Clinical Manifestations and Diagnosis of Hepatitis B Virus Infection in Children and Adolescents

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Clinical manifestations and diagnosis of hepatitis B

virus infection in children and adolescents
AUTHOR: Annemarie Broderick, MB, BCh, MMedSc, FRCPI
SECTION EDITOR: Elizabeth B Rand, MD
DEPUTY EDITOR: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Apr 13, 2023.
INTRODUCTION
Hepatitis B virus (HBV) infection remains a global public health problem despite the
availability of an effective vaccine. A substantial number of children are infected, even in
countries where infants are routinely immunized against HBV. Infected children in these
countries usually are adoptees or children of immigrants or become infected in childhood.
The epidemiology, clinical manifestations, screening, and diagnosis of HBV infection in
children and adolescents are discussed below. The management of HBV infection in this age
group is discussed separately. (See "Management of hepatitis B virus infection in children
and adolescents".)
Other topic reviews with related material include:
● (See "Hepatitis B virus: Clinical manifestations and natural history".)
● (See "Hepatitis B virus: Overview of management".)
● (See "Hepatitis B virus immunization in infants, children, and adolescents".)
● (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)
● (See "Hepatitis B virus: Clinical manifestations and natural history".)
● (See "Hepatitis B and pregnancy", section on 'Mother-to-child transmission'.)
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EPIDEMIOLOGY
In the United States, the incidence of acute HBV in children <15 years was less than 0.02
cases per 100,000 population in 2015 [1] and has fallen further to 0.0 per 100,000 population
aged <19 years in 2019 [2]. This represents an almost 90 percent decrease since 1991, when
recommendations for universal HBV vaccination of infants were implemented. (See
"Hepatitis B virus immunization in adults".)
In the United States and in several other non-endemic countries, most cases of acute HBV
infection develop in patients with risk factors such as intravenous drug use or sexual contact
with an infected individual, in those living in communities with a large proportion of
immigrants from regions where HBV is endemic, and in certain groups where HBV is
endemic (such as Native Americans, including Alaska Natives) [3]. The majority of children
with chronic HBV infections are immigrants from high-endemicity areas, have parents who
were immigrants, or became exposed through other household contacts [4,5].
Worldwide, the population prevalence of HBV infection is highest in the Western Pacific
region (primarily in China, Mongolia, Vietnam, Philippines, and Papua New Guinea) and
African regions, as shown in this list and in this HBV prevalence map [6]. Even within
high-endemicity regions, there can be substantial variation in HBV prevalence between
countries and subpopulations. As an example, in a comprehensive report on HBV in Asian
and Pacific countries, HBV seroprevalence within Singapore varied in the three main ethnic
groups, from 4.2 percent (3.4 to 5.0) in Chinese people, to 2.2 percent (0.7 to 3.6) in Malay
people, and 0.6 percent (0.0 to 1.4) in Indian people [7]. These findings demonstrate the
limitations of the broad classification systems often used to report HBV endemicity and risk.
(See "Epidemiology, transmission, and prevention of hepatitis B virus infection" and
"Epidemiology, transmission, and prevention of hepatitis B virus infection", section on
'Epidemiology of chronic HBV'.)
In countries where HBV is endemic, perinatal transmission remains the most important
cause of chronic infection because of high rates of disease in pregnant women. Perinatal
transmission also occurs in non-endemic countries, including the United States, mostly in
children of HBV-infected mothers who do not receive appropriate HBV immunoprophylaxis
at birth [8,9]. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection",
section on 'Transmission of HBV'.)
CLINICAL MANIFESTATIONS
Infection with HBV is associated with characteristic changes in the serum levels of HBV
antigens and antibodies ( figure 1 and table 1). These markers are used to define
different clinical phases of HBV infection.
Acute hepatitis B virus infection — Acute HBV infection in children has a variable course
ranging from asymptomatic infection to fulminant hepatitis. Universal HBV vaccination has
substantially reduced the frequency of fulminant hepatitis. As an example, mortality in
Taiwan decreased from 5.36 to 1.71 per 100,000 during the last two decades of the 20th
century [10].
Clinical manifestations of acute HBV infection in children who develop symptoms are similar
to those in adults. The incubation period lasts one to four months. A serum sickness-like
syndrome may develop during the prodromal period, followed by constitutional symptoms,
anorexia, nausea, jaundice, and right upper quadrant discomfort. The symptoms and
jaundice generally disappear after one to three months, but some patients have prolonged
fatigue even after normalization of serum aminotransferase concentrations. On serologic
testing, acute HBV infection is characterized by hepatitis B surface antigen (HBsAg) and
immunoglobulin M antibody to hepatitis B core antigen (IgM anti-HBc) ( figure 1). (See
'Interpretation' below and "Hepatitis B virus: Clinical manifestations and natural history".)
However, some features are seen more commonly in certain age groups:
● The proportion of patients progressing to chronic infection is much higher in neonates

(up to 90 percent) compared with 1 to 5 percent in adults and intermediate values in
young children.
● Most older children and adolescents have mild constitutional symptoms during acute
HBV infection. Fulminant hepatitis is rare but can also be seen, particularly in infants
born to mothers with hepatitis B e-antigen (HBeAg)-negative chronic HBV (ie, HBsAg-
positive and HBeAg-negative) [11]. HBV vaccination does not consistently protect
against the development of fulminant hepatitis B in neonates or in
immunocompromised individuals.
● Gianotti-Crosti syndrome (characterized by papular acrodermatitis of the face,

extremities, and trunk, accompanied by lymphadenopathy) is seen in infants and young
children with acute HBV infection, in whom it may be the only clinical manifestation.
The syndrome is not specific to HBV infection, since it can be seen with other forms of
viral infection as well. (See "Gianotti-Crosti syndrome (papular acrodermatitis)".)
Management of acute HBV infection is discussed separately. (See "Management of hepatitis

