Viral Hepatitis

Viral Hepatitis The First Teaching Hospital of Zhengzhou University, Department of Infectious Disease Gu Junsheng

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Viral Hepatitis  Summarization:

A group of diseases caused by a group of hepatotropic viruses  HAV infection rate 80% 910 million  HBV infection rate 60% (all in China) carrier rate 10~15% 134 million  HCV infection rate 0.7~3.1%  HDV infection rate 1.6%  HEV  HGV 2  TTV transfusion-transmitted virus (1997) 

Summarization pathogens 

routes of transmission

HAV RNA heparnavirus fecal-oral route

     

clinical features

HEV RNA HBV DNA hepadnavirus HCV HDV HGV TTV

RNA flaviviridae blood / body fluid RNA mother to baby RNA flaviviridae DNA transfusion-transmitted virus

no chronic type chronic hepatitis

hepatocirrhosis liver cancer 3

Summarization  Clinical

Features:  Carrier state is most common.  Symptoms and signs such as the followings can usually be seen in all kinds of hepatitis:  Fatigue, anorexia, jaundice, discomfort in the right upper quadrant, hepatosplenomegaly, abnormity of liver function etc. 4

ETIOLOGY: HAV  Heparnavirus  RNA

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ETIOLOGY: HAV Characteristics ：  (1) Only one serotype and one Ag-Ab system  (2) HAV-IgM: appears early after the infection of HAV and disappears 6 months later.  (3) HAV-IgG: appears after the disappearance of HAV-IgM and last many years.  (4) Hepatotropic: self-copy in liver cells.  (5) HAV can not lead cytolysis directly. 

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ETIOLOGY: HAV  (6) 





Resistance: keep activity:

56℃: 30 min room temperature: one week partly inactivate: 60℃: 12h 70% `ethanol, 25 ℃: 3 min completely inactivate: seethe: 5 min ultraviolet radiation: 1 min

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ETIOLOGY: Structure of HBV envelope (7nm)



protein

spherical

HBsAg

synthesized in liver cells

lipid

no infectivity

Dane

Granule (42nm)

HBcAg

core (28nm)

HBV DNA (circular and partly doubled) DNAP

Question: Where is HBeAg ? 8

ETIOLOGY Tridimentional Structure of HBV

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ETIOLOGY Tabulate Structure of HBV

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ETIOLOGY : HBV  Genome    

S C P X

of HBV: region region region region

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ETIOLOGY Structure of HBV DNA

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ETIOLOGY: HBV MARKS  Marks     

of HBV 1. HBsAg, HBsAb 2. HBeAg, HBeAb 3. HBcAg, HBcAb 4. HBV DNA 5. HBV DNAP 13

ETIOLOGY: HBV MARKS  HBV

marks and the clinical significance:  HBsAg:  Stand for infection of HBV  HBsAb:  The only protective antibody stands for proper immune response to vaccination or natural infection(post-infection immunity).

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ETIOLOGY: HBV MARKS  HBeAg:

Comes during the virus` active copy (`soluble).  Stand for the infectivity of blood  HbeAb:  Virus copy is decreased (generally last for 1~2 years)  If mutation is at preC gene, HBeAg may be negative, but HBV is in active copying, and perhaps sometimes can exaggerate the state of illness. 

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ETIOLOGY: HBV MARKS  HBcAg:

Active virus copy  Infectivity of blood  HBcAb:  Virus copy and infectivity of blood decreased  HBc-IgM:  Acute phase or acute outbreak in chronic type  HBc-IgG ：  Past infection 16 

ETIOLOGY: HBV MARKS  Molecular

biology of HBV:  1. HBV DNA ：  Free HBV DNA ： The appearance in the blood indicates active copy of HBV.  Combined HBV DNA:  2. HBV DNAP: usually does not detect 17

The relationship of HBV marks in acute HBV infection

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ETIOLOGY: HCV Only human beings and orang are susceptible to HCV.  HCV always maintain a low concentration in blood.  HCVAg can not be detected in blood all along.  HCVAb is not a kind of protective antibody. On the contrary, HCVAb indicate infectivity of blood. 

