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MBBS IV - Junior Clerkship WCS > JC57 - Hepatitis B > Flashcards

JC57 - Hepatitis B Flashcards

1
Q

Standard workup tests for hepatitis

A 
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
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2
Q

Structure and genome of HBV

A

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
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3
Q

HBV proteins that indicate active infection

A

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

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4
Q
A
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5
Q

Pathogenesis of HBV infection

A

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

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6
Q

Transmission of HBV

A

Vertical transmission at birth
→ Typically mother-to-child

Blood transfusion/ contaminated blood products

Close contact as toddlers

Needles
→ IVDU, acupuncture, tattoo

Sexual contact

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7
Q

Reason for higher risk of chronic HBV infection in neonates

A

1) Immature immunity&raquo_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
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8
Q

HBV Serological markers and indications

A

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)

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9
Q

Differentiate Combinations of HBsAg, Anti-HBs, Anti-HBc +/- results

A
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10
Q

Titer of different HBV serological markers with time

A
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11
Q

HBV serological markers to ddx chronic flares vs acute infection

A
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12
Q

Function of HBeAg

A

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-)

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13
Q

Function of Anti-HBc

A

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

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14
Q

Functions of Anti-HBs

A

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”

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15
Q

Treatment of acute HBV infection

A

Supportive (eg. avoid hepatotoxins)

Antivirals if severe or prolonged

  • Tenofovir
  • Aim for 2 log drop in HBV DNA in 2 weeks
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16
Q

3 phases of chronic Hep B

A
17
Q

Causes of flares during chronic Hep B

A

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

18
Q

Role of Anti-HBe

A

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&raquo_space; FALSE e-seroconversion, continued damage to liver even with Anti-HBe +ve
19
Q

Complications of Chronic Hep B

A

Cirrhosis and HCC

RF for higher risk of cirrhosis: 
□ ↑age
□ Hepatic decompensation
□ Repeated severe acute exacerbation
□ HBV reactivation with HBeAg seroreversion
20
Q

HBV serological markers to monitor Chronic Hep B progression

A

□ Disease status: HBsAg, anti-HBs, anti-HBc
□ Disease activity: HBeAg, anti-HBe, HBV DNA
□ Co-infection: anti-HCV, anti-HDV, ± anti-HIV

21
Q

Panel of investigations for chronic Hep B

A

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

22
Q

Indicators to start Chronic Hep B treatment

A

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

23
Q

Targets for endpoint of chronic Hep B treatment

A

HBsAg loss

Undetectable HBV DNA on PCR

ALT normalization: ideally <1/2 ULN

+/- HBeAg seroconversion for HBeAg+ patients (remember some have HBeAg- chronic hepatitis)

24
Q

Prevention of HBV infection

Patient groups advised for vaccination

A

□ 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
25
Q

Prevention of Vertical Transmission of HBV

A

For infants, give 1 dose of HBIG + HBV vaccine

For mother, give nucleoside/nucleotide analogue
Start in last trimester, Stop 3mo after delivery

26
Q

List all Tx options for chronic Hep B

A

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)
27
Q

Interferon-α for chronic Hep B

  • MoA
  • Dosing
  • S/E
  • C/I
A

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

28
Q

Pros and Cons of IFN treatment

A
29
Q

Steroid use on Chronic Hep B

MoA
Use?

A

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

30
Q

Nucleoside and Nucleotide Analogues

MoA

A

Mechanism: block viral replication
□ ↓DNA synthesis by chain termination of (-) strand HBV DNA
□ Inhibit reverse transcription

↓further infection of healthy tissues

31
Q

HBV resistance mechanism against Nucleoside and Nucleotide Analogues

A

YMDD mutation***

32
Q

1st line drugs for Tx-naïve chronic Hep B patients

A

Entecavir (ETV)

Tenofovir alafenamide (TAF)

33
Q

Side effects of Nucleotide analogues

A

Proximal tubulopathy, leading to hypoPO4, osteomalacia

Increase bone turnover

34
Q

Side effects of Nucleotide analogues

TAF vs TDF, which is better

A

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
35
Q
A

MBBS IV - Junior Clerkship WCS (131 decks)

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