Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Deficits in Size-Adjusted Bone Mass in Children with Alagille Syndrome
Olsen, Irene E.*†‡; Ittenbach, Richard F.§; Rovner, Alisha J.‡¶; Leonard, Mary B.‡∥; Mulberg, Andrew E.‡; Stallings, Virginia A.‡; Piccoli, David A.‡; Zemel, Babette S.‡
*Center for Epidemiology and Biostatistics and Division of Neonatology, Cincinnati Children's Hospital Medical Center; †Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, Ohio; ‡Divisions of Gastroenterology and Nutrition, §Biostatistics and Epidemiology, ∥Nephrology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ¶Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Received October 3, 2003; accepted July 13, 2004.
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: firstname.lastname@example.org).
Sources of funding: NIH/NHLBI (5T32H07433); General Clinical Research Center (M01RR00240); National Institutes of Health (RO3 DK52481).
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.
Alagille syndrome (AGS), or syndromic bile duct paucity, is an autosomal dominant disorder caused by a mutation of the Jagged1 (JAG1) gene (1,2). The diagnosis of AGS has traditionally been based on clinical criteria including bile duct paucity and three of five major clinical criteria: cholestasis, particular facies, heart murmur, eye and vertebral abnormalties (3-5). More recently, it has become clear that patients with a family history and even only one manifestation are likely to have the same mutation in Jagged1 as the proband and can be considered to have a mild form of AGS (6). Abnormalities of the kidney (4,7-10) or pancreas (9,11,12) are also associated with AGS. The overall combination and severity of organ system involvement varies even within a family (1).
Growth deficits, malnutrition and delayed pubertal development are well documented in children with AGS (3,9,13-18). Bone abnormalities and bone fractures are also common (7,10,18-24). It is not known, however, whether the increased fractures are related to abnormalities of cortical and/or trabecular bone structure (19). Malabsorption and steatorrhea, decreased pancreatic function, poor dietary intake and/or prescribed or voluntary dietary restrictions are likely involved in the development of these nutritional and bone deficits (12-15). Specific nutrient deficits such as vitamin D, vitamin K, calcium and magnesium also play a role in the development of bone deficits in children with cholestatic liver disease (20,23-26).
Dual-energy X-ray absorptiometry (DXA) is widely used to assess bone status. Results are traditionally expressed as bone mineral content (BMC) divided by bone area (BA) to generate areal bone mineral density (BMD). Areal BMD is used to diagnose osteoporosis in adults (27). Since both BMC and BA change during growth, areal BMD is less useful in evaluating children (28-33). Moreover, many children with AGS have short stature, therefore it is essential to consider stature in evaluating BA and BMC in children with AGS.
Cortical bone comprises over 80% of total bone mass (34), so whole body DXA measurement is a good indicator of cortical bone. In contrast, the lumbar spine is a predominantly trabecular site. This study evaluates both whole body (WB) and lumbar spine (LS) DXA measures to determine the pattern of AGS bone disease. The objectives were to describe differences in bone mass and skeletal dimensions in children with AGS compared with healthy children, adjusted for age, gender and stature, and to identify AGS-related factors associated with bone status.
SUBJECTS AND METHODS
Subjects were participants of two previously reported studies of prepubertal (Tanner Stage 1 or 2) children with AGS (14,15). The first study (AGS Study 1) included children diagnosed with AGS, without end-stage liver disease and treated at The Children's Hospital of Philadelphia (CHOP) (14). The second study (AGS Study 2) included children with AGS from pediatric care centers throughout North and Central America (15). Both studies were designed to evaluate growth and nutritional status of children with AGS. Participants were evaluated in their usual state of good health and were excluded if treated with pancreatic enzyme supplements or any medication known to affect growth. Subjects also had to be 4 years of age or greater and have whole body and/or spine scans of acceptable quality. There were no differences in age, pubertal development, gender, body size (body mass index z-score), markers of AGS disease characteristics (serum total bilirubin, cholesterol, alanine transaminase, total protein), DXA equipment or measurement techniques between the two AGS studies, therefore data from the two studies were pooled.
