Chronic hepatitis B

1

Kar clinical profile, grading investigations
in hepatitis B

• Chronic hepatitis B
• HBsAg in serum gt 6 mth
• Predisposing Host factors1
• infection in the neonatal period
• subclinical acute infection
• presence of immunologic defects
• Age most important determinant2. Chronic
  infection in
• 90 of infants infected at birth,
• 25 to 50 children infected at 1 to 5 years,
• 5 to 10 infected as older children or adults
• 1. Koff RS. Semin Liver Dis 1981133-43 Alter
  Mj et al. 2. Gastroenterol Clin North Am
  199423437-55

2
Kar clinical profile, grading investigations
in hepatitis B

• Chronic hepatitis B Clinical manifestations
• History of acute hepatitis
• 30-50 in low/intermediate prevalence areas1
• Minority of patients in high prevalence areas
  (predominantly perinatal infection)
• Chronic hepatitis B
• Asymptomatic unless decompensated
• Nonspecific symptoms such as fatigue
• Presence and severity of fatigue correlate poorly
  with the severity of disease.2

• Fattovich G et al. Gut 199132294-8
• Hoffinagle JH. N Engl J med 1990323337-9

3
Kar clinical profile, grading investigations
in hepatitis B

• Chronic hepatitis B clinical manifestations
• Intermitent exacerbations - asymptomatic/acute
  hepatitis/hepatic failure
• Physical examination
• Normal or stigmata of chronic liver disease
• Decompensated cirrhosis Jaundice, splenomegaly,
  ascites, peripheral edema and encephalopathy
• Signs and symptoms more often in
• older patients1
• advanced histologic disease2
• 1. Schalm SW et al. Gut 197617781-6 2.
  Weissberg Jl et al. Ann Intern Med 1984101613-6

4
Kar clinical profile, grading investigations
in hepatitis B

• Chronic hepatitis extrahepatic manifestations
• Occur in 10 - 20
• Mediated by circulating immune complexes
• Polyarteritis nodosa1
• develops in 1 with chronic HBV infection
• 20 to 30 with PAN have HBsAg
• Glomerular disease nephrotic range proteinuria
• membranous nephropathy
• membranoproliferative glomerulonephritis
• Guillevin L, Lhote F, et al. PAN related to HBV.
  Medicine 199574238-53

5
Kar clinical profile, grading investigations
in hepatitis B

• Chronic hepatitis B
• Three potentially successive phases
• immunotolerant,
• immunoactive, and
• low or non-replicative

6
Kar clinical profile, grading investigations
in hepatitis B

• Three potentially successive phases
  immunotolerant, immunoactive, and low or
  non-replicative
• Immunotolerant phase
• Typically seen in perinatal and neonatal
  infection
• Can last from 10 - 30 years
• Serum HBsAg and HBeAg are detectable
• Serum HBV-DNA levels are high
• Serum aminotransferases normal or minimally
  elevated
• Liver histology shows minimal inflammation

7
Kar clinical profile, grading investigations
in hepatitis B

• Immunoactive phase
• Symptoms appear
• Flares of aminotransferases observed
• Serum HBV-DNA levels decrease
• Repeated flares common - associated with early
  progression to cirrhosis
• Associated with active liver inflammation
• May be followed by HBeAg - Anti HBe
  seroconversion - often with acute hepatitis like
  illness

8
Kar clinical profile, grading investigations
in hepatitis B

• Non-replicative phase
• Follows HBeAg - Anti HBe seroconversion
• HBV replication at very low levels
• Also termed inactive carrier state
• Transaminases tend to normalize
• May lead to resolution of HBV infection with
  HBsAg becoming undetectable and detectable
  anti-HBs
• Selection of mutant HBV - negative HBeAg
• May develop higher levels of HBV replication and
  progress to HBeAg negative chronic hepatitis.

9
Kar clinical profile, grading investigations
in hepatitis B

• Clinical manifestations
• Annual rate of progression to cirrhosis1
• 2.0 5.5 in HBeAg ve pts
• 810 in HBeAg -ve pts with chronic hepatitis
• Usual age at the time of diagnosis of cirrhosis
  is 4152 years1
• Predictors for progression to cirrhosis1
• older age
• serum HBV DNA detectable by non-PCR-based methods
• infection with HCV, HDV or HIV
• alcohol abuse
• recurrent severe acute exacerbation with bridging
  necrosis
• fibrosis stage at presentation
• severity of necroinflammation
• role of HBV genotype
• EASL Int Consensus Conf on Hepatitis. J Hepatol
  200338533-40

10
Kar clinical profile, grading investigations
in hepatitis B

• Laboratory investigations
• Serum aminotransferases
• HBV antigens
• HBsAg and HBeAg
• HBV antibodies
• anti-HBs, anti-HBc- IgG and IgM and anti-HBe
• Serum HBV DNA
• DNA hybridisation, qualitatively or
  quantitatively
• PCR based assays
• HBV genotyping

11
Kar clinical profile, grading investigations
in hepatitis B

• Key issues in laboratory investigations
• Standardisation of HBV DNA qualitative assays
• Clinical significance of low serum HBV DNA levels
  
• Distinction between inactive carrier state and
  HBeAg ve chronic hepatitis
• Surrogate tests to assess disease activity/viral
  replication quantification of IgM Anti-HBc or
  HBeAg levels needs standardisation
• HBV DNA levels associated with clinically
  significant virologic response should be
  determined

12
Chronic hepatitis B
Kar clinical profile, grading investigations
in hepatitis B
13
Interpretation of lab investigations
Kar clinical profile, grading investigations
in hepatitis B
14
Interpretation of lab investigations
Kar clinical profile, grading investigations
in hepatitis B
15
Kar clinical profile, grading investigations
in hepatitis B

• Liver biopsy
• Grading based on
• Periportal necrosis
• Interlobular necrosis
• Portal inflammation
• Staging based on
• Fibrosis
• Histological activity index (Knodell-Ishak score)

16
KNODELL-ISHAK SCORING SYSTEM
17
Kar clinical profile, grading investigations
in hepatitis B

• Liver biopsy
• Liver biopsy accepted an integral part of
  diagnosis and management of HBV
• Used for1
• confirming diagnosis of chronic hepatitis B,
• identifying other causes of liver diseases, and
• grading severity of necroinflammation and stage
  of fibrosis
• EASL International Consensus Conference on
  Hepatitis. J Hepatol 200338533-40

18
Kar clinical profile, grading investigations
in hepatitis B

• Liver biopsy
• Doubtful role of repeated liver biopsy in
  patients showing a sustained biochemical and
  virological response1
• Decision to repeat liver biopsy made on a case by
  case basis
• Liver biopsy size strongly influences grading and
  staging of chronic viral hepatitis2
• 1. EASL International Consensus Conference on
  Hepatitis. J Hepatol 200338533-40 2. Impact of
  liver biopsy size on histological evaluation of
  chronic viral hepatitis the smaller the sample,
  the milder the disease. Colloredo G, Guido M,
  Sonzogni A, Leandro G. J Hepatol. 2003
  Aug39(2)239-44

19
Kar clinical profile, grading investigations
in hepatitis B

• Limitations of liver biopsy
• Inter and intra-observer variation in
  grading/staging
• Degree of fibrosis does not correlate with
  disease activity
• Size of liver tissue
• Smaller tissue - underestimation of grade/stage
• 1.5 cms long, containing 4-6 portal tracts
  considered acceptable