1. Hepatitis Viruses
SAMUEL AGUAZIM .M.D.
Lange Chapter 41

2. Liver Functions Stores sugar needed for energy Absorbs good nutrients
Breaks down poisons (toxins) and drugs
Makes important proteins that help build new tissue and repair broken tissue
Produces bile, which helps remove waste from the body

3. What is Viral Hepatitis
Viral hepatitis is a systemic disease primarily involving the liver predominantly caused by 5 kinds of viruses at least
Viral hepatitis may be divided into 5 types according to etiology, that is hepatitis A, B, C, D and E
Although the agents can be distinguished by its antigenic properties, the 5 kinds of viruses may produce clinical similar illness

4. Causes of Acute Viral Hepatitis
hepatitis A virus (HAV), the etiologic agent of viral hepatitis type A (infectious hepatitis); hepatitis.
B virus (HBV), which is associated with viral hepatitis B (serum hepatitis);
hepatitis C virus (HCV), the agent of hepatitis C (common cause of posttransfusion hepatitis); or
hepatitis E virus (HEV), the agent of enterically transmitted hepatitis

5. Other Causes of Sporadic Hepatitis
yellow fever virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, rubella virus, and the enteroviruses, are discussed in other chapters.

6. Overview
Hepatitis viruses produce acute inflammation of the liver, resulting in a clinical illness characterized by fever, gastrointestinal symptoms such as nausea and vomiting, and jaundice.
Regardless of the virus type, identical histopathologic lesions are observed in the liver during acute disease.

7. Virus 
Hepatitis A 
Hepatitis B 
Hepatitis C 
Hepatitis D 
Hepatitis E 
Family
Picornaviridae
Hepadnaviridae
Flaviviridae
Unclassified
Hepeviridae
Genus
Hepatovirus 
Orthohepadnavirus 
Hepacivirus 
Deltavirus 
Hepevirus 
Virion
27 nm, icosahedral
42 nm, spherical
60 nm, spherical
35 nm, spherical
30–32 nm, icosahedral
Envelope No
Yes (HBsAg)
Yes
Genome
ssRNA
dsDNA
Genome size (kb)
7.5
3.2
9.4
1.7
7.2
Stability
Heat- and acid-stable
Acid-sensitive
Ether-sensitive, acid-sensitive
Heat-stable
Transmission
Fecal–oral
Parenteral
Prevalence
High
Moderate
Low, regional
Regional
Fulminant disease
Rare
Frequent
In pregnancy
Chronic disease
Never
Often
Oncogenic ?

9. HCV- most common cause of post transfusion hepatitis most prevalent blood-borne pathogen in the U.S.
HEV: Fatality in pregnant women

10. Many viruses cause hepatitis
Many viruses cause hepatitis. Of these, five medically important viruses are commonly described as “hepatitis viruses”:
hepatitis A virus (HAV)
hepatitis B virus (HBV)
non-A, non-B viruses, of which hepatitis C virus (HCV) is the most common
hepatitis D virus (HDV, delta agent)
Hepatitis E virus (HEV).

11. HEPATITIS A VIRUS Disease: HAV causes hepatitis A.
Important Properties:
enterovirus classified in the picornavirus family.
single-stranded positive polarity RNA genome
nonenveloped icosahedral nucleocapsid
replicates in the cytoplasm of the cell.
known as enterovirus 72.
one serotype
no antigenic relationship to HBV or other hepatitis viruses.

12. HAV

16. HAV Transmission & Epidemiology:
transmitted by the fecal-oral route.
appears in the feces 2 weeks before the appearance of symptoms.
Children are the most frequently infected group
summer camps and boarding schools.
fecally contaminated water or food such as oysters grown in polluted water and eaten raw.
Unlike HBV, HAV is rarely transmitted via the blood, because the level of viremia is low
chronic infection does not occur.

