Insights on the Pathophysiology of the Progression to Decompensated Hepato-Splenic Schistosomiasis
Main Article Content
Abstract
Hepato-splenic schistosomiasis is the most important etiology of non-cirrhotic portal hypertension. It represents a particular type of chronic liver disease, which presents unique characteristics that differentiate it from those found in cirrhosis. The relative preservation of liver parenchyma despite portal fibrosis was thought to yield a more benign course of hepato-splenic schistosomiasis in terms of synthetic dysfunction and late decompensations. However, a wide range of immunologic and vascular modifications is responsible for an otherwise progressive liver disease resulting in decompensated condition frequently undistinguished from hepatic cirrhosis. A predominant Th2 immune response type, in which a fibrogenic profile of cytokines and interleukins such as IL-13, provides an immune-inflammatory background that favors fibrosis and its progression. Intra-hepatic vascular changes with portal vein branch derangement and abnormal vascular proliferation also contribute to continued disarray of the liver architecture resulting in decompensated disease frequently undistinguished from hepatic cirrhosis. This article will review immunologic and pathophysiological aspects of hepato-splenic schistosomiasis that might explain disease progression and severity.
Keywords:
Schistosomiasis, portal hypertension, hepatosplenic schistosomiasis
Article Details
How to Cite
TIMES DE CARVALHO, Bernardo.
Insights on the Pathophysiology of the Progression to Decompensated Hepato-Splenic Schistosomiasis.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3774>. Date accessed: 11 may 2024.
doi: https://doi.org/10.18103/mra.v11i4.3774.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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4. Andrade ZA. Pathology of human schistosomiasis. Mem Inst Oswaldo Cruz. 1987;82(4):17-23.
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8. Fahim FA, Esmat AY, Hassan GK, Abdel-Bary A. Biochemical Changes in Patients with Combined Chronic Schistosomiasis and Viral Hepatitis C Infections. Dis Markers. 2000;16(3-4):111-118. doi:10.1155/2000/732754
9. Strickland GT, Elhefni H, Salman T, et al. Role of hepatitis C infection in chronic liver disease in Egypt. Am J Trop Med Hyg. 2002;67(4):436-442. doi:10.4269/ajtmh.2002.67.436
10. Roderfeld M, Padem S, Lichtenberger J, et al. Schistosoma mansoni Egg-Secreted Antigens Activate Hepatocellular Carcinoma-Associated Transcription Factors c-Jun and STAT3 in Hamster and Human Hepatocytes. Hepatology. 2019;0(0). doi:10.1002/hep.30192/suppinfo
11. Saharti S, Ding X, Massarani-Wafai R, Pambuccian SE. Fine-needle aspirate of the liver showing coexistence of Schistosoma japonicum ova and hepatocellular carcinoma. Diagn Cytopathol. 2018;46(8):716-720. doi:10.1002/dc.23969
12. Matsuda M, Fujii H. Chronic schistosomiasis japonica is an independent adverse prognostic factor for survival in hepatocellular carcinoma patients who have undergone hepatic resection: Clinicopathological and prognostic analysis of 198 consecutive patients. World J Surg. 2009;33(12):2644-2650. doi:10.1007/s00268-009-0228-7
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14. El-Garem AA. Schistosomiasis. Digestion. 1998;59(5):589-605. doi:10.1159/000007534
15. Times de Carvalho B, Lucia Coutinho A. Hemodynamic Changes in the Intra-Hepatic Circulation of Hepatosplenic Schistosomiasis: the Role of Hepatic Artery. J Gastroenterol Hepatol Res. 2018;7(2):2555-2560. doi:10.17554/j.issn.2224-3992.2018.07.746
16. Morais CNL de, Souza JR de, Melo WG, et al. Cytokine profile associated with chronic and acute human schistosomiasis mansoni. Mem Inst Oswaldo Cruz. 2008;103(6):561-568. doi:10.1590/S0074-02762008000600009
17. Wilson MS, Mentink‐Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol. 2007;85(2):148-154. doi:10.1038/sj.icb.7100014
18. Laosebikan AO, Thomson SR, Naidoo NM. Schistosomal Portal Hyptertension. J Am Coll Surg. 2005;200(5):795-806. doi:10.1016/j.jamcollsurg.2004.11.017
19. Hoffmann KF, Caspar P, Cheever AW, Wynn TA. IFN-gamma, IL-12, and TNF-alpha are required to maintain reduced liver pathology in mice vaccinated with Schistosoma mansoni eggs and IL-12. Journal of Immunology. 1998;15(8):4201-4210.
