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1 Korean J Gastroenterol Vol. 62 No. 3, pissn eissn REVIEW ARTICLE B 형간염바이러스잠재감염의정의, 진단그리고유병률 김연수 가천대학교의과대학가천대길병원내과학교실 Definition, Diagnosis, and Prevalence of Occult Hepatitis B Virus Infection Yun Soo Kim Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea Occult HBV infection is characterized by the absence of serum HBsAg with persistence of low level of intrahepatic HBV DNA. Several suggested mechanisms for the origin of occult HBV infection include strong suppression of viral replication and gene expression, mutation in the regulatory regions of HBV genome, formation of immunoglobulin-bound HBsAg, viral interference, and blockage of HBsAg secretion from infected hepatocytes. Standardized assays are not yet available, and sensitive HBV DNA amplification assay is necessary for the diagnosis of cryptic infection. Detection rate of HBV DNA is highest in IgG anti-hbc positive population. However, neither anti-hbc nor anti-hbs can be detected in a significant proportion of infected persons. Occult HBV infection occurs in a number of clinical settings and is highly prevalent in HCV-infected patients as well as in patients with cryptogenic chronic liver disease including hepatocellular carcinoma. (Korean J Gastroenterol 2013;62: ) Key Word: Occult hepatitis B virus infection 서 본 HBV 잠재감염 (occult HBV infection) 은 HBsAg 음성자에서간내 HBV DNA가검출되는것이다. 발생기전은불확실하나바이러스증식과유전자발현이억제되어나타나는현상으로설명되고있다. IgG anti-hbc 양성자에서잠재감염률이높고음성자의일부에서도감염이확인된다. 잠재감염자의간조직이나혈청의 HBV DNA 농도는매우낮고진단방법이표준화되지않아진단에어려움이있다. 만성 C형간염이나원인이불분명한만성간질환환자에서잠재감염률이높고 B형간염유행지역에서비유행지역에비해높다. 본고에서는 HBV 잠재감염의정의, 발생기전, 진단그리고유병률에대하여논하고자한다. 1. HBV 잠재감염의정의급성 B형간염에서 HBsAg이소실되면일반적으로바이러스가제거되고간염이완치되었음을의미한다. 그러나 HBsAg이음전된후에도저농도의바이러스혈증은지속될수있으며, 1 수년이경과한후에도간조직내에서는 HBV DNA가드물지않게검출된다. 2,3 만성 HBV 보유자에서는연 % 에서혈청 HBsAg이음전되나 4 HBsAg이소실된후에도대부분간조직내에서 HBV DNA가검출된다. 5 이는 HBsAg 검사만으로는 HBV 보유상태를진단하는데한계가있음을시사한다. HBV 잠재감염이란 HBsAg이음성이지만체내에 HBV DNA가저농도로존재하는경우이다. 2008년이탈리아타오르미나 (Taormina) 의전문가회의에서는 HBV 잠재감염의정의를 HBsAg 음성자에서혈청 HBV DNA 검출여부와관 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 김연수, , 인천시남동구남동대로 774번길 21, 가천대길병원내과 Correspondence to: Yun Soo Kim, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon , Korea. Tel: , Fax: , kimys@gilhospital.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 62 No. 3, September

