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Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Hepatology and Nutrition

Rethinking Growth Failure in Alagille Syndrome: The Role of Dietary Intake and Steatorrhea

Rovner, Alisha J.*; Schall, Joan I.*; Jawad, Abbas F.†; Piccoli, David A.*; Stallings, Virginia A.*; Mulberg, Andrew E.*; Zemel, Babette S.*

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From the Divisions of *Gastroenterology and Nutrition and †Biostatistics and Epidemiology at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Received August 6, 2001; accepted May 23, 2002.

Address correspondence to Babette Zemel, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, U.S.A. (e-mail: zemel@email.chop.edu).

Supported by the National Institutes of Health (R03 DK52481), the General Clinical Research Center (M01-RR00240) and the Nutrition Center at The Children's Hospital of Philadelphia.

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Abstract

Objective: To characterize the energy and nutrient intake, and the degree of fat malabsorption in children with Alagille syndrome (AGS) and to examine their cross-sectional associations with growth and nutritional status.

Methods: Prepubertal children with AGS were evaluated for dietary intake, growth, bone age, and body composition. Children and their families collected a three-day, weighed diet record at home. Stools were collected for 72 hours and the coefficient of fat absorption (COA) was determined.

Results: Children (mean age 6.7 ± 3.6 years) with AGS (n = 26) had low height-for-age z-scores (HAZ), weight-for-age z-scores (WAZ) (−1.9 ± 1.3 and −1.7 ± 1.1, respectively), and delayed skeletal maturation (−1.4 ± 1.8 years). Fifty-eight percent of the subjects were less than the 5th percentile for height and 54% were less than the 5th percentile for weight. At least 20% of children with AGS had low dietary intake for several nutrients including: calories, fat, calcium, vitamin D, and vitamin E. Children who consumed <2/3 Dietary Reference Intake (DRI) for calcium (n = 6) had a statistically significantly lower HAZ (−3.2 ± 1.3) than those who consumed >2/3 DRI (−1.5 ± 1.0), (P < 0.003). Ninety-six percent of the subjects had steatorrhea with a mean COA of 75 ± 16%.

Conclusions: These data suggest that prepubertal children with AGS are at-risk for poor nutrient intake which, compounded with steatorrhea, may have a negative effect on growth and nutritional status. Intervention studies to increase energy and nutrient intake are needed to determine the effect of improved dietary intake on growth and nutritional status of children with AGS.

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INTRODUCTION

Alagille syndrome (AGS) is an autosomal dominant disorder that is defined by paucity of interlobular bile ducts in addition to three of five of the following features: chronic cholestasis, congenital cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype (1,2). Less common clinical features include renal abnormalities, intracranial bleeding, and pancreatic insufficiency (3–6). The estimated incidence of AGS is 1 in 70,000 births, affecting all races worldwide and both sexes equally (7). AGS is caused by a defect in a single gene, Jagged1 (JAG1) (8). JAG1 is normally expressed during fetal development in the human heart, lung, kidney, and liver as well as other organs (9). Outcome and prognosis are highly variable and related to the severity of hepatic or cardiac involvement (2,4).

Growth failure, malnutrition, and delayed pubertal development are common in children with AGS (10,11). The etiology of the growth failure is unknown, but possible causes include insufficient caloric intake, steatorrhea from liver and/or pancreatic disease, and the primary defect in JAG1 (11). Wasserman et al. described resting energy expenditure (REE) in 13 prepubertal children 3 to 12 years old with AGS (10). REE was variable and related to nutritional status; those with the most elevated REE had significantly lower energy stores as indicated by percentage of body fat. Growth failure may be related to the skeletal involvement in AGS, although Hoffenberg et al. (12) did not find a relationship between the presence of vertebral anomalies and growth in 24 subjects ages 0 to 25 years. Poor growth may also be due to the defect in JAG1 since impaired growth in children with AGS exceeds that expected for the degree of liver disease. In a study by Sokol et al., children with AGS (n = 5) showed more severe depression of HAZ, WAZ, and WHZ than children with biliary atresia (n = 32), neonatal hepatitis (n = 8), and other chronic liver disorders (n = 11) (13).

