Fulminant Labrea Hepatitis - the role of hepatitis A (HAV), B (HBV), C (HCV), and D (HDV) infection: preliminary report

Fonseca, José Carlos Ferraz da; Ferreira, Luíz Carlos Lima; Brasil, Leila Melo; Castinho, Marcia da Costa; Moss, Robson; Barone, Marilde

doi:10.1590/S0036-46651992000600017

PRELIMIMARY REPORT

Fulminant Labrea Hepatitis - the role of hepatitis A (HAV), B (HBV), C (HCV), and D (HDV) infection. (Preliminary report)

José Carlos Ferraz da Fonseca^I,II; Luíz Carlos Lima Ferreira^I,III; Leila Melo Brasil^II; Marcia da Costa Castinho^II; Robson Moss^IV; Marilde Barone^V

^IFaculdade de Ciências da Saúde - Universidade do Amazonas

^IIInstituto de Medicina Tropical de Manaus - Núcleo de Virologia

^IIIInstituto de Medicina Tropical de Manaus - Núcleo de Antatomopatologia

^IVUnidade Hospitalar de Lábrea - Secretária de Estado da Saúde

^VOspedale Civile di Busto Arsizio, Varese, Italia

^{Address for correspondence} Address for correspondence: Prof. J. C. F. Fonseca Instituto de Medicina Tropical de Manaus - Núcleo de Virologia Av. Pedro Teixeira, 25 CEP 69.040-000, Manaus - Amazonas - Brasil

An unusual type of fulminant hepatitis, known as Labrea Hepatitis (Labrea Black Fever), has been documented in the Brazilian part of the Amazon Basin^{1,2,8,9,10,12,13} Described for over 50 years¹⁰, this disease is characterized by severe hepatitis (rapid course) resulting in hepatic failure and death ^2,12,13. Children, adolescent and young adults are mainly affected ^1,12. The availability of histopathological liver specimens from cases of Labrea Hepatitis, showing a specific picture of microvesicular steatosis (morula-like cells) and eosinophilic necrosis, has been pointed out by Brazilian authors⁹. This pattern are different from those of massive and submassive necroses found in ordinary fulminant viral hepatitis. Similar clinical and histologic features of Labrea Hepatitis were found in northern Colombia⁵, western Venezuela¹⁶ and Central African Republic¹⁷.

Recent studies suggest that hepatitis Delta virus (HDV) infection of hepatitis B virus (HBV) carriers is responsible for the etiopathogenesis of Labrea Hepatitis^2,13. Several studies have recently characterized the Amazon basin as a high endemic area for HBV and HDV infection^2,14,15.

The purpose of the present study was to confirm the participation of HDV in the etiopathogenesis of Labrea Hepatitis. Serum samples from 11 patients (4 males, 7 females; aged 3-38 years; mean age 13.1 years), with post-mortem histopathological diagnosis of Labrea Hepatitis were screened for the presence of hepatitis viral markers: HAV (IgM antibodies to hepatitis A [IgM anti-HAV], Hepanostika, Organon Teknika, B. V. Holland); HBV (hepatitis B surface antigen [HBsAg], IgM antibodies to hepatitis B core antigen [IgM anti-HBc], Sorin Biomedica, Saluggia, Italy); HCV (antibodies to hepatitis C [anti-HCV], Organon Teknika, UBI HCV EIA, N. Y., USA) and HDV (Delta antigen [HDAg], IgM antibodies to hepatitis Delta [IgM anti-HD], Sorin Biomedica, Saluggia, Italy) were submitted to the enzyme immunoassay (EIA).

Serum HBV-DNA (hepatitis B virus deoxyribonucleic acid) and HDV-RNA (hepatitis D virus ribonucleic acid) were assayed using molecular hybridization technique, as previously described^3,18.

