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__NOTOC__
{{Hepatitis B}}
{{Hepatitis B}}
{{CMG}}; '''Associate Editor In Chief:''' {{CZ}}
{{CMG}}; {{AE}} {{JS}}, {{SaraM}}


== Lab Tests==
==Overview==
The diagnosis of [[hepatitis]] is made by biochemical assessment of [[liver function]]. Initial laboratory evaluation usually reveals increased [[bilirubin]] levels; increased [[ALT]], [[AST]], and [[alkaline phosphatase]]; and decreased [[protein]]. [[Prothrombin time]] may be prolonged in cases of hepatocellular [[necrosis]] and [[hemoglobin]] may be low. Initial [[lymphopenia]] and [[neutropenia]] may be followed by [[lymphocytosis]]. [[Serologic]] markers such as [[HBsAg|Hepatitis B surface antigen]] ([[HBsAg]]) and anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis B e antigen and anti-HBeAg confirm the diagnosis of [[hepatitis B]]. These levels fluctuate throughout the course of the disease.<ref name="WHO-Guideline-Hepatitis-B">World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016</ref><ref name="CDC">Center for Disease Control and Prevention. Hepatitis B Epidemiology and Prevention of Vaccine-Preventable Diseases 2012.http://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html</ref><ref name="Hepatology">AASLD guidelines for treatment of chronic hepatitis B. Hepatology (2016)http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/full Accessed on October 10th, 2016</ref>


The tests, called [[assay]]s, for detection of hepatitis B virus infection involve [[blood plasma|serum]] or [[blood test]]s that detect either viral antigens (proteins produced by the virus) or [[antibody|antibodies]] produced by the host. Interpretation of these assays is complex.<ref name="pmid3331068">{{cite journal |author=Bonino F, Chiaberge E, Maran E, Piantino P |title=Serological markers of HBV infectivity |journal=Ann. Ist. Super. Sanita |volume=24 |issue=2 |pages=217–23 |year=1987 |pmid=3331068 |doi=}}</ref>
== Laboratory Findings==
The diagnosis of [[hepatitis]] is made by [[biochemical]] assessment of [[liver function]]. Initial laboratory evaluation should include:<ref name="WHO-Guideline-Hepatitis-B">World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016</ref><ref>{{cite book | last = Fields | first = Bernard | title = Fields virology | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2007 | isbn = 0781760607 }}</ref>
* Total and direct [[bilirubin]] (increased)
:* Severe disease is often associated with persistent [[bilirubin]] levels >340 mol/L
* [[ALT]] and [[AST]] (increased)
* [[Alkaline phosphatase]] (normal or mildly elevated)
* [[Prothrombin time]] (prolonged from synthetic defect, caused by hepatocellular [[necrosis]])
* [[Total protein]] (decreased)
* [[Globulin]] (mildly elevated)
* [[Complete blood count]]
:* Initial [[lymphopenia]] and [[neutropenia]], followed by relative [[lymphocytosis]]
:* [[anemia|Low hemoglobin]]


The hepatitis B surface antigen (''HBsAg'') is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or ''HBcAg''. During this 'window' in which the host remains infected but is successfully clearing the virus, [[IgM]] antibodies to the hepatitis B core antigen (''anti-HBc IgM'') may be the only serological evidence of disease.
A [[diagnosis]] is confirmed by the observation of specific [[antigens]] and/or [[antibodies]] in [[serum|sera]]. Three clinically useful antigen-antibody systems have been identified for [[hepatitis B]]:
*[[HBsAg|Hepatitis B surface antigen]] ([[HBsAg]]) and antibody to HBsAg (anti-HBs)
*Antibody (anti-HBc IgM and anti-HBc IgG) to hepatitis B core antigen (HBcAg)
*Hepatitis B e antigen (HBeAg) and [[antibody]] to HBeAg (anti-HBe)