Because growth failure in AGS begins in infancy and those who undergo liver transplantation do not have as much catch-up growth as children with other pediatric liver diseases, it has been suggested that there is a genetic basis for poor growth (14).

The contributions of dietary intake and fat malabsorption to growth and nutritional status have not been previously described in children with AGS. The goal of this study was to characterize the energy and nutrient intake, and the degree of fat malabsorption in children with AGS and to examine their cross-sectional associations with growth and nutritional status.

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MATERIALS AND METHODS

Subjects

Children with AGS evaluated at The Children's Hospital of Philadelphia, as well as from other pediatric gastroenterology centers throughout North and Central America, were invited to participate in this study. Subjects were identified by several mechanisms including personal physician contact, Pediatric GI Bulletin (internet site), and Liver Link, a newsletter from the Alagille Syndrome Alliance (family support group). AGS was defined as the presence of bile duct paucity in addition to three of five diagnostic criteria (chronic cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, characteristic facies) or the presence of Jag1 mutation. Exclusion criteria included: use of pancreatic enzyme supplementation, use of any medication known to affect growth and any significant illness unrelated to AGS. The Institutional Review Board at The Children's Hospital of Philadelphia approved the protocol. Informed written consent was obtained from the parent/guardian of each subject and assent was obtained from subjects over five years of age. Anthropometric data on healthy control children evaluated in the Nutrition and Growth Laboratory under similar conditions was available for comparison (15).

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Growth, Skeletal Maturation, and Nutritional Status

Body weight was determined with an electronic scale (Scalatronix Inc., Wheaton, IL) accurate to 0.1 kg and standing height was determined with a stadiometer (Holtain, Crymych, England). Midarm circumference (MAC) was measured with a flexible plastic tape measure (Ross Laboratories, Columbus, Ohio). Skinfold thickness was measured by calipers (Holtain Crymych, England) at four sites: triceps, biceps, subscapular, and suprailiac. Measurements were taken by a research anthropometrist in triplicate and the average used for analysis. Upper arm muscle area (UAMA) and upper arm fat area (UAFA) were derived from upper arm circumference and triceps skin fold using standard formulas. Weight, height, and body mass index were compared with the CDC 2000 growth charts and z-scores (HAZ, WAZ, BMIZ) were derived (16). BMI was computed weight (kg)/height (m)2 (weight/height (2)) for all subjects two years of age and older. Triceps, subscapular skinfolds, MAC, and midarm muscle mass area (MAMA) z-scores were computed using NCHS reference data (17). Fat-free mass, fat mass, and percentage body fat were determined from the four skinfold measurements using gender-specific equations for children (18).

Skeletal age was determined according to the method of Tanner-Whitehouse 3 (TW3) from radiographs of the left hand and wrist (19). All radiographs were scored by a single investigator (BZ). Bone age, based on the radius, ulna and short bones (RUS), was calculated for children ages 2 years and above, and a z-score was calculated using the RUS bone age calculator provided by Tanner et al. (19). Sexual maturation was rated according to the method of Tanner by physical examination by one investigator (AEM) for pubic hair and breast/genital maturation.

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LABORATORY AND FECAL FAT EVALUATION

A preliminary three-day diet record was analyzed and the fat content was documented by a research dietitian. If the dietary fat content was <2 g of fat per kilogram of body weight, the family was counseled to increase the fat intake of the subject for the fecal fat test. All subjects then recorded another three days of diet records in conjunction with a 72-hour stool collection. All stools during the 72 hours were collected in pre-weighed containers and stored in the freezer and were analyzed for total fat content (Mayo Laboratories, Rochester, MN) (20). Coefficient of fat absorption (COA) was determined by the following equation:EQUATION

Equation U1
Equation U1
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Subjects with a COA of <93% were considered to have steatorrhea.

Fasting blood samples were obtained and analyzed for liver function tests, bilirubin, prealbumin, albumin, prothrombin time (PT), and partial thromboplastin time (PTT) in the clinical laboratory of Children's Hospital of Philadelphia using standard techniques.

