Download In acute hepatitis - Sun Yat

Viral hepatitis
Wei-Min Ke
Department of Infectious Diseases
Sun Yat-sen University
Mar.13, 2009, Friday, Session 8~9
Classroom 503
Mar.20, 2008, Friday, Session 8~9
Classroom 503
1
• Ⅰ. Outline
• ⒈Definition
•
Viral hepatitis is one group infectious
diseases of liver lesions
•
caused by several hepatitis virus,
•
which includes hepatitis viruses A, B, C, D,
and E.
2
⒉ Clinical features of viral hepatitis
The manifestations of viral hepatitis are similar,
include fatigue, anorexia, hepatomegaly and
abnormal liver functions;
jaundice only in some patients.
3
Fatigue
Anorexia
Hepatomegaly
Jaundice
Hepatitis A and E only are responsible to
acute hepatitis,
Acute hepatitis
and mainly transmitted by fecal-oral route.
Fecal-oral route
4
But hepatitis B, C and D can be responsible to
acute or chronic hepatitis, cirrhosis and
hepatocellular carcinoma (HCC).
Acute hepatits
Chronic hepatitis
Cirrhosis
HCC
5
•
•
Hepatitis B, C and D are often transmitted by
parenteral transmission,
•
such as transfusion, injection and maternalinfant .
•Transfusion
Injection
6
Maternal-infant
Ⅱ. Etiology
The pathogens of viral hepatitis only are hepatitis
viruses included hepatitis A, B, C, D, and E.
From now on pathogenesis of hepatitis G,
transfusion transmitted virus (TTV), Sen virus (SENV)
has not been demonstrated to be causative of the liver
diseases.
7
• ⒈ Virology of Hepatitis A
• Hepatitis A virus (HAV) is small RNA virus.
•
•
•
•
The viral genome is about 7.5 kb in length
and has a single large open-reading frame
that encodes a polyprotein with structural and
nonstructural components.
•
Hepatitis A virus
particles
8
•
•
•
•
The virus replicates largely in the liver
and is assembled in the hepatocyte cytoplasm
as a 27-32 nm particle
with a single RNA genome
and an outer capsid protein (HAV Ag).
Hepatitis A virus (HAV) found in feces is helpful
to confirm the HAV present infection and
infectivity.
But hepatitis A virus infection is no chronic
carrier state.
9
• ⒉ Virology of Hepatitis B
•
Hepatitis B virus (HBV) is a double-shelled,
enveloped DNA virus, 42 nm in diameter.
•
Hepatitis B virus
10
•
•
•
•
•
•
•
The viral genome consists of partially doublestranded DNA, 3.2 kb in length,
and possesses four partially overlapping
open-reading frame
that encode the genes for:
①hepatitis B surface antigen ( S gene, HBsAg),
②hepatitis B core antigen (C gene,HBcAg),
③the HBV polymerase (P gene),
④and a small protein that seems to have
transactivating function (X gene, HBxAg).
11
•
•
•
The S gene has three start codons and is
capable of producing three different sizes of
HBsAg (small, medium, and large S).
The C gene has two start codons and can
produce two antigenically distinct products:
•
the HBcAg retained in hepatocytes until
assembled as core particles.
•
HBeAg secreted into the serum as a small
soluble protein.
12
•
•
•
Hepatitis B virus (HBV) consists of three
antigen and antibody systems.
HBV replicates in hepatocytes, appears in
blood and other body fluids, and spreads
mainly by blood.
13
• ⒊ Virology of Hepatitis C
• ①HCV is an RNA virus that belongs to the
family Flaviviridae that includes Dengue fever
virus and yellow fever virus.
HCV originally was identified by molecular
clone techniques in 1989.
HCV circulates as a double-shelled enveloped
virus, 30 to 60 nm in diameter.
Hepatitis C virus
14
The genome is a positively
stranded RNA molecule,
which is about 9.4 kb in length,
contains a single, large openreading frame,
encodes a large polyprotein,
post-translationally modified
into three structural and several
nonstructural polypeptides.
The structural proteins include two highly
variable envelope antigens (E1 and E2) and a
relatively conserved nucleocapsid protein (C).
15
• ⒋ Virology of Hepatitis D
• The hepatitis delta virus is a unique RNA
virus that requires HBV for replication.
•
•
The viral genome is a short, 1.7 kb circular
single-stranded molecule of RNA that has a
single open-reading frame.
Hepatitis D virus
16
• ⒌ Virology of Hepatitis E
• Hepatitis E virus (HEV) is a small nonenveloped,
single-stranded RNA virus.
The viral genome is 7.2~7.6 kb in length and
encodes three open-reading frames,
the first (ORF1) for the nonstructural proteins
responsible for viral replication,
the second (ORF2) for the capsid protein (HEV
antigen),
and the third (ORF3) for a short protein of
unknown function.