On the basis of serological tests, acute Delta infection was diagnosed in four patients (36.4%). Two of this had acute HBV and HDV infection (HBsAg, IgM anti-HBc, IgM anti-HD) and the other two had chronic HBV infection (without IgM anti-HBc and HBV-DNA) with superimposed acute HDV infection (one case: HBsAg, IgM anti-HD; one case: HBsAg, HDAg, HDV-RNA). Two patients (18.2%) had acute HAV and HBV infection (IgM anti-HAV, HBsAg, IgM anti HBc). Two patients (18.2%) had acute HBV infection alone (HBsAg, IgM anti-HBc). One (9.1%) had acute HAV infection alone (IgM anti-HAV). One (9.1%) had acute HBV and HCV infection (HBsAg, IgM anti-HBc, anti-HCV). Finally, one (9.1%) patient had acute HCV infection alone (Anti-HCV). The time between the first clinical manifestations and death of 11 patients, ranged from 3 to 8 days (mean of 4.6 days).

All specimens showed a diffuse small-droplet fatty change, lytic and eosinophylic necroses with different degrees of intensity, were also seen, without evidence of massive or submassive necrosis. "Morula-like cells" were more frequently found in HDV acute superinfection, as well as in HAV/HBV acute coinfection and acute HCV infection, and less often in other forms of viral hepatitis. Lobular architecture was preserved and portal tracts revealed bile duct proliferations, mononuclear inflamatory cells infiltration.

Figure 1 shows the presence of "morula-like" cells in hepatic tissue in the fulminant form of hepatitis A (HAV), B (HBV), C (HCV) and Delta (HDV).

In this series only 4/11 (36.4%) of the patients with Labrea Hepatitis had serological evidence of acute infection by HDV. These results differ from previous studies that demonstrate a great correlation (74.0%) between the infection by HDV and Labrea Hepatitis, suggesting that the "morula-like" cells are pathognomonic of HDV superinfection in HBsAg carriers².

Our study demonstrate that 63.6% of patients with Labrea Hepatitis had evidence of infection by HAV, HBV and HCV, either alone or simultaneously. These data differ from others authors who consider the infection by HDV the main cause of Labrea Hepatitis². The idea that other hepatitis viruses could be involved in the etiopathogenesis of Labrea Hepatitis, HBV infection alone, lesser contribution of HAV, and Non A - Non B agents, now termed hepatitis C virus⁷, was suggested recently². This hypothesis is strengthened in the present study.

The use of sophisticated and specific tests for serum markers of HBV (HBV-DNA), HCV (anti-HCV), and HDV (HDAg, HDV-RNA), permitted in this study the confirmation of the envolviment of other viral agents in the etiology of Labrea Hepatitis.

In additon, the etiopathogeny of Labrea Hepatitis could be related to genetic, immunological or age factors. This hypothesis thus remains controversial and requires further studies. On the other hand, experimental transmission studies shows antigenic variation of HDV in Bangui Hepatitis with the same clinical and histological characteristics of Labrea Hepatitis¹¹. In this study the authors suggest a possible role for a variant HDV strain which could be responsible for severe hepatitis in Bangui. Recent data, described a new hepatitis B virus strain⁴ and this new HBV variant (pre-core mutation) is responsible for fulminant hepatitis in Greek patients⁶.

The hypothesis that variant strains of HAV, HBV, HCV and HDV could determine changes in the immune response of local patients leading to this severe form of hepatitis should be taken in consideration. However only experimental studies and the use of advanced techniques such as RNA and DNA amplification, cloning and sequencing of these viral agents could confirm this hypothesis.

ACKNOWLEDGEMENTS

The authors are deeply thankful to Prof. Mario Rizzetto, Institute of Internal Medicine, University of Turin, Italy, by the realization of part of the sorological tests by molecular hybridization and for comments and suggestions.

Recebido para publicação em 13.02.1992.

Aceito para publicação em 13.08.1992.

