Insulin-like growth factor-I predicts sinusoidal obstruction syndrome following pediatric hematopoietic stem cell transplantation

Abstract

Sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT) initiated through damage of sinusoidal endothelium and inflammation. Insulin-like growth factor-l (IGF-l) maintains and repairs endothelium and intestinal mucosa. We hypothesized that low IGF-l levels may increase the risk of inflammatory complications, such as SOS, in HSCT-patients. We prospectively measured IGF-l concentrations in 121 pediatric patients before, during, and after allogeneic HSCT. Overall, IGF-l levels were significantly reduced compared with healthy sex- and age-matched children. IGF-I levels pre-HSCT and at day 0 were inversely associated with C-reactive protein levels, hyperbilirubinemia, and number of platelet transfusions within the first 21 days post-transplant. Low levels of IGF-I before conditioning and at day of transplant were associated with increased risk of SOS diagnosed by the modified Seattle criteria (pre-HSCT: OR = 1.7 (95% CI: 1.2–2.6, p = 0.01), and the pediatric EBMT criteria (pre-HSCT: 1.7 (1.2–2.5, p = 0.009) and day 0: 1.7 (1.3–2.5, p = 0.001)/SDS decrease in IGF-1). These data suggest that IGF-I is protective against cytotoxic damage and SOS, most likely through trophic effects on endothelial cells and anti-inflammatory properties, and may prove useful as a predictive biomarker of SOS.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: IGF-I and IGFBP-3 plasma levels as sex- and age-adjusted SD-scores during pediatric HSCT from before conditioning until 21 days post transplant.
Fig. 2: Associations between IGF-I levels and CRP during the first three weeks post-HSCT.
Fig. 3: Associations between IGF-I levels and bilirubin during the first three weeks post-HSCT.
Fig. 4: IGF-I levels before conditioning until three weeks post-transplant according to a diagnosis of SOS.

References

  1. 1.

    Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive disease). J Clin Exp Hepatol. 2014;4:332–46.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Coppell JA, Richardson PG, Soiffer R, Martin PL, Nancy A, Chen A, et al. Hepatic veno-occlusive disease following stem cell transplantatation: incidence, clinical course, and outcome. Biol Blood Marrow Transpl. 2010;16:157–68.

    Article  Google Scholar 

  3. 3.

    Corbacioglu S, Carreras E, Ansari M, Balduzzi A, Cesaro S, Dalle JH, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: A new classification from the European society for blood and marrow transplantation. Bone Marrow Transpl. 2018;53:138–45.

    CAS  Article  Google Scholar 

  4. 4.

    Eissner G, Multhoff G, Holler E. Influence of bacterial endotoxin on the allogenicity of human endothelial cells. Bone Marrow Transplant. 1998;21:1286–8.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transpl. 2011;46:1495–502.

    CAS  Article  Google Scholar 

  6. 6.

    Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Corbacioglu S, Carreras E, Mohty M, Pagliuca A, Boelens JJ, Damaj G, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the international compassionate-use program. Biol Blood Marrow Transpl. 2016;22:1874–82.

    CAS  Article  Google Scholar 

  8. 8.

    Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: Response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002;100:4337–43.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Corbacioglu S, Carreras E, Mohty M, Pagliuca A, Ballabio M, Hume R, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: an update from the international compassionate use program in 710 patients. Biol Blood Marrow Transpl. 2015;21:S108.

    Article  Google Scholar 

  10. 10.

    Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, et al. Defibrotide for pediatric and adult patients with hepatic veno-occlusive disease: Interim age subgroup survival analysis from an ongoing expanded access program in the US. Bone Marrow Transpl. 2015;50:S74–5.

    Article  Google Scholar 

  11. 11.

    Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: An open-label, phase 3, randomised controlled trial. Lancet. 2012;379:1301–9.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): A retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transpl. 2004;33:189–95.

    CAS  Article  Google Scholar 

  13. 13.

    Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, et al. Earlier defibrotide initiation post-diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome improves Day +100 survival following haematopoietic stem cell transplantation. Br J Haematol. 2017;178:112–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Carreras E, Grañena A, Navasa M, Bruguera M, Marco V, Sierra J, et al. On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease. Ann Hematol. 1993;66:77–80.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Mcdonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology. 1984;4:116–22.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kammersgaard MB, Kielsen K, Heilmann C, Ifversen M, Müller K. Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome. Bone Marrow Transpl. 2019;54:1406–18.

    Article  Google Scholar 

  17. 17.

    Juul A. Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res. 2003;13:113–70.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Liu S-J, Zhong Y, You X-Y, Liu W-H, Li A-Q, Liu S-M. Insulin-like growth factor 1 opposes the effects of C-reactive protein on endothelial cell activation. Mol Cell Biochem. 2014;385:199–205.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Thum T, Hoeber S, Froese S, Klink I, Stichtenoth DO, Galuppo P, et al. Age-dependent impairment of endothelial progenitor cells is corrected by growth hormone mediated increase of insulin-like growth factor-1. Circ Res. 2007;100:434–43.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, et al. Insulin-like growth factor-1 as a vascular protective factor. Circulation. 2004;110:2260–5.

    PubMed  Article  Google Scholar 

  21. 21.

    Barnard SA, Smith W, Mels CMC, Botha S, Schutte AE. Bioavailable IGF-1 is beneficially associated with biomarkers of endothelial function in young healthy adults: The African-PREDICT study. Growth Horm IGF Res. 2018;41:28–33.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Sukhanov S, Higashi Y, Shai SY, Vaughn C, Mohler J, Li Y, et al. IGF-1 reduces inflammatory responses, suppresses oxidative stress, and decreases atherosclerosis progression in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2007;27:2684–90.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Spies M, Wolf SE, Barrow RE, Jeschke MG, Herndon DN. Modulation of types I and II acute phase reactants with insulin-like growth factor-1/binding protein-3 complex in severely burned children. Crit Care Med. 2002;30:83–8.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Jeschke MG, Barrow RE, Suzuki F, Rai J, Benjamin D, Herndon DN. IGF-I/IGFBP-3 equilibrates ratios of pro- to anti-inflammatory cytokines, which are predictors for organ function in severely burned pediatric patients. Mol Med. 2002;8:238–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Zheng Y, Song Y, Han Q, Liu W, Xu J, Yu Z, et al. Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis. Am J Physiol - Endocrinol Metab. 2018;315:E638–49.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Howarth GS, Shoubridge CA. Enhancement of intestinal growth and repair by growth factors. Curr Opin Pharm. 2001;1:568–74.

    CAS  Article  Google Scholar 

  27. 27.

    Blijlevens NMA, Donnelly JP, DePauw BE. Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transpl. 2005;36:703–7.

    CAS  Article  Google Scholar 

  28. 28.

    van der Velden WJFM, Herbers AHE, Feuth T, Schaap NPM, Donnelly JP, Blijlevens NMA. Intestinal damage determines the inflammatory response and early complications in patients receiving conditioning for a stem cell transplantation. PLoS ONE. 2010;5:e15156.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Kornblit B, Müller K. Sensing danger: toll-like receptors and outcome in allogeneic hematopoietic stem cell transplantation. Nat Publ Gr. 2016;52:499–505.

    Google Scholar 

  30. 30.

    Weischendorff S, Kielsen K, Sengeløv H, Jordan K, Claus H, Pedersen AE, et al. Associations between levels of insulin-like growth factor 1 and sinusoidal obstruction syndrome after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transpl. 2017;52:863–9.

    CAS  Article  Google Scholar 

  31. 31.

    Jordan K, Pontoppidan P, Uhlving HH, Kielsen K, Burrin DG, Weischendorff S, et al. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2017;23:1170–6.