Shortly after the appearance of the HBsAg, another antigen named as the hepatitis B e antigen (''HBeAg'') will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the hepatitis B virus do not produce the 'e' antigen, so this rule does not always hold true. During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (''anti-HBe'') will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication.
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
 
|+
If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by [[IgG]] antibodies to the hepatitis B surface antigen and core antigen, (''anti-HBs'' and ''anti HBc IgG'').  A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously.
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Antigens}}
 
! style="background: #4479BA; width: 500px;" | {{fontcolor|#FFF|Description}}
Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers.<ref name="pmid17256718">{{cite journal |author=Lok AS, McMahon BJ |title=Chronic hepatitis B |journal=Hepatology |volume=45 |issue=2 |pages=507–39 |year=2007 |pmid=17256718 |doi=10.1002/hep.21513}}</ref>  Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum [[alanine aminotransferase]] levels and inflammation of the liver, as revealed by biopsy. Carriers who have seroconverted to HBeAg negative status, particularly those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.<ref name="pmid17935720">{{cite journal |author=Chu CM, Liaw YF |title=Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B |journal=Gastroenterology |volume=133 |issue=5 |pages=1458–65 |year=2007 |pmid=17935720 |doi=10.1053/j.gastro.2007.08.039}}</ref>
|-
 
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[HBsAg]]'''
More recently, [[PCR]] tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens. These tests are called [[viral load]]s and are used to assess a person's infection status and to monitor treatment.<ref name="pmid17051445">{{cite journal |author=Zoulim F |title=New nucleic acid diagnostic tests in viral hepatitis |journal=Semin. Liver Dis. |volume=26 |issue=4 |pages=309–17 |year=2006 |pmid=17051445 |doi=10.1055/s-2006-951602}}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" | Hepatitis B surface antigen is the earliest indicator of acute infection and is also indicative of chronic [[infection]] if its presence persists for more than 6 months. It is useful for the diagnosis of [[HBV]] infection and for [[screening]] of blood. Its specific [[antibody]] is anti-HBs. [[HBsAg]] indicates that the person is potentially [[infectious]].
 
|-
The original [[assay]]s for detection of hepatitis B virus infection involve [[blood plasma|serum]] or [[blood test]]s that detect either viral antigens (proteins produced by the virus) or [[antibody|antibodies]] produced by the host.  Interpretation of these assays is complex. The table below is organized chronologically, from top to bottom:
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBcAg'''
 
| style="padding: 5px 5px; background: #F5F5F5;" |Hepatitis B core antigen is derived from the protein envelope that encloses the [[viral]] DNA, and it is not detectable in the [[bloodstream]]. When HBcAg peptides are expressed on the surface of [[hepatocytes]], they induce an [[immune]] response that is crucial for killing infected cells. The HBcAg is a marker of the infectious viral material and it is the most accurate index of [[viral replication]]. Its specific [[antibody]] is anti-HBc.
{| class="wikitable"
|-
| '''Antigens''' || '''Antibodies'''  
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBeAg'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |Hepatitis B e antigen appearing during weeks 3 to 6 indicates an acute active infection at its most [[infectious]] period, and means that the patient is [[infectious]]. Persistence of this virological marker beyond 10 weeks shows progression to chronic infection and infectiousness. Continuous presence of anti-HBe indicates chronic or chronic active liver disease. HBeAg is not incorporated into [[virions]], but is instead secreted into the [[serum]]. Mutant strains of HBV exist that replicate without producing HBeAg. HBeAg’s function is uncertain. Its specific [[antibody]] is anti-HBe.
| The hepatitis B surface antigen ('''HBsAg'''<ref>{{MeshName|HBsAg}}</ref>) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection with this virus; however, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. || -
|-
|-  
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBxAg'''
| The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or '''HBcAg'''<ref>{{MeshName|HBcAg}}</ref> || During this 'window' in which the host remains infected but is successfully clearing the virus, [[IgM]] antibodies to the hepatitis B core antigen ('''anti-HBc IGM''') may be the only serologic evidence of disease.
| style="padding: 5px 5px; background: #F5F5F5;" |Hepatitis B x antigen is detected in HBeAg positive blood in patients with both acute and chronic hepatitis. HBxAg is a transcriptional activator. It does not bind to [[DNA]]. Its specific [[antibody]] is anti-HBx.
|-  
|-
| Shortly after the appearance of the HBsAg, another antigen named as the hepatitis B e antigen ('''HBeAg'''<ref>{{MeshName|HBeAg}}</ref>) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication; however, some variants of the hepatitis B virus do not produce the 'e' antigen at all, so this rule does not always hold true. || During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen ('''anti-HBe''') will arise immediately afterward.  This conversion is usually associated with a dramatic decline in viral replication.  
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBV DNA'''
|-  
| style="padding: 5px 5px; background: #F5F5F5;" |HBV DNA is detectable by PCR as soon as 1 week after initial infection, but the test is generally only performed for research purposes or to detect mutants that escape detection by current methods.
| - || If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by antibodies to the hepatitis B surface antigen ('''anti-HBs''').
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBV DNA Polymerase'''
| style="padding: 5px 5px; background: #F5F5F5;" |Tests for the presence of [[HBV]] [[DNA polymerase]], detectable within 1 week of initial infection, are only performed for research purposes.
|-
|}
|}