Hepatitis E virus
17
Ⅲ. Epidemiology
China is the high prevalent region of viral
hepatitis and anti-HAV-IgG positive rate is
about 80%.
There are 350 million of HBsAg carriers
around the world, about 120 million in our
country.
The current infections of HCV are 170
million around the world, about 30 million in
our country.
Prevalent rates of hepatitis D and E in
population are about 1% and 17% in our
country, respectively.
18
⒈ Hepatitis A
⑴ Sources of infection in hepatitis A
•
•
•
•
•
Hepatitis A is transmitted in acute phase of
the disease.
Fecal shedding of virus occurs before 2
weeks of the onset of disease and it can
persist to 30 days after onset of the disease.
There is no evidence for the existence of a
chronic form hepatitis A, and a carrier state.
19
• ⑵ Route of transmission in hepatitis A
•
•
Investigation of the source of hepatitis A cases
reveals that most are due to direct person-toperson exposure and,
•
to lesser extent, to direct fecal contamination
of food or water.
•
•
20
•
•
•
•
Consumption of shellfish from contaminated
waterways is a well-known but uncommon source
of hepatitis A.
310,000 of patients with hepatitis A were
reported in Shanhai city in 1988 due to
contaminated blood clam(毛蚶).
Blood clam
21
⑶ Susceptibility and Immunity in hepatitis A
• High-risk groups for acquiring hepatitis A include
travelers to developing areas of the world, children in
day care centers.
•
The baby under 6 months of age is not susceptible
to hepatitis A, because they acquire anti-HAV IgG
from your mother, and anti-HAV IgG is immune
protective.
•
Along with the increase of age the rate of covert
infection increases, the susceptibility to hepatitis A is
decreased.
•
Generally, the immunity to hepatitis A can maintain
for life.
22
⒉Hepatitis B
⑴ Sources of infection in hepatitis B
•
•
•
•
The patients with acute or chronic hepatitis B and
HBV carrier all can be regarded to the source of
infection.
However, chronic hepatitis B and HBV carrier are
important as the sources of infection.
23
⑵ Routes of transmission in hepatitis B
Hepatitis B is spread predominantly by the
parenteral route or by intimate person contact.
intimate person contact
Investigations of the source of hepatitis B reveal
that most adult cases are due to sexual or
parenteral contact.
24
Blood transfusion and plasma products are now
rarely infections for hepatitis B because of the
institution of routine screening of blood donations
for HBsAg and anti-HBc.
Transfusion
25
Maternal-infant spread of hepatitis B is another
important mode of transmission not only in
endemic areas of the world, but also in the country
among immigrants from the endemic areas.
Routine screening of pregnant women and
prophylaxis of newborns are now recommended.
Intrafamilial spread of hepatitis B also can occur,
although the mode of spread in this situation is not
well defined.
26
⑶ Susceptibility and Immunity in hepatitis B
Human without anti-HBs is susceptible to
hepatitis B virus.
•
•
•
•
By covert infection near 50% of human at
30 years of age acquire anti-HBs.
When the infection occurs in new neonate,
they easily become to chronic carrier,
because their immunity is not mature.
27
• ⑷Epidemic features of hepatitis B
•
•
•
•
•
Low epidemic region with <2% of HBsAg
carrier rate is found in north American, western
Europe and Australia.
Moderate epidemic region with 2~7% of
HBsAg carrier rate is reported in Eastern Europe,
Mediterranean, Japan and Pre-Soviet Union.
High epidemic region with 8~20% of HBsAg
carrier rate is reported in tropic Africa, Southeast
Asia and China.
28
• ⒊Hepatitis C
• ⑴ Sources of infection in hepatitis C
•
The sources of infection are acute or chronic
hepatitis C. 3.2% of anti-HCV positive rate among
population in our country.
⑵ Routes of transmission in hepatitis C
Hepatitis C is spread predominantly by the
parenteral route.
At highest risk are injection drug users and
persons with multiple parenteral exposures.
Sexual transmission of hepatitis C occurs but is
not common.
30
Maternal-infant spread occurs in about 5% of
cases, usually to infants whose mothers have high
levels of HCV RNA in serum.
Other potential sources of HCV are needlestick
accidents.
needlestick accidents
Since the introduction of routine screening of
blood for anti-HCV, post-transfusion hepatitis C
has become rare.
31
⑶Susceptibility and Immunity in hepatitis C
Humans are susceptible to HCV generally,
no protective immunity to in different species after
infection.
⒋ Hepatitis D
Hepatitis D is linked to hepatitis B, and
consequently its epidemiology is similar.
HDV can be spread by the parenteral route and
sexually.
32
⒌Hepatitis E
⑴ Sources of infection in hepatitis E
The source of infection only is acute case of hepatitis E.
⑵ Route of transmission in hepatitis E
HEV is spread by the fecal-oral route, and most
cases can be traced to exposure to contaminated
water under poor sanitary conditions .
