Antonácio, F.

Candeias, J. A. N.

Sette Junior, H.

Silva, L. C. da

English

Cadernos Espinosanos (E-Journal)

Rev. Inst. Med. trop .. São Paulo 16(4):226-231, julho-agosto, 1974 UDO 616.988.1 616.36-002 OCCURRENCE OF HEPATITIS-ASSOCIATED-ANTIGEN (HAA) SUBDETERMINANTS ad AND ay IN BWOD DONORS, ACUTE AND CHRONIC LIVER DISEASE J. A. N. CANDEIAS (1 ), F. ANTONÃCIO (2), H. SETTE JR. (3) and L. C. da SILVA (4) SUMMARY The sera of 120 individuais were examined for ad and ay subdeterminants of Australia antigen. Twenty out of 33 patients with acute viral hepatitis, not ideritified as post-transfusion cases, were ay positive ( 60. 6 % ) ; in a group of 76 blood donors the predominant subdeterminant was ad ( 80. 3 % ) . Three out of 4 cases of chronic aggressive hepatitis had an antigen-positive status and all were ad positive; all patients with chronic persistent hepatitis had an antigen-nega-tive status. ln 5 cases of postnecrotic cirrhosis, only two were positive for Aus-tralia antigen with an ad specificity. ln addition, it was studied the occurrence of antinuclear factor (ANF), smooth muscle antibodies (SMA), mitochondrial antibodies (MA) and Australia antigen in cases of chronic aggressive hepatitis and postnecrotic cirrhosis. INTRODUCTION The hepatitis-associated-antigen or Aus-tralia antigen was discovered by BLUMGERG 3 as a result of a study on multiple antigen specificities of serum proteins. Subsequent studies confirmed the association of this an-tigen with acute viral hepatitis and a variety of other conditions 4 , 5 , 15• 19• 22, 23 • Also some apparently normal individuais carry this antigen and the data obtained seem to be consistent with thé hypothesis that there is a genetic susceptibility to persistent infection with Australia antigen 6 , 8 , 20 • ln relation to chronic hepatic conditions it is probable that other etiological factors than the antigen are responsible for the development of the disease. Autoimmune processes induced by unknown factors are believed to play a part in their pathogenesis as the presence of va-rious autoantibodies seem to suggest 24 • ln addition to the subdeterminant a, com-mon to all antigens 12 there are three other subdeterminants, d, x and y. The d and y are mutually exclusive and, possibly, with the a subdeterminant reflect the genotype of the virus; the x subdeterminant is a possible component of the host 14• BANCROFT et al. 2 described two additional antigenic subdeterminants w and r. MAGNIUS & EsP-MARK 17 proposed the designation of e to another subdeterminant. The present report includes the result of a study on the occurrence of Australia anti-gen subdeterminants ad and ay in serum This wo~k was supported in part by the Ministério da Educação e Cultura do Brasil -CAPES, under a contract (3730/71) (1) Departamento de Microbiologia e Imunologia do Instituto de Ciências Biomédicas da Universidade de São Paulo, São Paulo, Brasil (2) Serviço de Transfusão de Sangue do Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil. (3), (4) ·Instituto Brasileiro de Estudos e Pesquisas em Gastroenterologia, São Paulo, Brasil e Ins-tituto de Medicina Tropical de São Paulo, São Paulo, Brasil 226 CANDEIAS, J. A. N.; ANTONÁCIO, F.; SETTE JR., H. & ~ILVA, L. C. da - Occurrence o~ h~pa-titis-associated-antigen (HAA) subdeterminants ad and ay m blood donors, acute and chromc llver disease. Rev. Inst. Med. trop. São Paulo 16:226-231, 1974. TABLE I Australia antigen subdeterminants in acute serum hepatitis patients and in normal blood donors Group Disease Number ---·--·· 1 Acute viral hepatitis 33 