HEPATOLOGY & GASTROENTEROLOGY DEPARTMENT

HEPATITIS B VIRUS
INTRODUCTION
EPIDEMIOLOGY & TRANSMISSION
CLINICAL PICTURES & DIAGNOSIS
INVESTIGATIONS
PREVENTIONS & TREATMENTS
REFERENCES

INTRODUCTION TO HBV
Chronic hepatitis B virus (HBV) is the ninth leading cause of death, with approximately 300
million chronic carriers of HBV worldwide. In the United States there are an estimated 1.2
million chronic carriers, accounting for roughly 17,000 hospitalizations and 5,500 deaths each
year. Hepatitis B belongs to the hepadnaviridae class of viruses. The hepatitis B infection usually
occurs in adolescents and adults and can lead to acute hepatitis, subclinical infection, or the
development of chronic infection.

Morphology of HBV
The hepatitis B virus, a hepadnavirus, is a partially double stranded DNA virus, composed of a
27 nm nucleocapsid core (HBcAg), surrounded by an outer lipoprotein coat (also called
envelope) containing the surface antigen (HBsAg).

Common features of all of these virusesare enveloped virions and virion-associated DNAdependent polymerases that can repair the gap in thevirion DNA template and have reverse
transcriptase activities. Hepadnaviruses show narrow host ranges, growing only in species close
to the natural host, like gibbons, and some of the monkeys.
Hepatocytes infected in vivo by hepadnaviruses produce an excess of noninfectious viral
lipoprotein particles composed of envelope proteins. Intracellular HBV is non-cytopathic and
causes little or no damage to the cell.

HBV life cycle

The HBV virion binds to a receptor at the surface of the hepatocyte.A number of candidate
receptors have been identified, including the transferrin receptor. The mechanism
of HBsAg binding to a specific receptor to enter cells has not been established yet.
Viral nucleocapsids enter the cell and reach the nucleus, where the viral genome is
delivered.In the nucleus, second-strand DNA synthesis is completed and the gaps in both
strands are repaired to yield a covalently closed circular (ccc) supercoiled DNA molecule that
serves as a template for transcription of RNAs.

These transcripts are polyadenylated and transported to the cytoplasm, where they are
translated into the viral nucleocapsid and precore antigen (C, pre-C), polymerase(P),
envelope L (large), M (medium), S (small)), and transcriptional transactivatingproteins (X).
The envelope proteins insert themselves as integral membrane proteins into the lipid
membrane of the endoplasmic reticulum (ER).The 3.5 kb species, spanning the
entire genome and termed pregenomic RNA (pgRNA), is packaged together with
HBV polymerase and a protein kinase into core particles where it serves as a template for
reverse transcription of negative-strand DNA. The RNA to DNA conversion takes place inside
the particles.
The new, mature, viral nucleocapsids can then follow two different intracellular pathways,
one of which leads to the formation and secretion of new virions, whereas the other leads to
amplification of the viral genome inside the cell nucleus.
In the virion assembly pathway, the nucleocapsids reach the ER, where they associate with
the envelope proteins and bud into the lumen of the ER, from which they are secreted via
the Golgi apparatus out of the cell.

EPIDEMIOLOGY OF HBV
HBV is found worldwide (Figure 1). The highest incidence of HBV seropositivity (anti-HBsAg)
is in sub-Saharan Africa, the Far-East (China, Malaysia, Indonesia, Philippines, Papua New
Guinea etc). Other high levels (more than 8% of the population infected) are in northern
South America, northern Canada and Alaska and Greenland. In these areas, the lifetime risk
of infection is more than 60% with infections in childhood especially common. In areas of
low seropositivity (less than 2% of the population with anti-HBsAg antibodies), the lifetime
risk of HBV infection is less than 20% with most infections occurring in adults who are in
elevated risk groups. In the United States, HBsAgseropositivity occurs in less than 2% of the
population but in Asian Americans chronic HBV may be as high as 10-15% of the population.
In Asian Americans, hepatocellular carcinoma is a leading cause of death. Half of all children

born to mothers with chronic HBV infection in America are Asian Americans. African
Americans also show a high rate of HBV seropositivity. In Egypt,the HbsAg Prevalence is
intermediate from 2-7 %.
HBV is spread parenterally, sexually (hetero and homosexually) and neonatally. The virus is
high in the blood/serum and in wounds. Moderate levels are found in semen, saliva and
vaginal secretions. Other body secretions show low or non-detectable levels of virus.