Large outbreaks have been described from
India, Pakistan, China, Northern and central Africa,
and Central American.
119,000 of patients with hepatitis E were
reported in south region of Xinjian in 1986 to 1988
due to contaminated source.
33
⑶Susceptibility and Immunity in hepatitis E
Covert infection is common in children and
clinical infection is often in adult.
•
•
Although anti-HEV IgG only persists in
6~12 months in circulation but re-infection
can not be seen.
34
• Ⅳ. Pathogenesis
• ⒈ Pathogenesis of Hepatitis A
• Although HAV has a cytopathic effect in tissue
culture,
•
more evidence indicates that hepatocyte injury
is secondary to host immune response.
•
•
35
• ⒉ Pathogenesis of Hepatitis B
• Clinical observations suggest that the immune
response of the host in hepatitis B is more important
than viral factors in the pathogenesis of liver injury.
•
•
•
⑴In HBV acute infection
Specific immune responses to multiple viral
antigens can be demonstrated in both major
histocompatibility complex class II and I restricted T
cells .
•
36
• ⑵In HBV chronic infection
• The patients fail to clear virus, both CD4+ and
CD8+ T cell are markedly reduced in chronic
infection.
• ⑶HBV infection in infants
• Infants with immature immune system, who
acquire HBV infection at birth,
•
have a very high rate of chronic infection and
replication typically has only mild liver injury.
•
37
•
•
⑷Severe form hepatitis B
HBV induced fulminant liver failure is
associated with a vigorous immune response,
low levels of virus, and massive hepatocellular
necrosis.
38
⒊ Pathogenesis of Hepatitis C
Mechanisms of viral persistence and of
hepatocellular injury in patients with chronic
HCV infection are poorly understood.
In generally, viral infection can produce
cellular injury by direct cytopathogenicity
and indirect immune-mediated injury.
39
⒋ Pathogenesis of Hepatitis D
•
There are some evidences that HDV Ag
and HDV RNA may be directly cytotoxic to
hepatocytes.
⒌ Pathogenesis of Hepatitis E
•
Mechanisms of hepatocellular injury
may be similar to hepatitis A.
40
• Ⅴ. Pathology
•
•
•
•
There
aren’t
morphological
features
distinguishing the different etiological types of
hepatitis.
Same pathologic changes can be seen in
different viral hepatitis, but same viral hepatitis
can occur different pathologic changes.
41
• ⒈Acute viral hepatitis(1)
• Hepatocyte ballooning, degeneration, and
acidophilic body formation are present.
• These changes are most prominent near the
terminal hepatic venule,
•
and in mild cases, the injury is confined to this
area alone.
Acidophilic body
formation
42
• ⒉Chronic viral hepatitis
• The range of histology findings is broad, from
minimal periportal lymphocytic inflammation to
active hepatitis with bridging fibrosis.
•
The simplified system in which inflammation is
graded from 0 to 4 .
•
and fibrosis is staged from 0 to 4 have been
developed by Scheuer.
43
Stage1
Stage2
Stage3
Stage4
According to liver biopsy sections:
Fibrin morphometrical measurements in fibrosis S1, S2, S3, S4 are 8.3%,
11.4%, 14.9%, 20.7% respectively.
Correspondingly, the liver parenchyma morphometrical measurements in
fibrosis S1, S2, S3, S4 are 91.7%, 88.6%, 85.1%, 79.3% respectively.44
• ⒊Severe form hepatitis
• ⑴Acute severe form hepatitis
• Massive or submassive forms of hepatic
necrosis are more than two-thirds of hepatic
parenchyma.
Massive necrosis
45
• ⑵Subacute severe form hepatitis
• Submassive forms of hepatic necrosis are
less than 50% of hepatic parenchyma.
Submassive necrosis
46
• ⑶Chronic severe form hepatitis
• Massive or submassive forms of hepatic
necrosis occur on the basis of chronic liver
diseases.
Chronic severe form hepatitis
47
• ⒋Cirrhosis(active and inactive)
• Active cirrhosis: distort the hepatic
architecture with obvious inflammation.
• Inactive cirrhosis: distort the hepatic
architecture with slight inflammation .
End-stage cirrhosis
48
Ⅵ.Manifestations
The average incubation periods
4 weeks(2~6weeks) in hepatitis A;
three months(1~6 months) in hepatitis B;
6 weekss (2 weeks~6 months) in hepatitis C
4~20 weeks in hepatitis D
6 weeks (2~9weeks) in hepatitis E
•
•
The spectrum of diseases in viral hepatitis is
very variable, from asymptomatic to fatal disease.
49
• ⒈Acute hepatitis
• ⑴ Icteric form of acute hepatitis
①Prodromal stage
• The prodromal stage of illness is marked by the
onset of fatigue, nausea, poor appetite, and vague
right upper quadrant pain.