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ETIOLOGY: HCV HCV-Ab will not transfer from positive to negative soon after anti-virus therapy.  The appearance of HCV-IgM indicate the activity of the disease.  HCV RNA positive blood also indicate infectivity. 

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ETIOLOGY: HDV HDV: Defective RNA virus HDV cannot copy itself without HBV or other DNA virus.

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ETIOLOGY: HEV  HEV:

Discharged through bile and stool  HEV-IgM and HEV-IgG:  Appear in blood almost at the same time but HEV-IgM disappears early. 

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EPIDEMIOLOGY 1. Source of infection

2. Transmitting routes

patients, the covert infection ones

fecal-oral route



A E B

blood

C

the acute, the chronic,

D

and the carriers

G  TTV

body fluid mother to baby sexually other routes

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EPIDEMIOLOGY  3.

Susceptibility and immunity:  Hepatitis A:  Few babies get infected with HAV within 6 months because they get HAV-IgG from their mothers through placenta.  Host will get permanent immunity after HAV infection.

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EPIDEMIOLOGY  3.

Susceptibility and immunity:  Hepatitis B:  Generally, new baby has no HBsAb from its mother, so all babies are susceptible to HBV.  As time going, many people can get immunity after covert infection. (In China, HBsAb can be detected in about half of people older than 30 years.) 25

EPIDEMIOLOGY  3.

Susceptibility and immunity:  Hepatitis C:  Anyone is susceptible to HCV.  HCV-Ab is not a protective antibody.  Hepatitis D:  HDV-IgG is not protective.  Hepatitis E:  All susceptible to HEV  Covert HEV infection is common in young children .  In adults, HEV infection usually results in overt infection. 26

EPIDEMIOLOGY  Distribution

of HAV infection:

 1.

Sporadic:  2. Epidemic outbreak:  More than 310,000 people got overt infection of HAV in Shanghai in 1988.  3. Seasonal distribution:  HAV: autumn and winter  HEV: rainy season or after flood  4. Geography distributing:  Not distinctly 27

EPIDEMIOLOGY:  degree  low

area

carrying rate 0.2~0.5%

 moderate

2 ~ 7%

 high

8~20%

area

Distribution of HBV infection distribution north America, west Europe, Australia east Europe, Mediterranean, Japan, Russia tropic Africa, south-east Asia, China

 HCV

& HDV  HEV infection is mainly in developing countries in Asia and Africa. 28

EPIDEMIOLOGY  Distribution

of HBV infection:  5% of world population (350 million) is in chronic carrier state of HBV ．  Asia and Africa with the carrying rate of about 8%~15%  Of HBV carrier state, 50%~70% is chronic hepatitis B. 29

EPIDEMIOLOGY acute HBV infection infection in infection in childhood>95% adults <10% 50-70% chronic HBV infection recovered

10-20% chronic hepatitis B 20% cirrhosis

HCC 1-5%

carrier state

recovered

liver failure 30

EPIDEMIOLOGY  HCV

infection:  170 million in the world (half of HBV)  HDV infection:  HEV infection:

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Pathogenesis of hepatitis A 

Hepatitis A:

 HAV→digestive   

tract →blood→liver→bile→stool

T cell→γ-interferon





CD T + 8



recognize

HLA-I Ag HAV-Ag Liver cell

lysed



released of HAV



Which will be cleared later

 Immune

complex 32

Pathogenesis of hepatitis B The pathological changes of liver cells is considered mainly due to cell-mediated immunity.  The main target antigen of immunoreaction is HBc-Ag.  Different immunoreaction, different clinical manifestations. 

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Pathogenesis: different result of HBV infection Carrier

state:  Get infected when the hosts’(new babies or young children) immunity is immature and result in immunological tolerance.  Those in adults belongs to factors of descendiblity. 34

Pathogenesis: different result of HBV infection Acute

hepatitis B:  Acute hepatitis is common in adults because they are always with normal immunity.