A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously. A number of persons who are positive for HBsAg may have very little viral multiplication, and hence may be at little risk of long-term complications or of transmitting infection to others.
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
 
More recently, [[PCR]] tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens. These tests are useful to assess a person's infection status and to monitor treatment.
[[Image:HBV serum markers.png|left|thumb|500px|Hepatitis B viral antigens and antibodies detectable in the blood following acute infection.]]
[[Image:Chronic HBV v2.png|left|thumb|500px|Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person]]
<br clear="left"/>
 
==Diagnostic Criteria==
 
{| class="wikitable" border="1"
|+
|+
! Stage of Hepatitis B !! Lab Findings
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Antibodies}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Description}}
|-
|-
| rowspan="4" |Chronic State
| style="padding: 5px 5px; background: #DCDCDC;" | '''[[Anti-HBs]]'''
| '''1.''' HBsAg-positive >6 months
| style="padding: 5px 5px; background: #F5F5F5;" | This is the specific [[antibody]] to hepatitis B surface antigen. Its appearance 1 to 4 months after onset of [[symptoms]] indicates clinical recovery and subsequent immunity to HBV. Anti-HBs can neutralize HBV and provide protection against HBV infection.
|-
|-
| '''2.''' Serum HBV DNA >20,000 IU/mL (10<sup>5</sup>copies/mL), lower values 2,000-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Anti-HBc'''
20,000 IU/mL (10<sup>4</sup>-10<sup>5</sup>copies/mL) are often seen in HBeAg-negative chronic hepatitis B
| style="padding: 5px 5px; background: #F5F5F5;" |This is the specific [[antibody]] to hepatitis B core antigen. [[Antibodies]] to HBc are of class IgM and IgG. They do not neutralize the [[virus]]. The presence of [[IgM]] identifies an early acute [[infection]]. In the absence of [[HBsAg]] and anti-HBs, it shows recent [[infection]]. IgG with no IgM may be present in chronic and resolved infections. Anti-HBc testing identifies all previously infected persons, including [[HBV]] carriers, but does not differentiate carriers and non-carriers.
|-
|-
| '''3.''' Persistent or intermittent elevation in ALT/AST levels
| style="padding: 5px 5px; background: #DCDCDC;" | '''Anti-HBe'''
| style="padding: 5px 5px; background: #F5F5F5;" |This is the specific [[antibody]] to hepatitis B e antigen. During the acute stage of infection the [[seroconversion]] from e antigen to e antibody is [[prognostic]] for resolution of [[infection]]. Its presence in the patient’s blood along with anti-HBc and in the absence of HBsAg and anti-HBs indicates low contagiousness and convalescence.
|-
|-
| '''4.''' Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
| style="padding: 5px 5px; background: #DCDCDC;" | '''Anti-HBx'''
| style="padding: 5px 5px; background: #F5F5F5;" |This is the specific [[antibody]] to hepatitis B x antigen. It appears when other [[virus|virological]] markers are becoming undetectable.
|}
====Laboratory and Histology findings in Chronic Hepatitis B Infection====
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+
