Hepatitis B

Globally, hepatitis B virus (HBV) infection is the most common form of chronic hepatitis around the world. Chronic
carriers can continue to transmit the disease for many years before becoming symptomatic.[22] Infection occurs
very often in early childhood when it is asymptomatic and then leads to the chronic carrier state. Chronic HBV
infection leads to increased risk for chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma (HCC).

Between 1990 and 2007 in the United States, the incidence of HBV infection declined from 8.5 cases to 1.5 cases
per 100,000 among all age groups, but the decline was most significant among children younger than 15 years.[23]
This has been due to increased awareness and identification of mothers who are hepatitis B surface antigen (HBsAg)
positive as well as adequate prophylaxis among exposed newborns.[18] Approximately 0.5% of the US population is
HbsAg positive, and 5% is hepatitis B core antibody (anti-HBc) positive.[24]

More than 2 billion people worldwide have been infected with HBV at some time, and approximately 350 million
people remain chronically infected.[24] There are approximately 4 million new cases per year, of which
approximately 25% become chronic carriers.[24, 18] The areas of highest incidence are Southeast Asia and the
Pacific Basin (excluding Japan, Australia, and New Zealand), sub-Saharan Africa, the Amazon Basin, parts of the
Middle East, the central Asian Republics, and some countries in Eastern Europe.[24] Low endemicity areas include
North America, Western and Northern Europe, Australia, and parts of South America. The carrier rate is less than
2%, and up to 5% of the population is infected with HBV.[24, 25, 26]

The age group most likely to be affected around the world is the newborn population, particularly in areas with a
high prevalence of disease and lack of identification of infected women whose infants are at risk for becoming
chronic carriers. In regions with widespread perinatal screening and adequate newborn prophylaxis, horizontal
transmission secondary to exposure to contaminated blood products, body fluids, or sexual contact become the
primary modes of transmission of HBV in the young adult population. In adult-onset disease, males are more likely
to go on to develop chronic disease, whereas females are more likely to develop anti-HBs antibodies.[24]

The following is a slide presentation on HBV from the Centers for Disease Control and Prevention (CDC).

Centers for Disease Control and Prevention (CDC) slide presentation on hepatitis B (HBV).
Pathophysiology and transmission

Hepatitis B disease is caused by HBV, an enveloped virus containing a partially double-stranded, circular DNA
genome and classified within the family hepadnavirus.[22, 26] The nucleocapsid core measures 27 nm in diameter
and is where the hepatitis B core antigen (HbcAg) is derived. The core is surrounded by a lipoprotein coat or
envelope, which is the HbsAg.[22, 24, 25, 27, 28] The envelope lipoprotein is produced in excessive amounts and
released into the circulation as HBsAg.[3]

HBV interferes with the functions of the liver while replicating in hepatocytes. The immune system is then activated
to produce a specific reaction to combat and attempt to eradicate the virus. Intracellular HBV is not cytopathic[29] ;
the inflammatory response develops as a result of the immune response.

HBV does not cross the placenta because of its size, and it cannot infect the fetus unless there have been breaks in
the maternal-fetal barrier, such as those that occur during amniocentesis. Women who are infected can transmit HBV
to the infant during delivery. Consequently, unless adequate prophylaxis is provided, the newborn is at high risk to
develop a chronic HBV infection, with its known long-term complications.[25]

Perinatal transmission from the mother to her newborn baby is the most important mode of infection. If a pregnant
woman is an HBV carrier and is also positive for hepatitis B "e" antigen (HBeAg), her newborn baby has a 90%
likelihood of becoming infected. Approximately 25% of infected infants will become chronic carriers. Most HbsAg
carriers are asymptomatic, potentially infectious, and a constant source of new infections.[27]

Less frequent, but important, modes of HBV transmission include transfer through percutaneous or parenteral
contact with infected blood, body fluids, and by sexual intercourse.[22, 28] A break in the skin or mucosal barrier is
required for transmission.[27]
HBV infection is transient in about 90% of adults and 10% of newborns and persistent in the remainder.[25]
Approximately 5-10% of adults progress to become asymptomatic carriers and develop chronic hepatitis. This can
lead to cirrhosis and hepatocellular carcinoma.[27]

Transfusion-related HBV infection occurs in approximately 1 in 200,000 transfusions. Some evidence shows that the
rate may be lower; however, this is still higher than the human immunodeficiency virus (HIV) and hepatitis C virus
(HCV)related risk of approximately 1 in 2,000,000.[30, 31, 32] Current rates for HBV are thought to be around 1
in 280,000 to 1 in 350,000, partially due to improved immunization and a decrease of infected products in the donor
pool.[30]

Infectivity

HBV is able to remain on any surface it comes into contact with for about 1 week without losing infectivity,[26, 27]
and an affected individual's blood is infective for weeks before the onset of any symptoms and throughout the acute
phase of the disease. The infectivity of chronically infected individuals varies from highly infectious (HBeAg
positive) to rarely infectious (hepatitis B "e" antibody [anti-HBe] positive).[24] HBeAg-positive specimens contain
high concentrations of infectious virions and HBV DNA, in contrast to anti-HBe positive samples, in which the
number of hepatitis B virions is substantially reduced.[24]