B virus infection in children and adolescents", section on 'Management of acute hepatitis B
virus'.)
Chronic hepatitis B virus infection — Most children with chronic HBV infection are
asymptomatic and grow and develop normally. Some children note vague right upper
quadrant discomfort and fatigue.
Chronic HBV infection is occasionally associated with extrahepatic manifestations including

polyarteritis nodosa and glomerulonephropathy; the latter is observed principally in
children. HBV infection can induce both membranous nephropathy and, less often,
membranoproliferative glomerulonephritis. The typical presentation is with nephrotic range
proteinuria. Approximately 30 to 60 percent of children with HBV-related membranous
nephropathy undergo spontaneous remission, usually in association with HBeAg to antibody
to HBeAg (anti-HBe) seroconversion (ie, conversion from HBeAg-positive to -negative and
from anti-HBe-negative to -positive [ie, appearance of HBeAb]). The incidence of HBV-
associated membranous nephropathy is falling as rates of HBV vaccination increase [12].
(See "Kidney disease associated with hepatitis B virus infection".)
On serologic testing, chronic HBV infection is characterized by persistently positive HBsAg. In

contrast with acute HBV, total anti-HBc is usually positive (because of the immunoglobulin G
[IgG] component), while IgM anti-HBc is negative (unless during a flare of chronic HBV)
( figure 1 and table 2). (See 'Interpretation' below.)
Natural history — The natural history of chronic HBV infection in children is variable,
depending upon age, mode of acquisition, and ethnicity. These differences are likely due to
immune tolerance that develops when infection occurs at an early age. The exact
mechanisms through which immune tolerance develops are unknown.
● Children with perinatally acquired HBV usually remain HBeAg-positive and have high
levels of viral replication that may persist for years or even decades, although histologic
injury is typically mild [13,14]. In an illustrative report from Taiwan that followed a
cohort of children with HBV infection born before the implementation of universal HBV
immunization, approximately 66 percent of children remained HBeAg-positive at 10
years of age [15]. Rates of spontaneous seroconversion (loss of HBeAg) are less than 2
percent per year in children younger than three years of age and increase to
approximately 8 percent per year during puberty and young adulthood [16,17]. In boys,
the rate of seroconversion increases with testosterone levels and earlier onset of
puberty [18]. Similarly, in girls, earlier age of menarche (before 11.5 years of age) is
associated with earlier spontaneous HBeAg seroconversion and a greater rate of HBV
clearance [19]. Children who seroconvert spontaneously tend to have higher alanine
aminotransferase (ALT) levels early in life compared with those who do not seroconvert
spontaneously. Annual rates of HBeAg seroconversion appear to be lower in Asian
populations, but the cumulative rate of HBeAb seroconversion still reaches 50 percent
by 25 years of age [20,21]. This may be because rates of HBeAg seroconversion are
lower in populations with perinatal HBV transmission and in those with HBV genotype C
compared with genotype B [22].
● By contrast, children with HBV infection that was not perinatally acquired (eg, those
born in non-endemic countries and who acquired the infection through parenteral
transmission) are very likely to clear HBeAg and HBV DNA from serum during the first
two decades of life [23]. In a 29-year longitudinal study of Italian children with chronic
HBV who underwent HBeAg seroconversion, 95 percent (81/85) of those without
cirrhosis had inactive HBV infection at most recent follow-up and 15 percent (13/89)
cleared HBsAg [24]. Despite the high rate of seroconversion, hepatocellular carcinoma
(HCC) developed in 2 percent of the cohort over 20 years, underscoring the serious
nature of chronic HBV infection.
Phases of chronic hepatitis B virus infection — Individuals with perinatally acquired

chronic HBV infection typically enter an immune-tolerant phase, from which they eventually
move on to an immune-active phase and thence to an inactive chronic HBV state or,
occasionally, to spontaneous clearance of the infection. The timing of this progression varies
between individuals, and the severity of liver injury may depend on the length of the
immune-active phase. Although the phases are defined by laboratory findings
( figure 2A-B), the combination of findings for some patients may not fall into a single
category. Therefore, longitudinal assessment is often needed to clarify the phase of
infection. Moreover, some patients may progress rapidly through one or more of these
phases, so each step may not be clinically apparent. (See "Hepatitis B virus: Clinical
manifestations and natural history".)
Immune-tolerant — This phase is characterized by normal or mildly elevated serum

aminotransferase activity (eg, ALT <1.5 times the upper limit of normal) and evidence of
active HBV replication (HBV DNA >20,000 international units/mL or 105 copies/mL)
( figure 2A). HBsAg and HBeAg are positive. Young children with vertically transmitted
disease typically enter this phase, which continues for months, years, or even decades,
before entering the immune-active phase. In some literature, this phase is known as phase 1
(but note that the phases do not necessarily occur in numerical order in clinical situations)
[25]. Treatment of patients in this phase is not recommended, because patients are unlikely
to respond and treatment with nucleoside or nucleotide analogs may induce drug resistance
and even cross-resistance to newer medications. (See "Management of hepatitis B virus
infection in children and adolescents", section on 'Selection of patients for antiviral
treatment'.)
The normal range of ALT levels varies with sex in children and by reporting laboratory. For
the purposes of making treatment decisions about chronic hepatitis B, a consensus guidance
suggests using an ALT threshold of <25 U/L for girls and <35 U/L for boys for consistency
with recommendations in adults [26], although the true normal range for ALT may be
somewhat lower [27]. ALT values should also be interpreted in the context of the patient's
prior ALT results.
Immune-active, HBeAg-positive (clearance) — This phase, sometimes known as