References

1. BENSABATH, G. & DIAS, L B. - Hepatite de Lábrea e outras hepatites fulminantes em Sena Madureira, Acre e Boca do Acre, Amazonas, Brasil. Rev. Inst. Med. trop. S. Paulo, 25: 182-194, 1983.
2. BENSABATH, G.; HADLER, S.C.; PEREIRA SOARES, M.C.; FIELDS, H.; DIAS, L.B.; POPPER, H. & MAYNARD, J.E. - Hepatitis Delta virus infection and Labrea hepatitis. Prevalence and role in fulminant hepatitis in the Amazon basin. J. Amer. med. Ass., 258: 479-483, 1987.
3. BONINO, F.; HOYER, B.; NELSON, J.; ENGLE, R.; VERME, G. & GERIN, J. - Hepatitis B virus DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver. Hepatology, 1: 386-391, 1981.
4. BRUNETTO, M.R.; STEMLER, M.; BONINO, F.; SCHODEL, F.; OLIVERI, F.; RIZZETTO, M.; VERME, G. & WILL, H. - A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J. Hepatol., 10: 258-261, 1990.
5. BUITRAGO, B.; POPPER, H.; HADLER, S.C.; THUNG, SWAN, N.; GERBER, M.A.; PURCELL, R.H. & MAYNARD, J.E. - Specific histologic features of Snta Marta Hepatitis: a severe form of hepatitis Delta - virus infection in Northern South America. Hepatology, 6: 1285-1292, 1986.
6. CARMAN, W.F.; HADZIYANNIS, S.; KARAYIANNIS, P.; FAGAN, E.A.; TASSOPOULOS, N.C.; WILLIAMS, R. & THOMAS, H.C. - Association of the precore variant of HBV with acute and fulminant hepatitis B infection. In: HOLLINGER, F.B.; LEMON, S.M. & MARGOLIS, H.S., ed. Viral hepatitis and Liver Disease. International Symposium on Viral Hepatitis and Liver Disease. Texas, 4-8 April, 1990 Proceedings. Baltimore, Williams & Wilkins, 1990. p.216-219.
7. CHOO, Q.L.; KUO, G.; WEINER, A.J.; OVERBY, L.R.; BRADLEY, D.W. & HOUGHTON, M. - Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science, 244: 359-362 1989.
8. DE PAOLA, D.; PINHEIRO, A.F.; DIAS, L.B. & LACERDA, P.R.S. - A Febre Negra na Amazônia. Hospital (Rio de J.), 71: 1303-1311, 1967.
9. DIAS, L.B. & MORAES, M.A.P. - Hepatite de Lábrea. Rev. Inst. Med. trop. S. Paulo, 15: 86-93, 1973.
10. DIAS, L.B. & COURA, J.R. - Hepatite de Lábrea. Estudo de revisăo em viscerotomias hepáticas nos anos de 1934 a 1940. Rev. Inst. Med. trop. S. Paulo, 27: 242-248, 1985.
11. FAURE, P.; PARANA, R.; VITVTSKI, L.; COVA, L.; LESBORDES, J.L. & TREPO, C. - Further evidence of immunological and genomic differences between the prototype HDV strain and a strain presumably associated with Spongiocytic Fulminant Hepatitis (SFH) in man and woodchuck. Prog. clin. biol. Res., 364: 452, 1991.
12. FONSECA, J.C.F.; FERREIRA, L.C.L.; GUERRA, A.L.P.S.; PASSOS, L.M. & SIMONETTI, J.P. - Hepatite fulminante e Febre Negra de Lábrea: estudo de cinco casos procedentes de Codajás, Amazonas, Brasil. Rev. Soc. bras. Med. trop.,16: 144-147, 1983.
13. FONSECA, J.C.F.; GAYOTTO, L.C.C.; FERREIRA, L.C.L.; ARAÚJO, J.R.; ALECRIM, W.D.; SANTOS, R.T.M.; SIMONETTI, J.P. & ALVES, V.A.F. - Labrea Hepatitis - Hepatitis B and Delta antigen expression in liver tissue: report of three autopsy cases. Rev. Inst. Med. trop. S. Paulo, 27: 224-227, 1985.
14. FONSECA, J.C.F. & SIMONETTI, J.P. - Epidemiology of the hepatitis Delta virus (HDV) in Brazil. Prog. clin. biol. Res., 234: 507-514, 1987.
15. FONSECA, J.C.F.; SIMONETTI, S.R.R.; SCHATZMAYR, H.G.; CASTEJON, M.J.; CESÁRIO, A.L.O. & SIMONETTI, J.P. - Prevalence of infection with hepatitis Delta virus (HDV) among carriers of hepatitis B surface antigen in Amazon State, Brazil. Trans. roy. Soc. trop. Med. Hyg., 82: 469-471, 1988.
16. HADLER, S.C.; MONZON, M.; PONZETTO, A.; ANZOLA, E.; RIVERO, D.; MONDOLFI, A.; BRACHO, A.; FRANCIS, D.P.; GERBER, A.; THUNG, S.; GERIN, J.; MAYNARD, J.E.; POPPER, H. & PURCELL, R.H. - Delta virus infection and severe hepatitis: an epidemic in the Yucpa indians of Venezuela. Ann. intern. Med., 100: 339-344, 1984.
17. LESBORDES, J.L.; RAVISSE, P.; GEORGES, A.J.; CHEVALIER, P.; PICHOUD, C.; VITVITSKI, C. & TREPO, L. - Studies of the role of HDV in an outbreak of fulminant hepatitis in Bangui (Central African Republic). Prog. clin. biol. Res., 264: 451-459, 1987.
18. SMEDILE, A.; RIZZETTO, M.; DENNISTON, F.; BONINO, F.; WELLS, F.; VERME, G.; CONSOLO, F.; HOYER, B.; PURCELL, R.H. & GERIN, J.L. - Type D hepatitis. The clinical significance of hepatitis D virus RNA in serum as detected by hybridization-based assay. Hepatology, 6: 1297-1302, 1986.

