The document provides an overview of viral hepatitis, focusing on hepatitis A (HAV) and hepatitis B (HBV). It discusses their transmission routes, epidemiology, clinical manifestations, diagnosis, and treatment strategies, including vaccine options for prevention. The document details the pathophysiology of each virus, highlighting concerns related to chronic infections and complications such as liver disease and hepatocellular carcinoma.

1. Viral Hepatitis
By : Dr ZEEL NAIK

2. Introduction
• The major hepatotrophic viruses responsible for viral hepatitis are hepatitis
A, hepatitis B, hepatitis C, delta hepatitis, and hepatitis E
• All share clinical, biochemical, immunoserologic, and histologic findings
• Both hepatitides A and E are spread through fecal–oral contamination;
whereas hepatitides B, C, and delta are transmitted parenterally
• Infection with delta hepatitis requires coinfection with hepatitis B
• Although the rates of acute infection have declined, viral hepatitis remains
a major cause of morbidity and mortality

3. HEPATITIS A
• Hepatitis A virus (HAV), or infectious hepatitis, is often a
selflimiting and acute viral infection of the liver posing a
health risk worldwide
• The infection is rarely fatal
• Although vaccine preventable, HAV continues to be one of
the most commonly reported infections

4. EPIDEMIOLOGY
• Various patient groups are at increased risk for infection with HAV.
• Children pose a particular problem with the spread of the disease
because they often remain clinically asymptomatic and are infectious
for longer periods of time than adults
• Traditionally, the most likely patient group to be affected is household
or close personal contacts of an infected person

5. EPIDEMIOLOGY
• HAV rates have increased among international travelers, injection-
drug users (IDUs), and men who have sex with men (MSM)
• Additional patient groups that are at risk include patients with chronic
liver disease and persons working with nonhuman primates
• In pregnant women, acute HAV infection may be associated with
maternal complications and preterm labor

6. Transmission
• Infection primarily occurs through the fecal–oral route, by person-to-
person, or by ingestion of contaminated food or water
• Incidentally, HAV’s prevalence is linked to regions with low
socioeconomic status and specifically to those with poor sanitary
conditions and overcrowding
• Rarely, the virus can be spread through blood or blood products

7. ETIOLOGY
• Hepatitis A is a RNA virus belonging to the genus Hepatovirus of the
Picornaviridae family
• Humans are the only known reservoir for the virus and transmission
occurs primarily through the fecal–oral route
• The virus is stable in the environment for at least a month and
requires heating foods to a minimum of 85°C (185°F) for 1 minute or
disinfecting with a 1:100 dilution of sodium hypochlorite (bleach) in
tap water for inactivation

8. PATHOPHYSIOLOGY
• HAV’s life cycle in the human host classically begins with ingestion of the virus.
Absorption in the stomach or small intestine allows entry into the circulation
and uptake by the liver
• Replication of the virus occurs within hepatocytes and gastrointestinal epithelial
cells
• New virus particles are released into the blood and secreted into bile by the
liver
• The virus is then either reabsorbed to continue its cycle or excreted in the stool.
The enterohepatic cycle will continue until interrupted by antibody
neutralization.

9. PATHOPHYSIOLOGY
• On biopsy, acute hepatitis is marked by hepatocellular degeneration,
inflammatory infiltrate, and hepatocyte regeneration
• Hepatocellular degeneration occurs as a result of immune-mediated
injury and not as a direct cytopathic effect of the virus

11. Diagnosis
• A diagnosis of HAV is based on clinical criteria of an acute onset of
fatigue, abdominal pain, loss of appetite, intermittent nausea and
vomiting, jaundice or elevated serum aminotransferase levels, and
serologic testing for IgM anti-HAV
• Serologic testing is necessary to differentiate the diagnosis from other
types of hepatitis

12. TREATMENT
• The majority of people infected with HAV can be expected to fully
recover without clinical sequelae
• Nearly all individuals will have clinical resolution within 6 months of
the infection, and a majority will have done so by 2 months. Rarely,
symptoms persist for longer or patients relapse
• The ultimate goal of therapy is complete clinical resolution.

