Viral hepatitis

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Viral hepatitisViral hepatitisWei-Min KeWei-Min Ke

Department of Infectious DiseasesDepartment of Infectious Diseases

Sun Yat-sen UniversitySun Yat-sen University

Mar.13, 2009, Friday, Session 8~9 ClassrooMar.13, 2009, Friday, Session 8~9 Classroom 503m 503

Mar.20, 2008, Friday, Session 8~9 ClassrooMar.20, 2008, Friday, Session 8~9 Classroom 503m 503

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• 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.

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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.

Fatigue Anorexia Hepatomegaly Jaundice

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Hepatitis A and E only are responsible to acute hepatitis,

and mainly transmitted by fecal-oral route.

Acute hepatitis

Fecal-oral route

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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

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• • Hepatitis B, C and D are often transmitted by pa

renteral transmission,

• such as transfusion, injection and maternal-infant .

•Transfusion Injection Maternal-infant

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Ⅱ. Etiology The pathogens of viral hepatitis only are hepatitis vir

uses 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.

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• 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 non

structural components.•

Hepatitis A virus particles

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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.

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• ⒉ Virology of Hepatitis B• Hepatitis B virus (HBV) is a double-shelled,

enveloped DNA virus, 42 nm in diameter. •

Hepatitis B virus

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• The viral genome consists of partially double-stranded 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 trans

activating function (X gene, HBxAg).

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• 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 prod

uce two antigenically distinct products:

• the HBcAg retained in hepatocytes until assembled as core particles.

• HBeAg secreted into the serum as a small soluble protein.

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• • Hepatitis B virus (HBV) consists of three an

tigen and antibody systems.

• HBV replicates in hepatocytes, appears in blood and other body fluids, and spreads mainly by blood.

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• ⒊ Virology of Hepatitis C• ①HCV is an RNA virus that belongs to the fam

ily 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

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The genome is a positively stranded RNA molecule,

which is about 9.4 kb in length,

contains a single, large open-reading 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).

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• 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

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• 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

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Ⅲ. Epidemiology China is the high prevalent region of viral he

patitis 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.

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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.

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• ⑵ Route of transmission in hepatitis A

• • Investigation of the source of hepatitis A cases

reveals that most are due to direct person-to-person exposure and,

• to lesser extent, to direct fecal contamination of food or water.

• •

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• • Consumption of shellfish from contaminated wat

erways is a well-known but uncommon source of hepatitis A.

• • 310,000 of patients with hepatitis A were reporte

d in Shanhai city in 1988 due to contaminated blood clam(毛蚶 ).

Blood clam

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⑶ Susceptibility and Immunity in hepatitis A• High-risk groups for acquiring hepatitis A include tr

avelers 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.

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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.

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⑵ Routes of transmission in hepatitis B Hepatitis B is spread predominantly by the pare

nteral route or by intimate person contact.

Investigations of the source of hepatitis B reveal that most adult cases are due to sexual or parenteral contact.

intimate person contact

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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

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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.

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⑶ Susceptibility and Immunity in hepatitis B Human without anti-HBs is susceptible to h

epatitis B virus.• • By covert infection near 50% of human at 3

0 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.

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• ⑷Epidemic features of hepatitis B• Low epidemic region with <2% of HBsAg carri

er rate is found in north American, western Europe and Australia.

• • Moderate epidemic region with 2~7% of HBs

Ag carrier rate is reported in Eastern Europe, Mediterranean, Japan and Pre-Soviet Union.

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• High epidemic region with 8~20% of HBsAg carrier rate is reported in tropic Africa, Southeast Asia and China.

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8%8% –– High High

22--7% 7% –– Intermediate Intermediate

<2% <2% –– LowLow

Geographic prevalence of Geographic prevalence of chronicchronic hepatitis Bhepatitis B

World Health Organisation. Geographical Prevalence of HBsAg. Data 1996 (unpublished)http://www.who.int/vaccines-surveilllance/graphics/htmls/hepbprev.htm

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• ⒊Hepatitis C

• ⑴ Sources of infection in hepatitis C• The sources of infection are acute or chronic hep

atitis 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.

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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.

Since the introduction of routine screening of blood for anti-HCV, post-transfusion hepatitis C has become rare.

needlestick accidents

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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 conseque

ntly its epidemiology is similar.

HDV can be spread by the parenteral route and sexually.

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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.

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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 6~1

2 months in circulation but re-infection can not be seen.

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•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. • •

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• ⒉ Pathogenesis of Hepatitis B• Clinical observations suggest that the immune re

sponse of the host in hepatitis B is more important than viral factors in the pathogenesis of liver injury.

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• ⑴In HBV acute infection• Specific immune responses to multiple viral antige

ns can be demonstrated in both major histocompatibility complex class II and I restricted T cells .

•

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• 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 ac

quire HBV infection at birth, • have a very high rate of chronic infection and r

eplication typically has only mild liver injury.•

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• ⑷Severe form hepatitis B• HBV induced fulminant liver failure is associat

ed with a vigorous immune response, low levels of virus, and massive hepatocellular necrosis.