phase 2, is characterized by elevated serum aminotransferase activity (eg, ALT >1.5 times the
upper limit of normal) and active HBV replication (HBV DNA is typically >20,000 international
units/mL or 105 copies/mL) ( figure 2A). HBsAg and HBeAg are positive. The ALT threshold
used to define this phase (and therefore as a criterion for treatment) has not been
established. We advocate using a threshold of ALT >45 international units/L (which is 1.5
times the upper limit of normal in most laboratories). Lower ALT thresholds have been
proposed [28], but this approach is more likely to lead to treatment of children in the
immune-tolerant phase, when treatment is much less likely to be effective.
Patients in this phase often clear HBeAg and move into the inactive chronic HBV phase; this
can occur spontaneously or in response to treatment. Children in this stage of HBV infection
who do not spontaneously clear HBeAg within several months are at risk for progressive liver
disease and are likely to benefit from treatment [26]. Spontaneous clearance of HBeAg early
in life is less likely for patients with genotype C as compared with other genotypes [29],
although genotyping is not part of routine clinical care. (See "Management of hepatitis B
virus infection in children and adolescents", section on 'Selection of patients for antiviral
treatment' and "Clinical significance of hepatitis B virus genotypes".)
Inactive chronic hepatitis B virus — This phase (sometimes referred to as the latent,
nonreplicative or carrier phase or phase 3) is characterized by normal levels of serum
aminotransferase activity and low or undetectable levels of HBV. HBsAg is positive and
HBeAg is negative. Up to 20 percent of patients have one or more reversions to the HBeAg-
positive immune-active phase, and 20 to 30 percent reactivate into HBeAg-negative HBV,
which is described below [30]. These reactivations may occur at any time, so regular
monitoring is necessary. Patients with either inactive chronic HBV or reactivated chronic HBV
remain at risk for complications of HBV such as HCC. (See 'Hepatocellular carcinoma' below
and "Management of hepatitis B virus infection in children and adolescents", section on
'Monitoring'.)
Immune-active, HBeAg-negative (reactivation) — Among patients with inactive

chronic HBV, 20 to 30 percent experience HBeAg-negative immune reactivation, also known
as HBeAg-negative chronic HBV or HBeAg-negative replicative phase, or phase 4 [31]. This
phase is characterized by a sharp increase in viral DNA levels increase (typically >2000
international units/mL), and ALT is normal or elevated, but HBeAg remains undetectable.
Most of these patients have HBV variants with precore or core promoter mutations. Patients
in this phase tend to have more virulent liver disease; they should be monitored for
complications, and antiviral therapy may be indicated. (See "Hepatitis B virus: Overview of
management", section on 'HBeAg-negative chronic hepatitis'.)
Resolved hepatitis B virus (loss of HBsAg) — A small minority of patients who clear
HBeAg also go on to clear the HBV infection, heralded by clearance of HBsAg and
appearance of antibody to hepatitis Bs (anti-HBs; also written HBsAb), sometimes known as
phase 5. The annual rate of this transition is probably around 1 percent in populations in
which HBV is acquired perinatally [32-34]. Although HBV is still present in hepatocytes, these
individuals rarely revert to active HBV infection. The risk of progressive liver disease is low,
but they remain at risk for HCC, and surveillance is warranted. (See 'Hepatocellular
carcinoma' below and "Hepatitis B virus: Clinical manifestations and natural history", section
on 'Resolution of chronic HBV infection'.)
Progression to cirrhosis — Cirrhosis occasionally develops during childhood in individuals

with chronic HBV infection. One of the largest studies included 292 consecutive children who
were HBsAg-positive and had elevated serum ALT levels [35]. Cirrhosis was found in 10
patients (3 percent) at a mean age 4.0±3.3 years. However, children with cirrhosis had a
higher prevalence of hepatitis D virus (HDV) infection and were more likely to have had blood
transfusions, suggesting that coinfection with HDV or hepatitis C virus (HCV) may have
contributed to disease progression in some children.
Although frank cirrhosis is unusual during childhood, development of moderate or severe

fibrosis is relatively common. In a series of 134 children with chronic HBV (mean age nine
years), 60 percent had portal expansion without bridging fibrosis, 20 percent had bridging
fibrosis, and 4 percent had cirrhosis [36]. These findings suggest that many individuals with
perinatally acquired chronic HBV are at risk for developing cirrhosis in the long term. (See
"Hepatitis B virus: Clinical manifestations and natural history", section on 'Sequelae and
prognosis of chronic HBV infection'.)
The risk of progression to cirrhosis among adults diagnosed with chronic HBV infection is
discussed separately. The risk is higher among individuals from areas endemic for HBV
infection, most of whom acquire the disease perinatally; for those with coinfections with
HCV, HDV, or HIV; and for those with HBV genotype C. Individuals who abuse alcohol
probably have accelerated disease progression. Men also have higher risk for exacerbations
of HBV, cirrhosis, and HCC compared with women. In transgenic mice, HBV acts as a sex
hormone-responsive virus, which may explain the lower rates of HCC and HBV viral load seen
in women compared with men; human correlation is awaited [37,38]. (See "Hepatitis B virus:
Clinical manifestations and natural history", section on 'Sequelae and prognosis of chronic
HBV infection' and "Clinical significance of hepatitis B virus genotypes", section on
'Genotypes/serotypes-disease progression and HBeAg seroconversion'.)
Hepatocellular carcinoma — HCC in children and adults with HBV infection has been
described in both Asian and Western populations [39-43]. Adults with perinatally acquired
HBV develop HCC at a rate of approximately 5 percent per decade [44]. The risk is related to
the duration of disease, degree of histologic injury, and replicative state of the virus (HBV
DNA levels). The risk is higher in patients who are HBeAg-positive for extended periods of
time and for those with precore mutants. The risk is increased further in the presence of
cirrhosis or concomitant infection with HCV or HIV. However, HCC has been described in
children who had undergone early HBeAg seroconversion, indicating that there is still a risk
for HCC even after viral replication ceases [45]. (See "Epidemiology and risk factors for
hepatocellular carcinoma", section on 'Hepatitis B virus'.)
Because of these risks, we suggest surveillance for HCC in individuals in all phases of HBV
infection, including those who have undergone seroconversion (converted to HBeAg-
negative), either spontaneously or after successful treatment. (See "Management of hepatitis
B virus infection in children and adolescents", section on 'Monitoring'.)
HBV genotype may influence HCC development in children differently than in young adults.
In Taiwan, the majority of children with HCC and chronic HBV infection have HBV genotype B
[46]. In contrast, most studies in young adults report an association between HBV genotype
C and HCC. (See "Clinical significance of hepatitis B virus genotypes", section on
'Hepatocellular carcinoma'.)
Universal childhood vaccination has led to a major decline in the incidence of HCC in
endemic countries. In Taiwan, for example, the average annual incidence in children six to
nine years of age has decreased from 0.7 to 0.57 to 0.36 per 100,000 between the years 1981
to 1986, 1986 to 1990, and 1990 to 1994, respectively [47]. Long-term studies have
substantiated this finding [48].
SCREENING
Who should be screened — The following groups should be screened for HBV infection
[26,31,49]:
● Screen regardless of vaccination history:
• Individuals born in areas with high or intermediate prevalence of HBV (regions in