20. Elbaz T, Esmat G. Hepatic and Intestinal Schistosomiasis: Review. J Adv Res. 2013;4(5):445-452. doi:10.1016/j.jare.2012.12.001
21. Dessein AJ, Hillaire D, Elwali NEMA, et al. Severe Hepatic Fibrosis in Schistosoma mansoni Infection Is Controlled by a Major Locus That Is Closely Linked to the Interferon-γ Receptor Gene. The American Journal of Human Genetics. 1999;65(3):709-721. doi:10.1086/302526
22. Zhu J, Xu Z, Chen X, et al. Parasitic antigens alter macrophage polarization during Schistosoma japonicum infection in mice. Parasit Vectors. 2014;7(1):122. doi:10.1186/1756-3305-7-122
23. Barron L, Wynn TA. Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. Eur J Immunol. 2011;41(9):2509-2514. doi:10.1002/eji.201141869
24. Yu Y, Wang J, Wang X, et al. Schistosome eggs stimulate reactive oxygen species production to enhance M2 macrophage differentiation and promote hepatic pathology in schistosomiasis. PLoS Negl Trop Dis. 2021;15(8):e0009696. doi:10.1371/journal.pntd.0009696
25. Mohamed‐Ali Q, Elwali NMA, Abdelhameed AA, et al. Susceptibility to Periportal (Symmers) Fibrosis in Human Schistosoma mansoni Infections: Evidence That Intensity and Duration of Infection, Gender, and Inherited Factors Are Critical in Disease Progression. J Infect Dis. 1999;180(4):1298-1306. doi:10.1086/314999
26. Warren KS. Pathophysiology and pathogenesis of hepatosplenic schistosomiasis mansoni. Bull N Y Acad Med. 1968;44(3):280-294.
27. Warren KS. Hepatosplenic schistosomiasis mansoni: an immunologic disease. Bull N Y Acad Med. 1975;51(4):545-550.
28. Andrade ZA. Schistosomiasis and liver fibrosis. Parasite Immunol. 2009;31:656-663. doi:10.1111/j.1365-3024.2009.01157.x
29. Andrade ZA, Baptista AP, Santana TS. Remodeling of hepatic vascular changes after specific chemotherapy of schistosomal periportal fibrosis. Mem Inst Oswaldo Cruz. 2006;101:267-272. doi:10.1590/S0074-02762006000900041
30. Strauss E. Hepatosplenic schistosomiasis: a model for the study of portal hypertension. Ann Hepatol. 2002;1(1):6-11.
31. Andrade ZA. Schistosomal hepatopathy. Mem Inst Oswaldo Cruz. 2004;99:51-57. doi:10.1590/S0074-02762004000900009
32. Silva CLM, Lenzi H, Silva V, Paulo F, Noël F. Cellular mechanisms involved in the increased contraction of portal veins from Schistosoma mansoni -infected mice. Parasitol Res. 2002;89(1):16-22. doi:10.1007/s00436-002-0711-7
33. Hidayat M, Wahid H. A study of the vascular changes in bilharzic hepatic fibrosis and their significance. Surg Gynecol Obstet. Published online 1971:997-1004.
34. Da Silva LC. Portal hypertension in schistosomiasis: pathophysiology and treatment. Mem Inst Oswaldo Cruz. 1992;87(suppl IV):183-186.
35. Andrade ZA. A double and paradoxical role for angiogenesis. Rev Patol Trop. 2013;42(3):259-264.
36. Oliveira L, Andrade ZA. Significance of bile-duct changes in schistosomiasis Significado das lesões dos ductos biliares na esquistossomose. Rev Soc Bras Med Trop. 2005;38(6):464-468.
37. Domingues ALC, Domingues LAW. Forma intestinal, hepatointestinal e hepatoesplênica. In: Malta J, ed. Esquistossomose Mansônica. Primeira. Editora Universitária da UFPE; 1994:95-105.
