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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 2013 in the United States, the incidence of HBV infection declined from
8.5 cases to 1 case per 100,000 among all age groups, but the decline was most significant
among children younger than 15 years. [23, 24] 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. [25]

More than 2 billion people worldwide have been infected with HBV at some time, and
approximately 350 million people remain chronically infected. [25] There are approximately 4
million new cases per year, of which approximately 25% become chronic carriers. [25, 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. [25] 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. [25, 26, 27]

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. [25]

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, 27] 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, 25, 26, 28, 29] 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 [30] ; 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. [26]

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. [28]

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, 29] A break in the skin or mucosal barrier is required for transmission. [28]

HBV infection is transient in about 90% of adults and 10% of newborns and persistent in the
remainder. [26] Approximately 5-10% of adults progress to become asymptomatic carriers and
develop chronic hepatitis. This can lead to cirrhosis and hepatocellular carcinoma. [28]

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. [31, 32, 33] 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. [31]

Infectivity

HBV is able to remain on any surface it comes into contact with for about 1 week without
losing infectivity, [27, 28] 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). [25] 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. [25]

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. [27]

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, 28, 34] The exact mechanism by which
HBV infection predisposes to hepatocellular carcinoma is unknown. [34]

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. [27, 28] 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. [26, 27, 28] 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. [27, 28]
The risk of maternal-fetal transmission can be as high as 90% among women positive for
HBsAg who are also positive for HBeAg. [26, 27]

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. [27] 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. [27, 25] 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. [26]

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. [25] 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. [27, 28]

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. [28] This condition develops in 40-50% of chronically infected
men and 15% of women. [25] 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. [35] 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. [28]

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. [36, 37] Although antivirals are not labeled as teratogens,
information is limited on human exposure during pregnancy. [38]

A systematic review and meta-analysis by Brown et al concluded that antiviral therapy


improves hepatitis B virus suppression and reduces mother-to-child transmission in women
with chronic hepatitis B virus infection with high viral load compared to the use of hepatitis
B immunoglobulin and vaccination alone. The study also added that the use of telbivudine,
lamivudine, and tenofovir appears to be safe in pregnancy with no increased adverse maternal
or fetal outcome. [39]

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.
[26, 28, 30]
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
sickness–like syndrome, acute necrotizing vasculitis, membranous glomerulonephritis, and
papular acrodermatitis of childhood. [26, 28, 30]

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. [25] Pregnancy and lactation are not considered contraindications for HBV
immunization. [26]

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. [27,
40]

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%. [27, 28]

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.
[26]
The vertical transmission rate is dramatically decreased when HBIG is given with the first
dose of HBV vaccine. [26, 27]

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. [26] 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. [26, 28] The
vaccine-induced immunity has been demonstrated to last at least 15 years, if not longer.
Booster doses are not recommended. [26, 27, 28] The CDC has recommended shortening the
interval for postvaccination serologic testing that assesses an infant's response to HepB
vaccination from age 9-18 months to age 9-12 months.. [41]