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1. Chronic hepatitis
•Hepatic inflammation and necrosis for
more than 6 months
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1

2. Chronic HBV infection
• Hepatitis B surface antigenemia
for six months or more.
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3. Risk of chronic
infection
• Related to two major factors
• Age at which infection is acquired
• Immune state of the host.
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4. Piecemeal
necrosis
• Also called interface
hepatitis
• disruption of the limiting
plate of periportal
hepatocytes by
inflammatory cells.
• Progression to cirrhosis is
not common.
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5. Bridging necrosis
•may progress
to cirrhosis.
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6. Classification of
chronic hepatitis
• depends on three
features.
• (1) cause
• (2) grade ( histologic
activity)
• (3) stage ( degree of
progression).
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7. Grading of chronic
hepatitis
• Portal tract inflammation
0 = none.
4 = severe limiting plate
necrosis
• Hepatic lobule inflammation
0 = none
4 = bridging necrosis
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8. Staging
• based on the degree of fibrosis.
•
•
•
•
0 - no fibrosis.
1 - mild fibrosis.
2 - moderate fibrosis.
3 - severe fibrosis, including
bridging fibrosis.
• 4 – cirrhosis.
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9. Piecemeal necrosis
• Also called interface
hepatitis
• erosion of the limiting
plate of hepatocytes
surrounding the portal
triads.
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10. Chronic active
hepatitis
•
•
•
•
Piecemeal necrosis is always
present
dense mononuclear infiltrate of the
portal tracts.
Portal inflammation extends
beyond the limiting plate into the
hepatic parenchyma.
destruction of the hepatocytes at
the periphery of the lobule.
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11. Bridging hepatic
necrosis
• severe and progressive
form of chronic active
hepatitis.
• Collapse of the reticulin
network is the hallmark
of bridging necrosis.
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12. Chronic persistent
hepatitis
•
•
•
•
Mononuclear inflammatory
infiltrate is contained within portal
tracts.
no extension of the
necroinflammatory process into the
liver lobule.
no piecemeal or bridging necrosis
Cirrhosis does not develop.
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13. Chronic active hepatitis
•
•
•
•
Piecemeal necrosis is always
present
dense mononuclear infiltrate of the
portal tracts.
Portal inflammation extends
beyond the limiting plate into the
hepatic parenchyma.
destruction of the hepatocytes at
the periphery of the lobule.
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14. Chronic active hepatitis
• Bridging hepatic necrosis is
a severe and progressive
form of chronic active
hepatitis.
• Collapse of the reticulin
network is the hallmark of
bridging necrosis.
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15. Fibrosis
• common and progressive.
• continuing hepatic necrosis.
• leads to cirrhosis, liver
failure, and death.
• Physical findings of chronic
liver disease and portal
hypertension are common
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16. Histologic hallmarks of
chronic active hepatitis
1. Portal and periportal
infiltrate of
lymphocytes, plasma
cells, and macrophages
2. piecemeal necrosis
3. Bridging necrosis
4. may progress to cirrhosis.
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17. Ground glass
hepatocytes
• Seen in Chronic
Hepatitis B
• best seen by aldehyde
fuschin or orcein
stain.
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18. neonatally acquired
infection
• risk of chronicity is very high
(up to 90%).
• neonates have an immature
immune system.
• transplacental passage of viral
proteins.
• fetus becomes tolerant to HBV
in utero.
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19. Risk of chronicity after
acute HBV infection
• about 1%.
• Most cases of chronic hepatitis
B in adults occur in patients
who never had a clinically
apparent acute viral hepatitis.
• Chronic disease only rarely
present as nonresolution of
acute hepatitis B.
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20. Risk of chronicity
increased in
• chronic hemodialysis
• exogenous
immunosuppression
following solid organ
transplantation
• cancer chemotherapy
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21. concomitant HIV
infection.
•20% – 30% remain
HBsAg positive
after acute
infection.
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22. Children < 6 years
•significant risk of
chronic infection
(approximately
30%).
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23. Lysis of liver cells depends on
the host immune response.
• good immune response clears
the virus (acute hepatitis).
• poor immune response - healthy
carrier state
• slightly better response insufficient to clear the virus
but cause continuing necrosis.
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24. very aggressive immune
response
• Fulminant hepatitis
• HBV infected hepatocytes are
destroyed
• HBV is completely cleared from
the body
• High mortality
• no future risk of cirrhosis in
survivors.
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25. “healthy carriers”
• normal serum
aminotransferase
• normal or near-normal liver
histologic findings
• no symptoms
• immunologically tolerant of the
virus
• prognosis is excellent
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26. Symptom – Chronic
hepatitis
• Fatigue - common symptom.
• Persistent or intermittent
jaundice is a common feature in
severe or advanced cases.
• Exacerbations occur
spontaneously.
• associated with evidence of
virologic reactivation.
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27. end-stage chronic
hepatitis.
• Complications of cirrhosis
1.
2.
3.
4.