which the prevalence of HBV disease is more than 2 percent), which includes many
immigrants and internationally adopted children. These regions include all of Africa
and Asia, Cape Verde islands, most of Eastern and Mediterranean Europe, the
Caribbean, and parts of South America, as shown in this list and this HBV
prevalence map. (See "Epidemiology, transmission, and prevention of hepatitis B
virus infection", section on 'Epidemiology of chronic HBV'.)
• Infants born to mothers with chronic HBV infection (hepatitis B e-antigen [HBeAg]-
positive or -negative).
Postvaccination testing of infants who received appropriate immunoprophylaxis at

birth is discussed separately. (See "Hepatitis B virus immunization in infants,
children, and adolescents", section on 'HBsAg-positive mother or mother with other
evidence of HBV infection'.)
• Pregnant individuals. (See "Prenatal care: Initial assessment", section on 'Hepatitis

B'.)
● Screen those who are not fully vaccinated (or who did not have HBV testing prior to
vaccination) if they have risk factors for horizontal transmission ( table 3) including:
• Children not vaccinated as infants who are living in communities where HBV is
endemic, including children born to immigrant parents from endemic areas.
• Household and sexual contacts of individuals with HBV infection.
• People who engage in high-risk behaviors. This includes those who use intravenous
or intranasal drugs, have unprotected sex with an infected partner or more than one
partner, people who engage in unprotected anal intercourse, and those with a
history of sexually transmitted disease.
• Any patient with hepatitis C virus (HCV) or HIV infection, due to common modes of
transmission. Coinfection with HCV and HBV increases the risk for progressive liver
disease, for hepatocellular carcinoma (HCC), and for HBV reactivation during
treatment for HCV. (See "Hepatitis C virus infection in children".)
Screening is also warranted for any individual who requests screening, regardless of
vaccination history or risk factors (because they may be reluctant to disclose or unaware of
risk factors). In addition, testing for HBV infection is warranted for any individual with
unexplained alanine aminotransferase (ALT) elevations (eg, >2 times the upper limit of
normal), as part of a diagnostic evaluation.
For adults, a less selective approach is used for HBV screening because the older population
has higher rates of HBV infection and lower vaccination rates compared with children. (See
"Hepatitis B virus: Screening and diagnosis in adults".)
Screening tests — Screening for HBV infection should be performed by testing for hepatitis
B surface antigen (HBsAg) and antibody to hepatitis Bs (anti-HBs). Simultaneous testing for
anti-HBc is essential for patients who are undergoing HBV screening prior to commencing
immunosuppressive therapy including biologic agents because this test will identify the rare
patient with resolved infection who is anti-HBs negative (see "Hepatitis B virus reactivation
associated with immunosuppressive therapy"). The Centers for Disease Control and
Prevention suggests including anti-HBc as part of routine screening ("triple panel" screening,
ie, anti HBs, HBsAg, and anti-HBc). This triple panel test can help identify persons who have
an acute HBV infection (anti-HBc IgM positive), or help distinguish between patients who are
immune due to prior infection (total anti-HBc positive) or immune due to vaccination (anti-
HBc negative) [49].
Results are interpreted as follows ( table 2):
● Positive HBsAg – Diagnostic of HBV infection. Anti-HBs will almost always be negative
(except during a brief window period as an infection resolves).
● Negative HBsAg, negative anti-HBs – Excludes HBV infection. These patients are not
immune and should be vaccinated (see "Hepatitis B virus immunization in infants,
children, and adolescents"). The possibility of acute HBV infection should be considered
in those with suggestive signs or symptoms; this diagnosis could be confirmed by
measuring IgM antibody to hepatitis B core antigen (IgM anti-HBc). (See 'Acute hepatitis
B virus infection' above.)
● Negative HBsAg, positive anti-HBs – Excludes HBV infection and confirms that the
patient is immune.
● Positive anti-HBc – Implies past or current HBV infection. Very rarely, this may be a false
positive, so the HBsAg and anti-HBs tests should be repeated if the result is
unexpected. If total anti-HBc is positive and anti-HBs is negative, further testing for IgM
anti-HBc is indicated to distinguish between acute and chronic HBV infection.
DIAGNOSTIC EVALUATION
Diagnostic testing — If HBV infection is diagnosed by the screening tests above, the patient
should be further evaluated with the following tests:
● Hepatitis B e-antigen (HBeAg)