2 144 김연수. B 형간염바이러스잠재감염의정의, 진단그리고유병률 계없이간조직내에서 HBV DNA가검출되는경우로하였다. 6 간조직을통한검사가가장이상적인검사임에는이견이없으나간조직은조직검사를통해서만얻을수있다는현실적인어려움때문에간조직뿐만아니라혈청도진단에이용되고있다. 그러나혈청 HBV DNA가음성이면서간내 HBV DNA가존재할수있으므로검사결과의적절한해석이요구된다. Mariscal 등 7 은 PCR법으로혈청 HBV DNA가음성이었던만성 C형간질환환자의 25.5% (25/98) 에서간내 HBV DNA가확인되었다고하였다. HBV 잠재감염에서가장중요한바이러스표지자는 IgG anti-hbc이며혈청검사소견에따라혈청양성 (seropositive) 잠재감염과혈청음성 (seronegative) 감염으로분류된다. 혈청양성은 anti-hbc와 anti-hbs가모두양성이거나둘중하나가양성이면서 HBV DNA가검출되는경우이며, 혈청음성이란두항체가모두음성이면서 HBV DNA가검출되는경우이다. HBV 잠재감염자의대부분은혈청양성의소견을보이며 anti-hbc만양성인경우에 HBV DNA 검출률이가장높다. 잠재감염자중약 20% 는 HBV 혈청표지자가모두음성이다. 8 드물게 HBsAg은음성이면서혈중 HBV DNA 농도는 HBsAg 양성자와동일한수준으로검출되는환자가있는데, 이는대부분 HBV S 유전자의 a 결정기 (a determinant) 의변이에기인하며일반적인 HBsAg 검사로검출되지않는변형된 HBsAg이존재하는경우이므로거짓 (false) 잠재감염이라부른다. 6 또한 HBV DNA가간조직에서검출된다는점이반드시감염력이있음을의미하지는않으며간세포에서유리된 progeny 바이러스가존재함을의미하지도않기때문에잠재감염 (occult HBV infection) 보다는잠재간염 (occult hepatitis B) 이더적절한용어라는주장도있다 HBV 잠재감염의기전 HBV 잠재감염이일어나는기전은확실치않다. 혈청양성잠재감염은급성간염으로부터회복되거나만성보유상태에서 HBsAg 농도가점차감소되어발생하는것으로알려져있다. 잠재감염자에서는 HBsAg이음전된후간세포내에증식과유전자발현이억제된상태의 cccdna 형태로 HBV DNA 가존재한다. 10 간조직내에서 cccdna, HBV RNA 전사체, 그리고 pregenomic RNA가검출되는점으로미루어바이러스변이보다는약한수준의증식이일어나고있는야생형바이러스감염이그원인으로제시되고있다. 11,12 HBV 유전자의변이, HBsAg이면역글로불린과결합한형태로존재하여검출되지않을가능성, 다른바이러스와중복감염시다른바이러스에의한증식억제 (viral interference), 간세포로부터 HBsAg이유출되지않을가능성등도잠재감염의기전으로제시되고있다. 13 가능성있는바이러스변이는다음과같다. X 유전자의변이는 X 단백의변화와더불어중복된유전자부위인 core promoter의변이를유발하여 HBV 증식을감소시킬수있으며 pres1의변이역시 S 단백의발현을감소시킬수있다. 또한 S 유전자의변이는 S 유전자와중복된 P 유전자의변이를유발할수있으며이는 polymerase의활성도에영향을미쳐바이러스증식과 S 단백의발현에영향을줄수있다. 14 또한간내염증반응으로증가하는 tumor necrosis factor-α와 interferon-γ 등의 cytokine은 HBV 유전자발현을억제하며, 만성음주시에도 HBsAg의발현이억제될수있다고보고되고있다. 15 혈청음성잠재감염의기전또한확실치않으나혈중항체농도가점차저하되면서 anti-hbc가음전되었을가능성, 변이로인하여 core 단백이발현되지않아 anti-hbc가형성되지않았을가능성등을고려할수있다. 16 혈청양성잠재감염과음성잠재감염이임상적으로차이가있는지여부는확실치않다. Anti-HBc 양성인잠재감염자에서는 HBV 항원에대한 T세포증식반응이 anti-hbc 음성감염자에비하여현저히증가되어있다고알려져있다. 이러한결과가시사하는바는혈청음성잠재감염은 anti-hbc 항체반응을유발하기에부족할정도의소량바이러스감염 (low-dose infection) 이원인일수있다는점이다 (primary occult HBV infection). 17 HBV DNA 농도는 anti-hbc 양성인 HBV 잠재감염자에서음성인감염자에비하여높다고알려져있다 HBV 잠재감염의진단간조직이나혈청에서 HBV DNA를추출하여 PCR법으로진단하는것이잠재감염의검사법으로인정되고있다. HBV DNA 검출률은혈청에비하여간조직이나말초단핵구에서높으므로가장이상적인진단법으로간조직을이용한검사가제시되고있다. 