Pathogenesis and management of viral hepatitis

PATHOGENESIS AND
MANAGEMENT OF
VIRAL HEPATITIS
1
Submitted to
Dr. Savitha RS
Asst. Professor
Dept. of Pharmacy Practice
JSS College of Pharmacy, Mysuru
Submitted by
Sai Siddharth M
M Pharma 1st semester
Roll No. 10
Dept. of Pharmacy practice
JSS College of Pharmacy, Mysuru
JSS COLLEGE OF PHARMACY, MYSURU

Viral Hepatitis
Viral Hepatitis is an infection that
causes liver inflammation and
damage.
Several different viruses causes
Hepatitis :-
 Hepatitis A Virus
 Hepatitis B Virus
 Hepatitis C Virus
 Hepatitis D Virus
 Hepatitis E Virus
2
HEPATITIS
HEPA :- LIVER
TITIS :-
INFLAMMATION

3

JSS COLLEGE OF PHARMACY, MYSURU 4
HEPATITIS A HEPATITIS B HEPATITIS C HEPATITIS D HEPATITIS E
TYPE RNA DNA RNA RNA RNA
INCUBATION
PERIOD
30 DAYS 90 DAYS 40 DAYS 40 DAYS 50 DAYS
ROUTE FAECO-ORAL
ROUTE
PARENTERAL
ROUTE
PARENTERAL
ROUTE
PARENTERA
L
FAECO-ORAL
ROUTE
SEVERITY MILD SEVERE MILD Severe MILD
CHRONICITY NONE 10% 50% - 60% Yes, co-
infection with
HBV
NONE

PATHOGENESIS
The Virus has special affinity to the liver
cells.
Once they are inside the liver, these cells
inoculate in the hepatocytes, which are
arranged in clusters called lobules and
start to multiply there.
The growth and multiplication of these
viruses doesn’t actually leads to liver cell
damage.
What happens is that these viruses leads to
change in antigen structure on the surface
of Hepatocytes. Due to this, the body
recognizes these new hepatocytes as a
foreign substances and starts to destroy
these Hepatocytes by the mechanism
called “SELF MEDIATED IMMUNE
DAMAGE”
5
HEPATITIS VIRUS
Through
Systemic
Circulation
Enters
Liver
Self Mediated Immune
Damage

The body tries to destroy the maxium number
of hepatocytes which are infected by the
mechanisms of:
 Apoptosis
 Necrosis
 Fibrosis.
Over a long run this leads to:-
 Severe liver cell damage
 Fibrosis
 Severe distortion of basic architecture of
liver.
• All these damage to liver leads to
deterioration of basic functions of liver.
• Since the liver performs so many vital
functions of our body, it leads to many
presentable clinical features in the patient.
6

CLINICAL FEATURES
Basically divided into three phases :-
Prodermal phase
Icteric phase
Convalescent phase.
7

SYMPTOMS :-
Incubation period: The virus multiplies and spreads without
causing symptoms.
Prodromal (pre-icteric) phase: Nonspecific symptoms occur;
they include profound anorexia, malaise, nausea and vomiting, a
newly developed distaste for cigarettes (in smokers), and often
fever or right upper quadrant abdominal pain. Urticaria and
arthralgias occasionally occur, especially in HBV infection.
Icteric phase: After 3 to 10 days, the urine darkens, followed by
Systemic symptoms often regress, and patients feel better
despite worsening jaundice. The liver is usually enlarged and
tender, but the edge of the liver remains soft and smooth. Mild
splenomegaly occurs in 15 to 20% of patients. Jaundice usually
peaks within 1 to 2 weeks.
Recovery phase: During this 2- to 4-week period, jaundice
fades.
Based on following
factors :-
• Type of Virus
• Age of the Patient
• General health of the
Patient
• Status of immune
system of patient
8

HEPATITIS A

PATHOPHYSIOLOGY
Hepatitis A Virus
systemic Circulation
Enters Liver
Replication within Hepatocytes / GI Epithelial Cells
New Viral particles secreted into bile
Virus reabsorbed Excreted in stools

CLINICAL PRESENTATION
Liver enzyme levels rise within the
first weeks of infection, peaking
approximately in the fourth week and
normalizing by the eighth week.
Conjugated bilirubinemia, clinically
evident as dark urine, precedes the
onset of the icteric period.
GI symptoms may persist or subside
during this time and some patients
may have hepatomegaly.
Duration of the icteric period varies
and corresponds to disease duration.
It averages between 7 and 30 days.

INTERPRETATION OF HEPATITIS-A SEROLOGIC TEST
RESULTS
LAB TEST RESULT INTERPRETATION
IgM anti-HAV
IgG anti-HAV
Negative
Negative
Susceptible to
infection
IgM anti-HAV
IgG anti-HAV
Positive
Positive
Acutely infected
Immune due to either
natural infection or
HAV vaccine
Serum HAV RNA is detectable
approximately 2 weeks prior to the onset of
symptoms or peak alanine aminotransferase
(ALT) levels and can persist for an average of
79 days after the onset of symptoms.
IgM anti-HAV is detectable 5 to 10 days
prior to symptomatic HAV infections in the
majority of patients.
IgG anti-HAV replaces IgM and indicates
host immunity following the acute phase of
the infection

MANAGEMENT
General Approach
• No specific treatment options exist for HAV infections.
• Instead, patients should receive general supportive care.
• Prevention and prophylaxis are key to managing the
virus.