•
Less common symptoms include fever,
headache, arthralgias, myalgias, and diarrhea.
• The duration persists 5~7 days.
•
50
②Icteric stage
The onset of dark urine marks the icteric stage of
illness, during which jaundice appears, and
symptoms of fatigue and nausea worsen.
If jaundice is severe, stool color lightens, and
pruritus may appear.
Physical examination usually shows jaundice and
hepatic tenderness.
In more severe cases, hepatomegaly and
splenomegaly may be present.
• The duration of jaundice is 2 to 6 weeks.
51
③Convalescence stage
The symptoms and jaundice disappear gradually,
and enlargement of liver and splenomegaly
recover to normal.
The duration is 1 to 2 months.
⑵Anicteric form of acute hepatitis
•
In patients with subclinical or aniteric forms of
acute hepatitis, This stage constitutes the entire
course of illness.
52
• The clinical features of acute hepatitis C
•
• Acute infection is rarely seen in clinical
practice because the vast majority of patients
experience no clinical symptoms.
•
•
Jaundice occasionally occurs with acute
infection,
• but it is rarely seen in chronic infection until
significant hepatic decompensation has occurred.
53
The clinical features of acute hepatitis D
Hepatitis D occurs in two clinical patterns,
termed coinfection and superinfection.
Delta coinfection is the simultaneous
occurrence of acute HDV and acute HBV
infections.
It resembles acute hepatitis B but may
manifest a second elevation in aminotransferase
levels associated with the period of delta virus
replication.
54
Acute delta superinfection is the occurrence
of acute HDV infection in a chronic HBV carrier.
Superinfection with HDV is more frequent than
coinfection and is far more likely to lead to chronic
hepatitis D.
Hepatitis D trends to be more severe than
hepatitis B alone
and is more likely to lead to fulminant hepatitis
and more likely to cause severe chronic hepatitis
and ultimately cirrhosis.
55
The clinical features of hepatitis E
Hepatitis E is frequently cholestatic, with
prominence of bilirubin and alkaline phosphatase
elevations.
Hepatitis E also trends to be more severe than
other forms of epidemic jaundice,
with a fatality rate of 1 to 2% and a particularly
high rate of acute liver failure in pregnant women.
56
• ⒉Chronic hepatitis
•
Indexes of injury degree of liver function
• ────────────────────
•
•
•
•
•
•
•
•
•
Liver function
Mild injury
Moderate injury
Severe injury
────────────────────────────────
ALT (U)
≤ 3 times
> 3 times
>3 times
TBIL(μmol/L)
17.1~34.2
>34.2~85.5
>85.5
A(g/L)
≥35
32~34
≤32
A/G
≥ 1.4
< 1.4~>1.0
≤1.0
νGlobulin (%) ≤21
> 22~ < 26
≥26
PTA (%)
> 70
70~60
< 60 ~ >40
Choline esterase > 5400
≤5400~ >4500
≤4500
_________________________________________________________
57
•
•
•
•
•
•
⒊Severe form hepatitis
⑴Acute severe form hepatitis (Fulminant hepatitis)
Indexes of liver failure occur within 2 weeks
①Sudden decrease in the size of liver;
②Hepatic encephalopathy;
③Jaundice deepen rapidly, serum bilirubin in a
high level is more than 10 times of normal
(≥171.1μmol/L);
58
Decreased liver size
Hepatic encephalopathy
deepen jaundece
• ④Ascites or toxic abdominal distension;
• ⑤Prolonged prothrombin time is more 26
seconds or PTA<40%.
• ⑥Hepatorenal syndrome.
ascites
lowed PTA
hepatorenal syndrome
59
• ⑵Subacute severe form hepatitis
• Indexes of liver failure occur after 15 days~24
weeks.
• ⑶Chronic severe form hepatitis
• Liver failure occurs on the basis of chronic
active hepatitis or cirrhosis.
60
• ⒋Cholestatic hepatitis
• The cholestatic hepatitis occurs occasionally as a
complication of acute viral hepatitis, especially
hepatitis A.
•
•
Patients may exhibit a relatively prolonged course
of several months dominated by cholestatic features,
including pruritus, dark urine, light stools, directreacting hyperbilirubinnemia, and elevation of
alkaline phosphatase.
Cholestatic hepatitis
61
• ⒌Hepatitis in particular crowd
• Infection in children is usually asymptomatic or,
if symptomatic, non-icteric.
•
•
•
•
Patients with more than 50 years of age have
the most severe disease.
The significant maternal and fetal mortality
associates with acute hepatitis E.
62
Ⅶ. Laboratory examination
⒈ Routing blood examination
White blood cell count is normal or slight
decreased, and lymphocytes are elevated in acute
hepatitis; sometimes atypical lymphocytes can be
seen.
