Basic discussion on Hepatitis Viruses along with structure, pathogenesis, clinical manifestations, laboratory diagnosis, and management.

1. Hepatitis Viruses- A & E
Dr.Suprakash Das
Assist. Prof.

2. INTRODUCTION
What Viral Hepatitis is?
 Viral hepatitis is an infection that predominantly affects the liver but may also have
systemic clinical manifestations.
 The vast majority of cases of hepatitis are caused by one of five hepatotropic viruses:
Hepatitis A virus (HAV);
Hepatitis B virus (HBV);
Hepatitis C virus (HCV);
Hepatitis D (delta) virus (HDV); and
Hepatitis E virus (HEV).
 HBV, HCV, and HDV Chronic hepatitis,
 HAV Acute Hepatitis.
 HEV causes acute hepatitis in normal hosts but can cause protracted and chronic hepatitis
in immunosuppressed patients.

3. INTRODUCTION
What Viral Hepatitis is?
 Liver involvement may also be seen on occasion as part of systemic
infections with
Herpes simplex virus,
Epstein-Barr virus (EBV),
Varicella-zoster virus,
Enteroviruses,
Adenoviruses,
Yellow fever virus,
Mumps, rubella, and rubeola,
 but these viruses do not cause infections that primarily affect the liver.

4. INTRODUCTION
What Viral Hepatitis is?
 The acute clinical illnesses caused by the five hepatitis viruses (A–E)
range from asymptomatic to fulminant and fatal.
 The chronic infections caused by HBV, HCV, and HDV range from
Subclinical persistent infections to
Rapidly progressive chronic liver disease with cirrhosis and
Increased risk for hepatocellular carcinoma (HCC).
 HEV can also cause protracted and chronic infections in
immunosuppressed patients.

7. Acute viral hepatitis
Clinical Manifestations
 The clinical manifestations of acute viral hepatitis are similar among the five hepatitis
viruses.
 No clinical features distinguish unequivocally one from the others,
 Asymptomatic infections with the hepatitis viruses are approximately 10 to 30 times more
common than symptomatic ones.
 The incubation periods of hepatitis vary with the individual virus.
 “flulike” illness (25% Patients). Symptoms include
Malaise,
Fatigue,
Myalgia, arthralgia, and
Headache.
Anorexia, nausea, and vomiting may occur, sometimes associated with alterations in
olfaction and taste.

8. Acute viral hepatitis
Clinical Manifestations
 Pharyngitis, coryza, and cough may also be present.
 Low-grade fever is common and more frequent in hepatitis A and E.
 Dark urine and clay-colored stools may appear, usually 1 to 5 days before the
onset of icterus,
 A substantial portion of patients never become jaundiced.
 With the onset of jaundice, the constitutional symptoms generally abate but may
continue during the entire icteric period.
 Right upper quadrant tenderness and discomfort are present as the liver
enlarges, and
 In some patients a cholestatic clinical picture may develop, suggesting
extrahepatic biliary obstruction.
 Splenomegaly and cervical lymphadenopathy are seen in 10% to 20% of
patients.

9. Acute viral hepatitis
Clinical Manifestations
 As patients recover, constitutional symptoms resolve, but usually some
liver enlargement persists, as do elevations of liver biochemical tests.
 The duration of the posticteric phase is variable and ranges from 2 to 12
weeks.
 It is usually more prolonged in hepatitis B and C.
 Complete resolution of clinical and laboratory abnormalities is to be
expected 1 to 2 months after the onset of jaundice in acute hepatitis A.
 3 to 4 months after the onset of jaundice in 75% of cases of uncomplicated
acute hepatitis B or C.
 In hepatitis E, acute cases are similar to those in hepatitis A
 Protracted infection in hepatitis E Immunosuppressed patients, and
severe and fatal infection can occur in pregnant women

10. Acute viral hepatitis
Laboratory Features
 Serum aspartate aminotransferase (AST) and the alanine aminotransferase (ALT) activities increase to
variable levels during the prodromal phase of acute hepatitis and precede elevations in bilirubin.
 The magnitude of AST and ALT elevations do not correlate closely with the extent of liver damage.
 Peak levels vary from 400 to 4000 international units (IU)/L, and maximums are usually reached when the
patient becomes icteric.
 Jaundice Billirubin 5 to 20 mg/dL and is usually equally divided between conjugated and unconjugated
fractions.
 Neutropenia and lymphopenia may be present initially, followed by lymphocytosis with atypical
lymphocytes.
 A diffuse but modest elevation of the serum globulin fraction is often present, and antibodies to smooth
muscle and to other cell constituents can be seen.
 Prothrombin times prolonged value may indicate
 Severe hepatic synthetic defect,
 Severe hepatocellular necrosis
 Poor prognosis.