5.
Ascites
Bleeding varices
Hepatic encephalopathy
Coagulopathy
Hypersplenism.
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28. extrahepatic complications of
chronic HBV
•
•
•
•
Arthralgias - due to deposition of
circulating hepatitis B antigenantibody immune complexes
Purpuric cutaneous lesions - due to
leukocytoclastic vasculitis
Glomerulonephritis - Immunecomplex
PAN - result of generalized
vasculitis
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29. Hyperglobulinemia and
circulating autoantibodies
• uncommon in
chronic hepatitis B.
• This is in contrast to
autoimmune
hepatitis.
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30. ALT
• more elevated than aspartate
aminotransferase ( as in acute
viral hepatitis B)
• Once cirrhosis is
established, AST tends to
exceed ALT.
• Alkaline phosphatase - normal
or only marginally elevated.
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31. IFN
• All human cells can
synthesize IFN-a or -b in
response to viral infection.
• IFN-g is produced mainly by
NK cells and by T
lymphocytes responding to
IL-12.
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32. IFN response
• induced by the presence of
double-strand viral RNA, which
can be made by both RNA and
DNA viruses.
• IFN receptors signal through
receptor-associated JAK
kinases and "STAT" proteins.
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33. IFN - 3 antiviral
effects
Induction of
1.oligo(A) synthetases
2.PKR.
3.Mx proteins.
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34. Induction of oligo(A)
synthetases
• result in the
activation of RNAse
L.
• RNAse L degrades
single-strand RNA.
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35. Induction of PKR
•
•
•
•
•
PKR negatively regulates the
translational initiation factor eIF2a.
This stops protein synthesis in the
infected cell.
IFN effects are not virus specific.
Infected-cell RNA and protein
synthesis are globally inhibited.
IFN may contribute to the death of
the infected cell.
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36. Induction of Mx
proteins
• Mx proteins are
particularly important
in inhibiting influenza
virus and vesicular
stomatitis virus
replication.
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37. Lamivudine
• directly block HBV replication
• converted intracellularly
into its active
triphosphorylated form.
• potent inhibitor of the HBV
reverse transcriptase.
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38. Lamivudine 5′triphosphate
• causes chain termination of the
elongating nucleic acid strand.
• poor substrate for both nuclear
and mitochondrial DNA
polymerases.
• Therefore, lamivudine has a
good safety profile.
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39. HIV and HBV
• Lamivudine inhibits reverse
transcriptase activity of both
HIV and HBV.
• Anti-Hbe seroconversion occur
in up to 20 %.
• Histological improvement is
seen in up to 50%.
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40. Interferon and lamivudine
are equally effective.
• Interferon requires
requires subcutaneous
injections for 4 months.
• Interferon is not
tolerated well.
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41. Lamivudine is preferred
as first-line therapy.
• Side effects of
lamivudine are
negligible.
• Lamivudine is given
orally
• very well tolerated.
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42. Resistance is the major
problem
• HBV has a high rate of
viral turnover.
• HBV reverse
transcriptase very
much error prone
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43. Adefovir
• inhibitor of the viral
polymerase.
• inhibits the replication
of lamivudine-resistant
HBV mutants.
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44. HBV - NEW ANTIVIRAL
DRUGS
• Tenofovir
• adenine nucleotide analogue
• has activity against the HBV
polymerase.
• Entecavir
•
•
•
•
guanosine analogue
highly selective for the HBV polymerase
no activity against HIV.
active against lamivudine-resistant HBV.
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45. L-deoxythymidine
• thymidine analogue
• selectively inhibits the
HBV polymerase
• active against
lamivudine-resistant
virus.
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46. Emtricitabine and
Clevudine
• nucleoside analogues
• not reliably active
against all lamivudineresistant variants.
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47. HCV
• major cause of
• chronic hepatitis
• Cirrhosis
• HCC
• Most common indication for
liver transplantation.
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48. chronic infection
• HCV produce chronic
infection in 90 % of
infected persons despite
a vigorous humoral and
cellular host immune
response.
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49. 2 different cellular
receptors for HCV
1. low-density lipoproteins
2. CD81
• cell surface protein called
tetraspanin
• expressed on most human
cells, except red blood cells
and platelets.
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50. The two main risk
factors.
1.Blood transfusion
from unscreened
donors
2.injection drug use
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51. Liver histology
• Best prognostic
indicator in
chronic
hepatitis C
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52. excellent
prognosis.
•Mild
necrosis, inflam
mation, and
limited fibrosis
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53. septal or bridging
fibrosis
•When
present, progressi
on to cirrhosis is
highly likely over
20 years.
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54. Long-term prognosis
• for chronic hepatitis C is
good.
• 60% = asymptomatic.
• very slowly progressive, if at
all, in the vast majority
• 25 % = progress to endstage cirrhosis.
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55. not predictive of
prognosis.