38. Reboucas G. MEDICAL REVIEWS Clinical Aspects of Hepatosplenic Schistosomiasis: A Contrast with Cirrhosis I. Vol 48.; 1975.
39. de Carvalho BT, Coutinho Domingues AL, de Almeida Lopes EP, Brandão SCS. Increased Hepatic Arterial Blood Flow Measured by Hepatic Perfusion Index in Hepatosplenic Schistosomiasis: New Concepts for an Old Disease. Dig Dis Sci. 2016;61(7):2118-2126. doi:10.1007/s10620-016-4080-y
40. Morgan J, Groszmann R, Rojkind M, Enriquez R. Hemodynamic mechanism of emerging portal hypertension caused by schistosomiasis in the hamster. Hepatology. 1990;11(1):98-104.
41. Sarin S, Mosca P, Sabba C, Groszmann R. Hyperdynamic ciculation in a chronic murine schistosomiasis model of portal hypertension. Hepatology. 1991;13(3):581-584.
42. Alves CA, Alves AR, Abreu WN, Andrade ZA. Hepatic artery hypertrophy and sinusoidal hypertension in advanced schistosomiasis. Gastroenterology. 1977;72(1):126-128.
43. Jorge PA, Zancaner W, Guimarães RF, Carvalhal S dos S. [Oxygen gradient and hepatic blood flow in hepatosplenic schistosomiasis mansoni, Symmers’ form]. Rev Assoc Med Bras. 1967;13(12):442-445.
44. Mies S, Braghirolli-Neto O, Beer A, et al. Systemic and hepatic hemodynamics in hepatosplenic manson’s schistosomiasis with and without propranolol. Dig Dis Sci. 1997;42(4):751-761.
45. Denié C, Vachiery F, Elman A, et al. Systemic and splanchnic hemodynamic changes in patients with hepatic schistosomiasis. Liver. 1996;16(5):309-312.
46. Da Silva LC, Carrilho FJ. Hepatosplenic schistosomiasis. Pathophysiology and treatment. Gastroenterol Clin North Am. 1992;21(1):163-177.
47. Coutinho A. Hemodynamic studies of portal hypertension in schistosomiasis. American Journal of Medicine. 1968;44:547-555.
48. Lautt WW. Control of hepatic arterial blood flow: independence from liver metabolic activity. Am J Physiol. 1980;239:H559-H564.
49. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249(5):549-556.
50. Strauss E. Hepatosplenic schistosomiasis:a model for the study of portal hypertension. Annals of Hepatology . 2002;1(1):6-11.
51. Ramos OL, Saad F, Leser WP. Portal hemodynamics and liver cell function in hepatic schistosomiasis. Gastroenterology. 1964;47:241-247.
52. Rebouças G. Clinical Aspects of Hepatosplenic Schistosomiasis: A Contrast with Cirrhosis. THE YALE JOURNAL OF BIOLOGY AND MEDICINE . 1975;48:369-376.
53. Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.
54. Palumbo E. Association Between Schistosomiasis and Cancer. Infectious Diseases in Clinical Practice. 2007;15(3):145-148. doi:10.1097/01.idc.0000269904.90155.ce
55. Shousha HI, Abdelaziz AO, Nabeel MM, et al. Schistosoma mansoni infection and the occurrence, characteristics, and survival of patients with hepatocellular carcinoma: an observational study over a decade. Pathog Glob Health. 2022;116(2):119-127. doi:10.1080/20477724.2021.1975081
56. El-Tonsy MM, Hussein HM, Helal TES, Tawfik RA, Koriem KM, Hussein HM. Schistosoma mansoni infection: Is it a risk factor for development of hepatocellular carcinoma? Acta Trop. 2013;128(3):542-547. doi:10.1016/j.actatropica.2013.07.024
57. El-Tonsy MM, Hussein HM, Helal TES, Tawfik RA, Koriem KM, Hussein HM. Human Schistosomiasis mansoni associated with hepatocellular carcinoma in Egypt: current perspective. Journal of Parasitic Diseases. 2016;40(3):976-980. doi:10.1007/s12639-014-0618-0
2. Silva CLM, Lenzi HL, Silva VFM, Paulo FO, Noël F. Cellular mechanisms involved in the increased contraction of portal veins from Schistosoma mansoni-infected mice. Parasitol Res. 2003;89:16-22. doi:10.1007/s00436-002-0711-7
3. Araujo FP, Quintas LEM, Noël F, Silva CLM. Schistosoma mansoni infection enhances host portal vein contraction: role of potassium channels and p38 MAP kinase. Microbes Infect. 2007;9:1020-1025. doi:10.1016/j.micinf.2007.04.007