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Pathogenesis: different result of HBV infection  Chronic

hepatitis B:  HBV infection sometimes results in chronic hepatitis because:  The host is always with decreased immune function or immunodeficiency.  Or with incomplete immunological tolerance  Other reasons such as gene mutation of HBV 36

Pathogenesis: different result of HBV infection  Fulminant         

hepatitis B: hypersensitivity large quantity of Ag-Ab complex activation of complement endotoxin TNF IL-1 IL-6 CTL necrosis of large quantity of liver cells

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ADCC Killer cell

liver celll infected with HBV Fab Fc Anti-LSP

Fab

cytolysis LSP: liver specific membrane lipoprotein

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Clinical Manifestations  Incubation     

Period: Hepatitis A: 15~45d Hepatitis B: 30~180d Hepatitis C: 15~150d Hepatitis E: 10~70d Hepatitis D: equal to hepatitis B (?) 39

Clinical Manifestations Acute Hepatitis: (mainly hepatitis A and E, occasionally hepatitis B and C ) Icteric type: 1. Preicteric phase 2. Icteric phase 3. convalescent period Anicteric type:

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Clinical Manifestations Acute Hepatitis

Icteric type: 2~4 months 1. Preicteric phase: 5~7d light fever, fatigue, nausea, vomiting, being disgusted with oil, abdominal distention, right upper quadrant pain ， ALT increased 2. Icteric phase: 3. Convalescent period: Anicteric type:

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Clinical Manifestations Acute Hepatitis Icteric type: 2~4 months 1. Preicteric phase: 5~7 d 2. Icteric phase: 2~6 weeks symptoms ? transient obstructive jaundice hepatosplenomegaly TBIL and ALT increased 3. Convalescent period: 1~2 months

Anicteric type: 42

Clinical Manifestations Acute Hepatitis Icteric type: 2~4 months 1. Preicteric phase: 2. Icteric phase: 3. Convalescent period: 1~2 months symptoms alleviated, jaundice subsidise, hepatosplenomegaly withdraw, and the liver function recovered gradually Anicteric type: 43

Clinical Manifestations Acute Hepatitis (hepatitis A; hepatitis E) Icteric type: Anicteric type: (subclinical infection?)

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Clinical Manifestations  Chronic

hepatitis:  Definition:  Chronic hepatitis is a descriptive term used to denote ongoing inflammation (> 6 months) of the hepatic parenchyma. HBV  The leading cause: HCV HDV 45

Clinical Manifestations  Chronic       

hepatitis: (Hepatitis B, C and D) Symptoms: low fever fatigue dizziness symptoms of alimentary tract jaundice discomfort in the right upper quadrant 46

Clinical Manifestations  Chronic

hepatitis: (Hepatitis B, C and D)  Signs:  hepatic face  hepatic palm, liver palm, palmar erythema  spider angioma, spider telangiectasia, spider nevi  jaundice  progressive splenomegaly 47

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Clinical Manifestations  Chronic    

 

  

hepatitis: (Hepatitis B, C and D) Liver function: alanine aminotransferase (ALT) aspartate aminotransferase (AST) alkaline phosphatase (AKP or ALP) gamma glutamyltranspeptidase (γ-GT) Both AKP and γ-GT denote `biliary obstruction or cholestasis.

total bilirubin(TBil) total protein (TP)

albumin (A)

globulin (G)

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Clinical Manifestations  Chronic  

hepatitis: (Hepatitis B, C and D) Prognosis: Stones will be penetrated through by dripping water.