Prophylaxis & Prevention
Two vaccines for HAV are
available - single-antigen
HAVRIX and VAQTA
Combination of HAV and
hepatitis B virus (HBV)
antigen vaccine TWINRIX

In situations of post exposure prophylaxis, either the vaccine or Ig can be
used.
Ig is used when pre exposure or post exposure prophylaxis against HAV
infection is needed in persons for whom vaccination is not an option.
For post exposure prophylaxis and for short-term pre exposure coverage of
<3 months, a single dose of 0.02 mL/kg is given intramuscularly.
For long-term pre exposure 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

HEPATITIS B VIRUS

PATHOPHYSIOLOGY

1.Attachment
2.Penetration
3.Uncoating
4.Replication
5.Assembly
6.Release

Clinical Presentation
Initial or Acute Phase
• Incubation period – 4 to 10 weeks. During this period, Anti-
HBcAg secreted, and viral replication takes place
• High serum HBV DNA & HBeAg levels
• ALT levels “may” increase, but patients remain asymptomatic
• Symptoms, if present, may include fever, anorexia, nausea,
vomiting, jaundice, dark urine, clay-colored or pale stools, and
abdominal pain.
• HBsAg does not become detectable until after significant viremia.
• The initial phase is considered immunotolerant because no hepatic
injury is sustained, as evidenced by generally normal ALT levels,
and the virus replicates profusely.

Immunoactive Phase
• Decrease in HBV DNA levels with ongoing secretion of
HBeAg.
• Patients are symptomatic with intermittent flares of hepatitis
and marked increases in ALT levels.
• More frequent flares are associated with disease progression
and reflect host immune response against HBV-infected
hepatocytes, increased cell death in an attempt to clear the
virus.
• The phase can last a few weeks in acute disease, and for years
in patients with chronic disease.
• As host defense strengthens, serum HBV DNA levels drop to
undetectable, ALT levels normalize, and liver
necroinflammation resolves.

Seroconversion Phase
HBeAg replaced with anti-HBeAg.
Factors favoring seroconversion
include female sex, older age,
biochemical activity, and genotype.
Flares of hepatitis with ALT levels
>5 times the upper limits of normal,
compared with <5 times the upper
limits of normal, correspond to
increased immune system activity
and precede seroconversion.

LAB TEST RESULT INTERPRETATION
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Negative
Susceptible to infection
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Positive
Immune due to natural infection
HBsAg
anti-HBc
anti-HBs
Negative
Negative
Positive
Immune due to hepatitis B vaccination
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
Positive
Positive
Positive
Negative
Acutely infected
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
Positive
Positive
Negative
Negative
Chronically infected
HBsAg
anti-HBc
Anti-HBs
Negative
Positive
Negative
Four interpretations possible: (a) Resolved infection (most
common); (b) false-positive anti-HBc, thus susceptible;
(c) low-level chronic infection; (d) resolving acute infection

PROPHYLAXIS

Management
Hep-B is incurable. Hence therapy is targeted at
supressing HBV Replication and prevent disease
progression.

Management
Pharmacologic Therapy
Drug therapy aims to suppress viral replication by either
immunomodulating agents or antivirals—the nucleos(t)ide agents.
Immune-mediating agents: interferon (IFN)-alfa and pegylated (peg)
IFN-alfa
Antivirals: lamivudine, telbivudine, adefovir, entecavir, and Tenofovir

Interferon
• IFN-alfa 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.
• Treatment for a minimum of 12 months is associated with greater sustained virologic response
(SVR) rates
• Conventional IFN therapy is plagued with numerous problems, including the inconvenience of
thrice-weekly injections (compared to once weekly for peg-IFN); however, standard IFN therapy
has virtually been replaced by the use of peg-IFN because of the benefits in ease of administration,
decreased side effect profile, and improvements in efficacy.
• The approved dose of pegylated interferon-α2a (Pegasys) for HBeAg-positive CHB is 180 mcg
subcutaneously once weekly for 48 weeks.

Lamivudine
Cytosine Nucleoside analog
Inhibits HBV DNA synthesis by being incorporated into growing DNA chains causing
premature chain termination
Effective in suppressing hepatitis B viral replication, normalizing ALT levels, and
improving liver histology.
Prolonged lamivudine therapy (up to 5 years) may be needed to sustain seroconversion
The adult dose is 100 mg orally once daily for treatment of CHB without HIV
coinfections. Pediatric dose is 3 mg/kg once daily up to a maximum dose of 100 mg
Adverse effects are minimal and include fatigue, diarrhea, nausea, vomiting, and
headaches. ALT levels should be monitored carefully because a two- to threefold increase
may be observed.

