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Translational Lessons from a Case of Combined Heart and Liver Transplantation for Familial Hypercholesterolemia 20 Years Post-operatively

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Abstract

We review the lessons from a case of combined heart and liver transplantation (CHLT) 20 years post-operatively from the molecular to clinical levels. CHLT replaces cardiac function and provides a new source of Low density lipoprotein–receptors (LDL-R) known to be deficient in Familial Hypercholesterolaemia. Little is known of the long-term outcomes of this strategy. We review the lessons from a case of CHLT 20 years post-operatively, which illustrate the successful transition from the molecular understanding of the pathophysiology to the clinical therapy. Most importantly, there is evidence that transplantation of multiple organs from a single donor promotes operational tolerance, especially in the case of the liver. This lady presented in severe heart failure with advanced atherosclerotic disease resulting in coronary artery and aortic valve stenosis. The serum LDL-C concentration of 13 mmol/L was refractory to conventional therapy. Genetic analysis showed a large deletion on one allele of the LDL-R, and a mutant allele that produced a receptor which was delayed in its transport to the cell membrane and had 10% of normal receptor activity. The patient had a normalised lipid-profile directly after CHLT (2.1 mmol/L), and this has remained stable since the time of operation. Apart from a minor episode of cardiac rejection at 3 weeks post-CHLT, the patient has had excellent heart and liver function throughout. This patient has not experienced any signs of rejection, despite only low-dose immunosuppression. We review what we have learnt from this case at the molecular and clinical levels.

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References

  1. Soutar, A. K., & Naoumova, R. P. (2007). Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nature Clinical Practice. Cardiovascular Medicine, 4, 214–225.

    Article  PubMed  CAS  Google Scholar 

  2. Sibley, C., & Stone, N. J. (2006). Familial hypercholesterolemia: a challenge of diagnosis and therapy. Cleveland Clinic Journal of Medicine, 73, 57–64.

    Article  PubMed  Google Scholar 

  3. Allen, J. M., Thompson, G. R., Myant, N. B., Steiner, R., & Oakley, C. M. (1980). Cadiovascular complications of homozygous familial hypercholesterolaemia. British Heart Journal, 44, 361–368.

    Article  PubMed  CAS  Google Scholar 

  4. Lopez-Santamaria, M., Migliazza, L., Gamez, M., Murcia, J., Diaz-Gonzalez, M., Camarena, C., et al. (2000). Liver transplantation in patients with homozygotic familial hypercholesterolemia previously treated by end-to-side portocaval shunt and ileal bypass. Journal of Pediatric Surgery, 35, 630–633.

    Article  PubMed  CAS  Google Scholar 

  5. Thompsen, J., & Thompson, P. D. (2006). A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis, 189, 31–38.

    Article  PubMed  CAS  Google Scholar 

  6. Thompson, G. R., Barbir, M., Davies, D., Dobral, P., Gesinde, M., Livingston, M., et al. (2009). Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis, 208(2), 317–321.

    Article  PubMed  Google Scholar 

  7. Starzl, T. E., Bilheimer, D. W., Bahnson, H. T., Shaw, B. W., Jr., Hardesty, R. L., Griffith, B. P., et al. (1984). Heart-liver transplantation in a patient with familial hypercholesterolaemia. Lancet, 1, 1382–1383.

    Article  PubMed  CAS  Google Scholar 

  8. Bilheimer, D. W., Goldstein, J. L., Grundy, S. M., Starzl, T. E., & Brown, M. S. (1984). Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. The New England Journal of Medicine, 311, 1658–1664.

    Article  PubMed  CAS  Google Scholar 

  9. Bilheimer, D. W. (1984). Regulation of LDL receptors in vivo. Agents and Actions. Supplements, 16, 191–203.

    PubMed  CAS  Google Scholar 

  10. Brown, M. S., & Goldstein, J. L. (1974). Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proceedings of the National Academy of Sciences of the United States of America, 71, 788–792.

    Article  PubMed  CAS  Google Scholar 

  11. Brown, M. S., & Goldstein, J. L. (1976). Familial hypercholesterolemia: a genetic defect in the low-density lipoprotein receptor. The New England Journal of Medicine, 294, 1386–1390.

    Article  PubMed  CAS  Google Scholar 

  12. Poustie, V. J., & Rutherford, P. (2001). Dietary treatment for familial hypercholesterolaemia. Cochrane Database Syst Rev, 1, CD001918.

    Google Scholar 

  13. Schmidt, H. H., Tietge, U. J., Buettner, J., Barg-Hock, H., Offner, G., Schweitzer, S., et al. (2008). Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation. Clinical Transplantation, 22, 180–184.