The concentration of HBV is highest in blood serum and wound exudates. A moderate concentration is found in
semen, vaginal fluid, and saliva, and low or undetectable levels are found in urine, feces, sweat, tears, and breast
milk.[26]

Hepatocellular carcinoma

More than 80% of hepatocellular carcinomas have integrated HBV sequences within the cell genome. Many copies
can be found and these are usually rearranged with deletions, inversions, and sequence reiterations. These
rearrangements are not transcriptionally active but rather interfere with normal cell cycle regulation.[22, 27, 33] The
exact mechanism by which HBV infection predisposes to hepatocellular carcinoma is unknown.[33]
Differential diagnosis and diagnostic studies

All patients with hepatitis B should be tested for hepatitis D virus (HDV). Other conditions that can coexist and
should be tested for are HCV and HIV infections.

The initial nonspecific diagnosis of hepatitis is made by the biochemical assessment of liver function. The initial
laboratory evaluation should include total and direct bilirubin, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), prothrombin time (PT), total protein, albumin, serum globulin,
and complete blood cell (CBC) count.[26, 27] The hallmark is the elevation in ALT, which can range from 2- to 100-
fold. However, the severity of the increase does not correlate with the prognosis.

Specific tests and evaluation

Specific testing for HBV requires evaluating for the presence of specific antigens and antibodies. HBV antigen and
antibodies have been classified into 3 clinically useful groups: (1) surface antigen and antibodies (HBsAg and anti-
HBs, respectively), (2) core antigen and antibodies (HBcAg and anti-HBc, respectively), and (3) "e" or precore
antigen and antibodies (HBeAg and anti-HBe, respectively). Testing for entire viral particles or virions and HBV
DNA are also available.

HBsAg can be detected in the serum from several weeks before the onset of symptoms and may persist for months
in chronic infections. The presence of HBsAg indicates that the woman is potentially infectious.[25, 26, 27] HBcAg
is not found in the blood stream. Other antigens present during the acute phase include virions, HBV DNA, HBV
DNA polymerase, and HBeAg. The presence of HBeAg is indicative of infectivity and disease severity.[26, 27] The
risk of maternal-fetal transmission can be as high as 90% among women positive for HBsAg who are also positive
for HBeAg.[25, 26]
Anti-HBc is the first antibody to appear. This test may reliably diagnose acute HBV infection. Anti-HBc
immunoglobulin (Ig) M appears early during the acute phase and usually disappears by 6 months; however, it can
persist in some cases of chronic hepatitis. Anti-HBc IgG appears during convalescence and generally remains
detectable for a lifetime.[26] HbsAg, HBeAg, and viral DNA are transiently present for approximately 6 months
before clearing; then, they are replaced by anti-HBs and anti-HBe.

Anti-HBe appears after anti-HBc and reflects decreased infectivity. Anti-HBs appears during recovery from the
acute phase and is evidence of resolution of the disease; this remains positive for the lifetime of the individual in
more than 80% of patients.[26, 24] The chronic carrier state is more likely to develop among patients whose HBsAg
consistently persists or in whom HBeAg remains positive for 2-3 months after the acute phase. This pattern is
observed in more than 90% of adult-onset disease. Approximately 10% of adults and more than 90% of infants that
are infected will go on to develop chronic disease.[25]

Chronic HBV and laboratory tests

Chronic disease develops in most neonates who are exposed and do not receive appropriate prophylaxis.
Approximately 1,000,000 individuals are chronically infected with HBV in the United States.[24] Chronic HBV
infection develops over many years, during which the disease goes through several phases. Some patients complain
of fatigue, anorexia, and malaise, whereas others are completely asymptomatic.

By definition, chronic HBV infection lasts for more than 6 months, with persistently positive HbsAg and anti-HBc
IgG with absence of an anti-HBs response. HBeAg is often present and correlates with elevated levels of HBV
DNA. The inflammatory response varies but is always milder than in the acute disease. It is an ongoing
inflammatory process that progresses to cirrhosis and increases the risk of hepatocellular carcinoma 100-fold.[26,
27]

Progression of disease is equated to viral replicative activity; this can be assayed by measuring serum ALT
concentrations. An elevated ALT suggests active disease with progression. Once the liver becomes cirrhotic, ALT
concentrations may decrease despite active inflammatory activity. In this phase, seroconversion is indicated by the
presence of anti-HBe and a decrease in HBV DNA. The presence of HBV DNA determines the infectivity of an
individual.

In addition to elevations in serum transaminases and bilirubin, patients with chronic HBV infection can develop
antinuclear (ANA), antimitochondrial (AMA), and antismooth muscle antibodies (ASMA).