4. Andrade ZA. Pathology of human schistosomiasis. Mem Inst Oswaldo Cruz. 1987;82(4):17-23.
5. Santo MCC do E, Gryschek RCB, Farias AQ, et al. Management and treatment of decompensated hepatic fibrosis and severe refractory Schistosoma mansoni ascites with transjugular intrahepatic portosystemic shunt. Rev Inst Med Trop Sao Paulo. 2022;64. doi:10.1590/s1678-9946202264026
6. Pereira LM, Melo MC, Lacerda C, et al. Hepatitis B virus infection in schistosomiasis mansoni. J Med Virol. 1994;42(2):203-206. doi:10.1002/jmv.1890420219
7. Pereira LM, Melo MC, Saleh MG, et al. Hepatitis C virus infection in Schistosomiasis mansoni in Brazil. J Med Virol. 1995;45(4):423-428. doi:10.1002/jmv.1890450412
8. Fahim FA, Esmat AY, Hassan GK, Abdel-Bary A. Biochemical Changes in Patients with Combined Chronic Schistosomiasis and Viral Hepatitis C Infections. Dis Markers. 2000;16(3-4):111-118. doi:10.1155/2000/732754
9. Strickland GT, Elhefni H, Salman T, et al. Role of hepatitis C infection in chronic liver disease in Egypt. Am J Trop Med Hyg. 2002;67(4):436-442. doi:10.4269/ajtmh.2002.67.436
10. Roderfeld M, Padem S, Lichtenberger J, et al. Schistosoma mansoni Egg-Secreted Antigens Activate Hepatocellular Carcinoma-Associated Transcription Factors c-Jun and STAT3 in Hamster and Human Hepatocytes. Hepatology. 2019;0(0). doi:10.1002/hep.30192/suppinfo
11. Saharti S, Ding X, Massarani-Wafai R, Pambuccian SE. Fine-needle aspirate of the liver showing coexistence of Schistosoma japonicum ova and hepatocellular carcinoma. Diagn Cytopathol. 2018;46(8):716-720. doi:10.1002/dc.23969
12. Matsuda M, Fujii H. Chronic schistosomiasis japonica is an independent adverse prognostic factor for survival in hepatocellular carcinoma patients who have undergone hepatic resection: Clinicopathological and prognostic analysis of 198 consecutive patients. World J Surg. 2009;33(12):2644-2650. doi:10.1007/s00268-009-0228-7
13. Filgueira NA, Saraiva CM de A, Jucá NT, Bezerra MF, Lacerda CM. Schistosomal liver fibrosis and hepatocellular carcinoma – case series of patients submitted to liver transplantation. Brazilian Journal of Infectious Diseases. 2018;22(4):352-354. doi:10.1016/j.bjid.2018.06.001
14. El-Garem AA. Schistosomiasis. Digestion. 1998;59(5):589-605. doi:10.1159/000007534
15. Times de Carvalho B, Lucia Coutinho A. Hemodynamic Changes in the Intra-Hepatic Circulation of Hepatosplenic Schistosomiasis: the Role of Hepatic Artery. J Gastroenterol Hepatol Res. 2018;7(2):2555-2560. doi:10.17554/j.issn.2224-3992.2018.07.746
16. Morais CNL de, Souza JR de, Melo WG, et al. Cytokine profile associated with chronic and acute human schistosomiasis mansoni. Mem Inst Oswaldo Cruz. 2008;103(6):561-568. doi:10.1590/S0074-02762008000600009
17. Wilson MS, Mentink‐Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA. Immunopathology of schistosomiasis. Immunol Cell Biol. 2007;85(2):148-154. doi:10.1038/sj.icb.7100014
18. Laosebikan AO, Thomson SR, Naidoo NM. Schistosomal Portal Hyptertension. J Am Coll Surg. 2005;200(5):795-806. doi:10.1016/j.jamcollsurg.2004.11.017
19. Hoffmann KF, Caspar P, Cheever AW, Wynn TA. IFN-gamma, IL-12, and TNF-alpha are required to maintain reduced liver pathology in mice vaccinated with Schistosoma mansoni eggs and IL-12. Journal of Immunology. 1998;15(8):4201-4210.