    CAS  Article  Google Scholar 

  32. 32.

    Vækst & Reproduktion—Metodeliste. 2020. https://hormlabvejl.regionh.dk/Metodeliste.asp

  33. 33.

    The Danish Accreditation Fund. Skovlunde D 2013. Accreditation for Medical Examination. http://published.danak.dk/register.asp?sag=06-1013&nohead=y&lang=e

  34. 34.

    Rigby RA, Stasinopoulos DM, Lane PW. Generalized additive models for location, scale and shape. J R Stat Soc Ser C Appl Stat. 2005;54:507–54.

    Article  Google Scholar 

  35. 35.

    Dignan FL, Wynn RF, Hadzic N, Karani J, Quaglia A, Pagliuca A, et al. BCSH/BSBMT guideline: Diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation. Br J Haematol. 2013;163:444–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Soliman A, ElZalabany M, Mazloum Y, Bedair S, Ragab M, Rogol A, et al. Spontaneous and provoked growth hormone (GH) secretion and insulin-like growth factor I (IFG-I) concentration in patients with beta thalassaemia and delayed growth. J Trop Pediatr. 1999;45:327–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Mohnike KL, Kluba U, Mittler U, Aumann V, Vorwerk P, Blum WF. Serum levels of insulin-like growth factor-I, -II and insulin-like growth factor binding proteins -2 and -3 in children with acute lymphoblastic leukaemia. Eur J Pediatr. 1996;155:81–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Arguelles B, Barrios V, Pozo J, Munoz MT, Argente J. Modifications of growth velocity and the insulin-like growth factor system in children with acute lymphoblastic leukemia: a longitudinal study. J Clin Endocrinol Metab. 2000;85:4087–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Harrela M, Koistinen H, Kaprio J, Lehtovirta M, Tuomilehto J, Eriksson J, et al. Genetic and environmental components of interindividual variation in circulating. Society. 1996;98:2612–5.

    CAS  Google Scholar 

  40. 40.

    Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives—a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transpl. 2015;50:781–9.

    CAS  Article  Google Scholar 

  41. 41.

    DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22:027–42.

    Article  Google Scholar 

  42. 42.

    Higashi Y, Quevedo HC, Tiwari S, Sukhanov S, Shai SY, Anwar A, et al. Interaction between insulin-like growth factor-1 and atherosclerosis and vascular aging. Cardiovascular Issues Endocrinol. 2014;43:107–24.

    Google Scholar 

  43. 43.

    Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015;168:481–91.

    PubMed  Article  Google Scholar 

  44. 44.

    Chen S, Hu M, Shen M, Wang S, Wang C, Chen F, et al. IGF-1 facilitates thrombopoiesis primarily through Akt activation. Blood. 2018;132:210–22.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Blijlevens NM. a. Implications of treatment-induced mucosal barrier injury. Curr Opin Oncol. 2005;17:605–10.

    PubMed  Google Scholar 

  46. 46.

    Richardson PG, Carreras E, Iacobelli M, Nejadnik B. The use of defibrotide in blood and marrow transplantation. Blood Adv. 2018;2:1495–509.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB. Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol. 1993;11:1729–36.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Naples JC, Skeens MA, Auletta J, Rangarajan H, Abu-Arja R, Horwitz E, et al. Anicteric veno-occlusive disease after hematopoietic stem cell transplantation in children. Bone Marrow Transplant. 2016;51:135–7.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Shimon I, Shpilberg O. The insulin-like growth factor system in regulation of normal and malignant hematopoiesis. Leukemia Res. 1995;19:233–40.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Financial support was obtained from The Research Council at Rigshospitalet and The Childhood Cancer Foundation (#2017–1997).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Maria Ebbesen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ebbesen, M., Weischendorff, S., Kielsen, K. et al. Insulin-like growth factor-I predicts sinusoidal obstruction syndrome following pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-01127-3

Download citation

Search