But white blood cells are increased in severe
form hepatitis.
Deceases of platelet, RBC and WBC can be
found in cirrhosis with hypersplenism.
63
• ⒉ Routing urine examination
The
detection
of
bilirubinuria
and
urobilinogen can make diagnosis of hepatitis
early and help to differential diagnosis of
jaundice.
Bilirubinuria and urobilinogen are positive
in hepatic cell jaundice at the same time.
Bilirubinuria
and
urobilinogen
are
predominently increased in obstructive and
hemolytic jaundice, respectively.
64
• ⒊Liver functions(1)
•
In acute hepatitis,
levels of serum
aminotransferase increase during the prodromal
phase, and the peak is typically heralded by
intense nausea, anorexia, and vomiting, which
precedes the onset of jaundice.
•
•
Peak aminotransferase levels are commonly
more than 500 IU/L and decrease at the rate of
75% per week initially and the decline more
slowly.
65
• Liver functions(2)
• Serum bilirubin
levels
peak
after
aminotransferase activity and usually less
than 171μmol/L.
•
The bilirubin levels fall more slowly than
the aminotransferase levels but will return to
normal by 2 weeks to 3 months.
66
In chronic hepatitis,
mild, moderate and
severe chronic hepatitis can be classified
according to the different levels of ALT, T Bilirubin,
Albumin, albumin/globulin, νGlobulin, choline
esterase and prothrombin activity.
•
•
In severe form hepatitis, hyperbilirubinemia
>171μmol/L, prolonged prothrombin time >26
second or prothrombin activity (PTA<40%) are
consistent with liver failure.
67
⒋Viral hepatitis marks
⑴Serology of hepatitis A (IgM, IgG antibodies against
HAV)
•
①Initially antibody is predominantly of the IgM
class, with that an IgG antibody soon appears.
•
•
②IgM antibody against HAV indicates current or
recent infection or convalescence (within a few
months), it may persist for up to 3~6 months.
•
•
③IgG antibody against HAV indicates current or
previous infection and immunity to HAV reinfection
and it can persist for several years or for life. 68
• ⑵Serology of hepatitis B
• ①HBsAg
• HBV surface antigen can be found in
serum, saliva, breast milk, semen in most
patients of acute or chronic infection.
•
HBsAg contains no nucleic acid and not
infectious itself.
•
HBsAg positive generally suggests HBV
infection.
69
• ②Anti-HBs
• Anti-HBs is an antibody to surface antigen.
•
It becomes positive late in convalescence in
most acute patients.
•
Anti-HBs is a protective antibody which
indicates past infection and immunity to HBV
reinfection.
70
• ③HBeAg
•
HBeAg is a core component of HBV.
•
•
•
•
•
HBeAg reflects Dane particle concentration
and infectivity.
It is transiently positive during active
replication, acute hepatitis and in some chronic
patients.
In some patients infected with pre-C mutant
produce no this antigen.
71
• ④Anti-HBe
• Anti-HBe is transiently positive during
convalescence and in some chronic patients
and carriers; not protective; reflects low
infectivity.
• ⑤HBcAg
•
HBcAg reflects HBV replication and
infectivity.
•
Because it is difficult to be detected in
laboratory, HBcAg do not be routinely used in
clinical setting.
72
• ⑥Anti-HBc
• Anti-HBc is positive in all acute and chronic
patients and in carriers; Thus, marker of HBV
infection; not protective; IgM anti-HBc may
reflect active HBV replication.
•
•
⑦HBV DNA
HBV DNA is indicative of replication of HBV
and infectivity and most useful in diagnosis of
HBV and in evaluation of the anti-virus
treatment.
HBV DNA
73
• ⑶Serology of hepatitis C
•
①Anti-HCV is an antibody to cloned core
or/and non-structure region polypeptide of HCV.
•
Anti-HCV becomes positive on average 1~3
months after clinical onset; not protective;
indicates infectious.
•
②HCV RNA suggests current infection of HCV
and the indicator of replication of the virus and
infectivity.
74
• ⑷Serology of hepatitis D
• IgM or IgG antibody against HDV is similar to
anti-HBc in indicating infection; not protective.
•
HDV RNA found in sera suggests replication of
HDV and infectivity.
⑸ Serology of hepatitis E
• IgM or IgG anti-HEV both can be detected in
acute of disease and is helpful to the diagnosis of
the HEV infection.
•
HEV RNA suggests the present infection.
75
⒍Ultrasonics
Morphology of liver and spleen can be
measured accurately.
⒎Liver biopsy
•
Liver biopsy can estimate liver injury and
prognosis and hepatic viral types sometimes.
•
If a liver biopsy is performed, it may
demonstrate the pathologic features of acute
viral hepatitis.
Liver biopsy
76
•
However, these are nonspecific, and in the
vast majority of cases biopsy is not indicated.