20. Elbaz T, Esmat G. Hepatic and Intestinal Schistosomiasis: Review. J Adv Res. 2013;4(5):445-452. doi:10.1016/j.jare.2012.12.001
21. Dessein AJ, Hillaire D, Elwali NEMA, et al. Severe Hepatic Fibrosis in Schistosoma mansoni Infection Is Controlled by a Major Locus That Is Closely Linked to the Interferon-γ Receptor Gene. The American Journal of Human Genetics. 1999;65(3):709-721. doi:10.1086/302526
22. Zhu J, Xu Z, Chen X, et al. Parasitic antigens alter macrophage polarization during Schistosoma japonicum infection in mice. Parasit Vectors. 2014;7(1):122. doi:10.1186/1756-3305-7-122
23. Barron L, Wynn TA. Macrophage activation governs schistosomiasis-induced inflammation and fibrosis. Eur J Immunol. 2011;41(9):2509-2514. doi:10.1002/eji.201141869
24. Yu Y, Wang J, Wang X, et al. Schistosome eggs stimulate reactive oxygen species production to enhance M2 macrophage differentiation and promote hepatic pathology in schistosomiasis. PLoS Negl Trop Dis. 2021;15(8):e0009696. doi:10.1371/journal.pntd.0009696
25. Mohamed‐Ali Q, Elwali NMA, Abdelhameed AA, et al. Susceptibility to Periportal (Symmers) Fibrosis in Human Schistosoma mansoni Infections: Evidence That Intensity and Duration of Infection, Gender, and Inherited Factors Are Critical in Disease Progression. J Infect Dis. 1999;180(4):1298-1306. doi:10.1086/314999
26. Warren KS. Pathophysiology and pathogenesis of hepatosplenic schistosomiasis mansoni. Bull N Y Acad Med. 1968;44(3):280-294.
27. Warren KS. Hepatosplenic schistosomiasis mansoni: an immunologic disease. Bull N Y Acad Med. 1975;51(4):545-550.
28. Andrade ZA. Schistosomiasis and liver fibrosis. Parasite Immunol. 2009;31:656-663. doi:10.1111/j.1365-3024.2009.01157.x
29. Andrade ZA, Baptista AP, Santana TS. Remodeling of hepatic vascular changes after specific chemotherapy of schistosomal periportal fibrosis. Mem Inst Oswaldo Cruz. 2006;101:267-272. doi:10.1590/S0074-02762006000900041
30. Strauss E. Hepatosplenic schistosomiasis: a model for the study of portal hypertension. Ann Hepatol. 2002;1(1):6-11.
31. Andrade ZA. Schistosomal hepatopathy. Mem Inst Oswaldo Cruz. 2004;99:51-57. doi:10.1590/S0074-02762004000900009
32. Silva CLM, Lenzi H, Silva V, Paulo F, Noël F. Cellular mechanisms involved in the increased contraction of portal veins from Schistosoma mansoni -infected mice. Parasitol Res. 2002;89(1):16-22. doi:10.1007/s00436-002-0711-7
33. Hidayat M, Wahid H. A study of the vascular changes in bilharzic hepatic fibrosis and their significance. Surg Gynecol Obstet. Published online 1971:997-1004.
34. Da Silva LC. Portal hypertension in schistosomiasis: pathophysiology and treatment. Mem Inst Oswaldo Cruz. 1992;87(suppl IV):183-186.
35. Andrade ZA. A double and paradoxical role for angiogenesis. Rev Patol Trop. 2013;42(3):259-264.
36. Oliveira L, Andrade ZA. Significance of bile-duct changes in schistosomiasis Significado das lesões dos ductos biliares na esquistossomose. Rev Soc Bras Med Trop. 2005;38(6):464-468.
37. Domingues ALC, Domingues LAW. Forma intestinal, hepatointestinal e hepatoesplênica. In: Malta J, ed. Esquistossomose Mansônica. Primeira. Editora Universitária da UFPE; 1994:95-105.
