Intrafan1ilial spread o f hepatitis B: Passage through several generations

Passage through several generations. Can 1993;7(1):23-27. Uncontrolled spread of hepatitis B virus (HBV) is describeJ in an immigrant Italian family. As many as four generations of offspring appear to have been infected, the source likely originating from a grear grandfather. Owrt liver disease in four of six members in the second generation as well as a history of hepatitis implicate~ the virus in the two generations which could not be tcstcJ. Five of seven asymptomatic sisters in generation llI were found to be carriers, and were both hepatitis B surface antigen (HBsAg)-positive and antihepatitis Be antigen antibody-positive. One sister lost HBsAg status shortly after discovery of her carrier status. The overt carrier rate in generation IV was reduceJ, suggesting later childhood acquisition of HBV infection. This family strongly emphasized the need for investigating patients with a positive family history of liver disease and screening family members of newly discovered HBsAg carriers to allow appropriate measures to be taken to limit the spread of HBV.

The mechanism of intratamtlial spread ha~ been linked both to vemcal transm iss ion ( I 0) and hnri:nntal spreaJ (6) among mcmhcr, nf the ~amc nr o ther families. At least one earlier study frnm North America found lnrlc li kelihood of hori:ontal or vert1c..1l ~pread ( l L ). To emphasize the u~cfulne~s li current effort~ to mmimi:c HRV spread an~! co shed a historical perspective on S/11.o\l ;YJ cl ,d gen eration, de mc me que des anteceden ts d'hepatite, idcnti fient le virus dans lcs J cux generation~ qu i n 'nnt pas r u ctre sou mises a l'epreuvc. C inq des sept soeurs asymptommiq ues de la gen eration lII ~e son t rcvelecs porccuses et pos itives a l'egard de l'antigcne de ourface J c l'hepc1tite B (AgsH B) et a l'egarJ d'un an t ico1 11s a nti-nntigcne de l'ltepatite Be. L\me des soeurs a perdu son statut AgsH B peu de tem po aprcs avo ir Jecouvert son statut de portcuse. Le taux de porreurs decla res dans la generation IV a ere moind re, donn ant a supposer un e acquisit io n plus tard ive <lurant l'enfance de !' infection au l lBV. Cerce famille soulign e nettemcnt la nccessitc de pratiquer un J cpistage chcz les patients qui prcsen ren t des a ntecedent~ fa miliaux pos itif, d'hepmite ct le Jepistage J es membres des families de porteurs AgsH B nouve llcment diagnostiqucs afin Jc promo uvoir les mesures appropriees pour limiter la propagation du H BV.

RESULTS
Affected and p1 \lhabl\ affected members are shown in Figure I. l liswrically, the great grnndfather (generation I [Gen I]) migrated fmm Valsini 111 smnhern Italy tn Tu rin in Maternal rrovincc. He was reported tu have died in his early 50, with ascllcs and jaund ice. In Gen II, four of six siblings werl· reported to h,l\'e had liver disease. The grandfat her (Gen 111) immigrated lll Momreal and was reported to have died in hb 50s with ascites and prohabk li ver cancer. The brother (Gen 112) apparently had c irrho,1s, hut was though1 to drink alcnh ul excessively.Two ,llhcr sisters 111 Italy have known livl'r diseasr and at least one recalled be ing told hepatitis B was the cause. U nfo rtunately, this branch nf the fan11ly declmeJ l\l be tested. There was nn h istory of liver disease ,m t he great grandmother (If grandmother's side. Gen Ill, seven females, were born in ltaly and immigrated in the early 1960, tu Moncre.il with their parents. T heir mean age at present 1s 40. 7 years. Two add1t ional siblings d ied as neonate~. None of the sisters is symptomatic, and lll1ly ,H1e has mild ly ahnorm,1l li\'er biochemistries (Gen Ill e,). Their abdommal ultrasound examinatiom were normal. Because of nn d 1ren serological evidence of H BV infcct10n in Gen I and 11, scrum ceruloplasmin, serum iron studies and a 1 anti t rypsin were measured in ,ix of ~even ,biers; the,c studil's were uniformly negative. In ad-d1unn, serology for anti-J-!Rc was negati ve in five sisters ofCicn Il l and two of their spnu~es.
The ,emlug1cal f111d111gs in the ,even sister,, four of tlH:i r spouses and n i 11e children me listed in Tahle I. Tcsb were repeated ar least th ree t ime, Jurrng a 24-month observauon perind.
All seven sbterb were found ro have e\'1dence of cxpl)Surc to 1-IBV. Five were initially HBsAg-po~itive and anti-HBeAg-positi ve. Within eight months of the initial tests, 11 '3 converted fro m HB·Ag-positive to anti-HBsAg antibody-positive a nd lost 1-IBsAg. This e\'ent was verified hy the finding of horderline negati ve 1-!BsAg on repeat testing. Two other :,isters had only a ntibodies; Ill s had an ti -HBsAg onl y and 1114 had only positi ve lgG ann-HikAg antibody found on all three tests. One of four spouses was HBsAg-positive nnd anti-HBeAg-positive while one wa~ positive only for anti -HB~Ag.
In Gen IV (mean age 15.7 yea rs) three children from lll5 (IV 7.l'l.9) were negative for H BV-related seroll)gy. Of the remaining six, IV 4 was positive fo r hoth HBsAg and 1-JBeAg. He abo had mild asparare aminotransferase a nd alanine aminotransferase elevatio ns. This subject has no kn own e ither risk facmrs for HBV infection. The brother and sister o f IV4 (]V J and IV5, respectively) both have anti -HBsAg and anti-HBeAg but me l1th crwise asymptomatic. O ne cousin , IVc,, was also ant i-HBsAg-positive. In addition , the neonate (Gen IV Io) was vaccinated against HBsAg, and Gen V2 and V1 were vaccinated because of close contact with Gen 11 Iz.  However, hecausc up to 70% of infections with HBV are subc linical (4), tracing source~ may be qu ite difficult.
Wh ile 5 to JO% of infected adu lts become ca rriers, as many as 90% of infected neonates born to HBeAgpositive mothers will be carri ers ( 19  lncrafamilial spread traced ro the paternal side is reported much less often tha n m aternal sources (26). The mec hanbm of spread under these circumstances relates either to subcli nical infection to the mother (consequently in wh om high replicative HBeAg-positivity occurs ) or mo re like ly co horizontal transm ission through close fam il ial contact (27). ch ildren of HBsAg-po~itive mothers (28,29). Plausible explanations include an improvemenr in socioeconomic conJitions and decreased family size ( which limits sibling spread). Nevertheless, HBV infcctivity remained high in Gen IV since four of six children had HBV markers. Therefore, one wonders why three of fo ur children cleared HBsAg in Gen IV and not in Gen Ill (since the rate of HBsAg clearance in carrier5 is no more than I to 2 % per year (30]). It is possib le that in Gen IV the children acquired subclinical hepamis horizontally, in which case the clearance is higher and carrier race is lower. The observation that passage oi HBV infection is much less efficient in anti-HBeAg-positive mothers supports this notion ( 4,19). A I though the mothers in Gen Ill began delivering m their early and late 20s, we a rc not cer-