    Article  PubMed  Google Scholar 

  14. Schmidt, H. H., Hill, S., Makariou, E. V., Feuerstein, I. M., Dugi, K. A., & Hoeg, J. M. (1996). Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. The American Journal of Cardiology, 77, 575–580.

    Article  PubMed  CAS  Google Scholar 

  15. Billingham, R. E., Brent, L., & Medawar, P. B. (1953). Actively acquired tolerance of foreign cells. Nature, 172, 603–606.

    Article  PubMed  CAS  Google Scholar 

  16. Shaw, B. W., Jr., Bahnson, H. T., Hardesty, R. L., Griffith, B. P., & Starzl, T. E. (1985). Combined transplantation of the heart and liver. Annals of Surgery, 202, 667–672.

    Article  PubMed  Google Scholar 

  17. Hoeg, J. M., Starzl, T. E., & Brewer, H. B., Jr. (1987). Liver transplantation for treatment of cardiovascular disease: comparison with medication and plasma exchange in homozygous familial hypercholesterolemia. The American Journal of Cardiology, 59, 705–707.

    Article  PubMed  CAS  Google Scholar 

  18. Valdivielso, P., Escolar, J. L., Cuervas-Mons, V., Pulpon, L. A., Chaparro, M. A., & Gonzalez-Santos, P. (1988). Lipids and lipoprotein changes after heart and liver transplantation in a patient with homozygous familial hypercholesterolemia. Annals of Internal Medicine, 108, 204–206.

    PubMed  CAS  Google Scholar 

  19. Barbir, M., Khaghani, A., Kehely, A., Tan, K. C., Mitchell, A., Thompson, G. R., et al. (1992). Normal levels of lipoproteins including lipoprotein(a) after liver-heart transplantation in a patient with homozygous familial hypercholesterolaemia. The Quarterly Journal of Medicine, 85, 807–812.

    PubMed  CAS  Google Scholar 

  20. Alkofer, B. J., Chiche, L., Khayat, A., Deshayes, J. P., Lepage, A., Saloux, E., et al. (2005). Liver transplant combined with heart transplant in severe heterozygous hypercholesterolemia: report of the first case and review of the literature. Transplantation Proceedings, 37, 2250–2252.

    Article  PubMed  CAS  Google Scholar 

  21. Strober, S., Dhillon, M., Schubert, M., Holm, B., Engleman, E., Benike, C., et al. (1989). Acquired immune tolerance to cadaveric renal allografts: a study of three patients treated with total lymphoid irradiation. N Engl J Med, 321, 28–33.

    Article  PubMed  CAS  Google Scholar 

  22. Sayegh, M. H., Fine, N. A., Smith, J. L., Rennke, H. G., Milford, E. L., & Tilney, N. L. (1991). Immunologic tolerance to renal allografts after bone marrow transplants from the same donors. Annals of Internal Medicine, 114, 954–955.

    PubMed  CAS  Google Scholar 

  23. Rana, A., Robles, S., Russo, M. J., Halazun, K. J., Woodland, D. C., Witkowski, P., et al. (2008). The combined organ effect: protection against rejection? Annals of Surgery, 248, 871–879.

    Article  PubMed  Google Scholar 

  24. Mazariegos, G. V., Reyes, J., Marino, I. R., Demetris, A. J., Flynn, B., Irish, W., et al. (1997). Weaning of immunosuppression in liver transplant recipients. Transplantation, 63, 243–249.

    Article  PubMed  CAS  Google Scholar 

  25. Devlin, J., Doherty, D., Thomson, L., Wong, T., Donaldson, P., Portmann, B., et al. (1998). Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology, 27, 926–933.

    Article  PubMed  CAS  Google Scholar 

  26. Koshiba, T., Li, Y., Takemura, M., Wu, Y., Sakaguchi, S., Minato, N., et al. (2007). Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transplant Immunology, 17, 94–97.

    Article  PubMed  CAS  Google Scholar 

  27. Takatsuki, M., Uemoto, S., Inomata, Y., Sakamoto, S., Hayashi, M., Ueda, M., et al. (2001). Analysis of alloreactivity and intragraft cytokine profiles in living donor liver transplant recipients with graft acceptance Transpl. Immunol., 8, 279–286.

    CAS  Google Scholar 

  28. Calne, R. Y. (1969). Strange english PIGS. Lancet, 2, 940–941.

    Google Scholar 

  29. Kamada, N., Brons, G., & Davies, H. S. (1980). Fully allogeneic liver grafting in rats induces a state of systemic nonreactivity to donor transplantation antigens. Transplantation, 29, 429–431.

