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Fat-Soluble Vitamins in Cystic Fibrosis and Pancreatic Insufficiency: Efficacy of a Nutrition Intervention

Bertolaso, Chiara; Groleau, Veronique; Schall, Joan I.; Maqbool, Asim; Mascarenhas, Maria; Latham, Norma E.; Dougherty, Kelly A.; Stallings, Virginia A.

Journal of Pediatric Gastroenterology and Nutrition: April 2014 - Volume 58 - Issue 4 - p 443–448
doi: 10.1097/MPG.0000000000000272
Original Articles: Hepatology and Nutrition
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Objectives: The aim of the study was to assess the impact of LYM-X-SORB (LXS), an organized lipid matrix that has been shown to be absorbable without pancreatic enzyme therapy on fat-soluble vitamin status in children with cystic fibrosis (CF) and pancreatic insufficiency (PI).

Methods: Children with CF and PI were randomized to daily LXS or an isocaloric placebo comparison supplement for 12 months. Serum vitamins A (retinol), D (25-hydroxyvitamin D[25D]), E (α-tocopherol, α-tocopherol:cholesterol ratio), and K (percentage of undercarboxylated osteocalcin [%ucOC] and plasma proteins induced by vitamin K absence factor II [PIVKA II]) were assessed at baseline and 12 months. Dietary intake was determined using 3-day weighed food records and supplemental vitamin intake by a comprehensive questionnaire.

Results: A total of 58 subjects (32 boys, age 10.3 ± 2.9 years [mean ± standard deviation]) with complete serum vitamin, dietary and supplemental vitamin data were analyzed. After adjusting for dietary and supplemental vitamin intake, serum retinol increased 3.0 ± 1.4 μg/dL (coefficient ± standard error) (adjusted R2 = 0.02, P = 0.03) and vitamin K status improved as demonstrated by a decreased percentage of undercarboxylated osteocalcin of −6.0% ± 1.6% by 12 months (adjusted R2 = 0.15, P < 0.001). These changes occurred in both the LXS and placebo comparison groups. No changes in serum 25D or α-tocopherol were detected. Both nutrition interventions increased caloric intake a mean of 83 ± 666 kcal/day by 12 months.

Conclusions: Vitamins A and K status improved, whereas vitamins D and E status was unchanged during 12 months of LXS and isocaloric placebo comparison supplement in children with CF and PI.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Address correspondence and reprint requests to Chiara Bertolaso, MD, The Children's Hospital of Philadelphia, 3535 Market Street, Room 1556, Philadelphia, PA 19104 (e-mail: bertolasoc@email.chop.edu).

Received 15 April, 2013

Accepted 26 November, 2013

www.clinicaltrials.gov registration no.: NCT00406536.

This study was supported by NIDDK (R44DK060302) and the Nutrition Center at The Children's Hospital of Philadelphia. The study was also supported by the National Center for Research Resources (grant UL1RR024134) and is now at the National Center for Advancing Translational Sciences (grant UL1TR000003). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

V.A.S. received consulting honoraria and travel expenses from companies with interest in CF care. The other authors report no conflicts of interest.

Approximately 90% of patients with cystic fibrosis (CF) in the United States have pancreatic insufficiency (PI) and are at risk for fat malabsorption and fat-soluble vitamin deficiency (1). Each fat-soluble vitamin has multiple and essential metabolic functions for human health. Vitamin A is essential for normal vision, epithelial cell integrity, epithelial proliferation, and immunity (2). Vitamin D is required for bone health and has a role in immune function and incidence of cancer, type 1 diabetes mellitus, autoimmune disease, and heart disease (3–6). Vitamin E prevents cell membrane oxidation and maintains neurological functions, and studies reported a role in cognitive function in infants with CF (7,8). Vitamin K is essential for bone calcification, coagulation, energy metabolism, and modulation of inflammation (2,9). Even with effective pancreatic enzyme medications and CF-specific vitamin and mineral supplements, a portion of patients with CF and PI have suboptimal fat-soluble vitamin status (10–14). LYM-X-SORB (LXS; Avanti Polar Lipids, Alabaster, AL) is a choline-rich structured lipid matrix that was shown to be absorbed without pancreatic enzymes in subjects with CF and PI, and improves growth and vitamin A status using a first-generation LXS formulation (15).

