R ev is t a d a S o c ie d a d e B ra s ile ira d e M e d i c in a T ro p ica l 2 9 ( 3 ) : 2 7 5 - 2 7 9 , m a i - j u n , 1 9 9 6 .
A CU TE EXA CERBA TIO N IN CH RO N IC
HEPA TITIS B V IRUS IN FECTIO N
M arcio V ieira Santos, M aria Irm a Seixas D uarte and A ntonio A lci Barone
A c a s e o f a n a c u t e e x a c e rb a t i o n o f liv er i n j u ry in a c h ro n i c H B V i n f e c t e d y o u n g m a le is re p o rt ed . T he c o rre la t io n b e t w e e n t h e s e v e re s y m p t o m a t ic hep at it is is d o n e w ith t h e his t o p a t ho lo gic f i n d i n g s o f e x t e n s e a re a s o f b ri d g i n g n e c ro s is o n t he I w e r b io ps y . T he s e ro lo g ic a l p a t t e rn f o r m a rk e rs o f H B V (H B s A g +, a n t i H B g -, H B e A g -, a n t i H B e +, a n t i H B C I g G + a n d I g M - ) c o n fi rm a c h ro n i c infe c t io n, a n a t he a u t h o rs p ro p o s e t hat t he e p is o d e o f s e v e re h ep at it is re la t es to t he re c e n t s p o n t a n e o u s s e ro c o n v e rt io n o f H B e A g to a n t i H B e . O t he r c a u s e s o f hep at it is w e re e x c l u d e d , a n d t he c o n t ro l liv e r b io p s y ( 6 m o nt hs la t e r) s h o w e d n o rm a l iz a t io n o f h e p a t ic a rc h it e c t u re a n d a b s e n c e o f m a rk e rs o f v ira l re p lica t io n in t is s ue a n d s e ru m . A re v iew o f lit e ra t u re is d o n e in a n a t t e m p t to e lu c i d a t e t h e d ia g n o s t ic p o s s ib ilit ies in t his ca s e , w ith e m p h a s is o n n e w im m u n o a s s a y s u s e f u l in d if fe re n t i a t in g b e t w e en a c u t e hep at it is B a n d a c u t e e x a c e rb a t i o n o f a c h ro n i c hep at it is b y t he s a m e v irus .
K ey - w o rd s : a c u t e e x a c e rb a t i o n . H B e A g - a n t i H B g s e ro co n v e rs io n . C h ro n i c H B V infe c t io n.
Chro nic hep atitis B virus infectio n results in a sp ectrum o f d isease entities ranging fro m the m o st sev ere fo rm o f chro nic activ e hepatitis to the asym p to m atic carrier state o f the Hep atitis B surface antig en (H BS A g). This w id e range o f liver injury am o ng chro nically infected hepatitis B virus (H BV ) p atients suggests a great d egree o f variability in the interactio n betw een the rep licating virus and the im m une resp o nses to the infected hep ato cy te7. It is w ell kno w n that H BV - sp ecific liv er cell injury, and subsequent viral clearance, is believ ed to b e m ed iated m ainly by cellular im m une m echanism s6.
Patients w ith chro nic H BV infectio n can be g enerally d ivid ed into tw o gro ups:
A) Tho se w ith chro nic liver disease (usually referred to as having chro nic type B hepatitis [CHB]). These patients have markers o f active viral replication, such as hepatitis Be antigen (HBe Ag) or HBV-DNA in serum or hepatitis Bc antigen (HBC A g) in the liver, in addition to abno rmal serum alanine aminotransferase
Lab o rató rio de Investig ação M éd ica em H ep atolo gia e de Pato lo g ia em D o en ças In f eccio sas , D ep artam en to de M oléstias In f eccio sas e Parasitárias, H ospital das Clínicas, Facu ld ad e d e M ed icina da U niversidade d e São Paulo, São Paulo, SP.
A d d r e s s t a D r. M árcio V ieira Santos. D ep artam en to de M oléstias In f eccio sas e Parasitárias. H C/FM USP. R. D r. Enéias
d e C arvalho A guiar 2 5 5 , C erq ueira C ésar, 0 5 4 0 3 - 9 0 0 São Paulo, SP, Brasil.
R eceb id o p ara p u b licação em 1 0 / 0 2 / 9 5 .
(ALT) activities and d etectable HBS Ag in serum and liver.
