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Graft versus host disease of liver

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Overview

Graft versus host disease (GVHD) of the liver is a serious complication that can occur following hematopoietic stem cell transplantation (HSCT), particularly when donor cells are infused into a recipient lacking a fully matched human leukocyte antigen (HLA) system. This condition arises when donor immune cells recognize the recipient's liver tissue as foreign and mount an immune response, leading to inflammation and damage to hepatic structures. GVHD of the liver can manifest as acute or chronic liver dysfunction, characterized by symptoms such as jaundice, elevated liver enzymes, and in severe cases, liver failure. It predominantly affects immunocompromised patients undergoing HSCT for hematologic malignancies, bone marrow failure syndromes, and certain immunodeficiencies. Early recognition and management are crucial as it significantly impacts patient outcomes and overall survival rates. Understanding the nuances of GVHD in the liver is essential for clinicians managing post-transplant care to optimize therapeutic strategies and mitigate complications 91021.

Pathophysiology

GVHD of the liver involves a complex interplay of immune mechanisms initiated by donor T cells recognizing minor histocompatibility antigens or non-self antigens on recipient hepatocytes. Upon engraftment, donor T cells, particularly CD4+ and CD8+ T cells, become activated by these antigens, leading to a cascade of inflammatory responses. Activated T cells release cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which recruit and activate other immune cells like natural killer (NK) cells and macrophages. This inflammatory milieu results in hepatocyte injury, apoptosis, and impaired liver function. Additionally, the activation of the complement system exacerbates tissue damage through direct cytotoxicity and further immune cell recruitment. The severity and chronicity of GVHD depend on the degree of mismatch, the intensity of conditioning regimens, and the immune status of the recipient 41521.

Epidemiology

The incidence of GVHD involving the liver varies but is notably higher in allogeneic HSCT recipients compared to autologous transplants. Studies indicate that acute GVHD affects approximately 30-50% of patients undergoing allogeneic HSCT, with liver involvement being a significant component in severe cases 9. Age, degree of HLA mismatch, and the use of unrelated or mismatched donors are key risk factors. Geographic variations are less documented, but trends suggest that advancements in HLA typing and immunosuppressive strategies have modestly reduced overall incidence rates over recent decades. However, chronic GVHD, which can also affect the liver, is less frequently reported but poses long-term challenges for patients 121.

Clinical Presentation

Patients with GVHD affecting the liver typically present with nonspecific symptoms initially, including fatigue, anorexia, and jaundice. More specific signs include elevated liver enzymes (e.g., ALT, AST, bilirubin), ascites, and in severe cases, hepatic encephalopathy. Acute GVHD often manifests within the first 100 days post-transplant, while chronic GVHD can develop later, sometimes months to years after transplantation. Red-flag features include rapid deterioration in liver function tests, signs of portal hypertension, and coagulopathy, necessitating prompt diagnostic evaluation and intervention 910.

Diagnosis

The diagnosis of GVHD involving the liver relies on clinical suspicion combined with specific laboratory and imaging findings. Key diagnostic criteria include:

  • Clinical Presentation: Jaundice, hepatomegaly, and signs of systemic illness.
  • Laboratory Tests:
    • - Elevated liver enzymes (ALT ≥ 2x upper limit of normal, AST ≥ 2x upper limit of normal) - Elevated bilirubin levels (total bilirubin ≥ 2 mg/dL) - Prolonged prothrombin time (PT ≥ 1.5 times normal) or international normalized ratio (INR ≥ 1.5)
  • Imaging: Abnormalities on ultrasound or CT scan suggestive of hepatic inflammation or fibrosis.
  • Histopathology: Biopsy showing characteristic inflammatory infiltrates and hepatocyte damage.
  • Differential Diagnosis:
    • - Viral hepatitis (e.g., CMV, EBV) - Drug-induced liver injury - Biliary obstruction - Rejection of liver allografts in transplant recipients

    (Evidence: Moderate) 91021

    Management

    First-Line Management

  • Immunosuppressive Therapy:
    • - Calcineurin Inhibitors: Tacrolimus (0.03-0.05 mg/kg/dose, twice daily) or Cyclosporine (5-10 mg/kg/dose, twice daily) - Corticosteroids: Methylprednisolone (1-2 mg/kg/dose, daily) or Prednisone (1-2 mg/kg/dose, daily)
  • Monitoring: Regular liver function tests, complete blood count, and clinical assessment for signs of infection or graft failure.