18. Pathogenesis HAV:
probably replicates in the GI tract and spreads to the liver via the blood. Hepatocytes are infected.
infection of cultured cells produces no cytopathic effect.
likely that attack by cytotoxic T cells causes the damage to the hepatocytes.
no chronic infection occur.
HAV Immune response
IgM antibody, detectable at the time jaundice appears followed 1—3 weeks later by the production of IgG antibody, which provides lifelong protection.
IgM Important in the laboratory diagnosis of hepatitis A.

19. Resistance (HAV)
Resistant to inactivation by heat at 60 0 C for one hour, ether & acid at pH 3.
Not affected by anionic detergents.
its infectivity can be preserved for at least 1 month after being dried and stored at 25°C and 42% relative humidity or for years at –20°C

20. HAV
The virus is destroyed by autoclaving (121°C for 20 minutes), by boiling in water for 5 minutes, by dry heat (180°C for 1 hour), by ultraviolet irradiation (1 minute at 1.1 watts), by treatment with formalin (1:4000 for 3 days at 37°C), or by treatment with chlorine (10–15 ppm for 30 minutes).

21. HAV
Heating food to >85°C (185°F) for 1 minute and disinfecting surfaces with sodium hypochlorite (1:100 dilution of chlorine bleach) are necessary to inactivate HAV.

22. HAV Clinical Findings:
Fever, anorexia (diminished appetite) nausea, vomiting, and jaundice are typical.
Dark urine, pale feces, and elevated transaminase levels are seen.
Most cases resolve spontaneously in 2—4 weeks.
short incubation period (3—4 weeks) or ( days), in contrast to that of hepatitis B, which is 10—12 weeks.
Laboratory Diagnosis:
The detection of IgM antibody is the most important test
Treatment: No antiviral therapy is available.

23. HAV Prevention:
a. Active immunization with a vaccine containing inactivated HAV is available.
b. Passive immunization with immune serum globulin prior to infection or early in the incubation period can prevent or mitigate the disease.
c. Observation of proper hygiene, eg, sewage disposal and hand washing after bowel movements, is of prime importance

24. HEPATITIS B VIRUS hepadnavirus family.
42-nm enveloped virion, icosahedral nucleocapsid
core containing a partially double-stranded circular DNA genome.
Important antigens
surface antigen (HBsAg): protein in the envelope which is important for laboratory diagnosis and immunization.
core antigen (HBcAg): located in the core (nucleocapsid)
e antigen (HBeAg): located in the core is an important indicator of transmissibility and active viral replication.

25. HBV
Electron microscopy of a patient’s serum reveals three different types of particles:
a few 42-nm virions and many 22-nm spheres and long filaments 22 nm wide, which are composed of surface antigen.
HBV is the only human virus that produces these spheres and filaments in such large numbers in the patient’s blood.

27. HBV Transmission & Epidemiology:
Four main modes of transmission are:
via blood
during sexual intercourse
perinatally from mother to newborn.
Intravenous ( IV)

28. HBV Facts found worldwide but is particularly prevalent in Asia.
more than 300 million people are chronically infected with HBV.
high incidence of hepatocellular carcinoma (hepatoma) in many Asian countries
Immunization against HBV in Taiwan has significantly reduced the incidence of hepatoma in children.
HBV vaccine is the first vaccine to prevent a human cancer.

29. HBV Pathogenesis & Immunity:
After entering the blood, the virus infects hepatocytes
viral antigens are displayed on the surface of the cells.
Cytotoxic T cells mediate an immune attack against the viral antigens
inflammation and necrosis occur.
probably the result of this cell-mediated immune injury
HBV itself does not cause a cytopathic effect.
Antigen-antibody complexes cause some of the early symptoms, eg, arthritis, and some of the complications in chronic hepatitis, eg, immune-complex glomerulonephritis, and vasculitis.