Normal blood donors 76 Totals 109 specimes collected from various groups of in-dividuals. ln some groups the presence of autoantibodies is studied. MATERIALS AND METHODS Australian antigen-positive sera from 120 individuais were examined for ad and ay subdeterminants. The major group includes 33 individuais with acute viral hepatitis and 76 normal blood donors. Another group of 11 individuais, 4 with chronic aggressive he-patitis, 2 with chronic persistent hepatitis and 5 with postnecrotic cirrhosis was in-cluded in this stu11y. All sera were concen-trated, before use, by polyacrylamide gel ( *) in order to improve the sensitivity of the test 1 • The immunodiffusion test used follows the orocedures described by ScHMIDT & LEN-~ETTE 21 with some modifications: the gel contained 0.8 % agarose in O.OI M tris (hy-droxymethyl), aminomethane buffer, 0.1 M NaCL, O. 001 M ethylenediaminetetraacetate and 0.05% sodium azide, with a final pH of 7,6. Human sera containing anti-HAA and refe-rence Australia antigen with specificities ad and ay were kindly suplied by Drs. J. W. Mosley and Y. Cossart. Our antisera to Aus-tralia antigen gave reactions of immunologic identity with those standard antisera. (*) L:yphogel, Gelman Instrument Co., Ann Ar• bor, Michigan ad ay No. I % No. 1 % 13 39.4 20 60.6 ; 61 80.3 15 19.7 74 68.9 35 31.1 RESULTS ln Table I is shown the distribution of ad and ay subdeterminants in 33 cases of acute viral hepatitis and in 76 normal blood do-nors. The first group shows a higher propor-tion of ay subdeterminants ( 60. 6 % ) com-pared to the blood donor group ( 19. 7 % ) . The ad subdeterminants had, as well, an unbalanced distribution in these groups, being the blood donor group predominantly ad in its specificity ( 80. 3 % ) , in relation to the acute viral hepatitis group ( 39. 4%). Table II presents pertinent data concer-ning the distribution of Australia a~tigen and its specificities in cases of _chr~mc a_g-gressive hepatitis and postnecr~t1c curho~1s. ln three patients with chromc aggress1ve hepatitis it was possible to detect the Aus-tralia antigen and ali were ad positive. ln 5 cases of postnecrotic cirrhosis, only 2 were Australia antigen-positive and in the charac-terization of the subdeterminant all two cases were ad positive. Table III presents the average values for some conventional liver tests in the patients with chronic aggressive hepatitis, chronic persistent hepatitis and postnecrotic cirrhosis. Raised total serum bilirubin was noted in 2 patients with chronic persistent hepatitis Australia antigen-negative, and in 5 patients with postnecrotic cirrhosis. The transamina-ses were raised in all patients. The albu-minaemia had normal values; the gamma-globulinaemia had normal or slightly increas-ed values. 227 CANDEIAS, J. A. N.; ANTONÃCIO, F.; SETTE JR., H. & SILVA, L. C. da - Occurrence of hepa-titis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver disease. Rev. Inst. Med. trop. São Paulo 16:226-231, 1974. TABLE II Australia antigen subdeterminan.ts in chronic aggressive hepatitis and postnecrotic cirrhosis patients Group Disease Chronic aggressive hepatitis Postnecrotic cirrhosls Totals Number 4 5 9 Number with AU antig,en 3 2 5 Number with antigenic subdeterminants ad ay 3 o 2 o 5 o TABLE III Biochemical findings in chronic aggressive hepatitis, chronic persistent hepatitis and postnecrotic cirrhosis patients Australia 1 SB SGOT SGPT ALE GAMM Group Disease Number 1 antigen mg % U/ml u/ml g% g% + 3 0.75 144 154 4.16 1-50 Chronic aggressive hepatitis - 1 0.50 120 240 4.40 1.99 + o - - - - -Chronic