•
•
Its use should be reserved for patients in whom
the diagnosis is uncertain
•
or in whom there is concern regarding
chronicity of a deteriorating course.
•
•
In the most severely ill patients biopsy may not
be possible because of abnormalities of clotting
function.
77
Ⅷ. Complications
⒈ Hepatic encephalopathy
•
The mechanism of hepatic encephalothy is
associated with
•
①toxin of ammonia and mercaptans;
•
•
②false neurotransmitters increase brain
octopamine, phenylephrine and decrease
dopamine;
•
• ③increased ratio of plasma aromatic amino
acids to branched-chain amino acids.
78
⒉ Bleeding of upper digestive tract
•
Gastrointestinal bleeding is caused by stress
gastritis aggravated by coagulopathy and portal
hypertension.
Gastrointestinal bleeding
⒊ Hepatorenal syndrome
•
Hepatorenal syndrome is associated with
volume depletion, acute tubular necrosis and
endotoxin.
79
Ⅸ. Diagnosis
• ① Epidemic evidences
•
Evidences of exposure to infection, but not
easy to obtain in sporadic cases in endemic areas.
• ② Clinical data
Case
history,
examinations.
symptoms
and
physical
• ③ Laboratory investigations
•
Liver function tests, detection of viral markers.
80
• Ⅹ. Differential diagnosis
• ⒈Jaundice is caused by other reasons
• Jaundice results from hemolysis
and
extrahepatic obstruction.
extrahepatic obstruction
• ⒉Other hepatitis
• ⑴Other viral hepatitis
• Infections include other viruses such as
cytomegalovirus, Epstein-Barr virus and yellow
fever virus.
81
• ⑵Infective toxic hepatitis
• Jaundice can be caused by other infective
disease included leptospirosis, sepsis, typhoid
fever, pyogenic and amebic liver abscess, malaria,
salmonellosis and Q fever and so on.
• ⑶Liver injure result from drugs and
metabolism disorder
• Isoniazid, rifampin and inborn errors of
metabolism such as Wilson’s disease may lead to
acute hepatic necrosis.
Wilson’s disease
82
• Ⅺ. Prognosis
• ⒈Acute hepatitis
• Hepatitis A is typically a benign, self-limited
infection, with the majority of patients exhibiting
complete recovery within 3 months of the disease
onset.
•
Fulminant hepatitis A is rare, and chronic hepatitis
A does not exist.
•
•
In nonfatal cases, hepatitis E is followed by
complete recovery without chronic sequelae.
•
Case-fatality rate is 1~5%, but in pregnant women
83
is 10~40%.
• ⒉Chronic hepatitis
• Chronic infection is usually defined by detectable
HBsAg or IgG antibody against HCV in the serum for
a period of 6 months or longer.
•
•
•
•
Acute hepatitis B is about 10% at risk for
developing chronic infection, and acute hepatitis C is
about 50%.
Mild and moderate chronic hepatitis B are easy to
develop into cirrhosis, or hepatocellular carcinoma in
a few cases.
84
•
Severe chronic hepatitis can easily develop
into chronic severe form hepatitis or
decompensated cirrhosis.
• ⒊Severe form hepatitis
• Case-fatality rate can reach about 80%.
• ⒋Cholestatic hepatitis
•
Almost without exception,
the prognosis is
favorable.
85
Ⅻ. Treatment
• ⒈ Acute hepatitis(1)
•
There is on specific treatment for acute viral
hepatitis.
•
Major emphasis is placed on symptomatic
and supportive care.
•
Rest is advisable.
•
86
• Acute hepatitis(2)
• No specific dietary measures are indicated, but
most patients find a low-fat, high-carbohydrate
diet more palatable.
•
Alcohol, overwork and drugs of injury to liver
should be avoided.
•
• Vitamins and glucose solution infusion can be
given if it is necessary.
•
•
Anti-virus agent therapy such as recombinant
interferon and ribavirin can be used for acute
hepatitis C.
87
•
• ⒉ Chronic hepatitis
• ⑴ Symptomatic and supportive care
• Chinese Medicines included bifendate,
Oleanilic acid and Silymarinum.
•
•
Liver function protective
vitamins and glucurone.
agents
have
88
• ⑵Anti-virus agent therapy
• ①Interferon-α(conventional and pegylated)
• Conventional IFN-alpha has been replaced by
Pegylated IFN-alpha.
•
Indications of interferon in chronic hepatitis B are
active replication of HBV, active phase of hepatitis B,
low concentration of HBV DNA and anti-HBc IgM
positive.
Interferon
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• Pegylated IFN alpha
• [聚二乙醇化（长效）α－干扰素]
• Efficacy at one year:
• 1. HBV DNA suppression (<400 copies/ml):
•
HBeAg (+) 25%; HBeAg (-) 63%.