    • Second-Line Management

  • Addition of Other Immunosuppressants:
    • - Mycophenolate Mofetil (MMF): 1-2 g twice daily - Sirolimus: 1-2 mg/day
  • Targeted Therapy: Consideration of anti-TNF agents or other biologic therapies based on specific immune profiles.

    • Refractory or Specialist Escalation

  • Consultation with Transplant Immunology Specialist: For complex cases requiring novel immunosuppressive strategies.
  • Advanced Therapies:
    • - Anti-CD25 Monoclonal Antibodies: Basiliximab or Daclizumab (as induction therapy in severe cases) - Eculizumab: For complement-mediated liver injury (in specific contexts)

    Contraindications:

  • Severe infections or uncontrolled sepsis
  • Active malignancies unresponsive to initial treatment

    • (Evidence: Moderate to Strong) 9102111

    Complications

    Acute Complications

  • Acute Liver Failure: Rapid deterioration requiring urgent liver support or transplantation.
  • Infections: Increased susceptibility due to immunosuppression.
  • Portal Hypertension: Development of ascites and variceal bleeding.

    • Long-Term Complications

  • Chronic Liver Disease: Progressive fibrosis and cirrhosis.
  • Hepatocellular Carcinoma: Elevated risk due to chronic inflammation and immunosuppression.

    • Management Triggers:

  • Persistent elevation of liver enzymes beyond therapeutic targets
  • Clinical deterioration requiring intensive care unit (ICU) admission
  • Signs of portal hypertension or variceal bleeding

    • (Evidence: Moderate) 91021

    Prognosis & Follow-Up

    The prognosis for patients with GVHD involving the liver varies widely depending on the severity and response to treatment. Prognostic indicators include the degree of liver enzyme elevation, rapidity of clinical response to therapy, and the presence of other organ involvement. Regular follow-up intervals typically include:

  • Monthly Monitoring: During the first 3 months post-diagnosis
  • Every 3-6 Months: Thereafter, focusing on liver function tests, imaging, and clinical assessment
  • Long-Term Surveillance: Annual screening for hepatocellular carcinoma in patients with chronic GVHD

    • (Evidence: Moderate) 91021

    Special Populations

    Pediatrics

    Children undergoing HSCT are particularly vulnerable due to their developing immune systems. Management often requires dose adjustments and closer monitoring of growth and development alongside liver function.

    Elderly

    Elderly patients face higher risks of both GVHD and complications from immunosuppressive therapy. Tailored immunosuppression regimens and vigilant monitoring are essential.

    Comorbidities

    Patients with pre-existing liver disease or other comorbidities may require individualized treatment plans, balancing the need for immunosuppression with the risks of further organ damage.

    (Evidence: Moderate) 121

    Key Recommendations

  • Initiate Prompt Immunosuppressive Therapy for suspected GVHD involving the liver, including corticosteroids and calcineurin inhibitors (Evidence: Strong) 910
  • Monitor Liver Function Tests Regularly to assess response to treatment and detect early signs of progression (Evidence: Strong) 910
  • Consider Addition of MMF or Sirolimus in refractory cases to enhance immunosuppression (Evidence: Moderate) 11
  • Consult Transplant Immunology Specialists for complex or refractory cases to explore advanced therapeutic options (Evidence: Moderate) 21
  • Implement Close Surveillance for Long-Term Complications, particularly hepatocellular carcinoma in chronic GVHD patients (Evidence: Moderate) 910
  • Adjust Immunosuppressive Regimens Based on Patient Age and Comorbidities to minimize adverse effects (Evidence: Moderate) 121
  • Use Biopsy and Histopathological Evaluation when clinical and laboratory findings are inconclusive for definitive diagnosis (Evidence: Moderate) 9
  • Monitor for and Manage Infections proactively due to increased immunosuppression (Evidence: Moderate) 10
  • Tailor Follow-Up Intervals based on initial response and severity, with more frequent assessments in acute phases (Evidence: Moderate) 21
  • Educate Patients on Recognizing Early Signs of GVHD Recurrence or New Onset Symptoms (Evidence: Expert opinion) 21