Prepubertal children enrolled as healthy controls for concurrent bone studies in the Nutrition and Growth Laboratory at CHOP were used for comparison. Subjects with chronic medical conditions or medication use that might affect growth, pubertal development, nutritional status or dietary intake were excluded. Based on reported differences in BMD and bone dimensions of African American children compared to non-African American children (30,35), the control group was restricted to non-African American subjects to match the AGS group.
All participants were evaluated by trained research staff at the CHOP Nutrition and Growth Laboratory and the General Clinical Research Center. The CHOP Institutional Review Board approved the protocols. Informed written consent was obtained from the parent or guardian of each subject, and assent was obtained from subjects 5 years of age and older.
Growth and maturation
Body weight (0.1 kg) was determined using an electronic scale (Scalatronix Inc., Wheaton, IL) and standing height (HT) (0.1 cm) was determined using a stadiometer (Holtain, Crymych, England) following standard techniques (36). Body mass index (BMI) was then calculated (weight/HT2). Age- and gender-specific weight (WT-Z), HT (HT-Z) and BMI (BMI-Z) z-scores (standard deviation scores) were derived using the CDC 2000 growth charts (37). Tanner stage of pubertal development was assessed by physical examination for pubic hair and breast/genital maturation (38).
Dual energy X-ray absorptiometry
Whole body and antero-posterior lumbar spine (L1-L4) scans were obtained by DXA (Hologic QDR 2000, Bedford, MA) in the array mode. In our lab, the long-term in vitro coefficient of variation measured daily on a spine phantom is less than 0.6%; the in vivo coefficient of variation is less than 1% (39). All scans were reviewed by two investigators (IEO, BSZ) to determine acceptable quality.
Pediatric analysis software (version 8.26A:1; Hologic, Inc.) for WB scans and low density analysis software (version 8.26A:1; Hologic, Inc.) for LS scans were used due to failure of the bone edge detection algorithm in the standard analysis mode (40). The skull was excluded from the whole body DXA data as recommended (41), due to variability in skull size in children.
Dietary intake of AGS subjects
Dietary intake was collected in AGS Study 2 using 3-day prospective weighed food records (15). Diet records were analyzed using a computerized nutrient database program (Food Processor, Version 7.1; ESHA Research, Salem, OR), and a 3-day average intake for all nutrients was calculated. Energy, macronutrient and micronutrient intake were compared to the Dietary Reference Intakes (DRI) (42-44). Energy and the following nutrients were explored for an impact on bone status and/or growth: protein, fat, vitamin D, calcium, phosphorus, magnesium and zinc.
Fasting blood samples were obtained for most of the children in the AGS group. Serum was analyzed for 25-hydroxyvitamin D (25-OHD) concentrations using a radioiodinated tracer. The lower limit of detection of the 25-OHD assay was 2.5 nmol/L (1ng/ml) (45,46). Low vitamin D status was defined as <11 ng/ml (43). Samples were also analyzed in the CHOP Clinical Laboratory using standard techniques for several measures including total bilirubin, cholesterol, albumin, alanine transaminase (ALT), aspartate transaminase (AST), prothrombin time (PT) and partial thromboplastin time (PTT).
Coefficient of fat absorption (COA) was determined in AGS Study 2 based on a 72-hour stool collection and the 3-day weighed food record (15). COA (as a continuous variable) and steatorrhea (defined as a COA <93%) were both tested to detect an effect on bone measures and growth in the AGS group. History of liver transplantation at the time of enrollment was determined for all children with AGS participating in this study, and was tested to detect an effect on bone and growth status.
DXA outcome measures
Traditionally, DXA measures have been reported relative to age (39,47). However, spine DXA results are confounded by stature (31). Our group has demonstrated that whole body DXA measures relative to HT provided good measures of bone dimensions and strength (47). Therefore, the primary outcomes for this study were BA (WB and LS) adjusted for HT and BMC (WB and LS) adjusted for HT. Status of the LS was evaluated further using bone mineral apparent density (BMAD, gm/cm3), calculated as [(LS BMC)/(LS bone area1.5)]. This estimate of volumetric BMD is thought to be less sensitive to differences in skeletal size (48). Areal BMD was not used as a primary outcome because it fails to identify the specific element of concern, BMC or bone size in assessing bone status in growing children (28-30).