● Antibody to HBeAg (anti-HBe)
● IgG and IgM antibodies to hepatitis B core antigen (typically ordered as [total] anti-HBc
and IgM anti-HBc)
● HBV DNA
● Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
If acute HBV infection is suspected clinically, initial diagnostic testing is with anti-HBc (total
and IgM), as well as ALT, AST, hepatitis B surface antigen (HBsAg), and antibody to hepatitis
Bs (anti-HBs) if not already done.
Interpretation — The results are interpreted as follows:
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● Acute HBV – The combination of positive HBsAg and IgM anti-HBc is diagnostic of
acute HBV infection. HBeAg is positive in the early phase and then converts to negative
as anti-HBe appears ( figure 1). (See 'Acute hepatitis B virus infection' above.)
● Chronic HBV – The diagnosis of chronic HBV infection is based on persistence of HBsAg
for more than six months, with positive (total) anti-HBc and negative IgM anti-HBc.
● Phase of chronic HBV – The phase of chronic HBV infection is determined by the other
results, as outlined in the figure ( figure 2A) and detailed above. (See 'Phases of
chronic hepatitis B virus infection' above.)
Determination of the phase of chronic HBV infection has important implications for
treatment:
• Most children with chronic HBV acquired the infection perinatally, and most will be
in the immune-tolerant phase (normal or mildly elevated serum aminotransferase
activity and high HBV DNA levels). Children in this phase sometimes clear HBeAg
and convert to inactive chronic HBV spontaneously and are unlikely to respond to
treatment. (See 'Immune-tolerant' above.)
• Children in the immune-active phase (elevated ALT and elevated HBV DNA) may be
in the process of spontaneous clearance. They are also the most likely to respond to
treatment. Decisions about initiating treatment are discussed in a separate topic
review. (See "Management of hepatitis B virus infection in children and adolescents",
section on 'Selection of patients for antiviral treatment'.)
Further evaluation — For patients with confirmed chronic HBV infection, further evaluation
includes laboratory assessment for severity of liver disease; testing for coinfection with other
hepatotropic viruses (hepatitis C and A) and for HIV if any risk factors are present;
surveillance for hepatocellular carcinoma (HCC); and, sometimes, liver biopsy (in candidates
for antiviral treatment). This evaluation and subsequent treatment decisions are discussed in
a separate topic review. (See "Management of hepatitis B virus infection in children and
adolescents", section on 'Post-diagnosis evaluation'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Diagnosis of hepatitis
B" and "Society guideline links: Hepatitis B vaccination" and "Society guideline links:
Management of hepatitis B" and "Society guideline links: Benign prostatic hyperplasia".)
SUMMARY AND RECOMMENDATIONS
● Prevalence – In the United States, the majority of children with chronic hepatitis B virus
(HBV) infection are immigrants from areas with endemic HBV infection ( HBV
prevalence map), have immigrant parents, or became exposed through other
household contacts. Perinatal transmission of HBV declined sharply after universal
hepatitis B vaccination of infants was initiated in 1991. (See 'Epidemiology' above.)
● Natural history – The natural history of chronic HBV infection in children is variable,
depending upon age and mode of acquisition, ethnicity, and/or HBV genotype. Children
with perinatally acquired HBV usually remain hepatitis B e-antigen (HBeAg)-positive and
have high levels of viral replication for prolonged periods, although histologic injury is
typically mild ( figure 2B). By contrast, children with HBV disease that was not
perinatally acquired (ie, horizontal transmission) tend to have higher alanine
aminotransferase (ALT) levels and frequently clear HBeAg and HBV DNA from serum
during the first two decades of life. (See 'Natural history' above.)
● Acute HBV – If acute HBV infection is suspected clinically, initial diagnostic testing
should include hepatitis B core antigen (anti-HBc; total and immunoglobulin M [IgM])
( figure 1).
● Screening for chronic HBV
• Indications – Screening for HBV is recommended for all patients with risk factors
( table 3), including internationally adopted children, immigrants from high-
prevalence areas and their children, household contacts of individuals with HBV
infection, adolescents who engage in high-risk behaviors, and any patient with
hepatitis C virus (HCV) or HIV infection (due to common modes of transmission).
(See 'Who should be screened' above.)
• Screening tests – Screening is done by serologic testing for hepatitis B surface

antigen (HBsAg) and antibody (anti-HBs). Positive HBsAg is diagnostic of chronic
HBV infection, and positive anti-HBs indicates immunity (due to immunization or
recovery from infection). (See 'Screening tests' above.)
● Further testing for HBsAg-positive patients – Patients with positive HBsAg should be
further evaluated with serum ALT and aspartate aminotransferase (AST), HBV DNA, and
HBeAg. (See 'Diagnostic evaluation' above and 'Interpretation' above.)
● Implications – These results determine the phase of HBV infection ( table 1 and
figure 2A-B), which has important implications for treatment decisions:
• Children in the immune-tolerant phase of chronic HBV (normal or mildly elevated