Figure 1

TRANSMISSION OF HBV
The hepatitis B virus can survive outside the body for at least 7 days. During this time, the
virus can still cause infection if it enters the body of a person who is not protected by the
vaccine. The incubation period of the hepatitis B virus is 75 days on average, but can vary

from 30 to 180 days. The virus may be detected within 30 to 60 days after infection and can
persist and develop into chronic hepatitis B.
In highly endemic areas, hepatitis B is most commonly spread from mother to child at birth
(perinatal transmission), or through horizontal transmission (exposure to infected blood),
especially from an infected child to an uninfected child during the first 5 years of life. The
development of chronic infection is very common in infants infected from their mothers or
before the age of 5 years.
HBV is mainly found in the blood of infected individuals. Saliva, semen, vaginal secretions
and breast milk also contain the virus but in lower concentrations as compared to the blood.
Feces, nasal secretions, sputum, sweat, tears, urine and vomit have not been implicated in
the spread of Hepatitis B. Unless they are visibly contaminated with blood, the risk of
contracting hepatitis B from these fluids is practically nonexistent. Hepatitis B is not
transmitted by casual contact, hugging, by sharing eating utensils, through food or water,
etc.
After a person has been exposed to the HBV, the blood test (HBsAg) will become positive on
an average within 4 weeks (range 1- 9 weeks). Usually within 15 weeks of onset of the
symptoms, this test becomes negative in most individuals (except those who have
developed chronic infection).
Hepatitis B is also spread by percutaneous or mucosal exposure to infected blood and
various body fluids, as well as through saliva, menstrual, vaginal, and seminal fluids. Sexual
transmission of hepatitis B may occur, particularly in unvaccinated men who have sex with
men and heterosexual persons with multiple sex partners or contact with sex workers.
Infection in adulthood leads to chronic hepatitis in less than 5% of cases. Transmission of the
virus may also occur through the reuse of needles and syringes either in health-care settings
or among persons who inject drugs. In addition, infection can occur during medical, surgical
and dental procedures, tattooing, or through the use of razors and similar objects that are
contaminated with infected blood.

CLINICAL PICTURES OF HBV HEPATITIS

Acute HBV Hepatitis
Most people do not experience any symptoms during the acute infection phase. However,
some people have acute illness with symptoms that last several weeks, including:
Yellowish discoloration of the skin and eyes (jaundice)
Dark urine
Extreme fatigue
Nausea, vomiting
Abdominal pain
Some persons with acute hepatitis can develop acute (fulminant) liver failure. It is rare but
has serious complications. Fulminant hepatitis is a severe form of acute hepatitis that can be
life-threatening if not treated right away. The symptoms of fulminant hepatitis develop
suddenly and may include:
Mental disturbances such as confusion, lethargy, extreme sleepiness or hallucinations
(hepatic encephalopathy)
Sudden collapse with fatigue,
Jaundice is variable in degree and may be absent
Swelling of the abdomen

Chronic HBV Hepatitis

Infection with the virus becomes chronic depends upon the age at which a person becomes
infected. Children less than 6 years of age who become infected with the hepatitis B virus
are the most likely to develop chronic infections. More than 90% of healthy adults who are
infected with the hepatitis B virus will recover naturally from the virus within the first year.
Symptoms of liver damage (chronicity) may include the following:

 Fluid retention causing ascites and lower limb edema

Weight gain due to ascites
Persistent jaundice
Loss of appetite, weight loss, wasting
Vomiting of blood
Bleeding from various body orifices including nose, mouth, or rectum; or blood in the
stool
Hepatic

encephalopathy (excessive sleepiness, mental confusion, and in advanced

stages, development of coma)

COMPLICATIONS OF HBV INFECTIONS

Having a HBV infection can lead to serious complications, such as:
Scarring of the liver (cirrhosis) which may be extensive and impair the ability of liver to
function.
Liver cancer.
Liver failure. Acute liver failure is a condition in which the vital functions of the liver shut
down.
Other conditions such as kidney disease, inflammation of blood vessels or anemia.

DIAGNOSIS
It is not possible, on clinical grounds, to differentiate hepatitis B from hepatitis caused by
other viral agents. Hence, laboratory confirmation of the diagnosis is essential. A number of
blood tests are available to diagnose and monitor people with hepatitis B. They can be used
to distinguish acute and chronic infections. Laboratory diagnosis of hepatitis B infection
focuses on the detection of the hepatitis B surface antigen (HBsAg).
Acute HBV infection is characterized by the presence of HBsAg and immunoglobulin M (IgM)
antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also

seropositive for hepatitis B e antigen (HBeAg). HBeAg is usually a marker of high levels of
replication of the virus. The presence of HBeAg indicates that the blood and body fluids of
the infected individual are highly contagious.
Chronic infection is characterized by the persistence of HBsAg for at least 6 months with or
without concurrent HBeAg and immunoglobulin G (IgG) antibody to the core antigen
(HBcAg). Persistence of HBsAg is the principal marker of risk for developing chronic liver
disease and liver cancer later in life.