persistent hepatitis - 2 1.25 50 50 4.16 1.90 + 2 3.75 254 227 3.18 2.10 Postnecrotic cirrhosis - 3 1.70 74 108 3.06 2.63 SB serum bilirubin Finally, the incidence of smooth muscle antibodies, mitochondrial antibodies, antinu-clear factor, Australia antigen and antibodies is presented in Table IV. None of the cases presented Australia anti-bodies and the Australia antigen-positive patients, which include three cases of chro-nic aggressive hepatitis and two cases of postnecrotic cirrhosis were negative to mi-tochondrial antibodies and antinuclear factor. The smooth muscle antibodies were absent in all cases of chronic aggressive hepatitis and in one of the two cases of postnecrotic 228 cirrhosis, above mentioned; the other case of postnecrotic cirrhosis had smooth muscle antibodies in a titer of > 1 :250. DISCUSSION The results of our study largely confirm the different distribution of ad and ay subdeter-minants in acute viral hepatitis and in blood donors, as it has previously been shown 11, 13• The group of chronic aggressive hepatitis, chronic persistent hepatitis and postnecrotic CANDEIAS, J. A. N.; ANTONACIO, F.; SETTE JR., H. & SILVA, L. C. da - Occurrence of hepa-titis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver disease. Rev. Jnst. Med. trop. São Paulo 16:226-231, 1974. TABLE IV Immunological findings in chronic aggressive hepatitis and postnecrotic cirrhosis Australia antigen-positive patients Patient Group Disease Australia Australia SMA MA ANF antigen antibodies L.S.S. Chronic aggressive hepatitis + - - - -W.G. " " " + - - - -P.L. " " " + - - - -C.L.N. Postnecrotic cirrhosis + - + - -N.M. " " + - - - -SMA smooth muscle antibodies MA mitochondrial antibodies ANF = antinuclear factor -cirrhosis comprises too small a number of patients in which to base any conclusions. It should be mentioned, however, some pe-culiar findings obtained. The cases of chro-nic persistent hepatitis were all Australia antigen-negative and of the 4 patients with chronic aggressive hepatitis, 3 had Austra-lia antigen in their serum; two cases of post-necrotic cirrhosis were Australia antigen-po-sitive. This is an observation not in aggre-ment with data obtained in other studies 16• ' 25, but the limited number of cases studied -do not allow any conclusion. ln the charac-terization of the subdeterminants, all these five patients were identified as ad positive. ·Our data are probably a consequence of the limited number of observations or they might as well reflect the prevalence of that virai genotype at the moment the patients were infected. MosLEY 18 in a group of 32 pa-tients with "unresolved hepatitis" found 66% ad positive and 34% ay positive. GORDON ·et al. 10 found in 19 cases of chronic persis-tent hepatitis 13 ad positive and 6 ay posi-tive; in 23 cases of chronic active hepatitis the occurrence was 19 ad positive and 4 ay pos1t1ve. The terms "unresolved hepatitis" .and chronic persistent hepatitis are frequen-tly used to describle the sarne condition, how--ever the term chronic persistent hepatitis, as originally used by DEGROOT et al. 9 , was a histologic term related to a nonspecific hepatic inflammatciry reaction. This reac-tion could be the result of an anicteric virai hepatitis, an hepatitis in a subsiding stage or any reticuloendothelial inflammatory res-ponse to different infections in which the li-ver participates. ln V1sCHER's report.24 on Australia anti-gen and auto-antibodies in chronic hepa-titis the mutual exclusion between M and SM antibodies and Australia antigen is men-tioned. Our findings tend to support this study and the study of BuLKLEY et al. 7 in ca-ses of chronic aggressive hepatitis. However it is interesting to refer our data in relation to one case of postnecrotic cirrhosis, Aus-tralia antigen-positive and at the sarne time with a titer of SM antibodies of > 1. 