30. HBV Chronic Carrier
Unlike hepatitis A patients, about 5% of patients with hepatitis B become chronic carriers of HBV.
chronic carrier: someone who has HBsAg persisting in their blood for at least 6 months.
a persistent infection of the hepatocytes, which results in the prolonged presence of HBV and HBsAg in the blood.
more likely to occur when infection occurs in a newborn than in an adult, probably because a newborn’s immune system is less competent than an adult’s.
90% of those infected as neonates become chronic carriers.
neonatal infection is associated with a high risk of hepatocellular carcinoma.
Lifelong immunity occurs after the natural infection and is mediated by humoral antibody against HBsAg

31. Chronic Active Hepatitis
Active inflammation on biopsy
Fibrosis present
May progress to liver cancer
Will lead to cirrhosis
Due to Hep b: Tx with interferon and lamuvidine
Due to Hep c: Tx with interferon and ribavarin

32. HBV Clinical Findings:
Many HBV infections are asymptomatic and are detected only by the presence of antibody to HBsAg.
mean incubation period for hepatitis B is 10—12 weeks, which is much longer than that of hepatitis A (3—4 weeks).
clinical appearance of acute hepatitis B is similar to that of hepatitis A.
However, with hepatitis B, symptoms tend to be more severe, and life-threatening hepatitis can occur.
Most chronic carriers are asymptomatic, but some have chronic active hepatitis, which can lead to cirrhosis and death.

33. Liver cirrhosis cessation of enzymatic processes in the liver
consequence of repeated immune system attacks
cirrhosis cannot be cured
progress may be stopped if the cause is treated
cessation of enzymatic processes in the liver
Ascites, jaundice, internal bleeding, and hepatic encephalopathy
candidates for liver transplantation

34. Fulminant hepatitis
occurs in 1% of acutely infected individuals; more likely if HBV and HDV coinfect.
more severe symptoms, can be fatal
severe liver damage: ascites and bleeding
liver shrinkage

35. Primary hepatocellular carcinoma
Liver carcinoma follows HBV infection after 9-35 years
Chronic HCV infection can also result in hepatocellular carcinoma

37. Extrahepatic Findings of HBV infections
* Polyarteritis Nodosa
* Membranous nephropathy
* Membranoproliferative glomerulonephritis type 1.

38. On histology
CHRONIC HEPATITIS B may show pathonomonic ground glass hepatocyte inclusions
(arrows heads) which is a granular homogenous eosinophilic staining of cytoplasm caused by presence of HBsAg

39. Laboratory Diagnosis HBV:
The most important laboratory test for the detection of early HBV infection is the immunoassay for HBsAg.
HBsAg appears during the incubation period, first viral marker detected in the blood of HBV infection and is detectable in most patients during the prodrome and acute disease

41. HBeAg
arises during the incubation period and is present during the prodrome and early acute disease and in certain chronic carriers.
HBeAg has a high correlation with DNA polymerase activity.
presence is an important indicator of transmissibility, and, conversely
finding of HBeAb indicates low transmissibility

43. HBcAg found within the nuclei of infected hepatocytes
not generally in peripheral circulation except as an integral component of Dane particle.
Anti-HBc may be the only detected serologic marker during the early convalescent phase of an HBV infection “window phase”.

44. HBV Treatment:
Alpha interferon is clinically useful for the treatment of chronic hepatitis B infections.
Lamivudine that inhibit the reverse transcriptase of HIV also effective against the DNA polymerase of HBV.
HBV Prevention:
involves the use of either the vaccine or hyperimmune globulin or both.
(1)The vaccine, eg, Recombivax, contains HBsAg as the immunogen. Second generation vaccine is using recombinant DNA.
(2) Hepatitis B immune globulin (HBIG) contains a high titer of HBsAb because it is prepared from sera of patients who have recovered from hepatitis B.

46. Vaccine Recommended Newborns/youth Healthcare Workers IV drug users
Individual with multiple sexual partners

48. NON-A, NON-B HEPATITIS VIRUSES
describes the cases of hepatitis for which existing serologic tests had ruled out all known viral causes.
term is not often used because the main cause of non-A, non-B hepatitis, namely, hepatitis C virus, has been identified.

49. HEPATITIS C VIRUS Disease: HCV causes hepatitis C.
Disease: HCV causes hepatitis C.
Important Properties:
enveloped virion containing a genome of single-stranded, positive-polarity RNA.
member of the flavivirus family.
no virion polymerase.
Multiple serotypes exist.