11. Fulminant Hepatitis
 Fulminant hepatitis is defined as severe liver failure developing within 8 weeks of the onset
of symptoms and is the most feared complication of acute hepatitis.
 It is seen primarily with hepatitis B and D
 Hepatitis A infection older patients/ chronic hepatitis B or C infection.
 Hepatitis B infection of patients with underlying chronic hepatitis C.
 Fulminant hepatitis is hardly ever seen in patients with hepatitis C alone.
 Hepatitis E may lead to acute liver failure uncommonly in men and in up to 20% of pregnant
women.
 Hepatitis E is the leading cause in India, and hepatitis B is the leading cause in France and
Japan.
 Patients with acute fulminant hepatitis usually present with hepatic encephalopathy, which may
evolve into a deep coma.
 Liver size is reduced,
 Bilirubin rises,

12. Fulminant Hepatitis
 Prothrombin time is markedly prolonged
 Aminotransferase levels drop.
 Ascites and peripheral edema are present, consistent with hepatic failure.
 Cerebral edema is common, and
 Brainstem compression may occur.
 Gastrointestinal bleeding, sepsis
 Respiratory failure.
 Cardiovascular collapse and renal failure are terminal events.
 The mortality rate is high (>80% in patients with deep coma), but those who
survive have a complete clinical and laboratory recovery.
 Liver transplantation, if it can be performed in time, may be lifesaving in such
patients.

13. Complications of Acute Hepatitis
 Uncommonly, hepatitis A Relapsing hepatitis, occurring weeks to months after
apparent recovery from hepatitis A Protracted cholestatic hepatitis persist for up
to a year.
 During the prodromal phase of hepatitis B, a serum sickness–like syndrome may
develop, characterized by arthritis or arthralgias, rash, angioedema, and,
rarely, hematuria and proteinuria.
 Essential mixed cryoglobulinemia (EMC) and associated lymphoproliferative
disorders can complicate chronic (not acute) hepatitis C.
 Hepatitis C may be associated with abnormalities in lipoprotein and glucose
metabolism.
 The risk of chronic infection after acute hepatitis B in otherwise healthy adults is
appropriately 1%, whereas the corresponding risk of chronicity after acute
hepatitis C is 85% to 90%.
 Both chronic hepatitis B and C are associated with an increased risk of HCC.

14. Hepatitis A Virus
 HAV is a distinct member of the picornavirus family.
 HAV is a 27- to 32-nm spherical particle with cubic symmetry containing
a linear single-stranded RNA genome with a size of 7.5 kb.
 It is assigned to picornavirus genus, Hepatovirus.
 Only one serotype is known.
 Genomic sequence analysis divided HAV isolates into seven genotypes.
 HAV is stable to treatment with
 20% ether, acid (pH 1.0 for 2 hours)
 Heat (600C for 1 hour).

15. Hepatitis A Virus
The virus is destroyed by
Autoclaving (1210C for 20 minutes),
Boiling in water for 5 minutes,
Dry heat (1800C for 1 hour),
Ultraviolet irradiation (1 minute at 1.1 watts),
Treatment with formalin (1:4000 for 3 days at 370C), or
Treatment with chlorine (10–15 ppm for 30 minutes).
 Heating food to above 850C for 1 minute and disinfecting surfaces with sodium
hypochlorite (1:100 dilution of chlorine bleach) are necessary to inactivate HAV.
 The relative resistance of HAV to disinfection procedures emphasizes the need for
extra precautions in dealing with hepatitis patients and their products.

18. Hepatitis A Virus
Pathogenesis
 The transmission of HAV occurs via fecal-oral route, which includes
consumption of contaminated food or water and person to person contact.
 Polymerase chain reaction testing for blood donors is performed as transmission
through blood transfusion is noted on rare occasions.
 The dissemination of the HAV into the liver occurs via the portal vein after the
virus traverses the mucosa of the small intestinal wall.
 The virus particles subsequently replicate and are secreted into the biliary
canaliculi, reaching back to the small intestine through the bile ducts and being re-
excreted in the feces.
 Until the body responds with appropriate immune reaction in antibodies, the HAV
enterohepatic cycle continues.
 Human leukocyte antigen-restricted, HAV-specific CD8+ T lymphocytes and
natural killer cells have been implicated in the damage and destruction of infected
hepatocytes.

