1. Acute And Chronic Viral Hepatitis

2. Acute viral hepatitis is a systemic infection affecting the liver predominantly.
Almost all cases of acute viral hepatitis are caused by one of five viral agents:
hepatitis A virus (HAV)
hepatitis B virus (HBV)
hepatitis C virus (HCV)
hepatitis D virus (HDV)
hepatitis E virus (HEV)

3. Acute hepatitis A

4. EPIDEMIOLOGY
HAV infection generally follows one of two epidemiologic patterns:
countries where sanitary conditions are poor, most children are infected at an early age(100% of preschool children)
Industrialized countries, where the prevalence of HAV infection is low among children and young adults.
In the United States, the prevalence of anti-HAV was approximately 10% in children but 37% in adults.

5. Virology
Hepatitis A virus is heat-, acid-, and ether-resistant RNA virus in the hepatovirus genus
It survives heat exposure of 60°C for 60 minutes but is inactivated at 85°C for 1 minute.
An initial step in the life cycle of a virus is its attachment to a cell surface receptor.
Whatever the entry mechanism, once HAV enters a cell, the viral RNA is uncoated, cell host ribosomes bind to viral RNA, and polysomes are formed.

6. transmission
transmission of HAV is the fecal-oral route or ingestion of contaminated food or water.
Although rare, transmission of HAV by a parenteral route has been documented after transfusion of blood or blood products.

7. PATHOGENESIS After HAV is ingested and survives gastric acid
it traverses the small intestinal mucosa and reaches the liver via the portal vein.
Once the virus enters the hepatocyte, it starts replicating in the cytoplasm
When the virus is mature, it reaches the systemic circulation and into the biliary tree, and eventually excreted in the feces.

8. CLINICAL FEATURES
Infection with HAV result in an acute self-limited episode of hepatitis.
The incubation period is commonly 2 to 4 weeks,
Children younger than 2 years are usually asymptomatic; jaundice develops in only 20% of them,
whereas symptoms develop in most children (80%) 5 years or older.
The rate of symptoms is high in adolescents and adults.

9. CLINICAL FEATURES
Prodromal symptoms (few days to 2 weeks) include fatigue, weakness, anorexia, nausea, vomiting, and abdominal pain and Dark urine . A low-grade fever between 38° and 39°C.
Dark urine precedes other symptoms in approximately 90% of infected persons
Clinical jaundice:With the onset of clinical jaundice, the constitutional prodromal symptoms usually diminish
Extrahepatic manifestations are less frequent in acute HAV infection than in acute HBV infection and include:
rash (14%)
arthralgias (11 %)
leukocytoclastic vasculitis, glomerulonephritis, and arthritis,

10. CLINICAL FEATURES Right upper quadrant tenderness(85%)
Mild liver enlargement (85%)
Splenomegaly (15%)
cervical lymphadenopathy(15%)

11. Laboratory Features
The serum AST and ALT show a variable increase during the prodromal phase of acute viral hepatitis and precede the rise in bilirubin level
The acute level of these enzymes, however, does not correlate well with the degree of liver cell damage.
Peak levels vary from 400–4000 IU or more;

12. Laboratory Features
Total bilirubin rises to levels ranging from 5–20 mg/dL(equally divided between the conjugated and unconjugated fractions)
Neutropenia and lymphopenia are transient and are followed by a relative lymphocytosis.
Prolongation of the prothrombin time (PT) may reflect a severe hepatic synthetic defect, signify extensive hepatocellular necrosis, and indicate a worse prognosis.
Serum alkaline phosphatase may be normal or only mildly elevated,

13. Diagnosis
A diagnosis of acute hepatitis A requires demonstration of IgM anti-HAV in serum.
The test result is positive from the onset of symptoms and usually remains positive for approximately 4 months
IgG anti- HAV is also detectable at the onset of the disease, remains present usually for life

15. Treatment symptomatic treatment is the rule.
No specific medications are available to treat acute hepatitis A
symptomatic treatment is the rule.

16. Prevention Attention to sanitation
Administration of serum immune globulin (IG)(0.02 mL/kg is recommended as early after exposure as possible) up to 2 weeks
high-risk populations were targeted for immunization
universal childhood vaccination policy was adopted in 2006, with the hope of eventually eliminating indigenous HAV transmission in the United States.

