Liver Graft versus Host Disease after Allogeneic Peripheral Stem Cell Transplantation: Update on Etiopathogenesis and Diagnosis

Open access


Graft versus host disease (GVHD) is the main complication of allogeneic hematopoietic cell transplantation and is more frequent after peripheral stem cell transplants. Graft versus leukemia or lymphoma component of them is beneficial to eradicate residual tumor mass after previous treatment and conditioning regimen. A severe GVHD may endanger the patient's life. The most important liver manifestations of GVHD are increased serum alkaline phosphatase and bilirubin values. The last allows to estimate the GVHD severity. Sometimes, an increase of aminotransferases can mimic an acute hepatitis. Donor-derived hematopoietic cells appeared to turn in mesenchymal liver cells. Activated CD4(+) T cells, humoral and complement activation, a large number of cytokines and cytokine receptors are involved in GVHD development. Correct and early recognition of GVHD and its differentiation from the other liver diseases are essential for the medical practice.

1. TUNCER HH, RANA N, MILANI C, DARKO A, AL-HOMSI SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. 2012; 18: 1851-1860.

2. SCHOLL S, SAYER HG, MÜGGE LO, KASPER C, PIETRASZCZYK M, KLICHE KO, et al. Increase of interleukin-18 serum levels after engraftment correlates with acute graft-versus-host disease in allogeneic peripheral blood stem cell transplantation. J Cancer Res Clin Oncol. 2004; 130: 704-710.

3. HEALTH QUALITY ONTARIO. Extracorporeal photophoresis: an evidence-based analysis. Ont Health Technol Assess Ser. 2006; 6: 1-82.

4. TEISSEYRE M, TEISSEYRE J, KALICINSKI P, WOLSKA-KUSNIERZ B, ISMAIL H, BERNATOWSKA E, et al. Liver transplantation for severe hepatic graft-versus-host disease in two children after hematopoietic stem cell transplantation. Transplant Proc. 2010; 42: 4608-4610.

5. McDONALD GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. 2010; 51: 1450-1460.

6. DEL CAMPO L, LEÓN NG, PALACIOS DC, LAGANA C, TAGARRO D. Abdominal complications following hematopoietic stem cell transplantation. Radiographics. 2014; 34: 396-412.

7. NORVELL JP. Liver disease after hematopoietic cell transplantation in adults. Transplant Rev (Orlando). 2015; 29: 8-15.

8. TOBIN LM, HEALY ME, ENGLISH K, MAHON BP. Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease. Clin Exp Immunol. 2013; 172: 333-348.

9. AHMAD I, LABBÉ AC, CHAGNON M, BUSQUE L, COHEN S, KISS T, et al. Incidence and prognostic value of eosinophilia in chronic graft-versus-host disease after nonmyeloablative hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011; 17: 1673-1678.

10. PÉREZ-SIMON JA, ENCINAS C, SILVA F, ARCOS MJ, DÍEZ-CAMPELO M, SÁNCHEZ-GUIJO FM, et al. Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the national institutes health scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. Biol Blood Marrow Transplant. 2008; 14: 1163-1171.

11. FRIEDRICHS B, TICHELLI A, BACIGALUPO A, RUSSEL NH, RUUTU T, SHAPIRA MY, et al. Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial. Lancet Oncol. 2010; 11: 331-338.

12. TICHELLI A, GRATWOHL A. Vascular endothelium as ‘novel’ target of graft-versus-host disease. Best Pract Res Clin Haematol. 2008; 21: 139-148.

13. KIM I, KEAM B, LEE KH, KIM JH, OH SY, RA EK, et al. Glutathione S-transferase A1 polymorphisms and acute graft-vs.-host disease in HLA-matched sibling allogeneic hematopoietic stem cell transplantation. Clin Transplant. 2007; 21: 207-213.

14. MARTÍNEZ-BRAVO MJ, TALLÓN I, ESPIGADO I, PEREZ-SIMÓN JA, PÉREZ-ROMERO P, GRACIA-AHUFINGER I, et al. Influence of glutathione S-transferase T1 donor/recipient mismatch and anti-GSTT1 antibodies in hepatic graft-versus-host-disease. Immunol Lett. 2011; 141: 140-144.