HCC and laboratory tests

Persistent HBV infection is sometimes associated with histologically normal liver and normal liver function, but
about one third of chronic HBV infections are associated with cirrhosis and hepatocellular carcinoma.[27] This
condition develops in 40-50% of chronically infected men and 15% of women.[24] Men who acquired HBV
infection during childhood are the most likely to develop hepatocellular carcinoma. The average duration of HBV
disease before the development of hepatocellular carcinoma is 35 years.

Serum HBV DNA is the strongest predictor of progression to cirrhosis, regardless of ALT and HBeAg status.[34]
Tumors that are alpha-fetoprotein (AFP) positive with significant elevations above baseline are more aggressive and
associated with a shorter survival. AFP cannot be monitored during pregnancy due to fetal production of AFP. Most
women who are chronically infected with HBV complete childbearing before the onset of disease.[27]
Clinical management

Most individuals with HBV infection who acquire the disease during adulthood have self-limited disease and do not
require treatment. During pregnancy, viral hepatitis is associated with the lowest risk of obstetric complications
when compared with other potential hepatic complications, such as acute fatty liver of pregnancy, severe
preeclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). In most cases, no
special treatment is required during the acute phase. Bed rest is not mandatory.
Drug resistance mutations are one of the biggest concerns among individuals who are chronically infected with
active HBV disease. Current therapeutic options use single or combined antivirals such as lamivudine, adefovir, and
entecavir and less often include immunomodulatory drugs such as interferon (IFN).

Treatment with antivirals is recommended for patients with HBV DNA levels persistently greater than 10,000
copies/mL.[35] Although antivirals are not labeled as teratogens, information is limited on human exposure during
pregnancy.[36]
Prognosis

The risk for chronic HBV disease is highest among individuals with perinatally acquired HBV infection. Most
individuals who acquire the disease later in life will clear the infection. Prophylaxis of individuals at high risk and
patient education are the most important measures to prevent disease.

Complications of chronic hepatitis B include cirrhosis and hepatocellular carcinoma. In addition, extrahepatic
manifestations of HBV are seen in approximately 10-20% of patients.[25, 27, 29] These conditions develop as a
result of immune complex deposition within various organ systems or within the vasculature. The various
manifestations include a transient serum sicknesslike syndrome, acute necrotizing vasculitis, membranous
glomerulonephritis, and papular acrodermatitis of childhood.[25, 27, 29]
Prevention

All women presenting for prenatal care should be routinely tested for HBsAg early in their pregnancy to identify
those at risk for vertical transmission. In those cases in which prenatal information is not available or was not
obtained, HBsAg status should be established at the time of admission. This will allow at-risk newborns to be
appropriately immunized after birth. The routine vaccination of all infants at birth may be most cost effective in
developing countries.[24] Pregnancy and lactation are not considered contraindications for HBV immunization.[25]

Preexposure prophylaxis

Preexposure immunization (hepatitis b vaccine) is recommended for high-risk individuals, of which the most
important group to immunize is the newborn population. Furthermore, infants or adolescents not previously
immunized should be vaccinated, because they are the next most important group at risk for exposure.

There are certain high-risk groups that also benefit from immunization, such as persons with occupational risk,
students of healthcare professions, service providers in daycare programs caring for the developmentally disabled,
patients on hemodialysis, patients receiving blood products or transfusions, intravenous (IV) drug users, individuals
with multiple sexual partners regardless of sex, inmates at correctional facilities, household contacts of affected
individuals, transplant candidates, and travelers to areas with a high incidence of disease.[26, 37]

Postexposure prophylaxis

Postexposure immunization with hepatitis B immunoglobulin (HBIG) should especially be considered for neonates
born of mothers positive for HBsAg. Such infants often acquire chronic infection, especially when mothers are
HBeAg positive, in whom the risk of becoming chronic carriers is extremely high (90%). When HBIG is given
within the first hours, up to 24 hours after birth, the risk of HBV infection can be reduced to 20%.[26, 27]

Passive immunization with HBIG given immediately before or within 48 hours after exposure to HBV provides
immediate but temporary protection for 3-6 months. HBIG is usually not used for preexposure prophylaxis because
of cost, availability, and short-term effectiveness.[25] The vertical transmission rate is dramatically decreased when
HBIG is given with the first dose of HBV vaccine.[25, 26]

HBIG plus HBV vaccine

When administered within 24 hours after birth, HBIG and vaccination are 85-95% effective in preventing HBV
infection and the chronic carrier state. In contrast, administration of the HBV vaccine alone beginning within 24
hours after birth is 70-95% effective in preventing perinatal HBV infection.[25] With widespread vaccination, the
number of susceptible individuals would theoretically decrease, rendering the need for prenatal HbsAg testing
unnecessary. The problem is that vaccination programs do not provide 100% coverage, and there is a large
immigrant population that has not received adequate immunization.

An anti-HBs titer greater than 10 IU/L after 2-3 months is regarded as being protective. Repeat exposure is
associated with a rapid anamnestic response after reexposure.[25, 27] The vaccine-induced immunity has been
demonstrated to last at least 15 years, if not longer. Booster doses are not recommended.[25, 26, 27