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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. Ⅰ. Outline ⒈Definition Viral hepatitis is one group infectious diseases of liver lesions

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viral hepatitis

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

slide2

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.
slide3

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

slide4

Hepatitis A and E only are responsible to acute hepatitis,

and mainly transmitted by fecal-oral route.

Acute hepatitis

Fecal-oral route

slide5

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

slide6

Hepatitis B, C and D are often transmitted by parenteral transmission,

  • such as transfusion, injection and maternal-infant .
  • Transfusion Injection Maternal-infant
slide7

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.

slide8

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

slide9

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.

slide10

⒉ Virology of Hepatitis B

  • Hepatitis B virus (HBV) is a double-shelled, enveloped DNA virus, 42 nm in diameter.

Hepatitis B virus

slide11

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 transactivating function (X gene, HBxAg).
slide12

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 HBcAgretained in hepatocytes until assembled as core particles.
  • HBeAg secreted into the serum as a small soluble protein.
slide13

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.
slide14

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

slide15

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).

slide16

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

slide17

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

slide18

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.

slide19

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.
slide20

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.
slide21

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

slide22

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.
slide23

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.
slide24

⑵ Routes of transmission in hepatitis B

Hepatitis B is spread predominantly by the parenteral 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

slide25

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

slide26

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.

slide27

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.
slide28

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.
slide30

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.

slide31

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

slide32

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.

slide33

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.

slide34

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.
slide35

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.
slide36

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 .
slide37

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.
slide38

⑷Severe form hepatitis B

  • HBV induced fulminant liver failure is associated with a vigorous immune response, low levels of virus, and massive hepatocellular necrosis.
slide39

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.

slide40

⒋ Pathogenesis of Hepatitis D

  • There are some evidences that HDV Ag and HDV RNA may be directly cytotoxic to hepatocytes.

⒌Pathogenesis of Hepatitis E

  • Mechanisms of hepatocellular injury may be similar to hepatitis A.
slide41

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.
slide42

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

slide43

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.
slide44

Stage1

Stage3

Stage4

Stage2

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.

slide45

⒊Severe form hepatitis

  • ⑴Acute severe form hepatitis
  • Massive or submassive forms of hepatic necrosis are more than two-thirds of hepatic parenchyma.

Massive necrosis

slide46

⑵Subacute severe form hepatitis

  • Submassive forms of hepatic necrosis are less than 50% of hepatic parenchyma.

Submassive necrosis

slide47

⑶Chronic severe form hepatitis

  • Massive or submassive forms of hepatic necrosis occur on the basis of chronic liver diseases.

Chronic severe form hepatitis

slide48

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

slide49

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.
slide50

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.
slide51

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.
slide52

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.
slide53

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.
slide54

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.

slide55

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.

slide56

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.

slide57

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

_________________________________________________________

slide58

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);

Decreased liver size Hepatic encephalopathy deepen jaundece

slide59

④Ascites or toxic abdominal distension;

  • ⑤Prolonged prothrombin time is more 26 seconds or PTA<40%.
  • ⑥Hepatorenal syndrome.

ascites lowed PTA hepatorenal syndrome

slide60

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.
slide61

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

slide62

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.
slide63

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.

slide64

⒉ Routing urine examination

The detection of bilirubinuria and urobilinogen can make diagnosis of hepatitis early and help to differentialdiagnosis 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.

slide65

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.
slide66

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.
slide67

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.
slide68

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.
slide69

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.
slide70

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.
slide71

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.
slide72

④Anti-HBe

  • Anti-HBe is transiently positive during convalescence and in some chronic patients and carriers; not protective; reflects low infectivity.
  • ⑤HBcAg
  • HBcAgreflects HBV replication and infectivity.
  • Because it is difficult to be detected in laboratory, HBcAg do not be routinely used in clinical setting.
slide73

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

slide74

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.
slide75

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.
slide76

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

slide77

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.
slide78

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.
slide79

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 volume depletion, acute tubular necrosis and endotoxin.

Gastrointestinal bleeding

slide80

Ⅸ. Diagnosis

  • ①Epidemic evidences
  • Evidences of exposure to infection, but not easy to obtain in sporadic cases in endemic areas.
  • ②Clinical data

Case history, symptoms and physical examinations.

  • ③Laboratory investigations
  • Liver function tests, detection of viral markers.
slide81

Ⅹ. Differential diagnosis

  • ⒈Jaundice is caused by other reasons
  • Jaundice results from hemolysis and extrahepatic obstruction.
  • ⒉Other hepatitis
  • ⑴Other viral hepatitis
  • Infections include other viruses such as cytomegalovirus, Epstein-Barr virus and yellow fever virus.

extrahepatic obstruction

slide82

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

slide83

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 is 10~40%.
slide84

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.
slide85

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.
slide86

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.
slide87

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.
slide88

⒉ Chronic hepatitis

  • ⑴ Symptomatic and supportive care
  • Chinese Medicines included bifendate, Oleanilic acid and Silymarinum.
  • Liver function protective agents have vitamins and glucurone.
slide89

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

slide90

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
slide91

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.
slide92

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.
slide93

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.

Lamivudine

l

slide94

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

  • 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.

Plasma

Albumin

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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

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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 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.
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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 staphylococcal species, streptococcal species, and gram-negative rods.
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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.
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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
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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.
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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 results 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 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.
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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 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
  • ①Hepatitis 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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②Hepatitis 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.
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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

  • ①Hepatitis 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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②Hepatitis 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%.