17. postexposure prophylaxis
For postexposure prophylaxis of intimate contacts (household, sexual, institutional) of persons with hepatitis A, the administration of IG 0.02 mL/kg is recommended as early after exposure as possible;
it may be effective even when administered as late as 2 weeks after exposure.
Prophylaxis is not necessary for those:
who have already received hepatitis A vaccine,
casual contacts (office, factory, school, or hospital),
for most elderly persons, who are very likely to be immune,
or for those known to have anti-HAV in their serum

18. Prognosis
Clinical and biochemical recovery is to be expected 1–2 months after all cases of hepatitis A
FULMINANT HEPATITIS A(FHF) due to HAV is rarely seen in children, adolescents, or young adults.
The case-fatality rate of 0.3% in persons of all ages

19. Acute Hepatitis B

20. Viral Proteins and Particles
Virology
Hepatitis B virus is a DNA virus with a remarkably compact genomic structure.
Hepatitis B isolates fall into one of at least eight subtypes and eight genotypes (A–H).
Viral Proteins and Particles

21. Hepatitis B Virus

23. HBV Genom

24. The protein product of the S gene is HBsAg (major protein),

25. HBV Genom

26. The antigen expressed on the surface of the nucleocapsid core is referred to as hepatitis B core antigen (HBcAg), and its corresponding antibody is anti-HBc.
hepatitis B e antigen (HBeAg), a soluble, nonparticulate, nucleocapsid protein that is immunologically distinct from intact HBcAg

27. HBV Genom

28. groups with high rates of HBV infection include
Epidemiology
>350 million HBsAg carriers in the world.
groups with high rates of HBV infection include
spouses of acutely infected persons,
sexually promiscuous persons
health care workers exposed to blood
persons who require repeated transfusions especially with pooled blood product concentrates (e.g., hemophiliacs)
prisoners
family members of chronically infected patients.
persons with Down's syndrome, lepromatous leprosy, leukemia, Hodgkin's disease, polyarteritis nodosa; in patients with chronic renal disease on hemodialysis; and in injection drug users.

29. Epidemiology
Percutaneous inoculation has long been recognized as a major route of hepatitis B transmission,
in approximately two-thirds of patients with acute type B hepatitis, no history of an identifiable percutaneous exposure can be elicited.
HBsAg has been identified in almost every body fluid from infected persons, and at least some of these body fluids—most notably semen and saliva—are infectious, albeit less so than serum,

30. Epidemiology
Oral ingestion has been documented as a potential but inefficient route of exposure.
By contrast, the two nonpercutaneous routes considered to have the greatest impact are intimate (especially sexual) contact and perinatal transmission.

31. Perinatal transmission
occurs primarily in infants born to HBsAg carrier mothers
10% of infections may be acquired in utero,
most infections occur approximately at the time of delivery and are not related to breast feeding.
The likelihood of perinatal transmission of HBV:
90% of HBeAg-positive mothers
10–15% of anti-HBe-positive mothers
In most cases, acute infection in the neonate is clinically asymptomatic, but the child is very likely to become an HBsAg carrier

33. Clinical and Laboratory Features
incubation period for hepatitis B and D from 30–180 days (mean, 8–12 weeks)
Prodromal symptoms
icteric phase symptoms
hepatitis B is heralded by a serum sickness–like syndrome.
Complete clinical and biochemical recovery is to be expected 3–4 months after the onset of jaundice in three-quarters of uncomplicated, self- limited cases of hepatitis B
among healthy adults, acute hepatitis B is self-limited in 95–99%

35. Diagnosis
diagnosis of HBV infection can usually be made by detection of HBsAg in serum.
Infrequently, levels of HBsAg are too low to be detected during acute HBV infection, In such cases, the diagnosis can be established by the presence of IgM anti-HBc.
The titer of HBsAg bears little relation to the severity of clinical disease

36. Treatment
In hepatitis B, among previously healthy adults who present with clinically apparent acute hepatitis, recovery occurs in ~99%; therefore, antiviral therapy is not likely to improve the rate of recovery and is not required

37. Prevention(postexposure prophylaxis )
For perinatal exposure of infants born to HBsAg-positive mothers, a single dose of HBIG, 0.5 mL, should be administered IM in the thigh immediately after birth, followed by a complete course of three injections of recombinant hepatitis B vaccine to be started within the first 12 h of life.
For those experiencing a direct percutaneous inoculation or transmucosal exposure to HBsAg-positive blood or body fluids (e.g., accidental needle stick, other mucosal penetration, or ingestion), a single IM dose of HBIG, 0.06 mL/kg, administered as soon after exposure as possible, is followed by a complete course of hepatitis B vaccine to begin within the first week.

38. Prevention(postexposure prophylaxis )
For those exposed by sexual contact to a patient with acute hepatitis B, a single IM dose of HBIG, 0.06 mL/kg, should be given within 14 days of exposure, to be followed by a complete course of hepatitis B vaccine.
When both HBIG and hepatitis B vaccine are recommended, they may be given at the same time but at separate sites.

39. Clinical manifestations
The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease.
During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis
During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
Extrahepatic manifestations also can occur with both acute and chronic infection.