38. Reboucas G. MEDICAL REVIEWS Clinical Aspects of Hepatosplenic Schistosomiasis: A Contrast with Cirrhosis I. Vol 48.; 1975.
39. de Carvalho BT, Coutinho Domingues AL, de Almeida Lopes EP, Brandão SCS. Increased Hepatic Arterial Blood Flow Measured by Hepatic Perfusion Index in Hepatosplenic Schistosomiasis: New Concepts for an Old Disease. Dig Dis Sci. 2016;61(7):2118-2126. doi:10.1007/s10620-016-4080-y
40. Morgan J, Groszmann R, Rojkind M, Enriquez R. Hemodynamic mechanism of emerging portal hypertension caused by schistosomiasis in the hamster. Hepatology. 1990;11(1):98-104.
41. Sarin S, Mosca P, Sabba C, Groszmann R. Hyperdynamic ciculation in a chronic murine schistosomiasis model of portal hypertension. Hepatology. 1991;13(3):581-584.
42. Alves CA, Alves AR, Abreu WN, Andrade ZA. Hepatic artery hypertrophy and sinusoidal hypertension in advanced schistosomiasis. Gastroenterology. 1977;72(1):126-128.
43. Jorge PA, Zancaner W, Guimarães RF, Carvalhal S dos S. [Oxygen gradient and hepatic blood flow in hepatosplenic schistosomiasis mansoni, Symmers’ form]. Rev Assoc Med Bras. 1967;13(12):442-445.
44. Mies S, Braghirolli-Neto O, Beer A, et al. Systemic and hepatic hemodynamics in hepatosplenic manson’s schistosomiasis with and without propranolol. Dig Dis Sci. 1997;42(4):751-761.
45. Denié C, Vachiery F, Elman A, et al. Systemic and splanchnic hemodynamic changes in patients with hepatic schistosomiasis. Liver. 1996;16(5):309-312.
46. Da Silva LC, Carrilho FJ. Hepatosplenic schistosomiasis. Pathophysiology and treatment. Gastroenterol Clin North Am. 1992;21(1):163-177.
47. Coutinho A. Hemodynamic studies of portal hypertension in schistosomiasis. American Journal of Medicine. 1968;44:547-555.
48. Lautt WW. Control of hepatic arterial blood flow: independence from liver metabolic activity. Am J Physiol. 1980;239:H559-H564.
49. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: hepatic arterial buffer response. Am J Physiol. 1985;249(5):549-556.
50. Strauss E. Hepatosplenic schistosomiasis:a model for the study of portal hypertension. Annals of Hepatology . 2002;1(1):6-11.
51. Ramos OL, Saad F, Leser WP. Portal hemodynamics and liver cell function in hepatic schistosomiasis. Gastroenterology. 1964;47:241-247.
52. Rebouças G. Clinical Aspects of Hepatosplenic Schistosomiasis: A Contrast with Cirrhosis. THE YALE JOURNAL OF BIOLOGY AND MEDICINE . 1975;48:369-376.
53. Schistosomes, liver flukes and Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1-241.
54. Palumbo E. Association Between Schistosomiasis and Cancer. Infectious Diseases in Clinical Practice. 2007;15(3):145-148. doi:10.1097/01.idc.0000269904.90155.ce
55. Shousha HI, Abdelaziz AO, Nabeel MM, et al. Schistosoma mansoni infection and the occurrence, characteristics, and survival of patients with hepatocellular carcinoma: an observational study over a decade. Pathog Glob Health. 2022;116(2):119-127. doi:10.1080/20477724.2021.1975081
56. El-Tonsy MM, Hussein HM, Helal TES, Tawfik RA, Koriem KM, Hussein HM. Schistosoma mansoni infection: Is it a risk factor for development of hepatocellular carcinoma? Acta Trop. 2013;128(3):542-547. doi:10.1016/j.actatropica.2013.07.024
57. El-Tonsy MM, Hussein HM, Helal TES, Tawfik RA, Koriem KM, Hussein HM. Human Schistosomiasis mansoni associated with hepatocellular carcinoma in Egypt: current perspective. Journal of Parasitic Diseases. 2016;40(3):976-980. doi:10.1007/s12639-014-0618-0