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DIETARY ANALYSIS

Subjects and their families received detailed written and verbal instructions for collecting a three-day prospective weighed food record at home. A digital food scale, measuring cups, and spoons were provided. The family was instructed to have the child consume his/her usual diet during the three days. Diet records were analyzed using a computerized nutrient database program (Food Processor, Version 7.1 ESHA Research, Salem, OR). Energy, macronutrient, and micronutrient intake were compared to the 1989 Recommended Daily Allowance (RDA) (21). Calcium, folate, and vitamin B12 were compared to the updated Dietary Reference Intake (DRI)(22,23). For all nutrients, the average intake over the three days was calculated and the mean nutrient intake was used in the analysis. Vitamin and mineral supplements were recorded, but were excluded from the dietary intake analysis. For this study, inadequate intake was defined as consuming < 2/3 of the RDA or DRI for specific nutrients and adequate intake was defined as consuming > 2/3 of the RDA or DRI. Therefore, two groups of subjects were defined for each of the nutrients. In addition, dietary intake of children with AGS was compared to the dietary intake of children in the general United States population (Third National Health and Nutrition Examination Survey, Phase I, 1986–91-NHANES III) (24). Subjects were also grouped according to dietary fat intake as a percent of total calories (< 30% fat vs. ≥ 30% fat). Subjects with AGS consuming < 30% of total calories from fat were considered to have low fat intakes while those consuming > 30% of total calorie from fat were considered to have adequate fat intake.

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PHYSICIAN DIETARY RECOMMEDATIONS

Each referring physician was sent a questionnaire to document the individualized dietary recommendations for his/her patient with AGS with respect to calories, fat, protein, carbohydrates, and fiber. Reponses were categorized as recommending high, low, or no specific recommendations for dietary intake. The questionnaire also included queries about dietary supplements and current use of feeding tubes.

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DATA ANALYSIS

Statistical analyses were performed using SPSS version 10 (Chicago, IL) for Windows and STATA 6.0 (College Station, TX) for PC. Summary statistics of continuous variables were examined and described by mean, median, standard deviation, minimum, and maximum. Categorical variables were presented by frequency distribution. Results are expressed as mean ± standard deviation and proportions. At-risk nutrients were defined as < 2/3 of the RDA or DRI. For those nutrients defined as “at-risk”, the sample was divided into two groups: those with low levels (< 2/3 of the RDA or DRI) versus adequate levels (≥ 2/3 of the RDA or DRI). The two independent sample t test or the Mann-Whitney U test was used for the comparison of continuous variables between groups. The χ2 test and Fisher exact test were used for the comparison of categorical variables. Correlation analysis was used to examine bivariate relationships. Stepwise multiple regression analysis was used to examine the relationships between growth parameters (HAZ, WAZ, BMIZ) and intake of selected nutrients considered “at-risk” nutrients based on the proportion of subjects with low intakes. In addition, potential confounding factors such as age, cardiac involvement (yes, no), and coefficient of fat absorption were included as independent variables in the stepwise multiple regression models. Statistical significance was defined when P < 0.05.

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RESULTS

Thirty-four subjects with AGS from pediatric institutions throughout North and Central America participated in the study. Three subjects failed to complete diet records (2 male) and were not included in the analysis. Two subjects (1 male) were excluded because on physical examination they showed signs of the onset of pubertal development (Tanner stage ≥ 2) and one of these had undergone liver transplantation previously. This restricted the analysis to prepubertal children with AGS to avoid the complexities of interpreting growth, nutritional status, and dietary information in a group of children heterogeneous for maturation stage. Three subjects (2 males) who had undergone a liver transplantation were also excluded from the analysis because of the possibility of confounding factors. After these exclusions, there were 26 prepubertal subjects (14M, 12F) with a mean age of 6.7 ± 3.6 years (range, 1.8–12.4 years). Fifteen subjects had cardiac defects, most commonly pulmonic stenosis. Information about cardiac defects was not available for four subjects.

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Growth, Skeletal Maturation, and Nutritional Status

HAZ and WAZ were low for subjects with AGS (−1.9 + 1.3 and −1.7 + 1.1, respectively). There were no statistically significant differences between males and females for HAZ (−1.9 ± 1.4, −1.8 ± 1.2), WAZ (−1.7 ± 1.0, −1.6 ± 1.3) and BMIZ (−0.3 ± 1.2, −0.4 ± 1.4). There were no statistically significant differences in growth between subjects with cardiac involvement and those without cardiac involvement. BMIZ were not statistically significantly reduced. Table 1 presents comparisons of growth, nutritional status, and body composition for males and females with AGS compared with healthy controls.