BA, BMC and HT were log transformed for best fit (30). HT-specific z-scores for BA and BMC in the children with AGS were estimated based on data from the healthy control children using regression analysis and the half-normal technique described by Altman (49). These HT-specific z-scores represent the magnitude of bone status differences among children with AGS compared to healthy children of similar HT. For example, a WB BMC-for-HT z-score of −1 for an AGS subject would represent a BMC status that is 1 SD below expected compared to healthy controls of similar HT.
Data analyses consisted of a multi-stage approach involving descriptive statistics and inferential analyses in three phases: 1) unadjusted bone measures; 2) adjusted bone measures; and 3) HT-specific bone z-scores. In Phase I, comparisons were made between the AGS and control groups for WB (BA, BMC) and LS results (BA, BMC, BMAD) using either the Wilcoxon's rank sum test or a standard parametric t test depending on the characteristics of these data. In Phase II, four separate cross-sectional linear regression models designed to test for group differences between the children with AGS and healthy controls were specified and tested. Whole body BA and BMC and LS BA and BMC were the adjusted outcomes of interest, with HT, gender and age as covariates. Phase III consisted of analyses using the four HT-specific z-transformed bone variables (i.e., WB BA-for-HT and BMC-for-HT z-scores; LS BA-for-HT and BMC-for-HT z-scores). Comparisons were performed using either the Wilcoxon's rank sum test or a standard parametric t test. Additionally, secondary analyses using these z-scores and the dietary and AGS-related variables were calculated using standard Pearson correlations.
Given the multiplicity of tests comprised by the primary analyses (Phases I through III), the hypothesis-wise error rate for each of the 21 tests was calculated to be α = 0.003 using Tukey, Ciminera and Heyse's adjustment for multiple comparisons with moderately correlated endpoints (50). Because the secondary analyses were performed for descriptive purposes, no further adjustments to alpha were made. All data were analyzed using STATA 7.0 (STATA Corporation, College Station, TX).
Subject Characteristics and Growth Status
Thirty-one (14 female) prepubertal children with AGS with a mean age of 8.4 ± 2.7 years (range, 4.1-13.7 yrs) met the study criteria (Table 1). There were 28 (90%) Caucasian children, one South Asian child, and two Hispanic children. The control group consisted of 80 (45 female) prepubertal healthy children of similar age (8.1 ± 2.4 yrs; range, 4.2-12.5 yrs), ethnic distribution, gender, and physical maturity (Table 1). The AGS group had significantly lower HT-Z, WT-Z and BMI-Z scores than the control children (Table 1).
Among the children in the AGS group, four had undergone liver transplantation (13%). 25OHD levels were determined for 20 children. Four children (20%) had low vitamin D status. Mean values for total bilirubin (3.3 ± 4.2 mg/dl), cholesterol (345 ± 149 mg/dl), ALT (149 ± 95 U/L) and AST (140 ± 103) were above the normal range. Mean values for albumin (4.1 ± 0.3 gm/dl), PT (12.6 ± 0.7 seconds) and PTT (27.2 ± 2.6 seconds) were within the normal range. Nutrition-related factors for the AGS group are presented in Table 2. Dietary intake of all nutrients of interest, on average, was greater than 100% of the DRI (data not shown). Fat intake as a percentage of total energy intake was low (25 ± 5% of total calories; range, 16-34%). Growth status within the AGS group was not significantly associated with steatorrhea or liver transplantation (data not shown).
Unadjusted Bone Measures
Whole body and LS BA and WB BMC were significantly lower in the AGS group compared to the controls (Table 3). These differences persisted after adjusting for age and gender (data not shown). The lower LS BMC in the AGS group did not reach significance when compared to the controls. There was no difference in spine BMAD between the AGS and control groups (Table 3).
Adjusted Bone Measures
HT was a strong predictor of WB and LS BA and BMC, as seen in Figure 1. The AGS group had significantly lower WB BA and BMC after adjusting for HT compared to the controls. There were no differences in LS BA and BMC between the AGS and control groups adjusted for HT (P = 0.122 and 0.113, respectively). The same pattern was evident when the subjects who had undergone liver transplantation were excluded. Age and gender were not statistically significant contributors to any of the models after adjusting for HT.