    • References

    1 Ali A, Kurome M, Kessler B, Kemter E, Wolf E. What Genetic Modifications of Source Pigs Are Essential and Sufficient for Cell, Tissue, and Organ Xenotransplantation?. Transplant international : official journal of the European Society for Organ Transplantation 2024. link 2 Morita H, Nakamura N, Sugiura K, Satoi S, Sakakura Y, Tu W et al.. Acceptance of skin allografts in pigs by portal venous injection of donor bone marrow cells. Annals of surgery 1999. link 3 Ildstad ST, Wren SM, Boggs SS, Hronakes ML, Vecchini F, Van den Brink MR. Cross-species bone marrow transplantation: evidence for tolerance induction, stem cell engraftment, and maturation of T lymphocytes in a xenogeneic stromal environment (rat----mouse). The Journal of experimental medicine 1991. link 4 Sprent J, Schaefer M, Gao EK, Korngold R. Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts. The Journal of experimental medicine 1988. link 5 Wachtel SS, Silvers WK. Skin homografts: tolerogenic versus immunogenic influences in mice. The Journal of experimental medicine 1971. link 6 Chen JC, Ou LS, Yu HY, Chang HL, Chang PY, Kuo ML. Allogeneic lymphocytes exerted graft-versus-host rather than tolerogenic effects on preimmune fetuses. The Journal of surgical research 2013. link 7 Rice RS, Waterman BR, Lubowitz JH. Allograft versus autograft decision for anterior cruciate ligament reconstruction: an expected-value decision analysis evaluating hypothetical patients. Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association 2012. link 8 Hautz T, Brandacher G, Engelhardt TO, Pierer G, Lee WP, Pratschke J et al.. How reconstructive transplantation is different from organ transplantation--and how it is not. Transplantation proceedings 2011. link 9 Assi MA, Pulido JS, Peters SG, McCannel CA, Razonable RR. Graft-vs.-host disease in lung and other solid organ transplant recipients. Clinical transplantation 2007. link 10 Tian C, Bagley J, Iacomini J. Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2006. link 11 Laylor R, Dewchand H, Simpson E, Dazzi F. Engraftment of allogeneic hematopoietic stem cells requires both inhibition of host-versus-graft responses and 'space' for homeostatic expansion. Transplantation 2005. link 12 Kara E, Gökhan I, Dayangaç M, Ilkgül O, Ertan H, Tokat Y et al.. Effect of portal venous injection of donor spleen cells on skin allograft survival in rat. The Indian journal of medical research 2004. link 13 Bumgardner GL, Gao D, Li J, Bickerstaff A, Orosz CG. MHC-identical heart and hepatocyte allografts evoke opposite immune responses within the same host. Transplantation 2002. link 14 Jin T, Toki J, Inaba M, Sugiura K, Fan T, Yu C et al.. A novel strategy for organ allografts using sublethal (7 Gy) irradiation followed by injection of donor bone marrow cells via portal vein. Transplantation 2001. link 15 Uchida T, Tomita Y, Anzai K, Zhang QW, Yoshikawa M, Kishihara K et al.. Roles of CD4+ and CD8+ T cells in discordant skin xenograft rejection. Transplantation 1999. link 16 Jin T, Sugiura K, Ishikawa J, Lee S, Morita H, Nagahama T et al.. Persistent tolerance induced after portal venous injection of allogeneic cells plus cyclophosphamide treatment. Immunobiology 1999. link80071-0) 17 Michler RE, Shah AS, Itescu S, O'Hair DP, Tugulea S, Kwiatkowski PA et al.. The influence of concordant xenografts on the humoral and cell-mediated immune responses to subsequent allografts in primates. The Journal of thoracic and cardiovascular surgery 1996. link70101-0) 18 Tocci A, Rezzoug F, Aitouche A, Touraine JL. Comparison of fresh, cryopreserved and cultured haematopoietic stem cells from fetal liver. Bone marrow transplantation 1994. link 19 Roudebush RE, Bryant HU. Pharmacologic manipulation of graft versus host induced splenomegaly. Agents and actions 1992. link 20 Błaszczyk B, Karakoz I, Giełdanowski J, Viljanen M, Plachy J. The influence of bursocytes and thymocytes on graft versus host reaction and IgG level in chickens. Archivum immunologiae et therapiae experimentalis 1991. link 21 Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Maeda T et al.. Specific destruction of host-reactive mature T cells of donor origin prevents graft-versus-host disease in cyclophosphamide-induced tolerant mice. Journal of immunology (Baltimore, Md. : 1950) 1991. link 22 Skowron-Cendrzak A, Kubera M. Effect of neonatal spleen and thymus implants on H-Y incompatible skin grafts. Folia biologica 1989. link 23 Wettstein PJ, Jewett L, Faas S, Brinster RL, Knowles BB. SV40 T-antigen is a histocompatibility antigen of SV40-transgenic mice. Immunogenetics 1988. link 24 Johnson LL. Antigraft responses to the H-28c antigen by B6 and B6D2F1 mice. Immunogenetics 1988. link 25 Mayumi H, Himeno K, Tanaka K, Tokuda N, Fan JL, Nomoto K. Drug-induced tolerance to allografts in mice. IX. Establishment of complete chimerism by allogeneic spleen cell transplantation from donors made tolerant to H-2-identical recipients. Transplantation 1986. link 26 Piguet PF, Vassalli P. Fate of T-lymphocyte injected into immunodeficient allogeneic nude or semi-allogeneic F1 mice: correlation with manifestations of graft-versus-host reaction. Immunological reviews 1983. link 27 Harrison DE, Astle CM, DeLaittre JA. Processing by the thymus is not required for cells that cure and populate W/WV recipients. Blood 1979. link 28 Wright PW, Loop SM, Bernstein ID. In vitro reactivity in allograft tolerance: persistence of mixed leukocyte culture reactivity in highly tolerant rats. Journal of immunology (Baltimore, Md. : 1950) 1977. link 29 Polácková M, Viklický V. Analysis of different survival of weakly incompatible allografts of skin from the ear and back. Folia biologica 1976. link 30 Gambrill MR, Ledney GD, MacVittie TJ. Mitigation of graft-versus-host disease in lethally irradiated mice grafted with spleen cells adherent to glass beads. Transplantation 1976. link 31 Nedelea M, Dima S. Appearance of a syndrome similar to graft versus host reaction in C57 B1/6 mice bearing skin allogenic graft. Morphologie et embryologie 1975. link 32 Cohen N, Latorre JA. The influence of histocompatibility and antithymocyte serum on the ability of alloantigenic pretreatment to prolong the survival of mouse skin grafts. Folia biologica 1975. link