    Article  PubMed  CAS  Google Scholar 

  30. Starzl, T. E., Demetris, A. J., Trucco, M., Ramos, H., Zeevi, A., Rudert, W. A., et al. (1992). Systemic chimerism in human female recipients of male livers. Lancet, 340, 876–877.

    Article  PubMed  CAS  Google Scholar 

  31. Starzl, T. E., Demetris, A. J., Murase, N., Ildstad, S., Ricordi, C., & Trucco, M. (1992). Cell migration, chimerism, and graft acceptance. Lancet, 339, 1579–1582.

    Article  PubMed  CAS  Google Scholar 

  32. Spitzer, T. R., Delmonico, F., Tolkoff-Rubin, N., McAfee, S., Sackstein, R., Saidman, S., et al. (1999). Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation, 68, 480–484.

    Article  PubMed  CAS  Google Scholar 

  33. Lubaroff, D. M., & Silvers, W. K. (1973). Importance of chimerism in maintaining tolerance of skin allografts in mice. Journal of Immunology, 111, 65–71.

    CAS  Google Scholar 

  34. Racanelli, V., & Rehermann, B. (2006). The liver as an immunological organ. Hepatology, 43, S54–S62.

    Article  PubMed  CAS  Google Scholar 

  35. Tiegs, G., & Lohse, A. W. (2009). Immune tolerance: what is unique about the liver. J Autoimmun, 34(1), 1–6.

    Article  PubMed  Google Scholar 

  36. English, K., French, A., & Wood, K. J. (2010). Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell, 7, 431–442.

    Article  PubMed  CAS  Google Scholar 

  37. Martinez-Llordella, M., Lozano, J. J., Puig-Pey, I., Orlando, G., Tisone, G., Lerut, J., et al. (2008). Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. The Journal of Clinical Investigation, 118, 2845–2857.

    PubMed  CAS  Google Scholar 

  38. Yacoub, M. (2008). Heart transplantation: the end of the beginning. American Journal of Transplantation, 8, 1767–1768.

    Article  PubMed  CAS  Google Scholar 

  39. Hamour, I. M., Omar, F., Lyster, H. S., Palmer, A., & Banner, N. R. (2009). Chronic kidney disease after heart transplantation. Nephrology, Dialysis, Transplantation, 24, 1655–1662.

    Article  PubMed  Google Scholar 

  40. Lyster, H., Leaver, N., Hamour, I., Palmer, A., & Banner, N. R. (2009). Transfer from ciclosporin to mycophenolate-sirolimus immunosuppression for chronic renal disease after heart transplantation: safety and efficacy of two regimens. Nephrology, Dialysis, Transplantation, 24, 3872–3875.

    Article  PubMed  CAS  Google Scholar 

  41. Lee, J. H., Lee, S. K., Lee, H. J., Seo, J. M., Joh, J. W., Kim, S. J., et al. (2009). Withdrawal of immunosuppression in pediatric liver transplant recipients in Korea. Yonsei Medical Journal, 50, 784–788.

    Article  PubMed  Google Scholar 

  42. Benitez, C., Lozano, J. J., & Fueyo, A. S. (2009). Gene expression profiling and transplantation tolerance in the clinic. Transplantation, 88, S50–S53.

    Article  PubMed  CAS  Google Scholar 

  43. Rajamannan, N. M., Edwards, W. D., & Spelsberg, T. C. (2003). Hypercholesterolemic aortic-valve disease. The New England Journal of Medicine, 349(7), 717–718. doi:10.1056/NEJMc031360

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Magdi Yacoub Institute, Heart Science Centre, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Uxbridge, UK

    Michael Ibrahim, Ismail El-Hamamsy & Magdi H. Yacoub

  2. Department of Cardiology, Royal Brompton and Harefield NHS Foundation Trust, Middlesex, UB9 6JH, UK

    Mahmoud Barbir

  3. Heart Science Centre, Harefield Hospital, Hill End Road, Middlesex, UK, UB9 6JH

    Magdi H. Yacoub

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  1. Michael Ibrahim
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  4. Magdi H. Yacoub
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Correspondence to Magdi H. Yacoub.

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Ibrahim, M., El-Hamamsy, I., Barbir, M. et al. Translational Lessons from a Case of Combined Heart and Liver Transplantation for Familial Hypercholesterolemia 20 Years Post-operatively. J. of Cardiovasc. Trans. Res. 5, 351–358 (2012). https://doi.org/10.1007/s12265-011-9311-1

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