• 2. HBeAg seroconversion: 27% (32% at 2 year)
• 3. ALT Normalization:
• HBeAg (+) 39%;HBeAg (-) 38%.
• Drug resistance: No
90
• Special features of Pegylated IFN alpha
• 1. Baseline ALT levels positively correlates with the
chance of HBeAg seroconversion.
• 2. Associated with mild to moderate clinical side
effects including flu-like symptoms, bone marrow
suppression, depression, weight loss and thyroid
dysfunction.
91
• 3. Caution for hepatic decompensation
particularly in patients with moderate/severe
cirrhosis or severe reactivation of hepatitis.
• Suggested duration: 1 year.
• Sustained response after off-therapy: 30~40%.
• Indications to chronic hepatitis C
•
anti-HCV IgG and / or HCV RNA positive,
level of ALT increased.
• Regimen is 3 MU three times a week for
4~12 months.
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• ②Nucleoside analogs:
• 1. Lamivudine(拉米夫定）
• Dose of Lamivudine is 100mg/day, for 28 days;
a 98~100% reduction in circulating HBV DNA can
be seen,
•
but HBV DNA rebound is observed in the
majority of patients when treatment is stopped.
•
l
Lamivudine
93
•
•
•
•
•
•
•
•
•
•
Efficacy at one year:
1. HBV DNA supression (<300copies):
HBeAg (+) 60%; HBeAg (-)72%.
2. HBeAg seroconversion: 18% (26% at year 2)
3. ALT normalization:
HBeAg (+) 60%; HBeAg (-) 71%.
Drug resistance:
23%, 40%, 55%, 68%, 71% ( from year 1 to 5)
Suggested duration:
1. HBeAg (+): minimum 1 year and after at least 6
months with stable HBeAg seroconversion.
• 2. HBeAg (-): long-term treatment.
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Special features of lamivudine
1. Long term therapy is associated with improvement
of virological, biochemical and liver histological
parameters,
but development of drug resistance may reverse
the benefits.
2. Proven to be able to retard disease progression
including reducing the risk of hepatocellular
carcinoma in patient with chronic hepatitis B
infection with long-term therapy.
95
• 2. Adefovir（阿德福韦）
Efficacy at one year:
1. HBV DNA suppression (<400 copies/ml):
HBeAg (+) 21%; HBeAg (-) 51%.
2. HBeAg seroconversion: 12% (29% at year 2).
3. ALT normalization:
HBeAg (+) 48%; HBeAg (-)72%.
Drug resistance:
HBeAg (+): 0% (year 1), 3% (year 2-3), 20% (year 5).
HBeAg(-): 0%, 3%, 11%, 18%, 29% (from year 1 to 5).
96
Suggested duration:
• same as that for lamivudine.
Side effect of adefovir:
• Renal toxicity has been reported in higher
dosages and caution is needed in patients with
creatinine clearance less than 50ml/min.
97
•
•
•
•
•
•
•
•
Entecavir（恩替卡韦）
Efficacy at one year:
1. HBV DNA suppression (<300 copies/ml):
HBeAg (+)67%; HBeAg (-) 90%.
2. HBeAg seroconversion: 21% (31% at year 2).
3. ALT normalization:
HBeAg(+)68%; HBeAg(-)78%.
Drug resistance: <1%,<1%,<1.1%,<1.1%(from year
1 to 4).
• Suggested duration:
• same as that for lamivudine.
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Telbivudine (替比夫定)
Efficacy at one year:
1. HBV DNA suppression (<300 copies/ml):
HBeAg(+)60%; HBeAg(-)88%.
2. HBeAg seroconversion: 22%.
3. ALT normalization:
HBeAg(+) 77%, HBeAg (-)74%.
Drug resistance:
HBeAg(+)4.4%(year 1), 21.6%(year 2);
HBeAg(-)2.7%(year 1), 8.6%(year 2).
Suggested duration:
same as that for lamivudine.
99
• Management of drug resistance:
• General principle:
• Adding and switching to another
nucleoside/nucleotide analogue as early as
possible.
100
• ⒊Severe form hepatitis
• ⑴Supportive measures
•
•
①Strict confinement bed is necessary.
②Low protein diet is recommended in order to
control the source of ammonia.
•
③Anorexia and nausea may be so extreme that
oral intake of any kind is minimal, in such instances,
attention to fluid balance is important.
•
10~25% of glucose, vitamin B, C, K, albumin and
fresh blood plasma should be administered.
Plasma
Albumin
101
• ⑵ Regeneration of liver cells promoted
• Glucagon-insulin and hepatic growth factor can
be administered.
• ⑶Therapy of complications
• ①Hepatic encephalopathy
A.Oral administration has poorly absorbable
antibiotics such as neomycin, norfloxacin and
lactulose.
•
B.Levodopa has the function against false
neurotransmitters.
•
Levodopa
102
• C.Administration of branched-chain amino
acids can increase the ratio of plasma aromatic
amino acids to branched-chain amino acids.