Table 1
Table 1
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RUS skeletal maturation was determined for 21 subjects. On average, skeletal maturation was delayed for the entire group. The RUS z-score was –1.2 ± 1.7, representing an average delay of –1.2 ± 1.7 years. Males and females did not differ in the magnitude of the skeletal delay (−1.4 ± 1.5 vs. −1.2 ± 1.8 years). RUS z-score was significantly associated with z-scores for height and weight (r = 0.60, P = 0.004 and r = 0.56, P = 0.009, respectively), but not with other anthropometric measures of nutritional status, COA or cardiac defects. Children with AGS had markedly reduced UAMA compared to age and gender peers (Table 1). UAFA and triceps z-scores were also low. Subscapular skinfold z-score was −0.1 ± 0.9 indicating a normal pattern of fat storage on the trunk. There were no gender differences in nutritional status. Although there are no national reference data for percentage body fat, the mean percentage body fat (16.1 ± 4.1%) was not different from a healthy control group previously evaluated in our laboratory (17.1 ± 5.6%). Energy intake was not related to percentage body fat or other indicators of nutritional status.

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Laboratory and Fecal Fat Evaluation

Hepatic synthetic function was normal in all of the subjects with a mean albumin of 4.0 ± 0.2 g/dl (range 3.6–4.4 g/dl). PT was normal in 21 of 26 (81%) of the subjects. The majority of subjects had moderate cholestasis (Table 2).

Table 2
Table 2
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The mean COA was 75 ± 16% (range 50 to 97%) and steatorrhea (COA <93%) was present in 25 of 26 (96%) of the subjects. COA was significantly and positively associated with age (r = 0.48, P = 0.01), but not with growth status. COA was inversely associated with z-scores for triceps and subscapular skinfolds (r = −0.46, P = 0.02 and r = −0.41, P = 0.05, respectively).

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Dietary Intake Analysis and Physician Dietary Recommendations

On average the energy intake of subjects with AGS was 85 ± 27% of the RDA for calories and was similar for both males and females (85 ± 25% vs. 83 ± 29%). The macronutrient distribution of the diet was: 60 ± 8% calories from carbohydrates, 13 + 2% from protein, and 27 ± 8% from fat (Fig. 1) with males and females had similar pattern of macronutrient intake. As shown in Figure 1, children with AGS consumed less fat and more carbohydrates than healthy children in the United States. More than 20% of children with AGS were consuming < 2/3 of the RDA or DRI for several nutrients including: calories, vitamin D, vitamin E, and calcium (Table 3). Table 3 also compares the nutrient intake of children with AGS to the RDA/DRI and NHANES III.

Table 3
Table 3
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Fig. 1
Fig. 1
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Seventy-three percent of subjects had a fat intake that was less than 30% of total energy intake. Subjects who consumed <30% of calories from fat had statistically significant lower dietary vitamin E intakes (55 ± 51% vs. 210 ± 131% DRI, P = 0.0002) and lower zinc intake (147 ± 88% vs. 300 + 146, P = 0.003) than those who consumed an adequate fat intake. There was no statistically significant differences in calcium intake (112 + 55 vs. 122 + 53%) between subjects with AGS in the low fat intake group compared with the adequate fat group.

Dietary intake was significantly different among those with cardiac defects versus those without defects. In particular, energy intake was significantly lower (78 ± 17 vs. 113 ± 29% RDA, P = 0.002) among the group with cardiac defects. As expected, when total caloric intake was lower, other nutrient intakes were also lower as shown in Table 4. The macronutrient distribution of the diet (percent of energy from fat and protein) was similar between the groups.