13. TREATMENT
• No specific treatment options exist for HAV infections
• Instead, patients should receive general supportive care. In patients
who develop liver failure, transplant is the only option
• Although hepatocellular damage occurs through immune-mediated
responses, steroid use is not recommended.

14. PREVENTION OF HEPATITIS A
• HAV is easily preventable with vaccination
• Because children often serve as reservoirs of the disease, vaccine
programs have targeted children as the most effective means to
control HAV
• In October 2005, the FDA reduced the minimum age for the vaccines
to 12 months of age

15. Vaccines to Prevent Hepatitis A
• Two inactivated virus vaccines are currently licensed in the United States:
Havrix and Vaqta
• Both vaccines are inactivated virus and are available for pediatric and adult
use
• The differences in the two vaccines are in the use of a preservative and in
expression of antigen content
• Vaqta is formulated without a preservative and uses units of HAV antigen to
express potency
• Havrix uses 2-phenoxyphenol as a preservative and antigen content is
expressed as enzyme-linked immunosorbent assay units.

16. Vaccines to Prevent Hepatitis A
• Vaccine efficacy may be reduced in certain patient populations.
• In HIV (human immunodeficiency virus)-infected patients, greater
immunogenic response may correlate with higher baseline CD4 cell
counts
• Response to the HAV vaccine as determined by detection of anti-HAV
after vaccination found that among HIV patients, females and patients
with CD4 counts >200 cells/mm3 at vaccination had a higher response
rate

17. Vaccines to Prevent Hepatitis A
• The most common side effects of the vaccines include soreness and
warmth at the injection site, headache, malaise, and pain
• Reported serious adverse events include anaphylaxis, Guillain-Barre
syndrome, brachial plexus neuropathy, transverse myelitis, multiple
sclerosis, encephalopathy, and erythema multiforme
• The vaccine is considered safe
• Twinrix is a bivalent vaccine for hepatitides A and B that was approved
by the FDA in 2001

22. Immunoglobulin
• Ig is used when pre- or postexposure prophylaxis against HAV infection is
needed
• A sterile preparation of concentrated antibodies against HAV, Ig provides
protection by passive transfer of antibody
• Ig is most effective if given in the incubation period of the infection.
• Receipt of Ig within the first 2 weeks of infection will reduce infectivity and
moderate the infection in 85% of patients
• Patients who received at least 1 dose of the HAV vaccine at least 1 month
earlier do not need pre- or postexposure prophylaxis with Ig

23. Immunoglobulin
• Ig is available both as an intravenous (IV) and IM injection but for HAV
exposure, only the IM is used
• If given to infants or pregnant women, the thimerosal-free
formulation should be used

25. Immunoglobulin
• International travelers are the major patient population receiving preexposure
prophylaxis with Ig
• For people who were recently exposed to HAV and who had not been previously
vaccinated, Ig is indicated
• HAV vaccination or prophylaxis with Ig is recommended for travelers to countries
with high endemic rates of HAV
• Serious adverse events are rare
• Anaphylaxis has been reported in patients with Ig A deficiency

26. Immunoglobulin
• Dosing of Ig is the same for adults and children
• For postexposure prophylaxis and for short-term preexposure coverage of
<3 months, a single dose of 0.02 mL/kg is given intramuscularly
• For long-term preexposure prophylaxis of ≤5 months, a single dose of 0.06
mL/kg is used
• Either the deltoid or gluteal muscle may be used
• In children younger than 24 months of age, Ig can be given in the
anterolateral thigh muscle