! style="background: #4479BA; width: 250px;" | {{fontcolor|#FFF|Phase<ref name=Hepatology> AASLD guidelines for treatment of chronic hepatitis B. Hepatology (2016)http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/full Accessed on October 10th, 2016</ref>}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|ALT}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|HBV DNA}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|HBeAg}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Histology}}
|-
|-
|
| style="padding: 5px 5px; background: #DCDCDC;" |'''Immune-tolerant'''
| style="padding: 5px 5px; background: #F5F5F5;" |Normal
| style="padding: 5px 5px; background: #F5F5F5;" |Elevated (typically >1 million IU/mL)
| style="padding: 5px 5px; background: #F5F5F5;" |Positive
| style="padding: 5px 5px; background: #F5F5F5;" |Minimal [[inflammation]] and [[fibrosis]]
|-
|-
| rowspan="5" |Carrier State
| style="padding: 5px 5px; background: #DCDCDC;" |'''Immune-active phase (HBeAg-positive)'''
| '''1.''' HBsAg-positive >6 months
| style="padding: 5px 5px; background: #F5F5F5;" |Increased
| style="padding: 5px 5px; background: #F5F5F5;" |Elevated (≥20,000 IU/mL)
| style="padding: 5px 5px; background: #F5F5F5;" |Positive
| style="padding: 5px 5px; background: #F5F5F5;" |Moderate-to-severe inflammation or fibrosis
|-
|-
| '''2.''' HBeAg–, anti-HBe+
| style="padding: 5px 5px; background: #DCDCDC;" |'''Inactive CHB phase'''
| style="padding: 5px 5px; background: #F5F5F5;" |Normal
| style="padding: 5px 5px; background: #F5F5F5;" |Low or undetectable (<2,000 IU/mL)
| style="padding: 5px 5px; background: #F5F5F5;" |Negative
| style="padding: 5px 5px; background: #F5F5F5;" |Minimal necroinflammation and variable fibrosis
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Immune reactivation phase (HBeAg-negative)'''
| style="padding: 5px 5px; background: #F5F5F5;" |Increased
| style="padding: 5px 5px; background: #F5F5F5;" |Elevated (≥2,000 IU/mL)
| style="padding: 5px 5px; background: #F5F5F5;" |Negative
| style="padding: 5px 5px; background: #F5F5F5;" |Moderate-to-severe inflammation or fibrosis
|-
|}
 
==Serological Markers==
{| style="float: right;"
| [[Image:HBV serum markers.png|center|thumb|400px|Hepatitis B viral antigens and antibodies detectable in the blood following acute infection. - CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=14144661]]
|-
|-
| '''3.''' Serum HBV DNA <2,000 IU/mL
| [[Image:Chronic HBV v2.png|center|thumb|400px|Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person - By Offnfopt - Own work created from scratch using File:Chronic HBV v2.png as a reference., CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=39513687]]
|}[[Serological]] markers may vary throughout the course of the disease:<ref name="WHO-Guideline-Hepatitis-B">World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016</ref>
 
* Pre-S1 and pre-S2 [[antigens]] are present early in the [[incubation period]]. They are never detected in the absence of [[HBsAg]].
 
* Hepatitis B [[virions]], HBV DNA, [[DNA polymerase]], and HBeAg are then also detected.
 
* The presence of HBeAg is associated with relatively high [[infectivity]] and severity of disease.
 