Address for correspondence:

Prof. J. C. F. Fonseca

Instituto de Medicina Tropical de Manaus - Núcleo de Virologia

Av. Pedro Teixeira, 25

CEP 69.040-000, Manaus - Amazonas - Brasil

Publication Dates

Publication in this collection
11 Sept 2006
Date of issue
Dec 1992

History

Received
13 Feb 1992
Accepted
13 Aug 1992

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. BENSABATH, G. & DIAS, L B. - Hepatite de Lábrea e outras hepatites fulminantes em Sena Madureira, Acre e Boca do Acre, Amazonas, Brasil. Rev. Inst. Med. trop. S. Paulo, 25: 182-194, 1983.

[2] 2. BENSABATH, G.; HADLER, S.C.; PEREIRA SOARES, M.C.; FIELDS, H.; DIAS, L.B.; POPPER, H. & MAYNARD, J.E. - Hepatitis Delta virus infection and Labrea hepatitis. Prevalence and role in fulminant hepatitis in the Amazon basin. J. Amer. med. Ass., 258: 479-483, 1987.

[3] 3. BONINO, F.; HOYER, B.; NELSON, J.; ENGLE, R.; VERME, G. & GERIN, J. - Hepatitis B virus DNA in the sera of HBsAg carriers: a marker of active hepatitis B virus replication in the liver. Hepatology, 1: 386-391, 1981.

[4] 4. BRUNETTO, M.R.; STEMLER, M.; BONINO, F.; SCHODEL, F.; OLIVERI, F.; RIZZETTO, M.; VERME, G. & WILL, H. - A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J. Hepatol., 10: 258-261, 1990.

[5] 5. BUITRAGO, B.; POPPER, H.; HADLER, S.C.; THUNG, SWAN, N.; GERBER, M.A.; PURCELL, R.H. & MAYNARD, J.E. - Specific histologic features of Snta Marta Hepatitis: a severe form of hepatitis Delta - virus infection in Northern South America. Hepatology, 6: 1285-1292, 1986.

[6] 6. CARMAN, W.F.; HADZIYANNIS, S.; KARAYIANNIS, P.; FAGAN, E.A.; TASSOPOULOS, N.C.; WILLIAMS, R. & THOMAS, H.C. - Association of the precore variant of HBV with acute and fulminant hepatitis B infection. In: HOLLINGER, F.B.; LEMON, S.M. & MARGOLIS, H.S., ed. Viral hepatitis and Liver Disease. International Symposium on Viral Hepatitis and Liver Disease. Texas, 4-8 April, 1990 Proceedings. Baltimore, Williams & Wilkins, 1990. p.216-219.