B) Tho se w ithout liver disease, referred to as being in a “healthy” o r “inactiv e” HBg Ag carrier state. These patients have HBg Ag, but w ithout HBV-DNA or HBe Ag in serum, or d etectable HBC Ag and HBg Ag in the liver, having, usually, normal serum ALT levels, no active inflammation or hep atocellular necrosis in the liver bio psies9.
Stud ies o n the natural histo ry o f chro nic H BV infectio n ind icate that these tw o gro ups p ro bably rep resent tw o stages o f chro nic H BV infectio n: either sp o ntaneo u sly o r d uring treatm ent, p atients w ith CHB can lo se HBV- DNA and H Be A g fro m serum and then hav e a rem issio n w ith su bseq u ent ap p earance o f antibo d y to H Be A g (anti-H Bg). In this case, the d isease usually ev o lv es fro m chro nic hep atitis to the “healthy ” H Bg Ag carrier state. Sero co nv ersio n fro m H Be Ag to anti-H Be is thus a “critical” ev ent in the natural histo ry o f chro nic H BV infectio n, and can o ccu r directly after the acute p hase (acu te hep atitis) o r it m ay hap p en years later, o ften fo llo w ing a flare-up o f sym pto m s and increase in the ALT lev els, or, in o ther w o rd s, p resenting as an acu te exacerb atio n in the ev o lutio n o f a chro nic hep atitis9.
R elat o d e C as o . S ant o s M V , D u a rt e M R S, B a ro n e A A . A c u t e e x a c e rb a t i o n in c h ro n i c hep at it is B v irus infe c t io n . R ev is t a d a S o c ie d a d e B ra s ile ira d e M e d i c in a T ro p ica l 2 9 : 2 7 5 - 2 7 9 , m a i- j u n, 1 9 9 6 .
characterized by acute exacerbatio ns o f liver injury alternating w ith no rm al liver functio n, suggesting a d ynam ic interactio n betw een the virus rep licatio n and the im m une resp o nse6. A cute exacerbatio ns in chro nic B hep atitis are usually d efined as ep iso d es o f abrupt elev atio n o f A LT w ith o r w itho ut significant sym pto m aggrav atio n. Persistence o f H Be A g after sp o ntaneo us flares is referred to as “abo rtiv e sero co nv ersio n”9.
W e d escribe a case o f an acute exacerbatio n o f liv er injury in a chro nic H BV infected yo ung m ale w ho p ro bably acquired the d isease in the neo natal o r early child ho o d perio d , and w as asym p to m atic b efo re this ep iso d e o f acute exacerbatio n. O thers causes o f hep atitis w ere exclud ed by the av ailable co m m ercial assays and a p ercutaneo us liver bio p sy esp ecim en w as analised using im m u no histo chem ical techniques.
CA SE REPO R T
HAF, a 15-y ear-o ld y o ung m ale, natural fro m São Paulo - Brazil, lo o ked fo r m ed ical attentio n in A pril, 19 1994, w ith a 2 w eek histo ry o f right u p p er quad rant p ain, jaund ice, d ark urine and a 4 d ay histo ry o f lethargy and chang e in p erso nality . H e d enied fev er, head ache, d iarrho ea, and his p ast m ed ical histo ry w as unrem arkable. There w as no histo ry o f d igestiv e o r hep atic sym pto m s in the past. H e d enied intrav eno us drug ad d ictio n, sexual activity, p revio us blo o d transfusio ns, recent travel, as w ell as p revio us use o f m ed icatio ns o r exp o su re to to xins. Th e physical exam inatio n rev ealed an acutely ill, w ell d ev elo p ed p atient w ith jaund ice, w itho ut signs o f chro nic liv er d isease such as spid ers, hep ato m eg aly , sp leno m eg aly o r ascites. The card iac and p u lm o nary exam inatio n w as no rm al. H e w as lethargic, co nfused , but there w ere no fo cal neuro lo g ic d eficits, seizures o r m ening ism us. Th e lab o rato ry find ing s at ad m issio n and the sero lo g ic p attern are listed belo w :