50. HEPATITIS C VIRUS Transmission & Epidemiology:
transmitted via blood.
most common cause of posttransfusion hepatitis.
intravenous drug user: all new HCV infections
Sexual transmission and transmission from mother to child have been difficult to document.
most prevalent blood-borne pathogen - U.S.
4 million people in the U.S. (1—2% of the population) are chronically infected with HCV.
infects hepatocytes: 30-50% of cases progress to chronic liver diseases
Alcoholism: hepatocellular carcinoma
Cancer: caused by prolonged liver damage and rapid growth rate of hepatocytes as the cells attempt to regenerate rather than by a direct oncogenic effect of HCV.

51. Liver transplant

52. Clinical Findings HCV
acute infection with HCV is milder than infection with HBV.
Fever, anorexia, nausea, vomiting, and jaundice are common.
Dark urine, pale feces, and elevated transaminase levels are seen
Laboratory Diagnosis:
detecting antibodies to HCV in an ELISA.
Blood products can now be tested for Ab to HCV.

53. HCV Treatment & Prevention:
Sofosbuvir ( first line)
A combination of alpha interferon and ribavirin is the treatment of choice for chronic hepatitis C, but it is expensive and has side effects that can limit its use.
Patients with chronic HCV infection should be advised to reduce or eliminate their consumption of alcoholic beverages to reduce the risk of hepatocellular carcinoma and cirrhosis
Simeprevir

55. HEPATITIS D VIRUS (DELTA VIRUS)
Disease: Hepatitis D virus (HDV) causes hepatitis D (hepatitis delta).
  Important Properties & Replicative Cycle:
unusual in that it is a defective virus
cannot replicate by itself because it does not have the genes for its envelope protein.
HDV can replicate only in cells also infected with HBV, because HDV uses the surface antigen of HBV (HBsAg) as its envelope protein.
HBV is therefore the helper virus for HDV.

56. Transmission & Epidemiology HDV:
transmitted by the same means as is HBV
sexually, by blood
perinatally.
In the United States, most HDV infections occur in intravenous drug users who share needles.
HDV infections occur worldwide with a similar distribution to that of HBV infections.

57. HDV Pathogenesis & Immunity:
the pathogenesis of hepatitis caused by HDV and HBV is the same
the virus-infected hepatocytes are damaged by cytotoxic T cells.
There is some evidence that delta antigen is cytopathic for hepatocytes.
IgG antibody against delta antigen is not detected for long periods after infection
uncertain whether long term immunity to HDV exists.
Because HDV can replicate only in cells also infected with HBV, hepatitis delta can occur only in a person infected with HBV.
A person can either be infected with both HDV and HBV at the same time, ie, be “coinfected,” or be previously infected with HBV and then be infected with HDV.

58. HDV Laboratory Diagnosis:
detecting either delta antigen or IgM antibody to delta antigen in the patient’s serum.
Treatment:
Alpha interferon can mitigate some of the effects of the chronic hepatitis caused by HDV but does not eradicate the chronic carrier state
Prevention of HBV infection:
Vaccine
hyperimmune globulin

59. HEPATITIS E VIRUS major cause of enterically transmitted hepatitis.
common cause of water-borne epidemics of hepatitis in Asia, Africa, India, and Mexico
uncommon in the United States.
nonenveloped, single-stranded RNA virus tentatively classified as a member of the calicivirus family.
Clinically the disease resembles hepatitis A, with the exception of a high mortality rate in pregnant women.
Pregnant women who acquire HEV have a 20% fatality rate (compared to 0.5% for the rest of the population).
India, a country where HEV is endemic.

60. HEPATITIS G VIRUS
member of the flavivirus family, as is HCV.
unlike HCV, which is clearly the cause of both acute hepatitis and chronic active hepatitis and predisposes to hepatocellular carcinoma, HGV has not been documented to cause any of these clinical findings.

61. EVERY TIME YOU TAKE 2 STEPS FORWARD YOU HAVE SUCCEEDED IN ELIMINATING FAILURE AND BACKWARDNESS….
DRS