Kathleen M Loomes1, Cathie Spino2, Nathan P Goodrich3, Thomas N Hangartner4, Amanda E Marker4, James E Heubi5, Binita M Kamath6, Benjamin L Shneider7, Philip Rosenthal8, Paula M Hertel7, Saul J Karpen9, Jean P Molleston10, Karen F Murray11, Kathleen B Schwarz12, Robert H Squires13, Jeffrey Teckman14, Yumirle P Turmelle15, Estella M Alonso16, Averell H Sherker17, John C Magee18, Ronald J Sokol19. 1. Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA. 2. University of Michigan, Ann Arbor, MI. 3. Arbor Research Collaborative for Health, Ann Arbor, MI. 4. Department of Biomedical, Industrial & Human Factors Engineering, Wright State University, Dayton, OH. 5. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Medical Center, Cincinnati, OH. 6. Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. 7. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Houston, TX. 8. Division of Gastroenterology, Hepatology and Nutrition, University of California San Francisco, San Francisco, CA. 9. Division of Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Atlanta, GA. 10. Division of Gastroenterology, Hepatology and Nutrition, Indiana University, Riley Hospital for Children, Indianapolis, IN. 11. Division of Gastroenterology and Hepatology, University of Washington, School of Medicine, Seattle Children's Hospital, Seattle, WA. 12. Johns Hopkins School of Medicine, Baltimore, MD. 13. Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA. 14. Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO. 15. Washington University School of Medicine, St. Louis, MO. 16. Ann and Robert Lurie Children's Hospital, Chicago, IL. 17. Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. 18. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI. 19. Section of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.
Abstract
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsin deficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGS participants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
Osteopenia and bone fractures are significant causes of morbidity in children with cholestatic liver disease. Dual-energy X-ray absorptiometry (DXA) analysis was performed in children with intrahepatic cholestatic diseases who were enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis in the Childhood Liver Disease Research Network. DXA was performed on participants aged >5 years (with native liver) diagnosed with bile acid synthetic disorder (BASD), alpha-1 antitrypsindeficiency (A1AT), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Weight, height, and body mass index Z scores were lowest in CIC and ALGS. Total bilirubin (TB) and serum bile acids (SBA) were highest in ALGS. Bone mineral density (BMD) and bone mineral content (BMC) Z scores were significantly lower in CIC and ALGS than in BASD and A1AT (P < 0.001). After anthropometric adjustment, bone deficits persisted in CIC but were no longer noted in ALGS. In ALGS, height-adjusted and weight-adjusted subtotal BMD and BMC Z scores were negatively correlated with TB (P < 0.001) and SBA (P = 0.02). Mean height-adjusted and weight-adjusted subtotal BMC Z scores were lower in ALGSparticipants with a history of bone fractures. DXA measures did not correlate significantly with biliary diversion status. Conclusion: CIC patients had significant bone deficits that persisted after adjustment for height and weight and generally did not correlate with degree of cholestasis. In ALGS, low BMD and BMC reference Z scores were explained by poor growth. Anthropometrically adjusted DXA measures in ALGS correlate with markers of cholestasis and bone fracture history. Reduced bone density in this population is multifactorial and related to growth, degree of cholestasis, fracture vulnerability, and contribution of underlying genetic etiology.
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