* Anti-HBc is the first [[antibody]] to appear. The observation of anti-HBc in [[serum]] indicates [[HBV infection]], current or past.
:* IgM anti-HBc is present in high [[titre]] during acute [[infection]] and usually disappears within 6 months, although it can persist in some cases of [[chronic hepatitis]]. This test may therefore reliably diagnose acute HBV infection.
:* IgG anti-HBc generally remains detectable for a lifetime.
 
* Anti-HBe appears after anti-HBc and its presence correlates to a decreased [[infectivity]]. Anti-HBe replaces HBeAg in the resolution of the disease.
 
* Anti-HBs replaces [[HBsAg]] as the acute [[HBV infection]] is resolving. Anti-HBs generally persists for a lifetime in over 80% of patients and indicates immunity. [[Acute hepatitis]] patients who maintain a constant serum [[HBsAg]] concentration, or whose serum HBeAg persists 8 to 10 weeks after symptoms have resolved, are likely to become [[asymptomatic carrier|carriers]] and at risk of developing [[chronic liver disease]].
 
==Diagnostic Studies==
The following studies are used to examine pathological specimens for the presence of [[HBV]]-associated [[antigens]] or particles. They provide information about the relationship between HBV [[DNA replication]] and HBV [[gene expression]].
* [[Immunofluorescence]] studies
* [[In situ hybridization]]
* [[Immunohistochemistry]]
* Thin-section [[electron microscopy]]
 
==PCR==
More recently, [[PCR]] tests have been developed to detect and measure the amount of viral [[nucleic acid]] in clinical specimens. These tests are called [[viral load]]s and are used to assess a person's [[infection]] status and to monitor treatment.<ref name="pmid17051445">{{cite journal |author=Zoulim F |title=New nucleic acid diagnostic tests in viral hepatitis |journal=Semin. Liver Dis. |volume=26 |issue=4 |pages=309–17 |year=2006 |pmid=17051445 |doi=10.1055/s-2006-951602}}</ref>
 
==Recommendations for Monitoring Patients with Chronic HBV Infection: AASLD Practice Guidelines<ref name="Hepatology">AASLD guidelines for treatment of chronic hepatitis B. Hepatology (2016)http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/full Accessed on October 10th, 2016</ref>==
 
{| class="wikitable" width="80%"
|-
|-
| '''4.''' Persistently normal ALT/AST levels
| colspan="1" style="text-align:center; background:LightGreen" |[[AASLD guidelines classification scheme#Classification of Recommendations|Class I]]
|-
|-
| '''5.''' Liver biopsy confirms absence of significant hepatitis
| bgcolor="LightGreen" |<nowiki>"</nowiki>'''1.''' HBeAg-positive and HBeAg-negative patients who meet criteria for chronic hepatitis B should be evaluated for treatment.<nowiki>"</nowiki>
|-
|-
|
|}
 
{| class="wikitable" width="80%"
|-
|-
| rowspan="4" |Resolved
| colspan="1" style="text-align:center; background:LightCoral" |[[AASLD guidelines classification scheme#Classification of Recommendations|Class III]]
| '''1.''' Previous known history of acute or chronic hepatitis B or the presence of anti-HBc ± anti-HBs
|-
|-
| '''2.''' HBsAg-
| bgcolor="LightCoral" |<nowiki>"</nowiki>'''2.''' HBeAg-positive patients:
:*HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals. ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months.
:*Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month period of elevated ALT levels between 1-2 ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/mL and are >40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy shows moderate/severe inflammation or significant fibrosis. Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month period of elevated ALT levels >2 ULN should be considered for treatment.<nowiki>"</nowiki>
|}
 
{| class="wikitable" width="80%"
|-
|-
| '''3.''' Undetectable serum HBV DNA
| colspan="1" style="text-align:center; background:LightCoral" |[[AASLD guidelines classification scheme#Classification of Recommendations|Class III]]
|-
|-
| '''4.''' Normal ALT levels
| bgcolor="LightCoral" |<nowiki>"</nowiki>'''3.''' HBeAg-negative patients:
:*HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL should be tested for ALT every 3 months during the first year to verify that they are truly in the "inactive carrier state" and then every 6-12 months.
:*Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit.<nowiki>"</nowiki>
|}
|}