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Clinical Manifestations  Fulminant       

hepatitis: Definition: Morbidity: 0.2--0.5% Mortality: 80%, 70%, 60% Clinical types: acute fulminant hepatitis subacute fulminant hepatitis chronic fulminant hepatitis 51

Clinical Manifestations  Fulminant         

hepatitis: Main clinical manifestations of fulminant hepatitis progressive symptoms of alimentary tract progressive `hemorrhage tendency ascites hepatic encephalopathy and hydrocephalus hepatatrophia hepato-renal syndrome TBIL>171μmol/L PTA (thrombinogen activity)< 40% 52

Clinical Manifestations  Acute

fulminant hepatitis:  Begin with acute icteric hepatitis and the following clinical manifestations appear within 10 days:  Hepatic encephalopathy (alteration of character, fidgety, delirium, somnolence, coma, convulsion, hydrocephalus, pathologic reflexes)  jaundice deepened rapidly(TBIL>171μmol/L within 10 days)  liver shrinked in a short time  ascites  acute renal failure  PTA<40% 53

Clinical Manifestations  Subacute

fulminant hepatitis:  Begin with acute icteric hepatitis and the following clinical manifestations appear after 10 days:  veriest fatigue, awful anorexia, exceeding nausea, ferocious abdominal distension(flatus), obvious acites, veriest jaundice and hemorrhagic tendency, hepatic coma, hepato-renal syndrome 54

Clinical Manifestations  Subacute

fulminant hepatitis:  Rise as acute icteric hepatitis and appear the followings after 10 days:  SB>171μmol/L  PTA<40%  aminotransferase-bilirubin separation  ALT/AST converted  A/G inversion 55

Clinical Manifestations  Chronic

fulminant hepatitis:  Subacute fulminant hepatitis on a chronic hepatitis or hepatocirrhosis basis

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Clinical Manifestations Cholestatic

hepatitis:  Cholestasis can result from extrahepatic biliary obstruction or from intrahepatic causes, we will talk about the later only.  Generally last for 2~4 months

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Clinical Manifestations  Symptoms

and sings of Cholestatic hepatitis:  One deepened, one lightened:  urine color deepened, stool color lightened  One severe, one light:  severe jaundice, light symptoms  One big, one little:  big liver, little gallbladder  Both painful and itching:  feel painful when liver knocked 58

Clinical Manifestations  Laboratory

test of Cholestatic hepatitis:  Laboratory data show modest abnormalities in aminotransferase concentrations but marked elevations in:  AKP↑  γ-GT↑  TBil↑  cholesterin (cholesterol)↑  PTA>40% 59

Clinical Manifestations Hepatocirrhosis:

Hepatocirrhosis is characterized by hepatic necrosis, regeneration (formation of regenerative nodules), fibrosis, and architectural distortion.



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Clinical Manifestations Hepatocirrhosis is clinically divided into:  Compensatory hepatocirrhosis  Decompensatory hepatocirrhosis 

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Clinical Manifestations  Compensatory         

hepatocirrhosis: symptoms and signs: fatigue symptoms of alimentary tract jaundice hepatic facies hepatic palm spider angioma splenomegaly light esophagus varix

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Clinical Manifestations  Compensatory    

hepatocirrhosis: laboratory tests: ALT increased frequently but always light AST/ALT>1 Globulin compensatory



prognosis:

decompensatory liver cancer 63

Clinical Manifestations  Decompensatory

hepatocirrhosis:  Clinical manifestations of decompensatory hepatocirrhosis can be divided into two parts: one is related with the decreased liver function(similar to those in compensatory hepatocirrhosis ), another characterized by the following three is related with the increased portal pressure:  Splenomegaly  Esophagus varix: hematemesis (or hematochezia)  Ascites 64

Laboratory tests  Liver

function:  ALT, AST  γ-GT, AKP  TP, A, G  SBil  Urine bilirubin  Urobilinogen:  PT  PTA  Serum `ammonia

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Laboratory tests  Laborstory        

test: HAV-IgM HBV-Marks HBV-DNA test HCV-IgM/G HEV-IgM/G Biopsy of the liver tissue Blood routine test Urine routine test

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Assistant examinations  Assistant

examinations:  Ultrasonic examination is very useful to the diagnosis of fulminant hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer.