[7] 7. CHOO, Q.L.; KUO, G.; WEINER, A.J.; OVERBY, L.R.; BRADLEY, D.W. & HOUGHTON, M. - Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science, 244: 359-362 1989.

[8] 8. DE PAOLA, D.; PINHEIRO, A.F.; DIAS, L.B. & LACERDA, P.R.S. - A Febre Negra na Amazônia. Hospital (Rio de J.), 71: 1303-1311, 1967.

[9] 9. DIAS, L.B. & MORAES, M.A.P. - Hepatite de Lábrea. Rev. Inst. Med. trop. S. Paulo, 15: 86-93, 1973.

[10] 10. DIAS, L.B. & COURA, J.R. - Hepatite de Lábrea. Estudo de revisăo em viscerotomias hepáticas nos anos de 1934 a 1940. Rev. Inst. Med. trop. S. Paulo, 27: 242-248, 1985.

[11] 11. FAURE, P.; PARANA, R.; VITVTSKI, L.; COVA, L.; LESBORDES, J.L. & TREPO, C. - Further evidence of immunological and genomic differences between the prototype HDV strain and a strain presumably associated with Spongiocytic Fulminant Hepatitis (SFH) in man and woodchuck. Prog. clin. biol. Res., 364: 452, 1991.

[12] 12. FONSECA, J.C.F.; FERREIRA, L.C.L.; GUERRA, A.L.P.S.; PASSOS, L.M. & SIMONETTI, J.P. - Hepatite fulminante e Febre Negra de Lábrea: estudo de cinco casos procedentes de Codajás, Amazonas, Brasil. Rev. Soc. bras. Med. trop.,16: 144-147, 1983.

[13] 13. FONSECA, J.C.F.; GAYOTTO, L.C.C.; FERREIRA, L.C.L.; ARAÚJO, J.R.; ALECRIM, W.D.; SANTOS, R.T.M.; SIMONETTI, J.P. & ALVES, V.A.F. - Labrea Hepatitis - Hepatitis B and Delta antigen expression in liver tissue: report of three autopsy cases. Rev. Inst. Med. trop. S. Paulo, 27: 224-227, 1985.

[14] 14. FONSECA, J.C.F. & SIMONETTI, J.P. - Epidemiology of the hepatitis Delta virus (HDV) in Brazil. Prog. clin. biol. Res., 234: 507-514, 1987.

[15] 15. FONSECA, J.C.F.; SIMONETTI, S.R.R.; SCHATZMAYR, H.G.; CASTEJON, M.J.; CESÁRIO, A.L.O. & SIMONETTI, J.P. - Prevalence of infection with hepatitis Delta virus (HDV) among carriers of hepatitis B surface antigen in Amazon State, Brazil. Trans. roy. Soc. trop. Med. Hyg., 82: 469-471, 1988.

[16] 16. HADLER, S.C.; MONZON, M.; PONZETTO, A.; ANZOLA, E.; RIVERO, D.; MONDOLFI, A.; BRACHO, A.; FRANCIS, D.P.; GERBER, A.; THUNG, S.; GERIN, J.; MAYNARD, J.E.; POPPER, H. & PURCELL, R.H. - Delta virus infection and severe hepatitis: an epidemic in the Yucpa indians of Venezuela. Ann. intern. Med., 100: 339-344, 1984.

[17] 17. LESBORDES, J.L.; RAVISSE, P.; GEORGES, A.J.; CHEVALIER, P.; PICHOUD, C.; VITVITSKI, C. & TREPO, L. - Studies of the role of HDV in an outbreak of fulminant hepatitis in Bangui (Central African Republic). Prog. clin. biol. Res., 264: 451-459, 1987.

[18] 18. SMEDILE, A.; RIZZETTO, M.; DENNISTON, F.; BONINO, F.; WELLS, F.; VERME, G.; CONSOLO, F.; HOYER, B.; PURCELL, R.H. & GERIN, J.L. - Type D hepatitis. The clinical significance of hepatitis D virus RNA in serum as detected by hybridization-based assay. Hepatology, 6: 1297-1302, 1986.