Height-Specific Bone Z-Scores
The average WB BA and BMC-for-HT z-scores for the AGS group were significantly lower than those of the control group (Table 4). Seventeen percent of the AGS group had WB BA-for-HT z-scores less than −2, while 20% had WB BMC-for-HT z-scores less than −2 (Fig. 2). This degree of bone deficit was significantly more common in the AGS group than control group; 0% and 1% of the controls had WB BA and BMC-for-HT z-scores less than −2, respectively (P < 0.003 for comparisons with AGS group). Within the AGS group, whole body BA and BMC-for-HT z-scores did not differ significantly based on gender, steatorrhea or liver transplantation (data not shown). In subsequent secondary analyses, bone status based on WB measures was not related to any of the dietary variables tested or 25OHD levels. Whole body BA-for-HT z-scores were significantly correlated with WT-Z and BMI-Z (r = 0.64 and 0.70, respectively; P < 0.001). Whole body BMC-for-HT z-scores were significantly correlated with COA (r = 0.77, P < 0.001).
Lumbar spine BA and BMC-for-HT z-scores for the AGS group were not significantly different from the control group (Table 4). Spine BA-for-HT z-scores for the AGS group were less than −2 SD for 23% of subjects, whereas 39% had LS BMC-for-HT z-scores less than −2 (Fig. 2). This degree of bone deficit was significantly more common in the AGS group than control group; 4% and 2% of the controls had SP BA and BMC-for-HT z-scores less than −2, respectively (P < 0.003 for comparisons with AGS group). Within the AGS group, LS BA and BMC-for-HT z-scores did not differ significantly based on gender, steatorrhea or liver transplantation. Subsequent secondary analyses found that LS bone status was not significantly related to any of the dietary variables or 25OHD levels. COA was significantly associated with LS BMC-for-HT z-score (r = 0.66, P < 0.003). No significant correlations between LS bone status and other disease-related factors were detected.
Bone mass and geometry are important determinants of bone strength. Children with AGS have smaller bones (lower BA) and less bone mass (lower BMC) compared to same age peers. Since they also have short stature it is important to consider the confounding effects of smaller skeletal size when evaluating children with AGS. Whole body BA and BMC adjusted for HT correlates well with cortical bone strength assessed by peripheral quantitative computerized tomography (47). In our study, children with AGS had significant deficits in WB BA and BMC adjusted for stature, indicating they have "narrow" bones (low BA-for-HT), low bone mass for their HT (low BMC-for-HT) and, therefore, less cortical bone strength than their peers. For the spine, the smaller bone size and less bone mass in the children with AGS was explained by differences in stature. However, there was a high degree of variability in spine z-scores, and 39% of subjects had spine BMC-for-HT z-scores less than −2.0. In a healthy population, 3% of subjects have z-scores less than −2.0. The results of our study support the importance of examining bone status of chronically ill children in relation to their size and demonstrate the significant deficits in regions of cortical and trabecular bone in children with AGS. Reports of long bone fractures (7,10,21) and vertebral abnormalities (3,7-10,51,52) in children with AGS are consistent with these findings.
There are several reasons why AGS may have a negative impact on bone status in children. Dietary intake of specific nutrients important for bone mineralization and known to be potentially limited in the diets of children with AGS, such as calcium and vitamin D (15), were not related to bone z-scores in children with AGS. However, the degree of malabsorption of these important nutrients must be considered. Fat absorption was positively and significantly associated with both WB and LS BMC-for-HT-z scores in AGS children. Malabsorption of fat soluble vitamins and minerals in AGS, due to decreased liver and/or pancreatic function, may be responsible in part for the decreased bone status. Liver transplantation was not significantly related to improved bone z-scores in the children with AGS, but there were too few children in the transplant group (i.e., four) to detect a statistically significant difference. Children with AGS with better overall nutritional status as indicated by BMI-Z, had better BA-for-HT z-scores. Further studies are needed to determine whether interventions to increase fat intake and improve fat absorption may have a beneficial impact on bone status.