A LT - 1621 U/ L (0-18 U/ L) Bilirubin total - 17.2mg/ dL co njugated = 12.3mg/ dL Pro tein to tal = 6.0g/ dL A ibumin - 3.9g/ dL
• a 1 g lo bulin * 0.2g/ dL • a 2 glo bulin * 0.4g/ dL • (3 glo bulin = 0.5g/ dL • y glo bulin - l.lg / d L
A ST - 467 Ü/ L(0-18 U/ L) G G T = 20 U/ L(4-28 U/ L) A lkaline p ho sp hatase = 707 U/ L So d ium = 133mEq/ L Po tassium = 4.4mEq/ L
Urea nitro g en - 25mg/ dL(10-45mg/ dL) Creatinine = 0.1mg/ dL(0.6-l,4mg/ d L) A mylase = 46 U/ L(0-120 U/ L) Gluco se = 59mg/ dL(70-110mg/ dL) Prothro mbin time - 32“- 16%
Hb = l4.6g/ d L Her ■ 48% W BC co unt = 7.800/ mm^
neutrop hils - band s = 3% segm ented = 49% eo sino p hils - 2% baso p hils - 0% lymphocytes - 44% m o no cytes - 2% Platelet co unt: 308.000/ mm3 anti HAV Ig G + IgiM - anti HCV - HCV-RNA (PCR) - anti HDV
-H Bs A g + anti H Bs - anti H Bc IgG + IgM - H Be A g - A nti H Be +
Throm bin time = 23"
A ctivated partial thro m bo p lastin tim e=58" facto r V - 26" - 74%
anti-nuclear antibo d y - anti sm o o th-m uscle antibo d y - anti-mitochondrial antibo d y - anti-iiver/ kidney micro so mal antibo d ies
-anti CMV - Ig G + IgM - Paul-Bunnell <1/ 7
Ev o lut io n. The p atient w as ad m itted to the
intensive care unit and receiv ed suppo rtive care fo r hep atic insufficiency , w ith pro m p t im p ro v em ent in the lev el o f co nscio usness. There w ere no b leed ing co m p licatio ns, and the hep atic functio n im p ro v ed to a lev el that an em erg ency hep atic transp lantatio n w as unnecessary. A p ercutaneo us liver bio p sy w as d o ne o n May, 25 , 1994 and the hep atic tissue ev id enced extense areas o f brid ging necro sis, either b etw een p o rtal zo nes o r fro m po rtal zo nes to central v eins. These necro tic areas had their reticulin fram ew o rk co lap sed and their hep ato cy tes had d isap p eared . The p o rtal zo nes sho w ed a m o d erate m o no nu clear cell infiltrate, w itho u t p iecem eal necro sis o r ag g ressio n to the b ile d ucts. A sm all num ber o f neutro p hils w as also o bserv ed in the p o rtal z o n e s an d n e c r o tic a re a s . B a llo o n in g d eg eneratio n, w itho u t ev id ent asp ect o f g ro und -glass cell co uld also b e no ted in the p reserv ed p arenchym a. There w as a d iscrete hypertro p hy and hyp erp lasy o f the Kup ffer cells. No p o rtal fibro sis w as o bserv ed . The im m uno histo chem ical technique rev ealed a small num ber o f hep ato cy tes (less than 25% ) p o sitiv e to H BS A g and an ab sence o f H BC Ag o r HDV A g (antig en o f the H epatitis Delta Virus). At the tim e o f the first bio p sy , serum w as co llected and the PCR fo r HBV-DNA w as negative.
R elat o d e C as o . Sa nt o s M V , D u a rt e M R S, B a ro n e A A . A c u t e e x a c e rb a t i o n in c h ro n i c h ep at it is B v irus in fec t io n . R ev is t a d a S o c ie d a d e B ra s ile ira d e M e d i c in a T ro p ica l 2 9 : 2 7 5 - 2 7 9 , m a i- j u n, 1 9 9 6 .
zo nes w ere no t exp and ed and ev id enced a mild lim p ho cytic infiltratio n, w hich w as also o casio nally o bserv ed in the lo bular sp aces. The hyp ertro p hy and hip erp lasy o f Kupffer cells rem ained d iscrete. A sm all strip o f intralo bular fibro sis co uld b e o bserv ed .The im m uno histo chem ical technique had similar results w hen co m p ared to the first exam inatio n: few hep ato cy tes exp ressing H BS Ag and an ab sence o f H BC Ag. The sero lo g ical p attern fo r m arkers o f H BV p ersisted exactly the sam e d uring the six m o nth p erio d o f fo llo w -up , w ith no rm alizato n o f labo rato ry tests o f hep atic functio n.