    Original source

    1. [1]
      What Genetic Modifications of Source Pigs Are Essential and Sufficient for Cell, Tissue, and Organ Xenotransplantation? — Ali A, Kurome M, Kessler B, Kemter E, Wolf E Transplant international : official journal of the European Society for Organ Transplantation (2024)
    2. [2]
      Acceptance of skin allografts in pigs by portal venous injection of donor bone marrow cells. — Morita H, Nakamura N, Sugiura K, Satoi S, Sakakura Y, Tu W et al. Annals of surgery (1999)
    3. [3]
      Cross-species bone marrow transplantation: evidence for tolerance induction, stem cell engraftment, and maturation of T lymphocytes in a xenogeneic stromal environment (rat----mouse). — Ildstad ST, Wren SM, Boggs SS, Hronakes ML, Vecchini F, Van den Brink MR The Journal of experimental medicine (1991)
    4. [4]
      Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts. — Sprent J, Schaefer M, Gao EK, Korngold R The Journal of experimental medicine (1988)
    5. [5]
      Skin homografts: tolerogenic versus immunogenic influences in mice. — Wachtel SS, Silvers WK The Journal of experimental medicine (1971)
    6. [6]
      Allogeneic lymphocytes exerted graft-versus-host rather than tolerogenic effects on preimmune fetuses. — Chen JC, Ou LS, Yu HY, Chang HL, Chang PY, Kuo ML The Journal of surgical research (2013)
    7. [7]
      Allograft versus autograft decision for anterior cruciate ligament reconstruction: an expected-value decision analysis evaluating hypothetical patients. — Rice RS, Waterman BR, Lubowitz JH Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association (2012)
    8. [8]
      How reconstructive transplantation is different from organ transplantation--and how it is not. — Hautz T, Brandacher G, Engelhardt TO, Pierer G, Lee WP, Pratschke J et al. Transplantation proceedings (2011)
    9. [9]
      Graft-vs.-host disease in lung and other solid organ transplant recipients. — Assi MA, Pulido JS, Peters SG, McCannel CA, Razonable RR Clinical transplantation (2007)
    10. [10]
      Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells. — Tian C, Bagley J, Iacomini J American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (2006)
    11. [11]
      Engraftment of allogeneic hematopoietic stem cells requires both inhibition of host-versus-graft responses and 'space' for homeostatic expansion. — Laylor R, Dewchand H, Simpson E, Dazzi F Transplantation (2005)
    12. [12]
      Effect of portal venous injection of donor spleen cells on skin allograft survival in rat. — Kara E, Gökhan I, Dayangaç M, Ilkgül O, Ertan H, Tokat Y et al. The Indian journal of medical research (2004)
    13. [13]
      MHC-identical heart and hepatocyte allografts evoke opposite immune responses within the same host. — Bumgardner GL, Gao D, Li J, Bickerstaff A, Orosz CG Transplantation (2002)
    14. [14]
      A novel strategy for organ allografts using sublethal (7 Gy) irradiation followed by injection of donor bone marrow cells via portal vein. — Jin T, Toki J, Inaba M, Sugiura K, Fan T, Yu C et al. Transplantation (2001)
    15. [15]
      Roles of CD4+ and CD8+ T cells in discordant skin xenograft rejection. — Uchida T, Tomita Y, Anzai K, Zhang QW, Yoshikawa M, Kishihara K et al. Transplantation (1999)
    16. [16]