15. PIDALA J, BLOOM GC, ENKEMANN S, ESCHRICH S, LANCASTER J, ANASETTI C. Biomarkers to discern transplantation tolerance after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010; 16: 729-738.

16. HOSSAIN MS, ROBACK JD, POLLACK BP, JAYE DL, LANGSTON A, WALLER EK. Chronic GvHD decreases antiviral immune responses in allogeneic BMT. Blood. 2007; 109: 4548-4556.

17. TEN HOVE WR, VERSPAGET HW, BARGE R, LAMERS CB, VAN HOEK B. Liver chimerism after allogeneic blood stem cell transplantation. Transplant Proc. 2007; 39: 231-236.

18. WEN HS, WANG JM, ZHOU H, GONG SI, GAO L, WU Y. Migration and activation of T cells during development of graft-versus-host disease in a mouse model. Transplant Proc. 2013; 45: 713-718.

19. ALI SA, SHAH V, McKINNON R, VAN HARN M, JANAKIRAMAN N. Frequent expression of C4d in hepatic graft-versus-host disease: potential clue for diagnosis and distinguishing acute and chronic form. Transpl Immunol. 2010; 23: 77-80.

20. MIYAZAKI T, DOY M, UNNO R, HONDA A, IKEGAMI T, ITOH S, et al. Regulatory T cells and liver pathology in a murine graft versus host response model. Hepatol Res. 2009; 39: 585-594.

21. BRANDON JA, PEREZ J, JENNINGS CD, COHEN DA, SINDHAVA VJ, BONDADA S, et al. Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease. Am J Physiol Gastrointest Liver Physiol. 2010; 299: G602-613.

22. PAN B, ZHANG Y, SUN Y, CHENG H, WU Y, SONG G, et al. Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice. Cytokine. 2014; 68: 69-75.

23. CHENG H, ZENG LY, PAN B, SONG GL, TIAN J, CHEN C, et al. The role of Th17 cells in early onset of mice acute graft versus host disease. Zhonghua Xue Ye Xue Za Zhi. 2011; 32: 322-325.

24. LIM JY, CHO BS, MIN CK, PARK G, KIM YJ, CHUNG NG, et al. Fluctuations in pathogenic CD4+ T-cell subsets in a murine sclerodermatous model of chronic graft-versus-host disease. Immunol Invest. 2014; 43 :41-53.

25. MacDONALD KP, ROWE V, FILIPPICH C, JOHNSON D, MORRIS ES, CLOUSTON AD, et al. Chronic graft-versus-host disease after granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation: the role of donor T-cell dose and differentiation. Biol Blood Marrow Transplant. 2004; 10: 373-385.

26. HILL GR, MORRIS ES, FUERY M, HUTCHINS C, BUTLER J, GRIGG A, et al. Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF. Biol Blood Marrow Transplant. 2006; 12: 603-607.

27. EL-HAYEK JM, ROGERS TE, BROWN GR. The role of TNF in hepatic histopathological manifestations and hepatic CD8+ T cell alloresponses in murine MHC class I disparate GVHD. J Leukoc Biol. 2005; 78: 1001-1007.

28. BOUZZAOUI A, SPANEKO E, MUELLER G, MIKLOS S, HUBER E, HOLLER E, et al. Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease. Genes Immun. 2009; 10: 687-701.

29. WANG Z, MURPHY WJ. Relationship between CCR5 and acute graft-versus-host disease in murine bone marrow transplantation. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2006; 14: 934-940.

30. MIKLOS S, MUELLER G, CHANG Y, BOUZZAOUI A, SPANEKO E, SCHUBERT TE, et al. Preventive usage of broad spectrum chemokine inhibitor NR58-3.14.3 reduces the severity of pulmonary and hepatic graft-versus-host disease. Int J Hematol. 2009; 89: 383-397.