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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.

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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 m

ay be similar to hepatitis A.

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•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.

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• ⒈Acute viral hepatitis(1)• Hepatocyte ballooning, degeneration, and acid

ophilic body formation are present. • These changes are most prominent near the te

rminal hepatic venule,

• and in mild cases, the injury is confined to this area alone.

Acidophilic body formation

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• ⒉Chronic viral hepatitis• The range of histology findings is broad, from mi

nimal 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.

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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.

Stage1

Stage2

Stage3

Stage4

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• ⒊Severe form hepatitis

• ⑴Acute severe form hepatitis• Massive or submassive forms of hepatic necrosi

s are more than two-thirds of hepatic parenchyma.

Massive necrosis

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• ⑵Subacute severe form hepatitis• Submassive forms of hepatic necrosis are l

ess than 50% of hepatic parenchyma.

Submassive necrosis

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• ⑶Chronic severe form hepatitis• Massive or submassive forms of hepatic necro

sis occur on the basis of chronic liver diseases.

Chronic severe form hepatitis

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• 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

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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 ver

y variable, from asymptomatic to fatal disease.

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• 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.•

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②Icteric stage The onset of dark urine marks the icteric stage of i

llness, 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.

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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 a

cute hepatitis, This stage constitutes the entire course of illness.

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• The clinical features of acute hepatitis C

• • Acute infection is rarely seen in clinical practic

e because the vast majority of patients experience no clinical symptoms.

• • Jaundice occasionally occurs with acute infecti

on, • but it is rarely seen in chronic infection until sig

nificant hepatic decompensation has occurred.

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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.

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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.

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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.

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• 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

_________________________________________________________

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• ⒊Severe form hepatitis• ⑴Acute severe form hepatitis (Fulminant hepatiti

s)

• 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);

Decreased liver size Hepatic encephalopathy deepen jaundece

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• ④Ascites or toxic abdominal distension; • ⑤Prolonged prothrombin time is more 26 sec

onds or PTA<40%.• ⑥Hepatorenal syndrome.

ascites lowed PTA hepatorenal syndrome

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• ⑵Subacute severe form hepatitis• Indexes of liver failure occur after 15 days~24 w

eeks.

• ⑶Chronic severe form hepatitis• Liver failure occurs on the basis of chronic activ

e hepatitis or cirrhosis.

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• 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, direct-reacting hyperbilirubinnemia, and elevation of alkaline phosphatase.

Cholestatic hepatitis

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• ⒌Hepatitis in particular crowd• Infection in children is usually asymptomatic or, i

f symptomatic, non-icteric. • • Patients with more than 50 years of age have t

he most severe disease. • • The significant maternal and fetal mortality asso

ciates with acute hepatitis E.

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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.

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• ⒉ Routing urine examination The detection of bilirubinuria and urobilinog

en 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.

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• ⒊Liver functions(1)• In acute hepatitis, levels of serum aminotran

sferase 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.

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• Liver functions(2)• Serum bilirubin levels peak after aminotran

sferase 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.

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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 >1

71μmol/L, prolonged prothrombin time >26 second or prothrombin activity (PTA<40%) are consistent with liver failure.

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⒋Viral hepatitis marks⑴Serology of hepatitis A (IgM, IgG antibodies against

HAV)• ①Initially antibody is predominantly of the IgM cl

ass, 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.

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• ⑵Serology of hepatitis B

• ①HBsAg • HBV surface antigen can be found in seru

m, 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.

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• 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.

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• ③HBeAg • HBeAg is a core component of HBV.

• HBeAg reflects Dane particle concentration and infectivity.

• • It is transiently positive during active replicati

on, acute hepatitis and in some chronic patients.

• • In some patients infected with pre-C mutant

produce no this antigen.

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• ④Anti-HBe • Anti-HBe is transiently positive during conv

alescence and in some chronic patients and carriers; not protective; reflects low infectivity.

• ⑤HBcAg • HBcAg reflects HBV replication and infectivi

ty. • Because it is difficult to be detected in labo

ratory, HBcAg do not be routinely used in clinical setting.

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• ⑥Anti-HBc • Anti-HBc is positive in all acute and chronic p

atients 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

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• 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.

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• ⑷Serology of hepatitis D • IgM or IgG antibody against HDV is similar to a

nti-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 ac

ute of disease and is helpful to the diagnosis of the HEV infection.

• HEV RNA suggests the present infection.

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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 demon

strate the pathologic features of acute viral hepatitis.

Liver biopsy

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• 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 chronicit

y of a deteriorating course.• • In the most severely ill patients biopsy may not

be possible because of abnormalities of clotting function.

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Ⅷ. Complications ⒈ Hepatic encephalopathy

• The mechanism of hepatic encephalothy is associated with

• ①toxin of ammonia and mercaptans; • • ②false neurotransmitters increase brain octop

amine, phenylephrine and decrease dopamine; • • ③increased ratio of plasma aromatic amino aci

ds to branched-chain amino acids.

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⒉ Bleeding of upper digestive tract • Gastrointestinal bleeding is caused by stress

gastritis aggravated by coagulopathy and portal hypertension.