D ISCU SSIO N
The sero lo g ical p attern fo r m arkers o f HBV, caracterized by the ab sense o f d etectable anti H Bc-IgM ruled o ut acute-p hase infectio n by HBV5, as w ell as the negativ e results o f IgM anti-HAV, anti-HCV antibo d ies and PCR fo r HCV-RNA in serum, antibo d y to HDV (anti- H D V ) a n d th e n e g a ti v e r e s u l t o f im m uno histo chem ical fo r HDV in the liver bio p sy ruled o ut sup erinfectio ns w ith o ther hepato tro pic virus. The labo rato ry tests currently used fo r d iagno sis o f hep atitis E virus w ere no t av ailable at the tim e o f p atient illness : a serum sam p le w as sto red and tested retro spectiv ely fo r antibo d ies to this new d escribed virus, giving a negativ e reactio n by the m etho d o f Elisa.
The sero lo g ic tests fo r intectio n w ith o ther no n hepato tro pic virus such as cytomegalovirus, Ep stein-Barr virus w ere negativ e.
The ab sence o f m arkers o f viral rep licatio n o f HBV virus (H Bg A g and HBV-DNA ) in serum and the p resence o f anti-H Be , in ad d itio n to the ab sence o f H BC A g in the liver ind icates that activ e viral rep licatio n is subsid ing and d isease activity d ecreasing. Becau se tho se w ho have cleared HBg Ag frequently have tem porary e x a c e rb a tio n s o f h e p atitis b e f o re th e sero co nv ersio n, it has b een suggested this ev ent rep resents an “im m une clearance” o f hep ato cy tes co ntaining activ ely rep licating virus as w ell as H Bc A g/ HBe A g6 7 9.
The nu cleo cap sid e antigens o f H BV (in the co ntext o f HLA antigens) are the m o st impo rtant target fo r cyto xicity. Recent stud ies o n T cell resp o nse to H BV antig ens d uring acute exacerb atio ns o f CHB d em o nstrated that the T cell p ro liferative resp o nse to reco m binant H BC
A g and natural H Be A g w as higher in p atients w ith CHB than tho se in healthy H Bg A g carriers, and that there w as a further increase in T cell proliferative resp o nse to H BC Ag/ HBe A g during acute exacerbatio ns. In the reco v ery fro m th e se ac u te e x ac e rb atio n s w ith H Be A g sero co nv ertio n, the sam e study d em o nstrated a su bsid ence in T cell resp o nses to the sam e antigens9.
Stud ying the alteratio ns in quantitativ e serum HBV-DNA, H Be Ag (as ind icato rs o f viral rep licatio n) and anti-HBg p ro d uctio n, H Be Ag specific immunocom plex formation (as indicators o f an im m une resp o nsiv eness) befo re, during and after injury in H Be A g p o sitiv e p atients w ith CAH, M aruyama et al6 sho w ed that the increasing lev els o f viral rep licatio n o ccurred b e fo re the p e ak A LT le v e ls, and th en precip ito usly d eclined as ALT lev els p eaked and subsid ed . The ind icato rs o f im m une resp o nsiv eness (anti-H Be and H Bg Ag sp ecific im m uno co m p lex) increased in p arallel w ith HBV-DNA/ HBe Ag lev els, w ith the excep tio n o f the anti-H Be antibo d y , that p eaked so m ew hat later than HBV-DNA/ HBp Ag. The ability to p ro d uce anti H Be reflects the im m une co m p etence o f these patients w ith CAH, at least w ith resp ect to the H Be A g - sp ecific help er T cells and B cells, and is co nsistent w ith the p o ssibility that the liver cell injury is m ed iated by im m une m echanism s.
A no ther d iagno stic p o ssibility in this case is the existence o f H BV p reco re mutants. Variants o f H BV that d o no t exp ress H Be Ag hav e recently b een d escribed 2 3. The m o st co m m o n is the G-to -A sw itch at base 1896 o f HBV-DNA p reco re regio n. The em erg ence o f this p reco re mutants has b een asso ciated w ith fulm inant hepatitis and sev ere liv er d isease in p atients w ith anti-H Be p o sitiv e chro nic hep atitis1. In these cases, o ther m arkers o f viral rep licatio n (as HBV-DNA ) are exp ected to b e p resent, and that w as no t sho w n in the p resent report, m aking this hyp o thesis less p ro bable.