serum ALT and high HBV DNA, with positive HBeAg) are unlikely to respond to
antiviral treatment. This is the most common phase for children, most of whom
acquired the infection perinatally. (See 'Immune-tolerant' above.)
• Children in the immune-active phase of chronic HBV (markedly elevated ALT and
high HBV DNA) may be in the process of spontaneous clearance. They are also the
most likely to respond to treatment. Decisions about initiating treatment are
discussed in a separate topic review. (See 'Immune-active, HBeAg-positive
(clearance)' above and "Management of hepatitis B virus infection in children and
adolescents", section on 'Selection of patients for antiviral treatment'.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Maureen M Jonas, MD, who contributed to earlier
versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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virus-DNA integration in a 4-year-old boy. Hum Pathol 1986; 17:202.
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41. Giacchino R, Navone C, Facco F, et al. HBV-DNA-related hepatocellular carcinoma
occurring in childhood. Report of three cases. Dig Dis Sci 1991; 36:1143.
42. Pontisso P, Basso G, Perilongo G, et al. Does hepatitis B virus play a role in primary liver
cancer in children of Western countries? Cancer Detect Prev 1991; 15:363.
43. Hsu HC, Wu MZ, Chang MH, et al. Childhood hepatocellular carcinoma develops
exclusively in hepatitis B surface antigen carriers in three decades in Taiwan. Report of
51 cases strongly associated with rapid development of liver cirrhosis. J Hepatol 1987;
5:260.
44. Sokal EM, Paganelli M, Wirth S, et al. Management of chronic hepatitis B in childhood:
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2013; 59:814.
45. Wen WH, Chang MH, Hsu HY, et al. The development of hepatocellular carcinoma
among prospectively followed children with chronic hepatitis B virus infection. J Pediatr
2004; 144:397.
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children with chronic infection and hepatocellular carcinoma. Gastroenterology 2004;
127:1733.
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incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study
Group. N Engl J Med 1997; 336:1855.
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49. Conners EE, Panagiotakopoulos L, Hofmeister MG, et al. Screening and Testing for
Hepatitis B Virus Infection: CDC Recommendations - United States, 2023. MMWR
Recomm Rep 2023; 72:1.

Topic 5943 Version 41.0
GRAPHICS
Serologic responses to hepatitis B virus infection
Schematic representation of the serologic responses to acute and chronic HBV infection in relation to
the serum ALT concentration.
(Left panel) Acute infection is characterized initially by the presence of HBeAg, HBsAg, and HBV DNA
beginning in the preclinical phase. IgM anti-HBc appears early in the clinical phase; the combination
of this antibody and HBsAg makes the diagnosis of acute infection. Recovery is accompanied by
normalization of the serum ALT, disappearance of HBV DNA, HBeAg to anti-HBe seroconversion, and
subsequently HBsAg to anti-HBs seroconversion and switch from IgM to IgG anti-HBc. Thus, previous
HBV infection is characterized by anti-HBs and IgG anti-HBc.
(Right panel) Chronic infection is characterized by persistence of HBeAg (for a variable period), HBsAg,
and HBV DNA in the circulation; anti-HBs is not seen (in approximately 20% of patients, a non-
neutralizing form of anti-HBs can be detected). Persistence of HBsAg for more than 6 months after
acute infection is considered indicative of chronic infection.
HBV: hepatitis B virus; ALT: alanine aminotransferase; HBeAg: hepatitis B e-antigen; anti-HBe:
antibody to hepatitis B e-antigen; HBsAg: hepatitis B surface antigen; anti-HBs: antibody to hepatitis B
surface antigen; IgM: immunoglobulin M; anti-HBc: antibody to hepatitis B core antigen; IgG:
immunoglobulin G.
Graphic 69344 Version 5.0
Diagnostic tests to determine phase of acute or chronic hepatitis B virus

infection [1]
IgM Total
Anti- Anti-
HBsAg HBeAg anti- anti- HBV DNA ALT ¶ Interpret
HBs HBe
HBc HBc*
Acute HBV infection
+ + + ± +++ Elevated Early phase
+ ± + Elevated Window ph
+ + + ± Normal Recovery ph
Chronic HBV infection (HBsAg-positive for >6 months)
+ + + - - +++ Normal or Immune-to

mildly phase Δ
(Serum HBV
elevated
typically >1
million
international
units/mL)
+ + + - - +++ Persistently Immune-ac

elevated HBeAg-pos
(Serum HBV
>20,000
international
units/mL)
+ - + - + ++ Elevated Immune-ac
HBeAg-neg
(Serum HBV
>2000
international
units/mL)
+ - + + - to ++ Normal or Inactive chr

mildly HBV §
(Serum HBV
elevated
≤2000
international
units/mL)
- - ± ± ± + in liver; - to Normal Occult HBV

(generally + in serum
+)
ALT: alanine aminotransferase; anti-HBc: antibody to hepatitis B core antigen; anti-HBe: antibody to
hepatitis B e antigen; anti-HBs: antibody to hepatitis B surface antigen; HBeAg: hepatitis B e antigen;
HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus.
* This test is typically ordered as total anti-HBc, which includes IgM and IgG.
¶ The upper limits of normal for ALT in healthy adults are reported to be 29 to 33 units/L for males
and 19 to 25 units/L for females. For healthy children after infancy, the upper limits of normal are 25
to 38 units/L and 22 to 31 units/L for boys and girls, respectively.
Δ For patients with immune-tolerant chronic hepatitis B, liver biopsy or noninvasive tests show no
fibrosis and minimal inflammation. This is the initial phase seen in patients with perinatally acquired
HBV infection.
◊ For patients with immune active chronic hepatitis B, liver biopsy or noninvasive tests show chronic
hepatitis with moderate or severe necroinflammation with or without fibrosis. For patients who are
HBeAg positive, immune-active chronic hepatitis B (also known as the clearance phase) can last for 10
to 20 years, and may be associated with the loss of HBeAg. For patients who are HBeAg negative,
immune-active chronic hepatitis B is associated with immune reactivation and is also referred to as
HBeAg-negative chronic hepatitis B or HBeAg-negative replicative phase.
§ Patients with inactive chronic hepatitis B are HBeAg negative. In such patients, liver biopsy confirms
the absence of significant necroinflammation, but biopsy or noninvasive testing show variable levels
of fibrosis. This stage has also been referred to as the nonreplicative or carrier phase.
References:
1. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD
2018 hepatitis B guidance. Hepatology 2018; 67:1560.
Interpretation of the hepatitis B serologic panel
Tests Results Interpretation
HBsAg Negative Susceptible
anti-HBc Negative
anti-HBs Negative
HBsAg Negative Prior infection (inactive)
anti-HBc Positive
anti-HBs Positive
HBsAg Negative Immune due to hepatitis B