== References ==   
== References ==   
{{Reflist|2}}  
{{Reflist|2}}
 
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Latest revision as of 22:04, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2], Sara Mehrsefat, M.D. [3]

Overview

The diagnosis of hepatitis is made by biochemical assessment of liver function. Initial laboratory evaluation usually reveals increased bilirubin levels; increased ALT, AST, and alkaline phosphatase; and decreased protein. Prothrombin time may be prolonged in cases of hepatocellular necrosis and hemoglobin may be low. Initial lymphopenia and neutropenia may be followed by lymphocytosis. Serologic markers such as Hepatitis B surface antigen (HBsAg) and anti-HBsAg; anti-HBc IgM and anti-HBc IgG; hepatitis B e antigen and anti-HBeAg confirm the diagnosis of hepatitis B. These levels fluctuate throughout the course of the disease.[1][2][3]

Laboratory Findings

The diagnosis of hepatitis is made by biochemical assessment of liver function. Initial laboratory evaluation should include:[1][4]

  • Severe disease is often associated with persistent bilirubin levels >340 mol/L

A diagnosis is confirmed by the observation of specific antigens and/or antibodies in sera. Three clinically useful antigen-antibody systems have been identified for hepatitis B:

  • Hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs)
  • Antibody (anti-HBc IgM and anti-HBc IgG) to hepatitis B core antigen (HBcAg)
  • Hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe)
Antigens Description
HBsAg Hepatitis B surface antigen is the earliest indicator of acute infection and is also indicative of chronic infection if its presence persists for more than 6 months. It is useful for the diagnosis of HBV infection and for screening of blood. Its specific antibody is anti-HBs. HBsAg indicates that the person is potentially infectious.
HBcAg Hepatitis B core antigen is derived from the protein envelope that encloses the viral DNA, and it is not detectable in the bloodstream. When HBcAg peptides are expressed on the surface of hepatocytes, they induce an immune response that is crucial for killing infected cells. The HBcAg is a marker of the infectious viral material and it is the most accurate index of viral replication. Its specific antibody is anti-HBc.
HBeAg Hepatitis B e antigen appearing during weeks 3 to 6 indicates an acute active infection at its most infectious period, and means that the patient is infectious. Persistence of this virological marker beyond 10 weeks shows progression to chronic infection and infectiousness. Continuous presence of anti-HBe indicates chronic or chronic active liver disease. HBeAg is not incorporated into virions, but is instead secreted into the serum. Mutant strains of HBV exist that replicate without producing HBeAg. HBeAg’s function is uncertain. Its specific antibody is anti-HBe.
HBxAg Hepatitis B x antigen is detected in HBeAg positive blood in patients with both acute and chronic hepatitis. HBxAg is a transcriptional activator. It does not bind to DNA. Its specific antibody is anti-HBx.
HBV DNA HBV DNA is detectable by PCR as soon as 1 week after initial infection, but the test is generally only performed for research purposes or to detect mutants that escape detection by current methods.
HBV DNA Polymerase Tests for the presence of HBV DNA polymerase, detectable within 1 week of initial infection, are only performed for research purposes.
Antibodies Description
Anti-HBs This is the specific antibody to hepatitis B surface antigen. Its appearance 1 to 4 months after onset of symptoms indicates clinical recovery and subsequent immunity to HBV. Anti-HBs can neutralize HBV and provide protection against HBV infection.
Anti-HBc This is the specific antibody to hepatitis B core antigen. Antibodies to HBc are of class IgM and IgG. They do not neutralize the virus. The presence of IgM identifies an early acute infection. In the absence of HBsAg and anti-HBs, it shows recent infection. IgG with no IgM may be present in chronic and resolved infections. Anti-HBc testing identifies all previously infected persons, including HBV carriers, but does not differentiate carriers and non-carriers.
Anti-HBe This is the specific antibody to hepatitis B e antigen. During the acute stage of infection the seroconversion from e antigen to e antibody is prognostic for resolution of infection. Its presence in the patient’s blood along with anti-HBc and in the absence of HBsAg and anti-HBs indicates low contagiousness and convalescence.
Anti-HBx This is the specific antibody to hepatitis B x antigen. It appears when other virological markers are becoming undetectable.