Table 4
Table 4
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Effect of Dietary Intake, Steatorrhea, and Cardiac Defects on Growth and Nutritional Status

Due to the small sample size, stepwise multiple regression analysis was used to test the relationships between growth and nutritional parameters, allowing for potential effects of related variables such as age, gender, COA and cardiac defects. Information about cardiac defects was available for 22 of the 26 subjects. In separate multiple regression models HAZ, WAZ, and BMIZ were analyzed. The nutritional parameters included in the stepwise regression models were energy intake, fat (as a percent of energy intake), calcium, vitamin E and vitamin D intake as percent of recommended values, as these were determined to be the most “at-risk” nutrients (see above) The results are shown in Table 5. Calcium intake was significantly and positively associated with HAZ. (Fig. 2) A non-significant, but similar trend for calcium intake was also noted for WAZ. BMIZ was significantly associated with COA and presence of cardiac disease. In the multiple regression model, cardiac disease was associated with a difference in BMIZ of 1.4 (p = 0.006). There was an inverse association of COA with BMIZ (slope = 0.04, r = 0.01). There was no significant interaction between COA and cardiac disease in the prediction of BMIZ.

Table 5
Table 5
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Fig. 2
Fig. 2
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Physician's Dietary Recommendations

Twenty-five physicians returned the questionnaires for a response rate of 96%. Sixteen physicians (62%) recommended a high calorie diet, with eight making no recommendations about the sources of calories. In addition, 4 of the 16 physicians recommended a high calorie and low fat diet pattern; two physicians recommended a high calorie, low fat, and low cholesterol diet; one physician recommended a high calorie, high fat, and high protein diet, and one physician recommended a high calorie, low fat and high protein diet. There were no recommendations for fiber intake. Three subjects had gastrostomy feeding tubes and were on elemental formulas (Peptamen Jr., Nestle and Pregestimil, Mead Johnson). Although the majority of the physicians were prescribing high calorie diets, only 24% of the subjects were actually consuming > 100% RDA for calories based on the three-day food record data.

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Fat Soluble Vitamin Supplementation

As shown in Table 6, 60% of subjects were taking at least one fat soluble vitamin supplement. Forty-one percent were either taking one supplement that contained all of the fat-soluble vitamins or were taking separate supplements with all four fat soluble vitamins separately. Fifty-nine percent were taking supplements with vitamin E, with 17% taking a water soluble form (Tocopherol Polyethylene Glycol-1000 Succinate, TPGS -Twin Labs, NY). Forty-five percent were taking supplements with vitamin A, 45% with vitamin D, and 49% with vitamin K.

Table 6
Table 6
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DISCUSSION

This study is the first to characterize nutrient intake and degree of fat malabsorption in relation to growth and nutritional status in prepubertal children with AGS. On average, children with AGS consumed 85% of the RDA for energy and only 24% of subjects with AGS consumed less than 2/3 of the RDA for calories. The mean fat intake was also low at 27% of total energy. In addition to consuming a low energy and low fat diet, 96% of the subjects had steatorrhea, with some excreting up to 50% of their dietary fat. Overall growth status was remarkably poor in this study, with 58% of the subjects below the 5(th) percentile for height and 54% for weight. These growth findings are consistent with previous reports (10,13). Height and weight were associated with degree of delay skeletal age. Small body size in AGS occurs along with delayed maturation suggesting the potential for catch-up growth and a possible role for nutrition interventions to improve growth and nutritional status. Fat mass and fat free mass were well below expected for age, although the relative amount of these tissue compartments, as reflected by % body fat and BMIZ, were within the normal range. The pattern of fat distribution and z-scores for triceps and subscapular skinfolds, were not different from control subjects.

Calcium intake is poor in children in the US and is well below the recommended intake (25). The same was true for the subjects in this study with 24% consuming < 2/3 of the DRI. Poor calcium intake is even more alarming in children with AGS than healthy children because they are at risk for malabsorption of calcium, vitamin D, and magnesium due to cholestasis. It is likely that Ca/Mg soaps are formed with unabsorbed fatty acids. Calcium requirements for children with cholestatic liver disease are unknown. In this study height was significantly associated with calcium intake. These findings lend strong support for the need for studies of calcium metabolism and calcium supplementation in children with AGS.