• Level of HCV RNA
• Severity of acute hepatitis
• level of aminotransferase
activity
• presence or absence of
jaundice
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56. Hepatic iron
• Progression is
more likely when
hepatic iron is
increased.
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57. Duration of
infection
•Progression
is more
likely .
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58. Factors that accelerate
clinical progression
• alcohol intake - pronounced
effect
• coinfection with HIV-1 or
HBV
• male sex
• older age at infection.
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59. Fatigue
• Most common
symptom of
chronic
hepatitis C
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60. Other nonspecific
symptoms
• Depression
• Nausea
• Anorexia
• Abdominal discomfort
• Difficulty with
concentration.
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61. chronic hepatitis in 85%
• majority of these will have
elevated or fluctuating
serum ALT levels
• one third has persistently
normal ALT values, despite
continued liver injury and
detectable viremia.
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62. HCV infection is selflimiting in only 15%.
• In these patients HCV
RNA in serum becomes
undetectable and ALT
levels return to normal.
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63. Jaundice
• rarely seen in chronic HCV
infection until hepatic
decompensation has occurred.
• Acute infection is only rarely
seen
• vast majority of patients have
no clinical symptoms.
• Fulminant hepatitis is rare.
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64. HCV RNA
• appears in the blood
within 2 weeks of
exposure
• followed by an increase
in serum
aminotransferase levels
several weeks later.
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65. Essential mixed
cryoglobulinemia
• most common
immune-complex
mediated
extrahepatic
complication.
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66. Cryoglobulins
•found in 50% of
patients infected
with HCV.
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67. Clinical symptoms
•
•
•
•
•
•
•
develop in only 25%
Arthritis
Purpura
Raynaud’s phenomenon
Vasculitis
Peripheral neuropathies
Glomerulonephritis.
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68. Extrahepatic
manifestations
1. membranoproliferative
glomerulonephritis
2. porphyria cutanea tarda
3. leukocytoclastic
vasculitis
4. focal lymphocytic
sialadenitis
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69. Extrahepatic
manifestations
5.Mooren corneal ulcers
6.lichen planus
7.rheumatoid arthritis
8.non-Hodgkin’s
lymphoma
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70. Membranoproliferative
glomerulonephritis
• frequent extrahepatic
disease
• Most affected patients
also have essential
mixed
cryoglobulinemia.
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71. present with
•
•
•
•
nephrotic syndrome
non–nephrotic-range proteinuria
renal insufficiency.
Hypocomplementemia is
frequent
• Positive rheumatoid factor
common
• 10% - progress to end-stage
renal failure
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72. PCR
• confirmatory test
of choice.
• to monitor the
effects of therapy.
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73. Serologic assays
• used for screening
• indicates exposure to the virus
• Does not differente between
acute, chronic, and resolved
infection.
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74. RIBA test
• two serologic tests
• enzyme immunoassay (EIA)
• recombinant immunoblot
assay (RIBA).
• sensitivity of RIBA test is
lower than that of EIAs, but
their specificity is superior.
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75. Liver biopsy
•gold standard for
determining the
activity of HCVrelated liver
disease.
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76. Histologic staging
• only reliable predictor of
prognosis and the
likelihood of disease
progression.
• Liver biopsy is not
mandatory before the
initiation of treatment.
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77. Pegylated
interferons
• interferon bound to
polyethylene glycol.
• increases the half-life
• reduces the volume of
distribution.
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78. Interferon indication
• detectable levels of HCV
RNA
• who have persistently
elevated alanine
aminotransferase levels
• and a liver biopsy showing
at least moderate
fibrosis, necrosis and
inflammation.
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79. excellent prognosis
without therapy
• persistently normal alanine
aminotransferase levels
• and only minimal histologic
evidence of necrotic and
inflammatory changes or
changes.
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80. Pegylated
interferons
• allows once-weekly
dosing.
• sustain more uniform
plasma levels.
• Therefore, there is
enhanced viral
suppression.
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81. Ribavirin
• causes hemolysis.
• Fall in hemoglobin of 3 gm
occur in 5 to 10%.
• small percentage gets severe
hemolysis.
• close monitoring of blood
counts is important.
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82. Contraindication
• history of myocardial
infarction or cardiac
arrhythmia
• Because of the potential
to cause a sudden fall in
hemoglobin
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83. half-life
• long cumulative half-life.
• excreted by the kidney
• should not be used by patients
with renal insufficiency
• severe side
effects, particularly
hemolysis, can occur
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84. Teratogenic
• Avoid pregnancy during
therapy and for 6 months after
cessation of treatment.
• Use contraception during
therapy.
• pregnancy test is needed
before initiating ribavirin
therapy in women.
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85. Vaccination
• HCV-infected patients are
vaccinated against HAV and
HBV.
• high risk of severe liver
disease if superinfection
with these viruses occurs.
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86. HCV - prevention
•no effective vaccine
•no effective
postexposure
prophylaxis.
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87. pregnancy
• not contraindicated
• low rate of vertical
transmission
• Breast-feeding is not
contraindicated.
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