R elat o d e C as o . S ant o s M V , D u a rt e M R S, B a ro n e A A . A c u t e e x a c e rb a t i o n i n c h ro n i c hep at it is B v irus in fec t io n . R ev is t a d a S o c ie d a d e B ra s ile ira d e M e d i c in a T ro p ica l 2 9 : 2 7 5 - 2 7 9 , m a i- j un , 1 9 9 6 .
a c u te p h a s e in f e c tio n ) c a n b e th e o n ly sero lo g ical m eans o f d ifferentiating this situatio n, w hat is im p o rtant in term s o f p ro gno sis and p o ssib le treatm ent m o d alities7. Recent stud ies hav e fo cu sed o n the sero lo g y o f chro nic H BV infectio ns, using assays cap able o f d etecting antibo d y to H Be A g and H BS Ag in the p resence o f circulating H Be and H Bg A g 7. T h e u se o f th e s e e x p e rim e n ta l im m uno assays has m o d ified o ur v iew o f the sero lo g y o f chro nic H BV infectio n b y sho w ing that virtually all H BV chro nic carriers w ith liver d isease are p o sitiv e fo r b o th H Be A g and anti- H Be fo r m any years b efo re the lo ss o f H Bg Ag, and anti-H Bs p ro d uctio n can b e d etected as H BS A g - sp ecific im m une co m p lexes (ICs) in p arallel w ith liv er d am age in CAH p atients7.
These sam e exp erim ental assays, w hen ap p lied to acute H BV infectio n rev eal that p atients w ith CHB sho w significantly higher lev els o f free anti-H Be , H Be A g/ anti-HBe ICs and H BS A g/ anti-HBs ICs co m p ared w ith acute H BV p atients sera. Furtherm o re, the m o st sig nificant and p o ssib ly the m o st useful d ifference in the sero lo g y o f p atients w ith acute and chro nic H BV is the p resence o f a no v el sp ecificity o f IgG anti-H Bc antibo d y d esignated as anti W H Bc antibo d ies. Previo us stud ies hav e ind icated that the nucleo cap sid es o f H BV and the W o o d chuck hepatitis virus (an o ther m em b er o f the H ep ad nav irid ae fam ily) share a cro ss-reactiv e ep ito p e(s). So , it is d e m o n strate d th at h u m an an ti-H Bc antibo d ies reco g niz e W o o d chuck H BC Ag (W H BC A g), and that CHB p atient sera sho w significantly hig her lev els o f IgG anti-W H Bc co m p ared w ith acute hep atitis B p atient sera, w itho ut o v erlap values. The sam e autho rs p ro p o se a ratio o f IgM anti-H Bc/ 'IgG anti- W H BC that co uld b e p erfo rm ed in acute and chro nic H BV infectio ns in o rd er to d iscrim inate b etw een acute hep atitis B fro m sympto matic chro nic hep atitis B infectio n: an inv erse co rrelatio n b etw een IgM anti-H Bc and IgG anti-W HBc values existed in bo th p atients w ith acute and chro nic H BV infectio n7.
Recent stud ies o n the p rev alence o f H BS Ag subty p es (ad r, ad w , ay r and ay w ) hav e d em o nstrated d ifferences in their geo g rap hic d istribu tio n and their relatio nship w ith ep id em io lo g ic facto rs. M o re recently, H BS Ag subtyp es hav e b een asso ciated w ith H Be Ag/ anti H Be status and may, co nsequently , influence the d ev elo p m ent o f liver d isease in
the H BS Ag carriers. Fo r exam p le, in a restricted g eo g rap hic area o f Jap an, w ith a ho m o g eno us ep id em io lo g ical/ cultural backg ro u nd , ad r carriers tend to b e sero co nv erted to anti-H Be at an o ld er age than ad w carriers, and thus, adr carriers may d ev elo p chro nic liv er d isease m o re frequently than ad w carriers8. D ata o n H Bs A g subtyp es p rev alence in o ur geo g rap hic reg io n (São Paulo - Brazil) are no t av ailable, so , co nclusio ns based in the H BS A g subtyp e o f o ur p atient co uld no t b e d o ne, and it w as no t determ ined .