19. Proposed mechanisms of liver injury mediated by HAV.
(A) During HAV infection, the virus activates CD8+ T cells, generating virus-specific
CD8+ T cells. Activated virus-specific CD8 T-cells are differentiated into effector
cytotoxic T lymphocytes that specifically kill virus-infected cells, thus contributing to
liver injury.
(B) In patients with hepatitis A, high levels of IL-15 in the serum activate non-virus-specific
CD8+ T cells, which are capable of lysing both infected and uninfected hepatocytes.
(C) High levels of IL-18 have been detected in both macrophages and hepatocytes in IL-
18BP-deficient patients with fulminant hepatitis A. Due to lack of neutralizing activity
against IL-18, excessive and uncontrolled IL-18 activates NK cells, which subsequently
mediate the lysis of both infected and uninfected hepatocytes.
(D) In patients with severe hepatitis A, HAV seems to activate NKT cells in TIM-1
dependent manner. HAV-infected cells had higher cytotoxic activity in NKT cells carrying
longer form of TIM-1 than in NKT cells harboring the wild type TIM-1, thereby
contributing to liver injury. Apoptosis of HAV-infected hepatocytes mediated by MAVS-
IRF3/IRF7-dependent signaling has also been implicated in liver injury in a murine model
of HAV.

21. Hepatitis A Virus
Clinical presentation
 Incubation period 2-4 wk.
 Fever, malaise, jaundice most common presenting symptoms.
 Other common symptoms
Weakness,
Fatigue,
Nausea, vomiting,
Abdominal pain,
Arthralgias, Myalgias,
Diarrhea and Anorexia.
 Patients rarely enter a prolonged cholestatic phase through recovery, while relapsing
infections (10%-15% of patients) have been described as well.

22. Hepatitis A Virus
Clinical presentation
 The symptoms during the relapse are usually less severe than the initial infection.
The spectrum of infections can range from
 Asymptomatic patients without jaundice,
 Symptomatic patients with jaundice,
 Cholestasis with prolonged jaundice, to
 Relapsing infections or,
 Acute liver failure.
 Serum aminotransferases above 1000 U/dL are usually noted, with total
bilirubin typically ≤ 10 mg/dL, and alkaline phosphatase below 400 U/L.
 Usually the serum alanine aminotransferase (ALT) is higher than the aspartate
aminotransferase (AST).

23. Hepatitis A Virus
Clinical presentation
 In general, older patients are more likely to have severe hepatocellular
derangements, hospital admissions and higher mortality.
 These findings can be attributed to an impaired regeneration capacity of the
liver and a relatively weaker immune system in the older population.
 In addition to old age, higher mortality has been reported in males.
 Old age, underlying liver pathology and chronic viral hepatitis are reported
risk factors for acute liver failure.
 In patients who develop acute liver failure, higher mortality has been
associated with creatinine > 2 mg/dL (strongest predictor) total bilirubin
> 9.6 mg/dL and albumin < 2.5 g/L.

25. Hepatitis A Virus
Laboratory Diagnosis
 Specific antibodies against HAV (anti-HAV) in the serum can be detected.
 The diagnosis is confirmed by the presence of immunoglobulin (Ig) M anti-HAV.
 The antibodies can be detected at the time of onset of symptoms.
 Serum IgM levels peak during the acute infection and remain positive for up to 4 months
on an average from the onset of symptoms.
 Immunity is usually tested with HAV total antibody to determine HAV natural exposure
or secondary to vaccination.
 The presence of IgM antibodies without any clinical symptoms is indicative of HAV
infection in the past with persistent antibodies, asymptomatic infection or false positive
test.
 Liver biopsy or imaging studies are not required to make a diagnosis.
 If performed, a liver biopsy may show marked portal inflammation with typically a lesser
degree of necrosis, Kupffer cell proliferation, acidophil bodies, or ballooning when
compared to non-HAV viral hepatitis.