31. VIERLING JM, HREHA G, WANG H, BRAUN M. The role of biliary epithelial cells in the immunopathogenesis of nonsuppurative destructive cholangitis in murine hepatic graft-versus-host disease. Trans Am Clin Climatol Assoc. 2011; 122: 326-335.

32. ZHANG JL, HOU CM, WEI YL, LI XY, SUN DJ, FENG JN, et al. Influence of excessive complement activation on pathological process of acute graft versus host disease in mice. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010; 18: 1585-1589.

33. HASHINO S, KOBAYASHI S, TAKAHATA M, ONAZAWA M, NAKAGAWA M, KAWAMURA T, et al. Graft-versus-tumor effect after reduced-intensity allogeneic hematopoietic stem cell transplantation in a patient with advanced colon cancer. Int J Clin Oncol. 2008; 13: 176-180.

34. MAHGEREFTEH SY, SOSNA J, BOGOT N, SHAPIRA MY, PAPPO O, BLOOM AI. Radiologic imaging and intervention for gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. Radiology. 2011; 258: 660-671.

35. LEE JH, LEE JH, KIM DY, YUN SC, KIM SD, CHOI Y, et al. Pre-engraftment graft-versus-host disease after allogeneic hematopoietic cell transplantation for acute leukemia. Eur J Haematol. 2011; 87: 172-181.

36. YOU JY, YU YB, CHEN PC, TSAY SH, CHEN CC, HO CH, et al. Donor lymphocyte infusion induced acute hepatitis. J Chin Med Assoc. 2004; 67: 411-415.

37. RADHAKRISHNAN K, BISHOP J, JIN Z, KOTHARI K, BHATIA M, GEORGE D, et al. Risk factors associated with liver injury and impact of liver injury on transplantation-related mortality in pediatric recipients of allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 19: 912-917.

38. PIDALA J, CHAI X, KURLAND BF, INAMOTO Y, FLOWERS ME, PALMER J, et al. Analysis of gastrointestinal and hepatic chronic graft-versus-host [corrected] disease manifestations on major outcomes: a chronic graft-versus-host [corrected] disease consortium study. Biol Blood Marrow Transplant. 2013; 19: 784-791.

39. PARALKAR VR, GORADIA A, LUGER SM, LOREN AW. Severe eosinophilia as a manifestation of acute graft-versus-host disease. Oncology. 2008; 75: 134-136.

40. LESESVE JF, ALLA F, DUGUÉ F, SALIGNAC S, CLÉMENT L, LECOMPTE T, et al. Evaluation of schistocyte monitoring after haematopoietic stem cell transplantation. Int J Lab Hematol. 2011; 33: 343-356.

41. ZIDAN H, LO S, WIEBE D, TALANO J, ALEMZADEH R. Severe hypercholesterolemia mediated by lipoprotein X in a pediatric patient with chronic graft-versus-host disease of the liver. Pediatr Blood Cancer. 2008; 50: 1280-1281.

42. YEH SP, LIAO YM, LO WJ, LIN CL, BAI LY, LIN CY, et al. Kinetics of T helper subsets and associated cytokines correlate well with the clinical activity of graft-versus-host disease. PLoS One. 2012; 7: e44416.

43. MAENG H, LEE JH, CHEONG JW, LEE ST, HAHN JS, KO YW, et al. Chronic graft-versus-host disease of the liver presenting as an acute hepatitis following nonmyeloablative hematopoietic stem cell transplantation. Int J Hematol. 2004; 79: 501-504.

44. MELÍN-ALDANA H, THORMANN K, DUERST R, KLETZEL M, JACOBSOHN DA. Hepatitic pattern of graft versus host disease in children. Pediatr Blood Cancer. 2007; 49: 727-730.

45. PROCHOREC-SOBIESZEK M, NASILOWSKA-ADAMSKA B, SZUMERA-CIEĆKIEWICZ A, TOMASZEWSKA A, HALABURDA K, SZCZEPIŃSKI A, et al. The significance of oral labial biopsy in hepatic graft-versus-host disease diagnosis in patients following allogeneic hematopoietic stem cell transplantation--a preliminary report. Ann Transplant. 2012; 17: 85-92.

