Hepatic decompensation □ Repeated severe acute exacerbation □ HBV reactivation with HBeAg seroreversion
HBV serological markers to monitor Chronic Hep B progression
□ Disease status: HBsAg, anti-HBs, anti-HBc
□ Disease activity: HBeAg, anti-HBe, HBV DNA
□ Co-infection: anti-HCV, anti-HDV, ± anti-HIV
Panel of investigations for chronic Hep B
Serological markers of HBV
LFT: ALT, AST Serum albumin (subacute and chronic liver disease) Bilirubin (high in late cirrhosis) PT/ INR
Degree of cirrhosis:
CBC with platelet (platelet depletion by splenomegaly)
Reversed A:G ratio: B cell activation, high globulin
Biochemical markers of cirrhosis, eg. AST:PLT ratio index (APRI), FibroTest
USG elastography: >7kPa
USG/CT abdomen features
Liver biopsy: gold standard, METAVIR score
Indicators to start Chronic Hep B treatment
Immune-active hepatitis:
→ Active disease: ALT ≥2 ULN
→ Active viral replication: HBV DNA >20000 (HBeAg+) or >2000IU/mL (HBeAg-)
Presence of cirrhosis WITH detectable HBV DNA
Before Use of immunosuppressants, eg. steroids, rituximab
Pregnant with high HBV DNA
Targets for endpoint of chronic Hep B treatment
HBsAg loss
Undetectable HBV DNA on PCR
ALT normalization: ideally <1/2 ULN
+/- HBeAg seroconversion for HBeAg+ patients (remember some have HBeAg- chronic hepatitis)
Prevention of HBV infection
Patient groups advised for vaccination
□ Care in handling infected material (healthcare worker)
□ Passive immunization by hepatitis B immune globulin (HBIG)
- for needle prick by HBV+ve blood
- For babies from HBV+ve mother
- For parenteral/ mucosal contact with HBV positive people e.g. sex
□ Active immunization by hepatitis B vaccine
- subunit vaccine, recombinant
- Combined with HBIG for neonates from HBV+ve mothers
- For all newborns and young children under 5
More high risk groups:
- Medical and paramedical personnel
- Family members of HBsAg carrier
- I/C subjects, eg. transplant patients
- Promiscuous persons
- Drug addicts
Prevention of Vertical Transmission of HBV
For infants, give 1 dose of HBIG + HBV vaccine
For mother, give nucleoside/nucleotide analogue
Start in last trimester, Stop 3mo after delivery
List all Tx options for chronic Hep B
Interferon-α (+/- Steroid Withdrawal therapy)
Nucleoside and Nucleotide Analogues
Nucleoside:
→ L-nucleoside: lamivudine
→ Cyclopentane: entecavir (first-line)
Nucleotide:
- Tenofovir disoproxil fumurate (TDF)
- Tenofovir alafenamide (TAF) (first-line)
Interferon-α for chronic Hep B
- MoA
- Dosing
- S/E
- C/I
MoA: Immunomodulation
→ Protects uninfected hepatocytes from virus entry and replication
→ ↑display of both viral antigen (HBsAg) and HLA-1 on infected hepatocytes
→ Accelerates specific cytotoxic T-cell response
→ ↑non-specific NK cell activity
→ Inhibits Ab production, eg. anti-HBc
Regimen:
□ Conventional: 3×/w for 16-24w subcutaneously
□ Pegylated: 1×/w for 48w subcutaneously
S/E: □ Flu syndrome □ GI upset: nausea, diarrhoea □ Psychological: depression (not severe), neuropsychiatric complications in HIV patients □ Haematological: Marrow suppression □ Liver: hepatotoxicity
C/I: PEG-IFN is rarely used due to poor tolerance. Also C/I in cirrhosis
Pros and Cons of IFN treatment
Steroid use on Chronic Hep B
MoA
Use?
Effect of steroid on chronic HB carrier:
□ During steroid therapy,
→ ↑viral replication (due to glucocorticoid response element) → ↑HBV DNA
□ Following steroid withdrawal at ~4-10w
→ Immune rebound occurs with ↑cytotoxic suppressor T-cells
→ Results in ↑immune attack on liver → ↓HBV DNA, ↑AST/ALT
Using the rebound immunity to enhance effect of IFN-a
Potentially dangerous and fatal in decompensated liver disease, or abnormal immunity
Nucleoside and Nucleotide Analogues
MoA
Mechanism: block viral replication
□ ↓DNA synthesis by chain termination of (-) strand HBV DNA
□ Inhibit reverse transcription
↓further infection of healthy tissues
HBV resistance mechanism against Nucleoside and Nucleotide Analogues
YMDD mutation***
1st line drugs for Tx-naïve chronic Hep B patients
Entecavir (ETV)
Tenofovir alafenamide (TAF)
Side effects of Nucleotide analogues
Proximal tubulopathy, leading to hypoPO4, osteomalacia
Increase bone turnover
Side effects of Nucleotide analogues
TAF vs TDF, which is better
Tenofovir disoproxil fumarate (TDF) and Tenofovir aladenamide (TAF)
S/E
- Proximal tubulopathy, leading to hypoPO4, osteomalacia
- Increase bone turnover
TAF advantages (first-line)
- Less renal damage, less bone turnover effect
- More stable in plasma, higher deliver to hepatocytes
- Better ALT normalization
TDF advantages:
- Better vs WT and lamivudine resistant HBV
- Can lower HBV DNA levels cf TAF