• D.Mannitol and lasix can alleviate brain edema.
103
• ② Bleeding
• Prophylaxis against upper gastrointestinal
hemorrhage with agents such as H2 receptor
antagonists (Ranitidine) is beneficial.
•
•
•
•
It is also seasonable to administer a trial of
subcutaneous vitamin K to treat coagulopathy
possibly related to vitamin K deficiency.
Fibrinogen, fresh plasma, prothrombin complex
and dicynone can be administered in the patients
with long prothrombin time.
104
③Infection
•
•
•
Infections develop in as many as 80% of
patients with severe form hepatitis, and bacteremia
is present in 20~25% overall.
The most common bacteria is plated are
staphylococcal species, streptococcal species, and
gram-negative rods.
105
•
•
•
•
•
Fungal infections develop in up to one third of
patients with severe form hepatitis. The majority of
these are caused by candida albicans.
A reasonable empirical regimen might include
penicillin,
a
third-generation
cephalosporin,
quinolones, metronidazole and fluconazole.
106
• ④Renal Failure (hepatorenal syndrome)
• It is important to avoid the various factors of
volume depletion.
• The measures of expanding blood volume
include administer of low molecular dextran,
plasma and serum albumin.
•
Dopamine and lasix can increase blood stream
of kidneys and urine.
• ⑤Artificial liver support system
107
• ⑥Liver transplantation(1)
Liver transplantation has transformed the
management of patients with decompensated
cirrhosis and liver failure.
•
The decision to perform transplantation in a
patient with severe form hepatitis must balance the
likelihood of spontaneous recovery with the risks of
surgery and long-term immunosuppression.
108
• Liver transplantation(2)
• Contraindications
to
transplantation
are
irreversible brain damage, active extrahepatic
infection, and multiple organ failure syndrome.
•
•
Liver transplantation may yield favorable
results of 30~40% survival for 5 years.
109
ⅩⅢ. Prevention
• ⒈Control of source of infection
• ⑴Isolation of patients
• The patients with acute hepatitis A and E must be
isolated for 21 days, respectively.
•
But patients with acute hepatitis B, C and D
should be isolated for HBsAg and HCV RNA
negative, respectively.
• ⑵Management of carrier
•
Asymptomatic carrier of HBV and HCV should
not be as blood donor and take works in
kindergarten.
110
• ⒉Disruption of routes of transmission
• ⑴Hepatitis A and E
• Prevention requires attention to public and
personal health measures.
•
Strict adherence to hand-washing in the
hospitals and daycare or institutional settings is
important in preventing person-to-person spread.
•
Travelers to endemic areas should be advised
to avoid drinking water or beverages with ice from
sources of unknown purity and eating uncooked
shellfish or uncooked and unpeeled fruits and
vegetables.
111
• ⑵Hepatitis B, C and D
• The stress of prevention is disruption of
transmission by blood and body fluids.
•
•
•
•
Every blood donor must be screened on
HBsAg and anti-HCV with more sensitive
detective methods.
The excreta of patients, needles and other
medical supplies, and personal utensils should
be identified, carefully handled, and discarded.
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• ⒊Protection of the susceptible population
• ⑴Active immunization
• ①
Hepatitis A
•
The live attenuated vaccine, produced by serial
passage of HAV in cell culture to produce a virus
with reduced infectivity but retained antigenicity, is
available.
•
The vaccine induces the development of
antibodies in 65% of vaccine recipients.
live attenuated
hepatitis A vaccine
113
• ② Hepatitis B
• Safe and effective vaccines have been
developed for the prevention of hepatitis B.
•
•
•
•
The vaccine is administered in three doses;
initially and 1 month and 6 months later, and
usually elicits production of anti-HBs in the recipient.
The duration of this protection varies, but
probably is of the order of 5 years.
114
•
After accidental needle stick and of infants born
to HBsAg-positive mothers, the first vaccine dose
is combined with HBIG,
•
hepatitis B immune
globulin,HBIG
In any case, it is established that administration
of the vaccine to individuals already infected or
immune is not harmful.
115
• ⑵ Passive immunization
• ① Hepatitis A
• Close contacts of patients with hepatitis A
should receive passive immunization with
immune serum globulin as soon as possible, no
more than 7 to 10 days after exposure.
•
•
It may be expected to afford protection for up to
35 days.
116
• ② Hepatitis B
•
Passive immunoprophylaxis is used in four
•
•
•
•
•
situations:
A. neonates born to HBsAg-positive mothers,
B. after needlestick exposure,
C. after sexual exposure,
D. after liver transplantation in patients who
were HBsAg positive before transplantation.
Neonates administered with hepatitis B vaccine
and hepatitis B immune globulin (HBIG) can
enhance protective rate up to 90%.
117
Thank you for your attention!
118