Deficits in Size-Adjusted Bone Mass in Children with Alagille Syndrome
Irene E. Olsen
Center for Epidemiology and Biostatistics, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, Ohio
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorRichard F. Ittenbach
Divisions of Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorAlisha J. Rovner
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Search for more papers by this authorMary B. Leonard
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Divisions of Nephrology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorAndrew E. Mulberg
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorVirginia A. Stallings
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorDavid A. Piccoli
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorCorresponding Author
Babette S. Zemel
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Address all correspondence and reprint request to Dr. Babette S. Zemel, The Children's Hospital of Philadelphia, Division, GI and Nutrition, CHOP North, Room 1560, 34th Street & Civic Center Boulevard, Philadelphia, Pennsylvania 19104 (e-mail: [email protected]).Search for more papers by this authorIrene E. Olsen
Center for Epidemiology and Biostatistics, Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, Ohio
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorRichard F. Ittenbach
Divisions of Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorAlisha J. Rovner
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Search for more papers by this authorMary B. Leonard
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Divisions of Nephrology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorAndrew E. Mulberg
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorVirginia A. Stallings
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorDavid A. Piccoli
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorCorresponding Author
Babette S. Zemel
Divisions of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Address all correspondence and reprint request to Dr. Babette S. Zemel, The Children's Hospital of Philadelphia, Division, GI and Nutrition, CHOP North, Room 1560, 34th Street & Civic Center Boulevard, Philadelphia, Pennsylvania 19104 (e-mail: [email protected]).Search for more papers by this authorSources of funding: NIH/NHLBI (5T32H07433); General Clinical Research Center (M01RR00240); National Institutes of Health (RO3 DK52481).
ABSTRACT
Objectives:
To describe bone status in children with Alagille syndrome (AGS) and healthy control children adjusted for age, gender and height (HT), and to identify dietary intake and AGS-related factors associated with bone status.
Methods:
Prepubertal children with AGS and healthy controls comparable in age and ethnicity were evaluated. Subjects were ≥4 years of age, prepubertal and had whole body (WB) and/or lumbar spine (LS) dual energy X-ray absorptiometry (DXA) scans of acceptable quality. Anthropometric (weight, HT), diet and AGS-specific data (e.g., coefficient of fat absorption, labs, liver transplantation) were also collected. Bone area (BA), bone mineral content (BMC) and HT were log transformed for best fit. Bone data were analyzed unadjusted, adjusted for gender, age and HT, and as HT-specific z-scores.
Results:
AGS and control groups were similar in age, pubertal status and ethnicity. Children with AGS were small-for-age, had decreased BA and BMC-for-age, and decreased WB BA and BMC-for-HT z-scores compared to healthy controls. Prevalence of low BMC-for-HT z-scores (< −2) among AGS subjects was 20% for the WB and 39% for the LS. Bone mineralization was positively related to fat absorption but not dietary intake.
Conclusions:
Children with AGS have deficits in bone size and bone mass relative to body size. Modifiable factors, such as treatment of malabsorption should be explored as an early focus of AGS care to prevent bone fragility.
REFERENCES
- 1Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16: 243–51.
- 2Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16: 235–42.
- 3Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 1975; 86: 63–71.
- 4Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987; 110: 195–200.
- 5Piccoli DA. Alagille Syndrome. In: FJ Suchy, RJ Sokol, WF Balistreri, editors. Liver Disease in Children. Philadelphia: Lippincott Williams & Wilkins, 2001: 327–42.
- 6Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet 2003; 40: 891–5.
- 7Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995; 127: 220–4.
- 8Krantz ID, Rand EB, Genin A, et al. Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet 1997; 70: 80–6.
10.1002/(SICI)1096-8628(19970502)70:1<80::AID-AJMG15>3.0.CO;2-T CAS PubMed Web of Science® Google Scholar
- 9Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999; 29: 822–9.
- 10Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999; 29: 431–7.
- 11Chong SK, Lindridge J, Moniz C, Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts. J Pediatr Gastroenterol Nutr 1989; 9: 445–9.
- 12John HA, Loomes K, Weyler R, Stallings VA, Piccoli DA, Mulberg AE. A study of pancreatic function in 17 children with Alagille Syndrome. (abstract). Gastroenterology 1998; 114: A885.
- 13Sokol RJ, Stall C. Anthropometric evaluation of children with chronic liver disease. Am J Clin Nutr 1990; 52: 203–8.
- 14Wasserman D, Zemel BS, Mulberg AE, et al. Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome. J Pediatr 1999; 134: 172–7.
- 15Rovner AJ, Schall JI, Jawad AF, et al. Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr 2002; 35: 495–502.
- 16Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Does liver transplantation affect growth pattern in Alagille syndrome? Liver Transpl 2000; 6: 582–7.
- 17Holt RI, Broide E, Buchanan CR, et al. Orthotopic liver transplantation reverses the adverse nutritional changes of end-stage liver disease in children. Am J Clin Nutr 1997; 65: 534–42.
- 18Suchy FJ, Burdelski M, Tomar BS, Sokol RJ. Cholestatic liver disease: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2002; 35(Suppl 2): S89–S97.
- 19Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis 2001; 21: 525–34.
- 20Heubi JE, Hollis BW, Specker B, Tsang RC. Bone disease in chronic childhood cholestasis. I. Vitamin D absorption and metabolism. Hepatology 1989; 9: 258–64.