27. Immunoglobulin
• Ig can interfere with the response of other vaccines and should be
delayed
• The measles, mumps, and rubella (MMR) vaccine should be delayed
for a minimum of 3 months after receipt of Ig
• The varicella vaccine must be delayed for 5 months. Conversely, Ig
should not be given to patients who received the MMR within 2
weeks or the varicella vaccine within 3 weeks

28. HEPATITIS B
• Although a vaccine was made available in 1981, HBV has acutely
infected more than 2 billion people globally, leading to chronic
infection in more than 350 million people
• Chronic infection with HBV is a major public health issue as it serves
as a reservoir for continued HBV transmission and poses a significant
risk of death resulting from liver disease
• More than 1 million people per year die as a result of liver cirrhosis
and hepatocellular carcinoma (HCC).

29. EPIDEMIOLOGY and Transmission
• Areas of high prevalence, approximately 45% of the global
population, are of special concern because most infections are of
infants and children and >90% of cases lead to a chronic carrier state
• HBV is transmitted sexually, parenterally, and perinatally
• In areas of high HBV prevalence, perinatal transmission from mother
to infant is most common, whereas in areas of intermediate
prevalence, horizontal transmission from child to child is most
common.

30. EPIDEMIOLOGY and Transmission
• Sexual contact, both homosexual and heterosexual, and injection-
drug use are the predominant forms of transmission in low-endemic
countries such as the United States
• Transmission can occur through contact with infected body fluids in
the absence of blood, as the virus may be stable in the environment
for a number of days

31. EPIDEMIOLOGY and Transmission
• International travel was the most prevalent identifiable risk factor,
followed by injection drug use and sexual or household contact with a
hepatitis B-infected person
• Among children younger than 15 years of age, the largest overall risk
factor in 2004 was international travel.3 No cases were documented
for patients receiving transfusions or on hemodialysis

32. ETIOLOGY
• The HBV is a DNA virus of the family Hepadnaviridae. It is a partially
double-stranded, circular DNA with 3,200 base pairs that typically
infects liver cells, although it has been found in kidney, pancreas, and
mononuclear cells
• Resistance mutations may contribute to genotype virulence and
hence impact severity of liver disease in infection

33. PATHOPHYSIOLOGY
• Upon infection, replication of the virus begins by attachment of the virion
to the hepatocyte cell surface receptors
• The particles are transported to the nucleus where the DNA is converted
into closed, circular DNA that serves as a template for pregenomic RNA
• Viral RNA is then transcribed and transported back to the cytoplasm where
it can alternatively serve as a reservoir for future viral templates or bud
into the intracellular membrane with the viral envelope proteins and infect
other cells

34. PATHOPHYSIOLOGY
• HBV itself does not seem to be pathogenic to cells; rather, it is
thought that the immune response to the virus is cytotoxic to
hepatocytes
• Antigen nonspecific inflammatory responses triggered by T cells may
be responsible for most hepatic injury, with progression to cirrhosis
and HCC

35. PATHOPHYSIOLOGY
• In an acute infection, however, the cytotoxic T-cell response is critical to
viral clearance
• If the response is weak, chronic infection is likely
• Moreover, liver injury is likely caused by secondary, nonspecific
inflammation activated by the initial cytotoxic lymphocyte response and as
an attempt by the immune system to clear the virus by destroying HBV
antigen presenting hepatocytes
• Destruction of hepatocytes results in release of circulating, and hence
increased, ALT levels

36. Cirrhosis
• Cirrhosis results as the liver attempts to regenerate while in an
environment of persistent inflammation
• An estimated 20% of all chronic hepatitis B patients develop
complications of hepatic insufficiency and portal hypertension as
their compensated cirrhosis progresses to decompensated cirrhosis
within a 5-year period
• Typically, the initial clinical findings of decompensated cirrhosis are
ascites, jaundice, variceal bleed, encephalopathy, or a combination of
symptoms

37. Hepatocellular Carcinoma
• HBV is a known risk factor for
the development of HCC and in
areas of high HBV endemicity, a
major complication of the
infection
• Many patients with HCC have no
signs of decompensated
cirrhosis.