INVESTIGATION
1. Serology
Acute Infection
HBV contains several antigens to which infected persons can make immune response. These
antigens and their antibodies are important in identifying HBV infection.
Hepatitis B surface antigen (HBsAg). It is an indicator of an active infection. In acute liver
failure from hepatitis B, the liver damage is mediated by viral clearance and so HBsAg is
negative, with evidence of recent infection shown by the presence of hepatitis B core IgM.
HBsAg appear in the blood late in the incubation period, but before the prodromal phase of
acute type B hepatitis. It appears 6weeks after infection and disappear by 3 months. It also
may be present only for a few days and disappearing even before the jaundice has
developed. The persistence of this antigen for longer than 6 months indicates chronic
infection.
Antibody to HBsAG (anti-HBs). It usually appear about 3-6 months after the onset of the
disease if the patient cleared the virus and persist for many years perhaps permanently.
Presence of this antibody indicates the presence of immunity. Anti-HBs implies either a
previous infection if present with anti-HBc or previous vaccination if anti-HBc is not present.
There is a condition called window phase or window period in which during this period, both

serological markers HBsAg and Anti-HBs are negative which is because, although Anti-HBs
are present, they are actively bound to the HBsAg. Other serological markers, IgM against
HBc can be positive at this point.
Hepatitis B core antigen (HBcAg). It is not found in the blood but antibody (anti-HBc) to it
appears early in the illness
Antibody to hepatitis B core antigen (anti-HBc). It appears early and rapidly reaches a high
titre, which subsides gradually and then persists. Anti-HBc is initially of IgM type, and later
on IgG appear. Anti-HBc (IgM) is important in revealing acute HBV infection in window
phase.
Hepatitis B e antigen (HBeAg).It is an indicator of viral replication. In acute hepatitis B it may
appear transiently. Its appearances are followed by the production of antibody (anti-HBe).

Chronic Infection
Chronic HBV infection is marked by the presence of HBsAg for more than 6 months and antiHBc (IgG) in the blood. Usually HBeAg or anti-HBe is also present. The absence of

HBeAgimplies low viral replication except in HBeAg-negative chronic hepatitis B (also called
pre-core mutant infection) in which high level of viral replication,serum HBV-DNA and
hepatic necro-inflammation are seen despite of negative HBeAg.

2. Viral load and genotype

Polymerase chain reaction (PCR). HBV-DNA can be measured by PCR. Viral loads are usually
in excess of 105 copies/mL in the presence of active viral replication, as indicated by the
presence of e antigen. In contrast, in those with low viral replications, viral loads are less
than 105 copies/mL. Measurement of viral load is important in monitoring antiviral therapy
and identifying patients with pre-core mutants. Specific HBV genotypes (A-H) can also be
identified using PCR. This may be useful in guiding the therapy as genotype A tends to
respond better to pegylated interferon alfa, compared to genotype C and D.

PREVENTION AND TREATMENT OF HBV HEPATITIS

Prevention
There are general measures and specific measures to prevent from Hepatitis B infection. The
aim of the general measures is to prevent exposure of the virus. These includes screening of
blood before transfusion, strict regulations and instrument sterilization for all procedures,
implementing the infection control practices such as hand hygiene and use of gloves before
doing procedure, use of disposable syringes, and avoid recapping of the used needles.
For the specific measures, Hepatitis B vaccines are recombinant vaccines produces by using
HBsAg synthesized by the yeast into which a plasmid containing the gene for HBsAg has
been inserted. Purified HBsAG is obtained by lysing the yeast cells. The vaccine is given in
series of three intramuscular doses at 0, 1, and 6 months. The series of three doses induce a
protective antibody response. The vaccine should be administered only in deltoid muscle of
adults and children or in the anterolateral thigh muscle of neonates and infants.
Hepatitis B immunoglobulin (HBIG) together with vaccination are given as post-exposure
prophylaxis to neonates born to HBsAg positive mothers and those exposed to HBV but
unvaccinated or without vaccine response.

Treatment
The aim of treatment is to decrease HBV DNA and to prevent complications. The modalities
of treatment are antiviral therapy, control of manifestations of liver cirrhosis and liver cell
failure if it happens and liver transplantation. Antiviral therapy is indicated when HBV DNA is
more than 20 000 IU/ml and increase ALT twice upper limit of normal in patients without
cirrhosis, in patients with compensated cirrhosis and detectable HBV DNA by Polymerase
Chain Reaction should be considered for antiviral therapy (but not interferon) regardless of
the serum ALT level and the patients with chronic hepatitis on liver biopsy should be treated
.

The available treatments are Lamuvidine (Zeffix) 100 mg orally daily for at least five years
gives good results in 35-50% of patients with stoppage of progression of cirrhosis, Entecavir
and Adefovir which are another nucleoside analogue are more effective that Lamuvidine and
reduce HBV DNA more quickly andPegylated Interferon Alpha that is given once weekly for
six month to one year according to patients response. Results are slightly better than those
of short acting Interferons. It has many side effects including flu like manifestations,
depression, reversible hair loss, thyroid dysfunction and bone marrow depression. In this
case, the patients should be closely monitored.
Liver transplantation is done in end stage liver disease. It is now a valid option in many parts
of the world with excellent long-term survival (70-90%) and good quality of life.

References
1. Textbook of Internal Medicine Cairo University
2.Textbook of Paediatrics Cairo University
3.Textbook of Microbiology and Immunology Cairo University
4. http://www.who.int/mediacentre/factsheets/fs204/en/
5. http://www.askdrmakkar.com/hepatitis_homeopathic_treatment.aspx

6. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index2.html#electron

7.http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/liver/viral_hepatitis_b
.pdf

8. http://www.medicinenet.com/hepatitis_b/page3.htm