Entecavir
• Guanosine nucleoside analog that acts by inhibiting HBV replication
at three different steps
• The drug is dosed at 0.5 mg daily for adults with treatment-naïve or
non–lamivudine-resistant infections and at 1 mg daily in lamivudine-
refractory patients

Adefovir
• Adenosine nucleotide analog that inhibits DNA polymerase.
• It is dosed at 10 mg daily for 1 year in adults
• The most common side effects include asthenia, abdominal pain,
diarrhea, dyspepsia, headaches, nausea, and flatulence.
• It is also associated with nephrotoxicity.

Tenofovir
• Acyclic adenine nucleotide reverse transcriptase inhibitor
• Tenofovir is preferred over adefovir for CHB infections because of
greater effectiveness in inhibiting viral replication and lack of
resistance
• The dose of tenofovir is 300 mg orally once daily taken on an empty
stomach.
• Dose adjustments are required in patients with renal dysfunction
because tenofovir is primarily renally excreted.

HEPATITIS C

PATHOGENESIS

• 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.
• The HCV RNA levels plateau at 105 to 107 international units/mL (108 to 1010
international units/L) and precede a peak in ALT levels and the onset of
symptoms.
• Rising ALT levels indicate hepatic injury and cell necrosis and may exceed
values 10 times the upper limits of normal.
• Typically, symptoms occur 7 weeks after the infection, with a range of 3 to 12
weeks.
• Symptoms include fatigue, anorexia, weakness, jaundice, abdominal pain, or
dark urine.
• Acute infections rarely progress to fulminant hepatitis, although the course can
be severe and prolonged.

• 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.
• 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.
On physical examination, hepatomegaly is usually present.
• Chronic inflammation of the liver from chronic HCV infection may result in fibrosis.
• An estimated 20% of chronic HCV patients will develop cirrhosis and half of those
patients will progress to either decompensated cirrhosis or HCC.
• HCV is also rarely associated with extrahepatic manifestations.
• The most common is cryoglobulinemia, a local deposition of immune complexes that cause
vasculitis. Typical manifestations involve the skin and internal organ damage, predominantly
affecting the kidneys.

INTERPRETATION OF HEPATITIS-C
SEROLOGIC TEST RESULTS
LAB TEST REPORT INTERPRETATION
anti-HCV Negative Susceptible to infection
anti-HCV Positive Acutely or chronically infected

Management
Pharmacologic
• Combination therapy of a once-weekly injection of peg-IFN, a daily
oral dose of ribavirin, and either boceprevir or telaprevir.

Interferon
• Two peg-IFNs available

Ribavirin
• Ribavirin, a synthetic guanosine analog, is ineffective as a
monotherapy for HCV and its exact mechanism of action is unknown.

Protease Inhibitors

HEPATITIS D

Hepatitis-D
Management
• Hepatitis D infection is possible only if the patient is also infected with
HBV; therefore, hepatitis B vaccination can indirectly prevent
hepatitis D infections.
• The recommended treatment for HDV is pegylated interferon for 48 to
72 weeks.
• Firstline oral agents for treating HBV infections (e.g., tenofovir) may
be considered in patients coinfected with HDV and HBV if HBV DNA
levels are high.

INTERPRETATION OF HEPATITIS-D
IgM anti-HDV
HDVAg
HBsAg
HBeAg
anti-HBc
Positive
Positive
Positive
Positive
Positive
Acute HBV-HDV coinfection

HEPATITIS E

Hepatitis-E
• Hepatitis E is found worldwide, but acute cases occur primarily in Central and
Southeast Asia, the Middle East, North Africa, and Mexico.
• Hepatitis E is a nonenveloped single-stranded messenger RNA virus of the
Hepevirus genus.
• The HEV is similar to HAV in that the virus is found in contaminated feces, thus
infecting people via the fecal–oral route.
• Hepatitis E infections are usually self-limiting and rarely result in hepatic
complications.
• Chronic hepatitis E occurs rarely and is more likely to occur in
immunocompromised individuals such as patients with human
immunodeficiency virus (HIV) or posttransplant recipients.
• Because hepatitis E is transmitted via the fecal–oral route, good personal
hygiene and proper disposal of sanitary waste are the most effective ways to
prevent viral acquisition.

INTERPRETATION OF HEPATITIS-E
IgM anti-HEV
IgG anti-HEV
Negative
Negative
Susceptible to infection
IgM anti-HEV Positive Acutely infected
IgG anti-HEV Positive Immune due to natural infection

Recovery from the Hepatitis
• Depends upon :-
i. Type of Virus
ii. Status of health and Immune system of patient.
iii. Age of the patient

Age of the Patient
HEPATITIS A
and
HEPATITIS E
Children
Adults
LESS SYMPTOMS
70% - 90% JAUNDICE

Age of the Patient
HEPATITIS B
Children
Adults
LONG TERM CHRONIC
INFECTION
LESS CHANCES FOR
CHRONIC INFECTIONS

REFERENCES
• Central Bureau of Health Intelligence, Ministry of Health and Family Welfare, National Health
Profile. New Delhi : 2016
• National Guidelines for Diagnosis and Management of Viral Hepatitis, Ministry of Health and
Family Welfare, 2018

Pathogenesis and management of viral hepatitis

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