40. spider angiomata

41. PREVENTION OF HEPATITIS B
• Prophylaxis against HBV can be achieved by vaccination or by passive
immunity in postexposure cases with hepatitis B immunoglobulin
• Vaccination is the most effective strategy to prevent infection

42. PREVENTION OF HEPATITIS B
• Available vaccines include two single-antigen products and three
combination products
• The two single-antigen products are Recombivax HB and Engerix-B
• Twinrix is a combination vaccine for HAV and HBV in adults.
Comvax and Pediarix are used for children and are used for HBV
along with other scheduled vaccines

43. NONPHARMACOLOGIC THERAPY
• All chronic HBV patients should be counseled on preventing disease
transmission
• Sexual and household contacts should be vaccinated
• To minimize further liver damage, all chronic HBV patients should
avoid alcohol and be immunized against HAV

44. NONPHARMACOLOGIC THERAPY
• Herbal medicines are an intriguing option to many patients.
• Four common preparations include Phyllanthus, milk thistle,
glycyrrhizin (licorice root extract), and a mixture of herbs known as Liv
52
• Meta-analysis of existing studies demonstrated that milk thistle and
Liv 52 do not affect the course of liver disease.
• Herbal treatment is not recommended for patients with chronic
hepatitis B

45. Interferon
• IFN-α2b therapy was the first approved therapy for treatment of HBV
and improves long-term outcomes and survival
• Acting as a host cytokine, it has antiviral, antiproliferative, and
immunomodulatory effects in chronic HBV

46. Interferon
• Treatment for a minimum of 12 months is associated with greater
sustained virologic response rates than treatment for 4 to 6 months
• Seroconversion can occur during or after therapy is complete.
• An extended treatment duration of 24 months may benefit the
difficult-to-treat HBeAg-negative patien

47. Interferon
• Conventional IFN therapy is plagued with numerous problems,
including the inconvenience of thrice-weekly injections; however,
standard interferon therapy has virtually been replaced by the use of
pegylated IFN (PEG-IFN) because of the benefits in ease of
administration, decreased side effect profile, and improvements in
efficacy
• Compared to conventional IFN, PEGIFN has a longer half-life enabling
once-weekly injections

48. Interferon
• Studies comparing PEG-IFN-α2a monotherapy with PEG-IFN-α2a–
lamivudine combination therapies suggest that combination therapy
caused greater HBV DNA suppression than PEG-IFN-α2a
monotherapy, PEG-IFN-α2a monotherapy better achieved HBeAg
seroconversion than lamivudine monotherapy with no difference in
combination therapy, and combination therapy resulted in less
lamivudine resistance than lamivudine monotherapy

49. Lamivudine
• Lamivudine, a nucleoside analog, has antiviral activity against both
HIV and HBV
• It is dosed at 100 mg daily; the optimal duration of treatment is
unknown
• In both HBeAg-positive and –negative patients, lamivudine
demonstrates profound viral suppression

50. Lamivudine
• Seroconversion rates increase with duration of therapy and are at
50% by the fifth year of therapy
• Seroconversion rates are less than 20% after 1 year of therapy and
will relapse in up to 58% of patients
• Relapse rates are highest among Asian patients

51. Adefovir
• Adefovir dipivoxil is an acyclic nucleoside analog of adenosine
monophosphate
• The drug acts by inhibiting HBV DNA polymerase.
• It is dosed at 10 mg daily for 1 year, although the optimal duration of
therapy is unknown
• A 48-week course of treatment is effective in improving histologic findings,
reducing serum HBV DNA and ALT levels, and increasing HBeAg
seroconversion in both HBeAg-negative and -positive patients

52. Adefovir
• Historically, increases in serum creatinine limited treatment to doses
of 30 mg/ day or less
• In patients treated chronically at a dose of 10 mg daily, the incidence
of nephrotoxicity was the same as placebo
• In patients with developing lamivudine resistance as demonstrated by
rising HBV DNA levels, the addition of adefovir was more effective if
done while ALT levels were still normal