Laboratory and Histology findings in Chronic Hepatitis B Infection

Phase[3] ALT HBV DNA HBeAg Histology
Immune-tolerant Normal Elevated (typically >1 million IU/mL) Positive Minimal inflammation and fibrosis
Immune-active phase (HBeAg-positive) Increased Elevated (≥20,000 IU/mL) Positive Moderate-to-severe inflammation or fibrosis
Inactive CHB phase Normal Low or undetectable (<2,000 IU/mL) Negative Minimal necroinflammation and variable fibrosis
Immune reactivation phase (HBeAg-negative) Increased Elevated (≥2,000 IU/mL) Negative Moderate-to-severe inflammation or fibrosis

Serological Markers

Hepatitis B viral antigens and antibodies detectable in the blood following acute infection. - CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=14144661
Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person - By Offnfopt - Own work created from scratch using File:Chronic HBV v2.png as a reference., CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=39513687

Serological markers may vary throughout the course of the disease:[1]

  • The presence of HBeAg is associated with relatively high infectivity and severity of disease.
  • IgM anti-HBc is present in high titre during acute infection and usually disappears within 6 months, although it can persist in some cases of chronic hepatitis. This test may therefore reliably diagnose acute HBV infection.
  • IgG anti-HBc generally remains detectable for a lifetime.
  • Anti-HBe appears after anti-HBc and its presence correlates to a decreased infectivity. Anti-HBe replaces HBeAg in the resolution of the disease.
  • Anti-HBs replaces HBsAg as the acute HBV infection is resolving. Anti-HBs generally persists for a lifetime in over 80% of patients and indicates immunity. Acute hepatitis patients who maintain a constant serum HBsAg concentration, or whose serum HBeAg persists 8 to 10 weeks after symptoms have resolved, are likely to become carriers and at risk of developing chronic liver disease.

Diagnostic Studies

The following studies are used to examine pathological specimens for the presence of HBV-associated antigens or particles. They provide information about the relationship between HBV DNA replication and HBV gene expression.

PCR

More recently, PCR tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens. These tests are called viral loads and are used to assess a person's infection status and to monitor treatment.[5]

Recommendations for Monitoring Patients with Chronic HBV Infection: AASLD Practice Guidelines[3]

Class I
"1. HBeAg-positive and HBeAg-negative patients who meet criteria for chronic hepatitis B should be evaluated for treatment."
Class III
"2. HBeAg-positive patients:
  • HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals. ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months.
  • Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month period of elevated ALT levels between 1-2 ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/mL and are >40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy shows moderate/severe inflammation or significant fibrosis. Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/mL after a 3-6 month period of elevated ALT levels >2 ULN should be considered for treatment."
Class III
"3. HBeAg-negative patients:
  • HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL should be tested for ALT every 3 months during the first year to verify that they are truly in the "inactive carrier state" and then every 6-12 months.
  • Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit."

References

  1. ↑ 1.0 1.1 1.2 World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016
  2. ↑ Center for Disease Control and Prevention. Hepatitis B Epidemiology and Prevention of Vaccine-Preventable Diseases 2012.http://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html
  3. ↑ 3.0 3.1 3.2 AASLD guidelines for treatment of chronic hepatitis B. Hepatology (2016)http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/full Accessed on October 10th, 2016
  4. ↑ Fields, Bernard (2007). Fields virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 0781760607.
  5. ↑ Zoulim F (2006). "New nucleic acid diagnostic tests in viral hepatitis". Semin. Liver Dis. 26 (4): 309–17. doi:10.1055/s-2006-951602. PMID 17051445.

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