28. Hepatitis A Virus
Management
 No specific treatment is available for HAV and the management is mainly symptomatic.
 The primary focus remains on improving sanitary conditions to minimize the transmission in the
community.
 Historically, immunoglobulins have been used in the prevention of HAV infections.
 With the availability of an effective vaccine, the use of immunoglobulins has been largely
abandoned except in infants below the age of 12 mo.
 Post exposure prophylaxis with hepatitis A vaccine has been approved since 2007 for
immunocompetent patients without chronic liver disease, who are between the ages of 12 mo
and 40 years of age.
 An inactivated HAV vaccine has been licensed in Europe since 1991, while a live attenuated
hepatitis A vaccine has been in use in China since 1992.
 The inactivated virus vaccine was first approved for use in United States in 1995.
 The vaccine has had significant effect on the decrease in HAV infections.
 Long term immune response up to 40 years in noted in over 90% patients who receive both doses
of the 2-vaccine series.

32. Hepatitis E Virus
 HEV is a single-stranded, nonenveloped RNA virus that is 27 to 34 nm in diameter.
 It is the single member of the genus Hepevirus in the family Hepeviridae.
 HEV has four genotypes in humans and up to 24 subtypes.
 HEV is primarily enterically transmitted.
 Genotypes 1 and 2 are spread by means of fecally contaminated water in endemic
areas and may be spread through blood transfusion, particularly in endemic areas.
 Person-to-person transmission is uncommon but has been documented in households.
 Highest rates of seroprevalence are in Asia, Africa, the Middle East, and Central
America.
 A relatively high seroprevalence (21%) has been found in the United States, apparently
related to infection with attenuated genotypes 3 and 4, which are of limited
pathogenicity and which have been linked to animal-reservoir (predominantly
swine) exposure.

33. Hepatitis E Virus
 The incubation period of illness is 14 to 60 days (mean, 40 days), and clinical
illness appears to be similar to acute hepatitis from other hepatotropic viruses,
although perhaps more severe than that seen with HAV.
 Fulminant hepatitis can occur, with case-fatality rates of 0.9% to 2.8% in men
and up to 20% in pregnant women, particularly in the third trimester.
 The reason for the markedly increased mortality in pregnant women is unclear but
may be related to increased virus replication observed in pregnancy.
 Most HEV infected patients are either asymptomatic or may develop mild, self-
limited, HAV-like illness.
 The zoonotic genotypes HEV 3 and 4 have been increasingly reported as causes
of chronic hepatitis almost exclusively in those who are immunocompromised.
 Less than 5% of acutely infected HEV patients will progress to acute liver failure
and those patients are more likely to be pregnant, malnourished, or have a
preexisting liver condition.

36. Hepatitis E Virus
 HEV virions exist in two forms in the infected host, non-enveloped
(neHEV) and quasi-enveloped (eHEV) particles.
 Virions secreted in feces are non-enveloped, spherical particles of
approximately 27–34 nm in diameter.
 However, virions secreted in circulating blood and supernatant of infected
cell cultures are quasi-enveloped as they are covered with a lipid envelope.
 Although neHEV particles are more infectious, eHEV particles are resistant
to antibody neutralization against the viral capsid protein.
 The HEV capsid proteins assemble into virion particles, binds host cells,
and elicit neutralizing antibodies

41. Hepatitis E Virus
 HEV infection can be diagnosed either indirectly by detecting serum anti-HEV
antibodies or directly by detecting the HEV genome in blood or other bodily
fluids.
 Following an incubation period of 2 to 6 weeks, an initial short lived IgM
response is followed by longer-lasting IgG antibodies.
 Commercial enzyme immunoassays and rapid immunochromatographic kits based
on ORF2/ORF3 peptides or recombinant antigens from HEV1 can detect the
presence of IgM or IgG antibodies induced by the four major genotypes of HEV,
representing a single serotype.
 At clinical presentation, anti-HEV IgM levels had already reached the peak
level, but they remained at relatively high levels for 8 weeks.
 IgM antibodies declined rapidly thereafter, falling below the cut-off level among
most patients after 32 weeks.
 HEV IgG levels were rising when patients presented.

42. Hepatitis E Virus
 The antibody reached peak levels about 4 weeks after the onset of symptoms and
was maintained at high levels for more than 1 year.
 The presence of anti-HEV IgM is a marker of acute infection.
 “Point-of- care” assays have also been developed to test for anti-HEV IgM
antibodies.
 These immunochromatographic assays are easy to use, give a result within a few
minutes, and are ideally suited to resource-limited settings.
 The presence of anti-HEV IgG alone is a marker of past infection.
 Detection and quantification of HEV RNA in blood and other compartments are
based on real-time PCR with primers targeting conserved regions between HEV
genotypes.
 The loop-mediated isothermal amplification (LAMP) assay, has been
developed for the detection of HEV RNA.