⒊ Hepatorenal syndrome • Hepatorenal syndrome is associated with volu

me depletion, acute tubular necrosis and endotoxin.

Gastrointestinal bleeding

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Ⅸ. Diagnosis• ① Epidemic evidences• Evidences of exposure to infection, but not eas

y to obtain in sporadic cases in endemic areas.

• ② Clinical data Case history, symptoms and physical examinati

ons.

• ③  Laboratory investigations• Liver function tests, detection of viral markers.

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•Ⅹ. Differential diagnosis• ⒈Jaundice is caused by other reasons• Jaundice results from hemolysis and extrahepati

c obstruction.

• ⒉Other hepatitis

• ⑴Other viral hepatitis• Infections include other viruses such as cytome

galovirus, Epstein-Barr virus and yellow fever virus.

extrahepatic obstruction

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• ⑵Infective toxic hepatitis• Jaundice can be caused by other infective disea

se 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

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•Ⅺ. Prognosis• ⒈Acute hepatitis• Hepatitis A is typically a benign, self-limited infectio

n, 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 compl

ete recovery without chronic sequelae. • Case-fatality rate is 1~5%, but in pregnant women

is 10~40%.

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• 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 developi

ng 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.

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• 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 f

avorable.

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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.

•

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• 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 g

iven if it is necessary.• • Anti-virus agent therapy such as recombinant i

nterferon and ribavirin can be used for acute hepatitis C.

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•  

• ⒉ Chronic hepatitis

• ⑴ Symptomatic and supportive care • Chinese Medicines included bifendate, Ole

anilic acid and Silymarinum. • • Liver function protective agents have vitami

ns and glucurone.

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• ⑵Anti-virus agent therapy

• ①Interferon-α(conventional and pegylated)• Conventional IFN-alpha has been replaced by Pegy

lated IFN-alpha.• Indications of interferon in chronic hepatitis B are a

ctive 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

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• 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.

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• 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, lev

el of ALT increased. • Regimen is 3 MU three times a week for 4~1

2 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

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• 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.

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• 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).

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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.

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• 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.

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• Management of drug resistance:

• General principle: • Adding and switching to another

nucleoside/nucleotide analogue as early as possible.

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• 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.

AlbuminPlasma

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• ⑵ Regeneration of liver cells promoted• Glucagon-insulin and hepatic growth factor can b

e 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

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• 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.

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• ② Bleeding• Prophylaxis against upper gastrointestinal hem

orrhage with agents such as H2 receptor antagonists (Ranitidine) is beneficial.

• • It is also seasonable to administer a trial of sub

cutaneous 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.

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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 staphylo

coccal species, streptococcal species, and gram-negative rods.

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•

• • Fungal infections develop in up to one third of pa

tients with severe form hepatitis. The majority of these are caused by candida albicans.

• • A reasonable empirical regimen might include p

enicillin, a third-generation cephalosporin, quinolones, metronidazole and fluconazole.

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• ④Renal Failure (hepatorenal syndrome)• It is important to avoid the various factors of vol

ume depletion. • The measures of expanding blood volume inclu

de administer of low molecular dextran, plasma and serum albumin.

• Dopamine and lasix can increase blood stream of kidneys and urine.

• ⑤Artificial liver support system

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• ⑥Liver transplantation(1) Liver transplantation has transformed the manag

ement 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.

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• Liver transplantation(2)

• Contraindications to transplantation are irreversible brain damage, active extrahepatic infection, and multiple organ failure syndrome.

• • Liver transplantation may yield favorable result

s of 30~40% survival for 5 years.

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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 shoul

d be isolated for HBsAg and HCV RNA negative, respectively.

• ⑵Management of carrier• Asymptomatic carrier of HBV and HCV should no

t be as blood donor and take works in kindergarten.

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• 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.

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• ⑵Hepatitis B, C and D• The stress of prevention is disruption of trans

mission by blood and body fluids. • • Every blood donor must be screened on HBs

Ag and anti-HCV with more sensitive detective methods.

• • The excreta of patients, needles and other m

edical 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

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•  ②  Hepatitis B• Safe and effective vaccines have been develope

d for the prevention of hepatitis B. • • The vaccine is administered in three doses; initiall

y and 1 month and 6 months later, and usually elicits production of anti-HBs in the recipient.

• • The duration of this protection varies, but probabl

y is of the order of 5 years.

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• After accidental needle stick and of infants born to HBsAg-positive mothers, the first vaccine dose is combined with HBIG,

•

In any case, it is established that administration of the vaccine to individuals already infected or immune is not harmful.

hepatitis B immune globulin,HBIG

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• 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.

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•  ② Hepatitis B• Passive immunoprophylaxis is used in four situ

ations: • A. neonates born to HBsAg-positive mothers,• B. after needlestick exposure, • C. after sexual exposure,• D. after liver transplantation in patients who wer

e HBsAg positive before transplantation. • Neonates administered with hepatitis B vaccine

and hepatitis B immune globulin (HBIG) can enhance protective rate up to 90%.

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Thank you for your attention!