Impaired growth in children with AGS exceeds that expected for the degree of liver disease, and is likely not the result of cholestasis alone (7). In a study by Sokol et al.(13), children with AGS showed more severe depression of HAZ, WAZ and WHZ than children with biliary atresia, neonatal hepatitis and other chronic liver disorders. These deficits in height, weight, fat, and fat-free mass might be due to the primary gene defect in JAG1. However, the severity of AGS is extremely variable, and unlike other chronic pediatric liver diseases, it often has other organ system involvement that may impair growth. Cardiac involvement, including peripheral pulmonic stenosis, tetralogy of Fallot, and ventricular septal defect, is common in children with AGS (2,4). Children with congenital heart disease are often malnourished, have growth failure, have poor caloric and nutrient intake, and may need more calories than healthy children to achieve normal growth (26). Our study found that subjects with cardiac defects had lower energy intake after adjusting for COA, and had lower BMIZ than subjects without cardiac defects. This study also demonstrated inadequate dietary intake for several nutrients in the entire samples. Steatorrhea was present in 96% of subjects examined. Thus, dietary intake and malabsorption contribute, at least in part, to growth failure and poor nutritional status in AGS. In addition, other disease-related factors, such as heart and kidney involvement, must be carefully considered before growth failure in AGS is directly attributed to the gene defect.

There are no generally agreed upon dietary guidelines for children with AGS. In this study, the majority of the physicians made high calorie dietary recommendations, yet only 24% of subjects consumed high calorie diets, and another 24% consumed < 2/3 RDA for calories. Recommendations from physicians for fat intake were not consistent. In general, children with AGS in this study consumed low fat diets, which puts them at-risk for calorie and vitamin deficiencies. Ballew et al. (27) described nutrient intakes and dietary patterns in healthy children according to fat intake and found that subjects who were consuming < 29% fat were more likely to be consuming less calcium, zinc, and vitamin E than children who were consuming ≥29% fat. In our sample of children with AGS, this was true for zinc and vitamin E intake but not calcium. All children with AGS should undergo an assessment of their nutritional status and dietary intake and receive dietary counseling from a pediatric registered dietitian with monitoring of intake to ensure adequate energy and nutrient intake.

Fat soluble vitamin supplementation is an essential component of clinical care in children with AGS. Almost half of the children in this study were taking one supplement that contained all four fat soluble vitamins. This is often considered appropriate for other pediatric populations with steatorrhea without chronic liver disease, but may not be the optimal supplement for this population. It provides a fixed ratio of the vitamins, which may result in an excess intake of vitamin A. Also, it does not contain the best form of vitamin E for children with cholestasis. Supplementing each of these vitamins individually to meet the specific needs of children with chronic cholestasis is optimal. Routine serum vitamin levels must be checked and fat soluble vitamin supplementation should be adjusted to achieve levels within normal ranges. In one study of children with AGS, 42% had vitamin E deficiency (28); however, no mention was made whether these children were routinely supplemented with vitamin E. Vitamin E deficiency has been documented in children with cholestasis on large doses of alpha tocopherol or alpha tocopheryl acetate (70–200 IU of Vitamin E/kg/day) (29). A multicentered trial of water soluble d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) demonstrated that this form of vitamin E was safe and effective and reversed or prevented vitamin E deficiency during childhood cholestasis (29). Only 17% of our sample was taking this water soluble supplement. TPGS is more readily absorbed than other forms of Vitamin E and enhances the absorption of vitamin D in children with cholestasis (30).

These data suggest that inadequate energy intake contributes to poor growth in children with AGS. Poor vitamin or mineral intake, in addition to clinically significant fat malabsorption, may be factors leading to the pattern of poor growth and nutritional status in children with AGS. In particular, the role of calcium as a growth-limiting factor in children with AGS requires further investigation. Guidelines for the nutritional care of children with AGS are needed, and should include the goal of optimizing growth potential and overall nutritional status. For adequate guidelines to be developed, well-designed studies of increased energy and nutrient intake in children with AGS are needed to provide the data upon which to make dietary recommendations.

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Acknowledgment:

The authors thank The Alagille Syndrome Alliance for their support, Mercy Medical Airlift for providing charitable transportation to families, the 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 gratefully acknowledge the many gastroenterologists who referred their patients to us.

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Keywords:

Alagille syndrome; Children; Nutrition; Steatorrhea; Growth; Body composition

© 2002 Lippincott Williams & Wilkins, Inc.

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