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Diagnosis Epidemiology:  Symptoms and signs:  Laboratory tests: 

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Differential diagnosis  Jaundice  

caused by other reasons: Hemolytic jaundice Extrahepatic obstructive jaundice

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Differential diagnosis  Hepatitis

caused by other reasons:  1. Hepatitis caused by other virus (but not always called viral hepatitis): Epstein-Barr virus and CMV  2. Hepatitis caused by nonviral infection disease  3. drug-related hepatitis  4. Alcoholic liver disease  6. Wilson’s disease  7. Budd-chiari syndrome

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Treatment  Principle    

of treatment: Give priority to rest and alimentation Use drugs as supplement No drinking and not being tired Avoid drugs that may do harm to the liver

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Treatment  Acute

hepatitis A:  Acute hepatitis C:  Use interferon-α early  3 M.U. i.H. q.o.d. 3~6 months  Ribavirin 800~1200mg/d  Aim: seroconversion of HCV RNA

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Treatment  Chronic 

hepatitis: Liver protection therapy:

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Treatment  Chronic

hepatitis:  Anti-virus therapy(1. interferon):  Indications:  ① Active replication of HBV  ② Active hepatitis (80U/L
Treatment  Chronic

hepatitis:  Anti-virus therapy (1. interferon)  Contraindications:  Age: too young or too old (beyond 10~60y)  Decompensatory hepatocirrhosis  Organ function failure: heart failure, renal failure, liver failure 75

Treatment      



Anti-virus therapy in chronic hepatitis B: 1. Interferon: Dose and method: 3 M.U~6 M.U. i.H. q.o.d. Period of treatment: 6 months~1 year Target: Inhibition of HBV replication HBeAg and HBV DNA turn negative (seroconversion) It is difficult to turn HBsAg from positive to negative. 76

Treatment  Anti-viral

therapy in chronic hepatitis B:  2.Lamivudine (`Nucleoside `analogues):  Lamivudine has been approved by the FDA for treating HIV and chronic hepatitis B.  It has potent activity as a reverse transcriptase inhibitor (as an RNA chain terminator in HBV reverse transcription) of both HIV and HBV. 77

Treatment  Anti-viral

therapy in chronic hepatitis:  2.Lamivudine (Nucleoside analogues):  ① Active replication of HBV  ② Active hepatitis with increased ALT(﹥ 200u/l )  ③ Positive HBeAg and HBV DNA:  ④ HBeAg negative, anti-HBe & HBV DNA positive (mutation of Pre-C gene)  ⑤ TBil < 50μmol/L 78  ⑥ Older than 16 years

Treatment  Anti-viral 

therapy in chronic hepatitis: 2. Lamivudine (Nucleoside analogues):



Dose and method:  100mg/d. p.o.  period of treatment: 1 ~3 years  Serum HBV DNA decreases more than 90% within about 2 weeks. And the rate of HBV DNA seroconversion may be 70~90% 2 months later.

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Treatment  Immunity

modulation therapy in chronic hepatitis B  Thymosin  IL-2

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Treatment  Fulminant

hepatitis:  General and supporting therapy:  bed rest  low-protein diet (20 to 30 g/day)  the administration of enemas to cleanse the bowel  the use of oral lactulose (30 to 60 ml every 2 to 6 hours until loose stools are achieved)  treatment with all sedatives is contraindicated 81

Treatment  Fulminant

hepatitis:  General and supporting therapy:  Fresh-frozen plasma for coagulation defects  Monitored and treated carefully for gastrointestinal bleeding:  cimetidine  omeprazole  somatostatin: octreotide 82

Treatment  Fulminant

hepatitis:  General and supporting therapy:  Careful attention to all details of "routine" medical management is most important, such as fluid and electrolyte balance, acid-base balance.

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Treatment  Anti-infection

therapy  Management of acute renal failure  Promote liver cell regenesis: PHGF  Liver transplantation

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Treatment Carriers:

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Prevention 

There are only vaccinations of HAV and HBV.

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Class is over

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