46. VAN DER EIJK AA, PAS SD, CORNELISSEN JJ, DE MAN RA. Hepatitis E virus infection in hematopoietic stem cell transplant recipients. Curr Opin Infect Dis. 2014; 27: 309-315.

47. LUFT T, COZELMANN M, BENNER A, RIEGER M, HESS M, STROHHAECKER U, et al. Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease. Blood. 2007; 110: 4535-4542.

48. DÖRING M, ROHRER KM, ERBACHER A, GIESEKE F, SCHWARZE CP, BADER P, et al. Human leukocyte antigen DR surface expression on CD14+ monocytes during adverse events after hematopoietic stem cell transplantation. Ann Hematol. 2015; 94: 265-273.

49. LEE DH, HUH SJ, YOON HH, LEE SW, KIM KH, KIM SH. Clinical significance of anti-mitochondrial antibodies in a patient with chronic graft-versus-host disease following hematopoietic stem cell transplantation. Korean J Hematol. 2011; 46: 200-202.

50. ERTURK SM, MORTELÉ KJ, BINKERT CA, GLICKMAN JN, OLIVA MR, ROS PR, et al. CT features of hepatic venoocclusive disease and hepatic graft-versus-host disease in patients after hematopoietic stem cell transplantation. AJR Am J Roentgenol. 2006; 186: 1497-1501.

51. McDONALD GB. Review article: management of hepatic disease following haematopoietic cell transplant. Aliment Pharmacol Ther. 2006; 24: 441-452.

52. DEEG HJ, SPAULDING E, SHULMAN HM. Iron overload, hematopoietic cell transplantation, and graft-versus-host disease. Leuk Lymphoma. 2009; 50: 1566-1572.

53. KAMBLE RT, SELBY GB, MIMS M, KHARFAN-DABAJA MA, OZER H, GEORGE JN. Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006; 12: 506-510.

54. ZHAO J, REN H, QIU Z, WANG M, LIU W, XU W, et al. The influence of liver dysfunction before transplantation and during conditioning period on the outcome of allogeneic hematopoietic stem cell transplantation. Zhonghua Nei Ke Za Zhi. 2014; 53: 99-103.

55. PAVLETIC SZ, SMITH LM, BISHOP MR, LYNCH JC, TARANTOLO SR, VOSE JM, et al. Prognostic factors of chronic graft-versus-host disease after allogeneic blood stem-cell transplantation. Am J Hematol. 2005; 78: 265-274.

56. WOJNAR J, GIEBEL S, HOLOWIECKA-GORAL A, MARKIEWICZ M, WYLEZOL I, KOPERA M, et al. Prediction of nonrelapse mortality for patients surviving 100 days after allogeneic hematopoietic stem cell transplantation. Transplant Proc. 2007; 39: 3375-3379.

57. KANSU E. Thrombosis in stem cell transplantation. Hematology. 2012; 17 Suppl 1: S159-162.

58. SONG MK, CHUNG JS, KIM S, SEOL YM, KIM SG, SHIN HJ, et al. Hepatic artery resistance index at doppler ultrasonography is a useful parameter of hepatic graft-vs-host disease after allogeneic stem cell transplantation. Transplant Proc. 2010; 42: 3717-3722.

59. SILVA F, PÉREZ-SIMÓN JA, CABALLERO VELAZQUEZ T, ENCINAS C, SÁNCHEZ-GUIJO FM, DÍEZ-CAMPELO M, et al. Liver function tests and absolute lymphocyte count at day +100 are predictive factors for extensive and severe chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant. Am J Hematol. 2010; 85: 290-293.

60. BURNIER L, SALLER F, KADI L, BRISSET AC, SUGAMELE R, BAUDINO L, et al. Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease. Blood. 2010; 115: 3390-3397.

Journal Information


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 169 169 25
PDF Downloads 58 58 15