Various av erage annual co nv ersio n rates fo r HBe A g to anti-H Be hav e b een rep o rted in ad ults; these rates range fro m 2.3% to 25% in v ario us parts o f the w o rld 4. W ith resp ect to o ther facto rs affecting the clearance o f H Be Ag sp ecifically in child ren, stud ies hav e sho w n that the p resence o f sym pto m s, a negativ e m aternal H Bg A g status, and the infectio n o ccurring later in life, are co rrelated w ith a higher H Be A g clearance rate4.
The p atient rep o rted in this rev iew w as a 14 y ears o ld b o y that d enied the m o st im p o rtant risk facto rs related to H BV infectio n, includ ing sexual activity. His m o ther serum w as o b tained and the b io ch em ical and sero lo g ic analysis rev ealed a no rm al hep atic functio n and a negativ e result fo r H BgAg w ith a p o sitiv e result fo r anti-H Bs and anti-H Bc IgG antibo d ies, p ro ving a p revio us co ntact w ith H BV w ith ad q uired resistance to H BV infectio n. So , it is p o ssible to assum e that o ur p atient had p ro bably b een infected d uring the p erinatal p erio d b y his mo ther, o r d uring early child ho o d . At least, it is p o ssib le to infer that so m etim e in her life, the p atient’s m o ther had activ e H BV rep licatio n, and w as ab le to transm it H BV to her infants o r ho useho ld co ntacts.
R elat o d e C as o . S ant o s M V , D u a n e M R S , B a ro n e A A . A c u t e e x a c e rb a t i o n in c h ro n i c hep at it is B v irus in fe c t io n . R ev is t a d a S o c ie d a d e B ra s ile ira d e M e d i c in a T ro p ica l 2 9 : 2 7 5 - 2 7 9 , m a i- j u n , 1 9 9 6 .
nu cleo cap sid e antig ens, but sp aring the hep ato cy tes exclu siv ely p ro d u cing H Bg Ag, r e s u l t i n g in a n i m p r o v e m e n t o f clinicai/ laboratorial and histo pathologic findings, w ith chang e to the “healthy ” H BS A g carrier state.
RESUM O
D e s c re v e - s e u m c a s o d e e x a c e rb a ç ã o a g u d a s i n t o m á t i c a e m u m p a c i e n t e c r o n i c a m e n t e in fe c t a d o p e l o V H B , m o s t ra n d o - s e c o rre la ç ã o e n t re o q u a d ro c l ín i c o g ra v e ( c o m i n s u fic iê n c ia h e p á t ica t ra n s it ó ria ) e o s a c h a d o s his t o p at o ló gico s d e hep at it e s e v e ra c o m e x t e n s a s á re a s d e n e c ro s e e m p o n t e . O p e rf i l s o ro ló gico p a ra m a rc a d o re s d o V H B (A g H B S
+ , a n t i H B S A g H B e -, a n t i H B e +, a n t i H B C I g G + I g M - ) c o n fi rm o u in f e c ç ã o c rô n ic a , e o s a u t o res le v a n t a m a h ip ó t e s e d e q u e a h ep a t it e t e n h a s e c o iT e la c io n a d o â re c e n t e s o ro co n v e rs ã o A g H B e p a r a a n t i- H B e . O ut ra s et io lo gias p o s s ív e is f o ra m
d e s c a rt a d a s e s e c o n t o u c o m b ió p s ia c o n t ro le 6 m e s e s d e p o i s , m o s t r a n d o n o r m a l i z a ç ã o d a a rq u it e t u ra h e p á t ic a e a u s ê n c i a d e m a rc a d o re s d e re p li c a ç ã o v ira l n o t e cid o e n o s o ro . R ev is a- s e a lit e ra t ura s o b re o d ia g nó s t ico d i f e re n c i a l c a b ív e l n e s t a s it u a ç ã o , d a n d o ê n f a s e a no v o s e n s a io s s o ro ló gico s út eis n a d if e re n c i a ç ã o e n t re in f e c ç ã o a g u d a p e l o V H B e e x a c e rb a ç ã o a g u d a d e u m a h ep a t it e c rô n i c a p e lo m es m o a g e n t e .
P a l a v r a s - c h a v e s : E x a c e r b a ç ã o a g u d a . S o ro co n v e rs ã o A g H B e - a nt i H b ^ I n fe c ç ã o c rô n ic a p e l o V H B .
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