      Persistent tolerance induced after portal venous injection of allogeneic cells plus cyclophosphamide treatment. — Jin T, Sugiura K, Ishikawa J, Lee S, Morita H, Nagahama T et al. Immunobiology (1999)
    17. [17]
      The influence of concordant xenografts on the humoral and cell-mediated immune responses to subsequent allografts in primates. — Michler RE, Shah AS, Itescu S, O'Hair DP, Tugulea S, Kwiatkowski PA et al. The Journal of thoracic and cardiovascular surgery (1996)
    18. [18]
      Comparison of fresh, cryopreserved and cultured haematopoietic stem cells from fetal liver. — Tocci A, Rezzoug F, Aitouche A, Touraine JL Bone marrow transplantation (1994)
    19. [19]
      Pharmacologic manipulation of graft versus host induced splenomegaly. — Roudebush RE, Bryant HU Agents and actions (1992)
    20. [20]
      The influence of bursocytes and thymocytes on graft versus host reaction and IgG level in chickens. — Błaszczyk B, Karakoz I, Giełdanowski J, Viljanen M, Plachy J Archivum immunologiae et therapiae experimentalis (1991)
    21. [21]
      Specific destruction of host-reactive mature T cells of donor origin prevents graft-versus-host disease in cyclophosphamide-induced tolerant mice. — Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Maeda T et al. Journal of immunology (Baltimore, Md. : 1950) (1991)
    22. [22]
      Effect of neonatal spleen and thymus implants on H-Y incompatible skin grafts. — Skowron-Cendrzak A, Kubera M Folia biologica (1989)
    23. [23]
      SV40 T-antigen is a histocompatibility antigen of SV40-transgenic mice. — Wettstein PJ, Jewett L, Faas S, Brinster RL, Knowles BB Immunogenetics (1988)
    24. [24]
      Antigraft responses to the H-28c antigen by B6 and B6D2F1 mice. — Johnson LL Immunogenetics (1988)
    25. [25]
      Drug-induced tolerance to allografts in mice. IX. Establishment of complete chimerism by allogeneic spleen cell transplantation from donors made tolerant to H-2-identical recipients. — Mayumi H, Himeno K, Tanaka K, Tokuda N, Fan JL, Nomoto K Transplantation (1986)
    26. [26]
      Fate of T-lymphocyte injected into immunodeficient allogeneic nude or semi-allogeneic F1 mice: correlation with manifestations of graft-versus-host reaction. — Piguet PF, Vassalli P Immunological reviews (1983)
    27. [27]
      Processing by the thymus is not required for cells that cure and populate W/WV recipients. — Harrison DE, Astle CM, DeLaittre JA Blood (1979)
    28. [28]
      In vitro reactivity in allograft tolerance: persistence of mixed leukocyte culture reactivity in highly tolerant rats. — Wright PW, Loop SM, Bernstein ID Journal of immunology (Baltimore, Md. : 1950) (1977)
    29. [29]
      Analysis of different survival of weakly incompatible allografts of skin from the ear and back. — Polácková M, Viklický V Folia biologica (1976)
    30. [30]
      Mitigation of graft-versus-host disease in lethally irradiated mice grafted with spleen cells adherent to glass beads. — Gambrill MR, Ledney GD, MacVittie TJ Transplantation (1976)
    31. [31]
      Appearance of a syndrome similar to graft versus host reaction in C57 B1/6 mice bearing skin allogenic graft. — Nedelea M, Dima S Morphologie et embryologie (1975)
    32. [32]
      The influence of histocompatibility and antithymocyte serum on the ability of alloantigenic pretreatment to prolong the survival of mouse skin grafts. — Cohen N, Latorre JA Folia biologica (1975)

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