vaccination*
anti-HBc Negative
anti-HBs Positive
HBsAg Positive Acutely infected
anti-HBc Positive
IgM anti-HBc Positive
anti-HBs Negative
HBsAg Positive Chronically infected
anti-HBc Positive
IgM anti-HBc Negative
anti-HBs Negative
HBsAg Negative Four interpretations possible ¶
anti-HBc Positive
anti-HBs Negative
HBsAg: hepatitis B surface antigen; anti-HBc: hepatitis B core antibody; anti-HBs: hepatitis B surface
antibody; IgM: immunoglobulin M; HBV: hepatitis B virus.
* Antibody response (anti-HBs) can be measured quantitatively or qualitatively. A protective antibody

response is reported quantitatively as 10 or more milli-international units (≥10 mIU/mL) or
qualitatively as positive. Postvaccination testing should be completed one to two months after the
third vaccine dose for results to be meaningful.
¶ Four interpretations:
1. Might be recovering from acute HBV infection.
2. Might have had prior infection and test not sensitive enough to detect very low level of anti-HBs
in serum.
3. Might be susceptible with a false positive anti-HBc.
4. Might be undetectable level of HBsAg present in the serum, and the person is actually
chronically infected.
Centers for Disease Control and Prevention, Hepatitis B information for health professionals: Interpretation of hepatitis B
serologic test results. Available from the CDC website.
Phases of perinatally acquired hepatitis B virus infection
ALT: alanine aminotrasferase; HBV: hepatitis B virus; IU: international units; HBsAg: hepatitis B s
antigen; HBsAb: hepatitis B s antibody; HBeAg: hepatitis B e antigen; HBeAb: hepatitis B e antibody;
HCC: hepatocellular carcinoma; AFP: alpha fetoprotein.
* All patients with HBV infection should have baseline assessment for risk of HCC and follow-up
monitoring. We generally monitor AFP and liver ultrasound every 12 months beginning in late
childhood. For patients with elevated AFP, cirrhosis, or a family history of hepatocellular carcinoma,
we begin monitoring earlier and monitor more closely.
Course of chronic HBV infection
The course of chronic HBV infection is considered to consist of four phases: immune tolerance,
immune clearance (HBeAg-positive chronic hepatitis), inactive carrier, and reactivation (HBeAg-
negative chronic hepatitis), although not all patients go through every phase.
Characteristics of each phase:

Immune tolerance: HBeAg+, high HBV DNA (usually >10 8 IU/mL), and persistently normal ALT
HBeAg-positive chronic hepatitis: HBeAg+, fluctuating high HBV DNA (usually >10 5 IU/mL), and
fluctuating ALT (usually >ULN)
Inactive carrier: HBeAg–, persistently low HBV DNA (usually <2000 IU/mL), and normal ALT
HBeAg-negative chronic hepatitis: HBeAg–, fluctuating moderate HBV DNA (usually 10 3 -10 7
IU/mL), and fluctuating ALT (usually >ULN but may be intermittently normal)
HBeAg: hepatitis B e antigen; anti-HBe: antibody to HBeAg; HBV: hepatitis B virus; ALT: alanine
aminotransferase; ULN: upper limit of normal.
Reproduced with permission from: Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we knew in 1981
and what we know in 2005. Hepatology 2006; 43:S173. Copyright © 2006 John Wiley & Sons, Inc.
Groups at increased risk for hepatitis B virus
Individuals at risk for HBV due to vertical transmission (ie, mother to child
transmission)
Individuals born in regions with high (≥8%) or intermediate (≥2%) prevalence rates for HBV,
including immigrants and adopted children*
Infants born to pregnant persons who are HBsAg-positive ¶
US-born persons not vaccinated as infants whose parents were born in regions with high HBV
endemicity (≥8%)*
Individuals at risk due to horizontal transmission (ie, percutaneous or mucosal

exposure to blood or body fluids contaminated with blood) Δ
Household contacts of HBsAg-positive persons

Needle sharing or sexual contacts of HBsAg-positive persons
Individuals who have ever injected drugs
Individuals with multiple sexual partners and/or history of sexually transmitted infections
Men who have sex with men
Inmates of correctional facilities or other detention settings
Individuals with HIV infection ◊
Individuals with current or past HCV infection §
Individuals with end-stage kidney disease on maintenance renal dialysis
Other individuals
Individuals with elevated alanine aminotransferase or aspartate aminotransferase levels of

unknown origin
Individuals who request HBV testing
In the United States, screening for HBV includes [4] :

Risk-based screening – For all individuals (including children and adolescents), screen those
who have any of the risk factors listed in the table if they might have been susceptible during the
period of increased risk ¥ . For those with ongoing risk factors (ie, for horizontal transmission)
who remain susceptible, continue to test periodically. Δ
Universal screening – For individuals ≥18 years of age, screen at least once in a lifetime.
However, for those without risk factors for HBV, screening is generally not needed if there is
documentation of completing a hepatitis B vaccine series and evidence of immunity (anti-HBs
≥10 milli-international units/mL) after vaccination. ‡
Pregnancy screening – Screen all pregnant people during each pregnancy, regardless of
vaccination status of history of prior testing.
Refer to UpToDate content on screening and diagnosis of HBV, HBV immunization, and HBV and
pregnancy for more detailed information on screening and vaccination.
HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; US: United States; HIV: human
immunodeficiency virus; HCV: hepatitis C virus; anti-HBs: hepatitis B surface antibody; anti-HBc:
hepatitis B core antibodies; HBIG: hepatitis B immune globulin.
* If HBsAg-positive persons are found in first-generation immigrants of a family, subsequent