18 간조직을이용한잠재감염의진단은침습적검사를하여야한다는단점이외에도검사법이아직표준화되지않았다는문제점이있다. DNA 추출은가장효율적인방법을이용해야하며포르말린고정조직의검출률은냉동 (snap-frozen) 조직보다낮다는점을유의해야한다. 18 Real time PCR 법이나 nested PCR법이권유되고있으며시발체 (primer) 는 HBV 유전자형에따른차이를보이지않고보존성이높은 (highly conserved) 부위에서제작하여야한다. PCR 검사의위양성혹은위음성을피하기위하여적어도 3개의 HBV 유전자영역에서시발체를제작하여검사하며이중 2개이상에서양성반응을보일때진단할수있다. 19 PCR을이용한검 The Korean Journal of Gastroenterology

3 Kim YS. Definition, Diagnosis, and Prevalence of Occult Hepatitis B Virus Infection 145 사는매우예민하여오염에의한위양성의가능성이있으므로검사시마다적절한음성대조를포함시켜야한다. 잠재감염자의혈청 HBV DNA 농도는대부분 200 IU/mL 이하로낮으므로혈청을이용한검사시에는적어도 1 ml의혈청에서 DNA를추출하여야하며 6 HBV DNA 농도 10 IU/mL, 그리고 HBsAg 농도 0.1 ng/ml 이하를검출할수있는예민한검사가권유되고있다. 20 혈액은행에서는 human immunodeficiency virus (HIV) RNA, HCV RNA, 그리고 HBV DNA를동시에검사할수있는 nucleic acid amplification techniques (NAT) 가이용되기도한다. 20 Anti-HBc는잠재감염의이상적인검사는아니지만 PCR 검사가불가능한상황에서는혈청양성잠재감염의진단에대리표지자로이용될수있으며특히수혈이나장기이식을받는경우유용하게사용될수있다. 10 그러나전술한바와같이혈청음성잠재감염자가존재하므로주의하여야하고특히 HIV 감염자나장기이식등면역결핍환자에서는 anti-hbc 가음성반응을보일수있다 HBV 잠재감염의유병률 HBV 잠재감염의빈도는 HBV 보유자의유병률에따라지역적으로큰차이를보인다. 즉유병률이높은지역에서는 anti-hbc 양성자에서 41-90% 의높은잠재감염률을보이는반면, 유병률이낮은지역에서는 5-20% 정도를보인다. 18,21 HBV 유행지역에서는 anti-hbc 양성률이높을것으로예상되는데, anti-hbc 양성여부뿐만아니라지역적인차이도 HBV 잠재감염률에영향을미친다. 우리나라에서도 ALT가정상인사람에서 16% 의잠재감염률이보고된바있다. 22 국내에서간조직을이용한 Kim 등 21 의연구에의하면 anti-hbc 만양성인환자의경우 56%, anti-hbc와 anti-hbs가모두양성인경우 31% 로높았던반면, anti-hbc가음성인경우 14% 로나타났다. 잠재감염의빈도는대상환자에따라서도차이를보인다. 한보고에의하면원인이확실치않은만성간질환환자를대상으로검사하였을때잠재감염률은 30% 로높게나타났다. 23 이와같은연구결과가시사하는점은 HBV 잠재감염에의하여병리학적이상이초래될수있다는점이다. 또한 HBV 잠재감염은원인이불분명한간세포암의중요한원인으로제시되고있다. 원인불명의간세포암환자에서 anti-hbc 양성률은높게보고되고있으며 22-87% 에서잠재감염이확인되었다. 24,25 중국인을대상으로시행한연구에서도원인미상의만성간질환환자의 28%, HBsAg 음성인간암의 70%, 심지어 HBsAg 음성인건강인의 11% 에서도잠재감염이확인되었다고하였다. 또한 anti-hbc 양성인경우감염률은현저히증가 하여원인미상의만성간질환환자의 100%, HBsAg 음성인간암의 87%, 그리고 HBsAg 음성인건강인의 34% 에서감염이확인되었다고하였다. 26 간질환이없는이탈리아인을대상으로시행한연구에서도 16.3% (16/98) 의간조직내에서 HBV DNA가검출되었으며 anti-hbc 양성자의 62.5% (10/16), 그리고음성자의 7.3% (6/82) 에서 HBV DNA가검출되었다고하였다. 이는 HBV 잠재감염이건강인에서도드물지않게존재함을시사한다. 19 한편자발적혈액공여자에서는 HBV 잠재감염률이낮다고보고되고있다. 미국등 HBV 비유행지역에서는 anti-hbc 양성공여자의 % 로감염률이낮은반면유행지역에서는 6% 정도로보고되고있다. 9 그러나 Yuen 등 27 은홍콩에서 0.11% (11/9,967), 0.13% (4/3,044) 의감염률을보고하여 HBV 유행지역일지라도혈액공여자의잠재감염률은매우낮다고하였다. 이러한연구결과의차이는진단방법의차이에기인하였을것으로생각된다. 