250. LOPES 16 in a study about the diagnostic va-lue of auto-antibodies and Australia antigen in chronic hepatic conditions considers three different groups, comprising group I, pro-longed forms of acute hepatitis, group II, chronic persistent hepatitis and group III, chronic aggressive hepatitis of intense acti-vity and chronic active hepatitis in a cirrho-tic phase. ln 19 cases belonging to the group III he found a proportion of 94. 7 % with an Australia antigen-negative status 229 CANDEIAS, J. A. N.; ANTONACIO, F.; SETTE JR., H. & SILVA,.L. C. da - Occurrence of hepa-titis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver disease. Rev. Inst. Med. trop. São Paulo 16:226-231, 1974. associated to the presence of auto-antibodies. Although evidence is limited, our observa-tion, inconsistent with those results, may con-firm the possible role of the persistent virai infection and autoimmune processes as indu-cing elements of a selfperpetuating inflam-matory reaction of the liver. A more detailed study including a significant number of cases is presently being developed. RESUMO Identificação dos subdetermi,wntes ad e ay do antígerw associado à hepatite ( AAH) em doadores de sangue e casos de doenças infecciosas aguda e crônica do fígado Examinaram-se 120 soros de diversos in-divíduos para a identificação dos subdeter-minantes ad e ay do antígeno Australia. De 33 casos de hepatite aguda não relacionados com transfusões de sangue, 20 foram ay po-sitivos ( 60,6 % ) ; em 76 doadores o sub-determinante predominante foi ad (80,3%). Em 4 casos de hepatite crônica agressiva, 3 positivos para o antígeno Australia foram identificados como ad. De 5 casos de cirrose pós-necrótica somente dois foram positivos para o antígeno Australia e também estes foram ad positivos. Estudou-se, igualmente, a ocorrência de fator anti-nuclear (F AN), anticorpos anti-músculo liso (AML), anticor-pos anti-mitocôndria (AM) e antígeno Aus-tralia nos casos de hepatite crônica agressiva e cirrose pós-necrótica. ACKNOWLEDGEMENTS The Authors are indebted to Dr. Mario Camargo who examined the sera for anti-nuclear factor, SM and M antibodies; to Drs. J. M. Mosley. and Y. Cossart who pro-vided reference Australia antisera and an-tigen. REFERENCES 1. ASHCAVAI, M. & PETERS, R. L. - He-patitis-Associated Antigen: Improved sensi-tivity in detection. A mer. J. Clin. Path. 55: 262-268, 1971. 2. BANCROFT, W. M.; MUNDON, F. K. & RUS-SEL, P. K. - Detection of addicional an-230 tigenic determinants of hepatitis B antigen. J. Immunol. 150:842-848, 1972. 3. BLUMBERG, B. S.; ALTER, H. J.; RID-DELL, N. M. & ERLANDSON, M. - Multi-ple antig-enic specificities of serum lipopro-teins detected with sera of transfused patients. Vox Sang. 9:124-145, 1964. 4. BLUMBERG, B. S.; GERSTLEY, B. J.; HUNGERFORD, D. A.; LONDON, W. T. & SUTNICK, A. I. - A serum antigen (Aus-tralia antigen) in Down's syndrome, Leuke-mia and hepatitis. Ann. Int. Med. 66:924-931, 1967. 5. BLUMBERG, B. S.; MELARTIN, L.; GUIN-TO, R. & LECHAT, M. - Lepromatous Ie-prosy and Australia antigen with comm-ents on the genetics of Ieprosy. J. Chron. Dis. 23: 507 -516, 1970. 6. BLUMBERG, B. S.; SUTNICK, A. I.; LON-DON, W. T. & MELARTIN, L. - Sex dis-tribution of Australia antigen. Arch. Intern. Med. 130:227-231, 1972. 