generations should be tested.
¶ To reduce the risk of perinatal transmission, infants born to HBsAg-positive mothers should receive
HBIG and hepatitis B vaccine as soon as possible and within 12 hours of birth and then complete the
hepatitis B series. Post-vaccination serology should be obtained at 9 to 12 months. Refer to the
UpToDate topic that discusses HBV immunization in infants.
Δ In unvaccinated individuals with ongoing HBV risk through percutaneous or mucosal exposure,
hepatitis B vaccine should be initiated at the time of screening; the need for subsequent doses will
depend upon the results. Post-vaccination serology should be performed to ensure immunity. For at-
risk persons who do not complete the vaccine series, repeat testing should be performed periodically
(eg, every 1 to 2 years).
◊ The presence of HBV coinfection informs the choice of antiretroviral regimen. In addition, patients
with HIV who are not immune should be vaccinated regardless of age or risk factors, since HBV
infection has an accelerated course in coinfected patients.
§ Patients with chronic HBV are at risk for HBV reactivation with direct-acting antiviral therapy for
hepatitis C. Refer to the UpToDate topic that provides an overview of the management of hepatitis C
infection.
¥ Susceptible persons include those who have never been infected with HBV (ie, HBsAg-negative, total
anti-HBc-negative, and anti-HBs-negative) and either did not complete a HepB vaccine series per the
Advisory Committee on Immunization Practices recommendations or who are known to be vaccine
nonresponders.
‡ For most patients who remain without risk factors for acquiring HBV, repeat screening is not
warranted. However, screening prior to blood, plasma, organ, tissue, or semen donation is routinely
performed, regardless of the person's prior history. In addition, screening is warranted prior to
initiating immunosuppressive therapy (eg, corticosteroids, biologics, cancer chemotherapy, anti-
rejection therapies) since persons with HBV are at risk for HBV reactivation. Refer to the UpToDate
topic on HBV reactivation.
References:
1. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
MMWR Recomm Rep 2008; 57:1.
2. Abara WE, Qaseem A, Schillie S, et al. Hepatitis B vaccination, screening, and linkage to care: Best practice advice from
the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med 2017; 167:794.
3. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD
2018 hepatitis B guidance. Hepatology 2018; 67:1560.
4. Conners EE, Panagiotakopoulos L, Hofmeister MG, et al. Screening and testing for hepatitis B virus infection: CDC
recommendations – United States, 2023. MMWR Recomm Rep 2023; 72:1.

Clinical Manifestations and Diagnosis of Hepatitis B Virus Infection in Children and Adolescents

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21/2/24, 19:59 Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents - UpToDate

Official reprint from UpToDate®

Clinical manifestations and diagnosis of hepatitis B

Literature review current through: Jan 2024.

Other topic reviews with related material include:

● (See "Hepatitis B virus: Clinical manifestations and natural history".)

● (See "Hepatitis B virus: Overview of management".)

● (See "Hepatitis B virus immunization in infants, children, and adolescents".)

● (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)

● (See "Hepatitis B virus: Clinical manifestations and natural history".)

● (See "Hepatitis B and pregnancy", section on 'Mother-to-child transmission'.)

different clinical phases of HBV infection.

● The proportion of patients progressing to chronic infection is much higher in neonates

● Gianotti-Crosti syndrome (characterized by papular acrodermatitis of the face,

Management of acute HBV infection is discussed separately. (See "Management of hepatitis

quadrant discomfort and fatigue.

Chronic HBV infection is occasionally associated with extrahepatic manifestations including

On serologic testing, chronic HBV infection is characterized by persistently positive HBsAg. In

Phases of chronic hepatitis B virus infection — Individuals with perinatally acquired

Immune-tolerant — This phase is characterized by normal or mildly elevated serum

Immune-active, HBeAg-positive (clearance) — This phase, sometimes known as

Immune-active, HBeAg-negative (reactivation) — Among patients with inactive

Progression to cirrhosis — Cirrhosis occasionally develops during childhood in individuals

Although frank cirrhosis is unusual during childhood, development of moderate or severe

● Screen regardless of vaccination history:

• Individuals born in areas with high or intermediate prevalence of HBV (regions in

Postvaccination testing of infants who received appropriate immunoprophylaxis at

• Pregnant individuals. (See "Prenatal care: Initial assessment", section on 'Hepatitis

• Household and sexual contacts of individuals with HBV infection.

Results are interpreted as follows ( table 2):

● Hepatitis B e-antigen (HBeAg)

Interpretation — The results are interpreted as follows:

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Screening for chronic HBV

• Screening tests – Screening is done by serologic testing for hepatitis B surface

• Children in the immune-tolerant phase of chronic HBV (normal or mildly elevated

Use of UpToDate is subject to the Terms of Use.

1. Schillie S, Vellozzi C, Reingold A, et al. Prevention of Hepatitis B Virus Infection in the

4. Ordög K, Szendrôi A, Szarka K, et al. Perinatal and intrafamily transmission of hepatitis B

Recomm Rep 2023; 72:1.

Serologic responses to hepatitis B virus infection

Graphic 69344 Version 5.0

Diagnostic tests to determine phase of acute or chronic hepatitis B virus

Acute HBV infection

+ + + ± +++ Elevated Early phase

Chronic HBV infection (HBsAg-positive for >6 months)

+ + + - - +++ Normal or Immune-to

+ + + - - +++ Persistently Immune-ac

+ - + + - to ++ Normal or Inactive chr

- - ± ± ± + in liver; - to Normal Occult HBV

Graphic 60627 Version 8.0

Interpretation of the hepatitis B serologic panel

Tests Results Interpretation

HBsAg Negative Susceptible

HBsAg Negative Prior infection (inactive)

HBsAg Negative Immune due to hepatitis B

HBsAg Positive Acutely infected

IgM anti-HBc Positive

HBsAg Positive Chronically infected

IgM anti-HBc Negative

HBsAg Negative Four interpretations possible ¶

* Antibody response (anti-HBs) can be measured quantitatively or qualitatively. A protective antibody

Graphic 60827 Version 7.0