만성 C형간질환에서는 HBV 잠재감염이 28-50% 로빈번하다고알려져있으며간질환의진행에영향을미칠수있다고제시되고있다. 7,28-31 일부의보고에서는간조직의 90% 에서 HBV DNA가확인되었다. 32 Cacciola 등 28 은 anti-hcv와 anti-hbc 모두양성인경우 100예중 46예에서, 그리고 anti-hbc가음성인 anti-hcv 양성자 100예중 20예에서 HBV 잠재감염이확인되어 HCV 감염자체가 HBV 잠재감염과긴밀히관계된다고보고하였다. 국내에서도 Jang 등 29 의보고에의하면 anti-hcv 양성자의 28% 에서간내 HBV DNA가검출되어유사한결과를보인다. 이는 C형간염과 B형간염의감염경로가유사하여발생하였을것으로추측된다. 또다른가능성으로 HCV와 HBV가중복감염된경우 HCV에의해 HBV 증식이억제되었을수도있다. 33 HCV core 단백에의해 HBV RNA 전사체 (3.5 Kb, 2.1 Kb) 들의합성과 HBsAg, HBeAg, 그리고 HBcAg의합성이현저히감소된다고보고되고있다. 34 또한주사용약물남용자나혈우병환자의 45-50%, 35 혈액투석환자의 %, 36,37 HIV 감염자의 8-51% 에서잠재감염이관찰된다고보고되고있다. 38 이러한결과들은경피적감염경로와면역억제상태가 HBV 잠재감염과관계됨을시사한다. 잠재감염의빈도는 anti-hbc의역가와도유의한상관관계를보인다고보고되고있다. Iizuka 등 39 은 anti-hbc 역가가 1:32 이하에서는잠재감염이없었으나 1:64부터 1:2,048 의농도를보인경우에는 4.3%, 그리고 1:4,096 이상인경우에는 38.5% 에서잠재감염이확인되었다고하였다. Vol. 62 No. 3, September 2013

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5 Kim YS. Definition, Diagnosis, and Prevalence of Occult Hepatitis B Virus Infection Chakravarti A, Verma V, Jain M, Kar P. Characteristics of dual infection of hepatitis B and C viruses among patients with chronic liver disease: a study from tertiary care hospital. Trop Gastroenterol 2005;26: Shih CM, Lo SJ, Miyamura T, Chen SY, Lee YH. Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells. J Virol 1993;67: Torbenson M, Kannangai R, Astemborski J, Strathdee SA, Vlahov D, Thomas DL. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology 2004;39: Minuk GY, Sun DF, Greenberg R, et al. Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology 2004;40: Besisik F, Karaca C, Akyüz F, et al. Occult HBV infection and YMDD variants in hemodialysis patients with chronic HCV infection. J Hepatol 2003;38: Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46: Iizuka H, Ohmura K, Ishijima A, et al. Correlation between anti-hbc titers and HBV DNA in blood units without detectable HBsAg. Vox Sang 1992;63: Vol. 62 No. 3, September 2013

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<30322E535453BABBB9AE2DC6EDC1FD2E687770> Covalently closed circular DNA activity in HBV infection 분당서울대학교병원내과 김진욱 Covalently closed circular DNA (cccdna) is a viral minichromosome from which HBV RNA replication intermediate (pregenomic RNA) is