53. Entecavir
• Entecavir is a guanosine nucleoside analog that acts by inhibiting HBV
polymerase
• An oral agent, it is more potent than lamivudine in suppressing serum HBV
DNA levels and is effective in lamivudine- resistant HBV
• The drug is dosed at 0.5 mg daily in treatment-naive or non–lamivudine-
resistant infections and at 1 mg daily in lamivudine-refractory patients
• In a 48-week trial comparing it to lamivudine, entecavir resulted in
significantly higher rates of histologic improvement, HBV DNA reduction
and undetectability, and ALT normalization

54. Entecavir
• Resistance is most likely to occur in patients with preexisting
lamivudine resistance
• In terms of safety, entecavir is comparable to lamivudine. Patients
switched from lamivudine to entecavir are at risk for hepatic flares,
although severe flares are unlikely

55. Telbivudine
• The most recently approved drug for HBV treatment is telbivudine, a
HBV-specific nucleoside analog
• Telbivudine acts as a competitive inhibitor of viral reverse
transcriptase and DNA polymerase

56. Telbivudine
• During a 1-year study, 5% of patients developed resistance and data
suggest telbivudine should not be used in patients with resistance to
lamivudine
• Varying degrees of hepatic impairment do not alter the kinetics of the
drug, nor does the coadministration of lamivudine or adefovir
• Combination therapy of telbivudine and lamivudine did demonstrate
greater seroconversion rates but the difference was not statistically
different from monotherapy
• The most commonly associated adverse event with telbivudine is upper
respiratory tract infection

57. ALTERNATIVE DRUG TREATMENTS
• Emtricitabine is a cytosine analog approved for use in HIV and with
activity against HBV. It is currently not approved for HBV
• Combination therapy has been proposed to counter the issues of
resistance
• YMDD mutants remain susceptible to adefovir

58. ALTERNATIVE DRUG TREATMENTS
• Adding adefovir to patients on lamivudine when HBV DNA levels
began to increase better maintained normal ALT levels and
suppressed HBV DNA than waiting to add adefovir until after ALT
levels increased
• Combination therapy with interferon and lamivudine creates less
resistance than lamivudine monotherapy,

59. SPECIAL POPULATIONS
• Most recently updated guidelines suggest lamivudine, adefovir, and
entecavir are possible agents for use in cirrhotic patients
• Lamivudine is indicated for children ages 2 years and older and
interferon is approved for use in children ages 1 year and older
• Entecavir is approved for adolescents ages 16 years and older,
whereas pegylated interferon and adefovir do not have indications for
pediatric dosing

60. HEPATITIS C
• HCV is approximately five times as common as HIV and is responsible for
an estimated 10,000 chronic liver disease-associated deaths per year
• More than 190,000 deaths from HCV-related disease are expected
between 2010 and 2019, with projected costs exceeding $10 billion
• Most acute infections are asymptomatic and the course of the infection
is insidious
• As a result, many patients are not diagnosed until significant disease
progression

61. EPIDEMIOLOGY
• HCV is the most common blood-borne pathogen
• The single largest risk factor for infection is injection drug use
• Some experts also consider other illicit drug use, for example
intranasal cocaine, as a risk factor because of the possible
contamination of drug paraphernalia not limited to syringes and
needles

62. EPIDEMIOLOGY
• Although sexual contact is considered an inefficient means of HCV
transmission, multiple sexual partners and coinfection with sexually
transmitted diseases, including HIV, increase the risk for HCV sexual
transmission

64. CLINICAL PRESENTATION
• In an acute HCV infection, most patients are asymptomatic and
undiagnosed
• HCV RNA is detectable within 1 to 2 weeks of exposure and levels rise
quickly during the initial weeks
• Typically, symptoms occur 7 weeks after the infection, with a range of
3 to 12 weeks