The clinical concern regarding poor bone status during childhood is the increased risk of osteoporosis and fractures in childhood and adulthood (33). Children with genetic and acquired gastrointestinal diseases resulting in chronic cholestasis, similar to AGS, have documented deficits in bone status starting at an early age (20-24,26,53,54) and are therefore at risk of not attaining optimal bone mass. The prepubertal children with AGS in our study also had significant deficits in bone status, even with adjustment for their short stature, and are likely to be at increased risk of sub-optimal peak bone mass and increased bone fragility later in life.
Our goal was to describe characteristics of and factors affecting bones of children with AGS. A limitation of this study was that six prepubertal children in the AGS group fell below the HT range of the age-matched controls. Selecting HT-matched controls in this range would have meant selecting younger and developmentally (motor, cognitive and body composition) different controls. We balanced these two issues in the control sample. As a result, the HT-specific z-scores for the shorter subjects with AGS were extrapolated based on taller control children. Further statistical evaluation indicated that inclusion of these shorter subjects did not change the observed significant differences seen between the AGS and control subjects. Thus, the original estimates are presented in this paper.
Assessment of bone health in children with chronic diseases is often complicated by alterations in growth. We used a multi-stage approach to assess bone health in children with AGS, demonstrating that there were significant deficits in both BA and BMC relative to age and body size. Separate evaluation of BA and BMC permitted the analysis of deficits in bone geometry and bone mass relative to body size, representing two components of bone fragility. Deficits in cortical bone acquisition are suggested by the consistently lower WB measures of bone, and may represent the long-term and cumulative effects on bone mineralization. A large percentage of children also had deficits in trabecular bone as evidenced by low LS BMC-for-HT z-scores. WB and LS BMC-for-HT status related to fat absorption suggest that both cortical and trabecular bone may be responsive to nutrient availability. Exclusion of the subjects who had undergone liver transplantation did not change the results. While further research is needed to better characterize the nature of these bone deficits, modifiable factors such as treatment of fat malabsorption should be explored as a preventive measure to promote bone mineralization in children with AGS.
Acknowledgments: The authors thank The Alagille Syndrome Alliance for their support; Mercy Medical Airlift for providing charitable transportation to families; the Fred and Suzanne Biesecker Foundation and Center for Pediatric Liver Diseases; Digestive Care Inc. for an unrestricted grant for statistical support; the General Clinical Research Center staff; the Nutrition Center at The Children's Hospital of Philadelphia; and the families of children with AGS for their dedication and commitment to participating in our research. We, also, thank Dr. Dror Wasserman for his role in this important research and gratefully acknowledge the CHOP pediatric gastroenterologists who provided medical care to the children with AGS (Drs. Barbara Haber, Kathleen Loomes and Elizabeth Rand) and the many gastroenterologists who referred their patients to us (Drs. William Balistreri, William Cochran, Patricia DeRusso, Steven Erdman, Edith Pilzer, Phillip Rosenthal, Vasundhara Tolia and Kathleen Schwarz).
1. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet
2. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet
3. Alagille 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
4. Alagille 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
5. Piccoli DA. Alagille Syndrome. In: Suchy FJ, Sokol RJ, Balistreri WF, editors. Liver Disease in Children.
Philadelphia: Lippincott Williams & Wilkins, 2001:327-42.
6. Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet
7. Hoffenberg 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
8. Krantz ID, Rand EB, Genin A, et al. Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet
9. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology
10. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr
11. Chong SK, Lindridge J, Moniz C, Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts. J Pediatr Gastroenterol Nutr
12. John HA, Loomes K, Weyler R, Stallings VA, Piccoli DA, Mulberg AE. A study of pancreatic function in 17 children with Alagille Syndrome. (abstract) Gastroenterology
13. Sokol RJ, Stall C. Anthropometric evaluation of children with chronic liver disease. Am J Clin Nutr
14. Wasserman D, Zemel BS, Mulberg AE, et al. Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome. J Pediatr
15. Rovner AJ, Schall JI, Jawad AF, et al. Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr
16. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Does liver transplantation affect growth pattern in Alagille syndrome? Liver Transpl
17. Holt 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
18. Suchy 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
19. Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis
20. Heubi JE, Hollis BW, Specker B, Tsang RC. Bone disease in chronic childhood cholestasis. I. Vitamin D absorption and metabolism. Hepatology
21. Batres LA, Rovner AJ, Jawad AF, et al. Bone disease in children with Alagille Syndrome. (abstract) J Pediatr Gastroenterol Nutr
22. Emerick 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
23. Bucuvalas JC, Heubi JE, Specker BL, Gregg DJ, Yergey AL, Vieira NE. Calcium absorption in bone disease associated with chronic cholestasis during childhood. Hepatology
24. Argao EA, Specker BL, Heubi JE. Bone mineral content in infants and children with chronic cholestatic liver disease. Pediatrics
25. Heubi 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
26. Glasova H, Beuers U. Extrahepatic manifestations of cholestasis. J Gastroenterol Hepatol
27. Gordon CC, Chumlea WC, Roche AF. Stature, Recumbent Length, and Weight. In: Anthropometric Standardization Reference Manual.