- 21Batres LA, Rovner AJ, Jawad AF, et al. Bone disease in children with Alagille Syndrome. (abstract) J Pediatr Gastroenterol Nutr 2001; 33: 366.
- 22Emerick KM, Sentongo TA, Brickman W, Pawlowska J, Grygottis JC, Whitington PF. Bone mineral density in pre-pubertal children with Alagille's Syndrome and progressive intrahepatic cholestasis (abstract). J Pediatr Gastroenterol Nutr 2001; 33: 366.
- 23Bucuvalas JC, Heubi JE, Specker BL, Gregg DJ, Yergey AL, Vieira NE. Calcium absorption in bone disease associated with chronic cholestasis during childhood. Hepatology 1990; 12: 1200–5.
- 24Argao EA, Specker BL, Heubi JE. Bone mineral content in infants and children with chronic cholestatic liver disease. Pediatrics 1993; 91: 1151–4.
- 25Heubi JE, Higgins JV, Argao EA, Sierra RI, Specker BL. The role of magnesium in the pathogenesis of bone disease in childhood cholestatic liver disease: a preliminary report. J Pediatr Gastroenterol Nutr 1997; 25: 301–6.
- 26Glasova H, Beuers U. Extrahepatic manifestations of cholestasis. J Gastroenterol Hepatol 2002; 17: 938–48.
- 27Gordon CC, Chumlea WC, Roche AF. Stature, Recumbent Length, and Weight. In: Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics Books, 1988: 3–8.
- 28Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF. Whole body bone mineral content in healthy children and adolescents. Arch Dis Child 1997; 76: 9–15.
- 29Molgaard C, Thomsen BL, Michaelsen KF. Whole body bone mineral accretion in healthy children and adolescents. Arch Dis Child 1999; 81: 10–5.
- 30Ellis KJ, Shypailo RJ, Hardin DS, et al. Z score prediction model for assessment of bone mineral content in pediatric diseases. J Bone Miner Res 2001; 16: 1658–64.
- 31Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am J Clin Nutr 1994; 60: 837–42.
- 32Heaney RP. Bone mineral content, not bone mineral density, is the correct bone measure for growth studies. Am J Clin Nutr 2003; 78: 348–52.
- 33Leonard MB, Zemel BS. Current concepts in pediatric bone disease. Pediatr Clin North Am 2002; 49: 143–73.
- 34Mundy GR. Bone remodeling. In: MJ Favus, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Philadelphia: Lippincott Williams & Wilkins, 1999: 30–8.
- 35Wang MC, Aguirre M, Bhudhikanok GS, et al. Bone mass and hip axis length in healthy Asian, black, Hispanic, and white American youths. J Bone Miner Res 1997; 12: 1922–35.
- 36 WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. [Report] Geneva, Switzerland: 1994.
- 37Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data 2000; 314: 1–27.
- 38Tanner JM. Growth at adolescence. 2nd ed. Oxford: Blackwell Scientific Publications, 1962.
- 39Leonard MB, Propert KJ, Zemel BS, Stallings VA, Feldman HI. Discrepancies in pediatric bone mineral density reference data: potential for misdiagnosis of osteopenia. J Pediatr 1999; 135(2 Pt 1): 182–8.
- 40Leonard MB, Feldman HI, Zemel BS, Berlin JA, Barden EM, Stallings VA. Evaluation of low density spine software for the assessment of bone mineral density in children. J Bone Miner Res 1998; 13: 1687–90.
- 41Taylor A, Konrad PT, Norman ME, Harcke HT. Total body bone mineral density in young children: influence of head bone mineral density. J Bone Miner Res 1997; 12: 652–5.
- 42 Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. [report] Washington, D.C.: National Academy Press, 2001.
- 43 Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride. [report] Washington, D.C.: National Academy Press, 1997.
- 44 Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, choldesterol, protein and amino acids. [report] Washington, D.C.: The National Academic Press, 2003.
- 45Hollis BW, Kamerud JQ, Kurkowski A, Beaulieu J, Napoli JL. Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with an I-125-labeled tracer. Clin Chem 1996; 42: 586–92.
- 46Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin-D status by radioimmunoassay with an I-125 labeled tracer. Clin Chem 1993; 39: 529–33.
- 47Leonard MB, Shults J, Elliott DM, Stallings VA, Zemel BS. Interpretation of whole body dual energy x-ray absorptiometry measures in children: comparison with peripheral quantitative computed tomography. Bone 2004; 34: 1044–52.
- 48Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res 1992; 7: 137–45.
- 49Altman DG. Construction of age-related reference centiles using absolute residuals. Stat Med 1993; 12: 917–24.
- 50Zhang J, Quan H, Ng J, Stepanavage ME. Some statistical methods for multiple endpoints in clinical trials. Control Clin Trials 1997; 18: 204–21.
- 51Hoffenberg EJ, Smith D, Sauaia A, Narkewicz MR, Sokol RJ. Growth is not related to the presence of vertebral anomalies in Alagille syndrome. J Pediatr Gastroenterol Nutr 1998; 27: 468.
10.1097/00005176-199810000-00043 Google Scholar
- 52Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatr Radiol 2002; 32: 114–9.
- 53Kobayashi A, Kawai S, Utsunomiya T, Obe Y. Bone disease in infants and children with hepatobiliary disease. Arch Dis Child 1974; 49: 641–6.
- 54DeRusso PA, Spevak MR, Schwarz KB. Fractures in biliary atresia misinterpreted as child abuse. Pediatrics 2003; 112(1 Pt 1): 185–8.
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