Location: Children's Nutrition Research CenterTitle: Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation
|JORDAN, KARINA - Baylor College Of Medicine|
|PONTOPPIDAN, PETER - Baylor College Of Medicine|
|UHLVING, HILDE - Baylor College Of Medicine|
|KIELSEN, KATRINE - Baylor College Of Medicine|
|Burrin, Douglas - Doug|
|WEISCHENDORFF, SARAH - Baylor College Of Medicine|
|CHRISTENSEN, IB - Rigshospitalet - Copenhagen University Hospital|
|JORGENSEN, MARIANNE - Baylor College Of Medicine|
|HEILMANN, CARSTEN - Baylor College Of Medicine|
|SENGELOV, HENRIK - Rigshospitalet - Copenhagen University Hospital|
|MULLER, KLAUS - Baylor College Of Medicine|
Submitted to: Biology of Blood and Marrow Transplantation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2017
Publication Date: 7/1/2017
Publication URL: http://handle.nal.usda.gov/10113/5801818
Citation: Jordan, K., Pontoppidan, P., Uhlving, H.H., Kielsen, K., Burrin, D.G., Weischendorff, S., Christensen, I.J., Jorgensen, M.H., Heilmann, C., Sengelov, H., Muller, K. 2017. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 23(7):1170-1176.
Interpretive Summary: Many infants that develop blood cancers are treated with radiation and chemotherapy which destroys their immune system. In order to restore the immune system, these infants receive a transplant of stem cells from a match donor, usually taken from bone marrow of a relative. After stem cell transplantation, these infants sometimes experience liver disease that may be related to the negative effects on the gastrointestinal tract (GI) caused by chemotherapy. The purpose of this human clinical study was to collect blood samples from 81 children and adults to test the idea that liver toxicity after stem cell transplantation is associated with increased GI toxicity and increased inflammation during the early post-transplantation period. The results of this study indicate that liver toxicity after stem cell transplantation is associated with an increased inflammatory markers during the phase of peak GI toxicity early after transplantation.
Technical Abstract: Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-regulating cytokines during the early post-transplantation period. We prospectively included 81 children and adults undergoing HSCT after myeloablative conditioning. Alanine aminotransferase (ALT), total bilirubin levels, and international normalized ratio were measured longitudinally until 3 months after the transplantation and related to levels of inflammatory markers (C-reactive protein [CRP], IL-6, and IL-10) and to plasma citrulline as a marker of intestinal toxicity during the first 3 weeks after HSCT. The majority of patients experienced ALT levels above the normal range (45 U/L) with significant increases at 3 months after HSCT. Increased levels of total bilirubin were observed in 26% during the 3-month period. Citrulline levels decreased significantly to a nadir at day 7 (B=.23; 95% confidence interval [CI], .12 to .35; P<.0001), but citrulline levels at nadir were not associated with parameters of liver toxicity. However, a faster reconstitution of mucosa with higher citrulline levels at day +21 correlated with lower bilirubin levels 3 months after HSCT (r=-.26, P=.034) and increased overall survival (hazard ratio, .88; 95% CI, .79 to .97; P=.008). Increased levels of CRP and IL-6 at day 7 after HSCT correlated positively with ALT and bilirubin, and in the multivariate analysis, IL-6 at day 7 appeared to be the only predicting risk factor for increased mean bilirubin during the early post-transplantation phase (B=.01; 95% CI, .01 to .02; P=.001) as well as maximum levels of bilirubin (B=.3; 95% CI, .12 to .48; P=.001) and occurrence of sinusoidal obstruction syndrome during the first 3 months after HSCT (odds ratio, 1.003; 95% CI, 1.001 to 1.005; P=.002). The results of this study indicate that liver toxicity after HSCT is associated with an increased inflammatory response mounted during the phase of maximal gastrointestinal toxicity in the early phase after transplantation.