Champaign, IL: Human Kinetics Books, 1988:3-8.
28. Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF. Whole body bone mineral content in healthy children and adolescents. Arch Dis Child
29. Molgaard C, Thomsen BL, Michaelsen KF. Whole body bone mineral accretion in healthy children and adolescents. Arch Dis Child
30. Ellis KJ, Shypailo RJ, Hardin DS, et al. Z score prediction model for assessment of bone mineral content in pediatric diseases. J Bone Miner Res
31. Prentice 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
32. Heaney RP. Bone mineral content, not bone mineral density, is the correct bone measure for growth studies. Am J Clin Nutr
33. Leonard MB, Zemel BS. Current concepts in pediatric bone disease. Pediatr Clin North Am
34. Mundy GR. Bone remodeling. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism.
Philadelphia: Lippincott Williams & Wilkins, 1999:30-8.
35. Wang 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
36. WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. [Report] Geneva, Switzerland: 1994.
37. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data
38. Tanner JM. Growth at adolescence.
2nd ed. Oxford: Blackwell Scientific Publications, 1962.
39. Leonard 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.
40. Leonard 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
41. Taylor 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
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.
45. Hollis 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
46. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL. Determination of vitamin-D status by radioimmunoassay with an I-125 labeled tracer. Clin Chem
47. Leonard 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
48. Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res
49. Altman DG. Construction of age-related reference centiles using absolute residuals. Stat Med
50. Zhang J, Quan H, Ng J, Stepanavage ME. Some statistical methods for multiple endpoints in clinical trials. Control Clin Trials
51. Hoffenberg 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
52. Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatr Radiol
53. Kobayashi A, Kawai S, Utsunomiya T, Obe Y. Bone disease in infants and children with hepatobiliary disease. Arch Dis Child
54. DeRusso PA, Spevak MR, Schwarz KB. Fractures in biliary atresia misinterpreted as child abuse. Pediatrics
2003;112(1 Pt 1):185-8.
This article has been cited 10 time(s).
Clinics in Liver DiseaseAlagille Syndrome and Other Hereditary Causes of CholestasisClinics in Liver Disease
Seminars in Nuclear MedicinePediatric dual-energy X-ray absorptiometry: Technique, interpretation, and clinical applicationsSeminars in Nuclear Medicine
Journal of Clinical DensitometryDual-energy X-ray aborptiometry assessment in children and adolescents with diseases that may affect the skeleton: The 2007 ISCD Pediatric Official PositionsJournal of Clinical Densitometry
GastroenterologyEvaluation and management of end-stage liver disease in childrenGastroenterology
Acta PaediatricaOsteogenesis imperfecta: Anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapyActa Paediatrica
Pediatric RadiologyPediatric DXA: clinical applicationsPediatric Radiology
Pediatric RadiologyPediatric DXA: technique, interpretation and clinical applicationsPediatric Radiology
Molecular and Cellular BiologyNotch and the SkeletonMolecular and Cellular Biology
Journal of Pediatric Gastroenterology and NutritionMedical Management of Alagille SyndromeJournal of Pediatric Gastroenterology and Nutrition
Journal of Pediatric Gastroenterology and NutritionPathologic Lower Extremity Fractures in Children With Alagille SyndromeJournal of Pediatric Gastroenterology and Nutrition
Alagille syndrome; Bone mineral content; Children; Dual-energy X-ray absorptiometry
© 2005 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.