65. CLINICAL PRESENTATION
• Mild and nonspecific symptoms, including fatigue, anorexia,
weakness, jaundice, abdominal pain, or dark urine
• Acute infections rarely progress to fulminant hepatitis, although the
course can be severe and prolonged

66. CLINICAL PRESENTATION
• Up to 85% of acutely infected patients will go on to develop a chronic HCV
infection, defined as persistently detectable HCV RNA for 6 months or more
• HCV RNA levels and ALT levels can fluctuate and even have periods of
undetectable HCV RNA and normal ALTs.
• Most patients will have few, if any symptoms. The most common symptom
is persistent fatigue
• Additional symptoms include right upper quadrant pain, nausea, or poor
appetite

67. DIAGNOSIS
• For many patients, a diagnosis of hepatitis C is incidental
• Some patients are diagnosed after persistently abnormal transaminases.
• Unfortunately, those patients who present with symptoms typically have
advanced disease
• A diagnosis of chronic HCV is confirmed with a reactive enzyme
immunoassay for anti-HCV
• Testing for anti-HCV is not routinely recommended because of the low
prevalence of HCV in the general population and the nonspecificity of the
test

68. NONPHARMACOLOGIC THERAPY
• All chronic HCV patients should be vaccinated against hepatitides A
and B
• Lifestyle changes are an important factor in reducing health
consequences in hepatitis C
• Continued alcohol use is a known risk factor for disease progression
and severity

69. NONPHARMACOLOGIC THERAPY
• Obesity is also a factor and patients should be encouraged to eat a
balanced diet and exercise regularly to maintain a normal weight
• Smoking may contribute to disease progression
• Patients should be encouraged to maintain good overall health, stop
smoking, and avoid alcohol and illicit drugs

70. PHARMACOLOGIC THERAPY
• The current standard of care for chronic HCV patients is a
combination therapy of a once-weekly injection of PEG-IFN and a
daily oral dose of ribavirin

71. Terminology for Therapeutic Response

72. Response Analysis
• For genotype 1, evaluation for an EVR at 12 weeks is recommended as
an indicator of the probability of achieving an SVR
• Because therapy is not without a significant side-effect profile and
because failure to achieve EVR is so strongly correlated with treatment
failure, some clinicians will terminate therapy early in genotype 1
patients
• Conversely, because genotypes 2 and 3 respond so well to therapy,
there are data to support early treatment termination in patients who
show an EVR at 4 weeks

73. Ribavirin
• When added to IFN, ribavirin significantly increases SVR rates,
especially among genotypes 2 and 3
• Ribavirin is dosed based on weight for optimal response
• Although monotherapy with PEG-IFN is an option for patients with
contraindications to ribavirin, ribavirin is ineffective as monotherapy
and should not be used alone.

75. Ribavirin - SEs
• Ribavirin-induced hemolytic anemia is an inevitable effect of therapy,
although varying in severity among patients
• Anemia results from ribavirin uptake into erythrocytes, inducing membrane
damage and resulting in hemolysis.
• Patients may complain of fatigue as hemoglobin levels decrease even
though dose reductions are not recommended until hemoglobin levels fall
to 10 g/dL
• The mean decrease in hemoglobin is 3 g/dL in the initial weeks of therapy;
thereafter levels stabilize until discontinuation of therapy
• Hemoglobin levels normalize once ribavirin is stopped

76. SEs
• Up to one-third of patients are expected to experience some degree of
depression during treatment partly because of interferon’s interference
with the serotonin pathways
• Although many patients can be managed with selective serotonin reuptake
inhibitors, various degrees of counseling and psychiatric consultations may
be necessary
• Severe depression and suicidal behaviors are rare but not undocumented
• More common side effects include flu-like symptoms, which can be
managed by acetaminophen or nonsteroidal inflammatory drugs

77. Special Populations

79. Jaundice