40. Chronic HBV

41. Chronic HBV(natural course)
The natural course of chronic hepatitis B virus infection is determined by the interplay between virus replication and the host immune response.
Chronic HBV infection generally consists of two phases:
an early replicative phase with active liver disease
a late or low replicative phase with remission of liver disease
In patients with perinatally acquired HBV infection, there is an additional immune tolerance phase in which virus replication is not accompanied by active liver disease

42. Replicative phase(Immune tolerance)
In patients with a perinatally acquired HBV infection, the initial phase is characterized by high levels of HBV replication
the presence of HBeAg and high levels of HBV DNA in serum—but no evidence of active liver disease as manifested by lack of symptoms, normal serum ALT concentrations, and minimal changes on liver biopsy .

43. Replicative phase(Immune tolerance)
The lack of liver disease despite high levels of HBV replication is believed to be due to immune tolerance to HBV
Experiments in mice suggest that the transplacental transfer of maternal HBeAg may induce specific unresponsiveness of T cells to HBeAg and to HBcAg, resulting in an ineffective cytotoxic T cell lysis of infected hepatocytes

44. Replicative phase(Immune tolerance)
The immune tolerance phase usually lasts 10 to 30 years, during which there is a very low rate of spontaneous HBeAg clearance
The low rate of viral clearance in adolescence and early adulthood accounts for the high frequency of maternal-infant transmission in Asian countries.

45. Replicative phase(Immune clearance)
The transition from the immune tolerant to the immune clearance phase occurs during the second and third decades in patients with perinatally acquired HBV infection.
During the immune clearance phase, spontaneous HBeAg clearance increases to an annual rate of 10 to 20 percent

46. Replicative phase(Immune clearance)
HBeAg seroconversion is frequently, but not always, accompanied by biochemical exacerbations (abrupt increases in serum ALT)
Exacerbations are believed to be due to a sudden increase in immune-mediated lysis of infected hepatocytes.
They are often preceded by an increase in serum HBV DNA and a shift of HBcAg (hepatitis B core antigen) from nuclear to cytoplasmic sites within hepatocytes
How these changes occur is not known.

47. Replicative phase(Immune clearance)
Most exacerbations are asymptomatic and are discovered during routine follow-up.
However, some are accompanied by symptoms of acute hepatitis and may lead to the incorrect diagnosis of acute hepatitis B in patients who are not previously known to have chronic HBV infection
Exacerbations may be associated with an elevation in the IgM anti-HBc titer, which may lead to misdiagnosis of acute HBV infection and an increase in the serum alpha-fetoprotein concentration
exacerbations are more commonly observed in men than in women . The reason for the gender difference is not clear, but a higher frequency of exacerbations in men may at least in part account for a higher incidence of HBV-related cirrhosis and HCC among men.

48. Replicative phase(Immune clearance)
In a small percentage of patients, exacerbations result in hepatic decompensation and rarely death from hepatic failure.

49. Replicative phase(Immune clearance)
Not all exacerbations lead to HBeAg seroconversion and clearance of HBV DNA from the serum, a phenomenon termed abortive immune clearance
These patients may develop recurrent exacerbations with an intermittent disappearance of serum HBV DNA with or without a transient loss of HBeAg
Such repeated episodes of hepatitis may increase the risk of developing cirrhosis and hepatocellular carcinoma (HCC).

50. Low or nonreplication phase (inactive carrier state)
Patients in the low or nonreplicating phase/inactive carrier state are HBeAg negative and anti-HBe positive.
In some patients, HBV DNA is undetectable in serum, even when tested by polymerase chain reaction assays, and liver disease is in remission as evidenced by normal serum ALT concentrations and the resolution of necroinflammation in liver biopsies.

51. Low or nonreplication phase (inactive carrier state)
Data indicate that significant liver disease can be found in patients with HBeAg- negative chronic HBV who have a persistently normal serum ALT.

52. Resolution of chronic HBV infection
 Some patients with chronic HBV infection become HBsAg negative.
The annual rate of delayed clearance of HBsAg has been estimated to be 0.5 to 2 percent in Western patients and much lower (0.1 to 0.8 percent) in Asian countries
Clearance was preceded by a decrease in HBV DNA.
HBsAg clearance may be preceded by decreasing levels of HBsAg .
In most reports, patients without cirrhosis who cleared HBsAg appeared to have a good prognosis. Despite a generally favorable prognosis, clearance of HBsAg does not preclude the development of cirrhosis or HCC.

53. Reactivation following seroconversion
A subset of patients who achieve HBeAg seroconversion experience reactivation. Reactivation can occur in patients who receive immunosuppressive therapy, but can also occur spontaneously

54. مهم

56. WHO SHOULD BE TREATED AND HOW
Patients in whom therapy is indicated: acute liver failure,
clinical complications of cirrhosis,
cirrhosis or advanced fibrosis with high serum HBV DNA,
prevention of reactivation of chronic HBV during chemotherapy or immunosuppression.