Dacylla Sampaio Costa, Lucas Arruda Moita, Even Herlany Pereira Alves, Ana Clara Silva Sales, Raiza Raianne Luz Rodrigues, Juliana Gomes Galeno, Thiago Nobre Gomes, Gustavo Portela Ferreira, Daniel Fernando Pereira Vasconcelos


Dengue virus (DENV) and Yellow Fever virus (YFV) are Flaviviruses transmitted by arthropod vectors that stand out as a major public health problem worldwide due to their high incidence rates and morbidity. They are related to the development of severe alterations, mainly associated with hemorrhagic and hepatic damages. In view of this information, the objective of this review is to describe the data available in the literature on the main histopathological alterations in the liver after infection by DENV and YFV. For so, a literature search was conducted in the PubMed and ScienceDirect databases for the selection of articles published between 2005 and 2018 with relevance on the subject under study. The search resulted in the selection of 20 articles, of which 15 assessed the histopathological alterations in the liver after infection by DENV and 5 evaluated liver tissue damage after YFV infection. All studies demonstrated the presence of the main tissue abnormalities typical of dengue and yellow fever infection, showing a greater severity of hepatic damage related to YF infection. The main histopathological alterations in the liver after infection by these arboviruses have been demonstrated; however, the knowledge regarding some tissue damage in the liver is limited. There is, therefore, the need for further studies to clarify the pathogenesis of the arboviruses under study and the role in the progression and severity of the lesions, especially related to liver damage.


Liver damage; Histology; Flavivirus; Dengue; Yellow fever.


- Daep CA, Muñoz-Jordán JL, Eugenin EA. Flaviviruses, an expanding threat in public health: focus on Dengue, West Nile, and Japanese encephalitis vírus. Journal of Neurovirology 2014; 20(6):539-60. [DOI: 10.1007/s13365-014-0285-z]

- Fernandez-Garcia MD, Mazzon M, Jacobs M, Amara A. Pathogenesis of Flavivirus Infections: Using and Abusing the Host Cell. Cell Host & Microbe 2009; 5(4):318-28. [DOI: 10.1016/j.chom.2009.04.001]

- Bhatt S, Gething PW, Brady OJ, Messina JP. The global distribution and burden o dengue. Nature 2013; 496(7446): 504-7. [DOI: 10.1038/nature12060]

- Diamond MS, Pierson TC, T. C. Molecular Insight into Dengue Virus Pathogenesis and Its Implications for Disease Control. Cell 2015; 162 (3):488-92. [DOI: 10.1016/j.cell.2015.07.005]

- Monath TP, Vasconcelos PF. C. Yellow fever. Journal of Clinical Virology 2015; 64:160-73. [DOI: 10.1016/j.jcv.2014.08.030]

- Quaresma JA, Pagliari C, Medeiros DB, Duarte MI, Vasconcelos PF. Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever. Reviews in Medical Virology, 2013; 23(5):305-18. [DOI: 10.1002/rmv.1752]

- Barrett, ADT. Yellow fever live attenuated vaccine: A very successful live attenuated vaccine but still we have problems controlling the disease. Vaccine 2017; 35(44):5951-5955. [DOI: 10.1016/j.vaccine.2017.03.032]

- WHO – WORLD HEALTH ORGANIZATION. Dengue: Guidelines for diagnosis, treatment, prevention and control. Genebra: World Health Organization, 2009. 160 p. [PMID: 23762963]

- Mayer SV, Tesh RB, Vasilakis N. The emergence of arthropod-borne viral diseases: A global prospective on dengue, chikungunya and zika fevers. Acta Tropica 2017; 166:155-163. [DOI: 10.1016/j.actatropica.2016.11.020]

- Lin CF, Wan SW, Chen MC, Lin SC, Cheng CC, Chiu SC, Hsiao YL, Lei HY, Liu HS, Yeh TM, Lin YS. Liver injury Downloaded from caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Laboratory Investigation 2008; 88(10):1079-89. [DOI:10.1038/labinvest.2008.70]

- Stock NK, Escadafal C, Achazi K, Cissé M, Niedrig M. Development and characterization of polyclonal peptide antibodies for the detection of Yellow fever virus proteins. Journal of Virological Methods 2015; 222:110-6. [DOI: 10.1016/j.jviromet.2015.06.006]

- Kularatne SA, Imbulpitiya IV, Abeysekera RA, Waduge RN, Rajapakse RP, Weerakoon KG. Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study. BMC Infection Diseases 2014; 14:141. [DOI: 10.1186/1471-2334-14-141]

- Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ. Dengue: a continuing global threat. Nature Reviews – Microbiology 2010; 8(12):S7-16. [DOI: 10.1038/nrmicro2460]

- Dias Junior LB, Alves VAF, Kanamurac C, Oikawa RTC, Wakamatsu A. Fulminant hepatic failure in northern Brazil: morphological, immunohistochemical and pathogenic aspects of Lábrea hepatitis and yellow fever. Transactions of the Royal Society of Tropical Medicine and Hygiene 2007; 101 (8):831-839 [DOI: 10.1016/j.trstmh.2006.10.007]

- Drumond BP, Fagundes LG, Rocha RP, Fumagalli MJ, Araki CS, Colombo TE. Phylogenetic analysis of Dengue virus 1 isolated from South Minas Gerais, Brazil. Brazilian Journal of Microbiology 2016; 47(1):251-8. [DOI: 10.1016/j.bjm.2015.11.016]

- Engelmann F, Josset L, Girke T, Park B, Barron A, Dewane J, Hammarlund E, Lewis A, Axthelm MK, Slifka MK, Messaoudi I. Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. Plos neglected tropical diseases 2014; 8(11):e3295. [DOI: 10.1371/journal.pntd.0003295]

- Paes MV, Lenzi HL, Nogueira AC, Nuovo GJ, Pinhão AT, Mota EM, Basílio-de-Oliveira CA, Schatzmayr H, Barth OM, Alves AM. Hepatic damage associated with dengue-2 virus replication in liver cells of BALB/c mice. Laboratory Investigation 2009; 89(10):1140-51. [DOI:10.1038/labinvest.2009.83]

- Sakinah S, Priya SP, Kumari S, Amira F, K P, Alsaeedy H, Ling MP, Chee HY, Higuchi A, Alarfaj AA, Munusamy MA, Murugan K, Taib CN, Arulselvan P, Rajan M, Neela VK, Hamat RA, Benelli G, Kumar SS. Impact of dengue virus (serotype DENV-2) infection on liver of BALB/c mice: a histopathological analysis. Tissue & Cell 2017; 49(1):86-94. [DOI: 10.1016/j.tice.2016.11.005]

- Wang J, Chen Y, Gao N, Wang Y, Tian Y, Wu J, Zhang J, Zhu J, Fan D, An J. Inhibitory effect of glutathione on oxidative liver injury induced by dengue virus serotype 2 infections in mice. PLoS One 2013; 8(1):e55407. [DOI: 10.1371/journal.pone.0055407]

- FERNANDES, N. C.A.; et al. Outbreak of Yellow Fever among Nonhuman Primates, Espirito Santo, Brazil. Emerging Infectious Diseases Emerging Infectious Diseases 2017; 23 (2): 1080-6059. [DOI:10.3201/eid2312.170685]

- Leal SG, Romano APM, Monteiro Romano APM, Monteiro RV, Melo CB, Vanconcelos PFC. Frequency of histopathological changes in Howler monkeys (Alouatta sp.) naturally infected with yellow fever virus in Brazil. Revista da Sociedade Brasileira de Medicina Tropical 2016; 49(1): 29-33. [DOI: 10.1590/0037-8682-0363-2015]

- Quaresma JA, Barros VL, Pagliari C, Fernandes ER, Andrade HF Jr, Vasconcelos PF, Duarte MI. Hepatocyte lesions and cellular immune response in yellow fever infection. Transactions of the Royal. Society of Tropical Medicine and Hygiene 2007; 101(2):161-8. [DOI: 10.1016/j.trstmh.2006.02.019]

- Paes MV, Pinhão AT, Barreto DF, Costa SM, Oliveira MP, Nogueira AC, Takiya CM, Farias-Filho JC, Schatzmayr HG, Alves AM, Barth OM. Liver injury and viremia in mice infected with dengue-2 virus. Virology 2005; 338(2):236-46. [DOI: 10.1016/j.virol.2005.04.042]

- Póvoa TF, Alves AMB, Paes MV. The pathology of severe dengue in multiple organs of human fatal cases: histopathology, ultrastructure and virus replication. PloS one 2014; 9(4): e83386. [DOI: 10.1371/journal.pone.0083386]

- Milligan GN, Sarathy VV, White MM, Greenberg MB, Campbell GA, Pyles RB, Barrett ADT, Bourne N. A lethal model of disseminated dengue virus type 1 infection inAG129 mice. Journal of General Virology 2017; 98(10):2507-2519. [DOI: 10.1099/jgv.0.000923]

- Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Srisawat C, Morchang A, Malakar S, Thuwajit P, Kooptiwut S, Suttitheptumrong A, Songprakhon P, Noisakran S, Yenchitsomanus PT, Limjindaporn T. A. Role of ERK1/2 signaling in dengue virus-induced liver injury. Virus Research, 2014 8; 188:15-26. [DOI: 10.1016/j.virusres.2014.03.025]

- França RF, Zucoloto S, da Fonseca BA. A BALB/c mouse model shows that liver involvement in dengue disease is immune-mediated. Experimental and Molecular Patholpgy 2010; 89(3):321-6. [DOI: 10.1016/j.yexmp.2010.07.00]

- Vieira WT, Gayotto LC, de Lima CP, de Brito T. Histopathology of the human liver in yellow fever with special emphasis on the diagnostic role of the Councilman body. Histopathology 1983; 7(2):195-208. [PMID: 6303935]

- Nguyen TA, Hoang L, Pham le D, Hoang KT, Okitsu S, Mizuguchi M, Ushijima. Norovirus and sapovirus infections among children with acute gastroenteritis in Ho Chi Minh City during 2005-2006, Journal of Tropical Pediatrics 2008; 54(2):102-13. [DOI: 10.1093/tropej/fmm096]

- Couvelard A, Marianneau P, Bedel C, Drouet MT, Vachon F, Hénin D, Deubel V. Report of a fatal case of dengue infection with hepatitis: demonstration of dengue antigens in hepatocytes and liver apoptosis. Human Pathology 1999; 30(9):1106-10. [PMID: 10492047]

- Srikiatkhachorn, A. Plasma leakage in dengue haemorrhagic fever. Thrombosis and Haemostasis 2009; 102(6):1042-9. [DOI: 10.1160/TH09-03-0208]

- Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Lew R, Innis BL, Kurane I, Rothman AL, Ennis FA. Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. Journal Infection Diseases 1999;179(4):755-62. [DOI: 10.1086/314680]

- Gonçalves D, de Queiroz Prado R, Almeida Xavier E, Cristina de Oliveira N, da Matta Guedes PM, da Silva JS, Moraes Figueiredo LT, Aquino VH. Imunocompetent mice model for dengue virus infection. The Scientific World Journal 2012; 2012:525947. [DOI: 10.1100/2012/525947]

- Jain D, Singh T. Dengue virus related hemophagocytosis: a rare case report. Hematology 2008; 13(5):286-8. [DOI: 10.1179/102453308X316095]

- Srichaikul T, Punyagupta S, Kanchanapoom T, Chanokovat C, Likittanasombat K, Leelasiri A. Hemophagocytic syndrome in Dengue hemorrhagic fever with severe multiorgan complications. Journal of the Medical Association of Thailand 2008; 91(1):104-9. [PMID: 18386553]

- Wong KF, Chan JK, Chan JC, Lim WW, Wong WK. Dengue virus infection-associated hemophagocytic syndrome. American Journal of Hematology, 1991; 38(4):339-40. [PMID: 1746547]

- Barth OM, Barreto DF, Paes MV, Takiya CM. Morphological studies in a model for dengue-2 virus infection in mice. Memórias do Instituto Oswaldo Cruz 2006; 101(8): 905-915. [DOI: 10.1590/S0074-02762006000800014]

- Limonta D, Falcón V, Torres G, Capó V. Dengue virus identification by transmission electron microscopy and molecular methods in fatal dengue hemorrhagic fever. Infection 2012; 40(6):689-94. [DOI: 10.1007/s15010-012-0260-7]

- Basílio-de-Oliveira CA, Aguiar GR, Baldanza MS, Barth OM, Eyer-Silva WA, Paes MV. Pathologic study of a fatal case of dengue-3 virus infection in Rio de Janeiro. Brazilian Journal of Infectious Diseases 2005; 9(4):341–347. [DOI: 10.1590/S1413-86702005000400012]

- Aye KS, Charngkaew K, Win N, Wai KZ, Moe K, Punyadee N, Thiemmeca S, Suttitheptumrong A, Sukpanichnant S, Prida M, Halstead SB. Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. Human Pathology 2014; 45(6):1221-33. [DOI: 10.1016/j.humpath.2014.01.022]

- Peeling RW, Artsob H, Pelegrino JL, Buchy P, Cardosa MJ, Devi S, Enria DA, Farrar J, Gubler DJ, Guzman MG, Halstead SB, Hunsperger E, Kliks S, Margolis HS, Nathanson CM, Nguyen VC, Rizzo N, Vázquez S, Yoksan S. Evaluation of diagnostic tests: dengue. Nature Reviews Microbiology 2010; 8(12 Suppl):S30-8. [DOI: 10.1038/nrmicro2459]

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