7. BULKLEY, B. H. ; HEIZER, W. D. ; GOLD-FINGER, S. E.; ISSELBACKER, K. J. & SHULMAN, N. R. - Distinction in chronic active hepatitis based on circulating hepa-titis associated antigen. Lancet 2:1323-1326, 1970. 8. CANDEIAS, J. A. N. - Studies of the He-patitis-Associat-ed-Antigen (HAA) in pa-tients with vira! hepatitis and in "normal" population groups. Rev. Microbial. 2:129-135, 1971. 9. DeGROOT, J. ; DF.SMET, P. ; GEDICK, P. ; KORB, G.; POPPER, H.; POULSEN, H.; SCHEUER, P. ; SCHMID, M. ; THALER, H.; UEHLINGER, E. & WEPLER, W. - Classi-fication of chronic hepatitis. Lancet 3: 626-628, 1968. 10. GORDON, I.; BERBERIAN, M.; STEVEN-SON, D. & REDEKER, A. G. - Distribu-tion of hepatitis B antigenic determinants in different forms of vira! hepatitis. J. Infect. Dis. 126: 569-573, 1972. 11. TWARSON, S.; MAGNIUS, L. & LINDHOLM, A. - Subtypes of hepatitis B antigen in blood donors and post-transfus.ion hepatitis: clinica! and epidemiological aspects. Brit. Med. J. 1:84, 1973. 12. KIM, C. Y. & TILLES, J. G. - Immuno-Iogic and electrophoretic heterogeneity of hepatitis-associated antigen. J. Infect. Dis. 123: 618-628, 1971. 13. KOK-DOORSCHODT, K. H. J.; ,A.KKER, R. & GISPEN, R. - Determination and distri-bution of two types of hepatitis-associated antigen. J. Infect. Dis. 126:117-122, 1972. CANDEIAS, J. A. N.; ANTONÃCIO. F.; SETTE JR., H. ,& SILVA, L. C. da - Occurrence of hepa-. titis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver· disease. Rev. Inst. Med. trbp. São Paulo 16:226-231, 1974. 14. LE BOUVIER, G. L, - Subspecificities of the Australia antigen complex. Amer. J. Dis. Child. 123: 420-424, 1972. 15. LONDON, W. T.; SUTNICK, A. I.; COYNE, V.; BLUMBERG, B. S.; MILLMAN, I. & VIERUCCI, A. - Australia antigen and he-patitis: recent observations on the serum protein polymorphisminfectious agent hypo-theses. O. M. A. Journal 1-06:480-484, 1972. 16. LOPES, J. D. - Valor de auto-anticorpos circulantes e de antígeno A iistralia no diag-nóstico das formas prolongadas e crônicas de hepatites. Doctoral thesis, São Paulo, 1972. 17. MAGNIUS, L. O. ,& ESPMARK, J. A. -New specificies in Australia antigen positive sera distinct from the Le Bouvier det·ermi-nants. J. Immunol. 109:1017-1027, 1972. 18. MOSLEY, J. W. - Personal communica-tion. 19. PRINCE, A. ·M. - An antigen detected in the blood during the incubation period of serum hepatitis. Proc. Nat. Acad. Sei. U.S.A. 60:814-821, 1968. 20. SALZANO, F. M. & BLUMBERG, B. S. -The Australia antigen · in Brazilian healthy 21. 22. 23. 24. 25. persons and in l•eprosy and leukemia pa-. tients. J. Olin. Path. 23:39-42, 1970. SCHMIDT, N.' J. ,& LENNETTE, E. H. Complement fixation and immunodiffusion tests for assay of hepatitis-associated "Aus-tralia" antigen and antibodies. J. Immunol. 105: 604-613, 1970. SMITH, J. B. Virar hepatitis hepatocellular 1969. & BLUMBERG, B. S. IJOstnecrotic cirrhosis and carcinoma. Lancet 2:953,. TURNER, G. C. ,& WHITE, G. B. B. - SH antigen in hemodialysis-associated hepatitis. Lancet 2:121-12_5, 1969. VIS CHER, T. L. - · A ustralia an tigen and autoantibodies in chronic hepatitis. Brit. Med. J. 2:695-698, 1970. WRIGHT, R.; McCOLLUMM, R. W. & KLATSKIN, G. - Australia antigen in acute• and chronic liver disease. Lancet 2:117-121,. 1969. Recebido para publicação em 19/11/1973. 231. 

Occurrence of hepatitis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver disease

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Occurrence of hepatitis-associated-antigen (HAA) subdeterminants ad and ay in blood donors, acute and chronic liver disease

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