The primary aim of this report was to assess the effect of second-generation LXS on fat-soluble vitamin status. These data were collected as a part of the randomized placebo-controlled trial to evaluate choline status in children with CF and PI with LXS supplementation compared with an isocaloric placebo comparison supplement. The secondary aim of this report was to compare the fat-soluble vitamin status in this present sample to that of participants from a series of CF nutrition studies during the past decade.

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METHODS

Subjects with CF, PI, and mild-to-moderate lung disease ages 5.0 to 17.9 years were recruited from 10 CF centers at the beginning of March 2007 (last study visit May 2011) to participate in the CF Avanti study, a placebo-controlled double-blind study evaluating the impact of second-generation LXS on choline status. The exclusion criteria included forced expiratory volume in 1 second <40% predicted, residual pancreatic lipase activity (fecal elastase >15 μg/g stool), liver disease (serum γ-glutamyltransferase >3 times reference range), or other chronic health conditions that may affect nutrient absorption or growth. The fecal elastase inclusion criteria (<15 ng/g) were selected for this study to increase the likelihood of participants with more complete PI. The γ-glutamyltransferase exclusion value was selected as the study-specific screening criteria and does not reflect that used in clinical care to diagnose liver disease. The subjects were randomized to 12 months of LXS or placebo comparison supplementation: 2 packets per day (64 g powder) for ages 5.0 to 11.9 years and 3 packets per day (96 g powder) for ages 12.0 to 17.9 years. This second-generation LXS had improved palatability and solubility characteristics, and was designed to be mixed with a variety of foods and beverages. The LXS was composed of lysophosphatidylcholine, triglycerides, and fatty acids, which form an organized choline-rich lipid matrix complexed to wheat flour and sugar. The comparison intervention (placebo) had similar calories, total fat and macronutrient distribution (protein 6%, carbohydrate 58%, lipid 34% of kcal), and only approximately 10% as much choline. The LXS and the placebo comparison intervention had the same calories: 157 kcal per packet and contained no fat-soluble vitamins except for vitamin E as α-tocopherol (4.8 and 1.6 mg/packet in LXS and placebo comparison intervention, respectively). This protocol was approved by the institutional review board at The Children's Hospital of Philadelphia (CHOP) and in each participating center. The verbal assent was obtained from all of the subjects and written informed consent was obtained from their parents or guardians.

Dietary intake was assessed at baseline and 12 months with 3-day weighed food records and analyzed (Nutrition Data System for Research, National Coordinating Center, University of Minnesota, Minneapolis, MN) (16). Supplemental intake of vitamins and minerals, including product, frequency, and dose, was assessed by a comprehensive questionnaire. The dietary reference intake (DRI) was used to evaluate nutrient intakes based on recommended dietary allowance (RDA) and adequate intake (AI) recommendations. The DRI are nutrient-based reference values used to assess diets of the general population (2,3,7). DRI intakes are designed to reduce the incidence of deficiency diseases and to help individuals optimize health and prevent disease. Specifically, the RDA is the evidence-based daily nutrient intake that is sufficient to meet requirements of nearly all (97.5%) of the healthy individuals by age and sex groups. Intakes of a few essential nutrients are evaluated by the AI value. The AI is an average daily intake based on less evidence and is an estimated nutrient intake assumed to be adequate. The percentage of RDA (%RDA) for vitamins A (retinol activity equivalents), D (calciferol), and E (α-tocopherol) and as percentage of AI (%AI) for vitamin K (phylloquinone) were calculated (2,3,7). Energy intake was also assessed and expressed as a percentage of estimated energy requirement for active children, as determined for children with CF and PI (17,18). The adherence to LXS or placebo comparison intervention intake was calculated as a percentage of packets consumed per total packets prescribed every 28 days during the 12-month study. The percentage adherence that was used to adjust calories and vitamin intake from LXS or placebo comparison intervention was based on the 28-day period within which the diet record assessment occurred.

Fasting serum vitamin A (retinol), vitamin D (25-hydroxyvitamin [25D]), vitamin E (α-tocopherol, and α-tocopherol:cholesterol ratio), and vitamin K (percentage of total osteocalcin as undercarboxylated osteocalcin [%ucOC]) were assessed at baseline and 12 months. For vitamin K status, serum plasma proteins induced by vitamin K absence factor II (PIVKA II) was also assessed in a subsample of participants. Retinol was analyzed by high-performance liquid chromatography (Craft Technologies, Wilson, NC). Serum retinol was considered low based on the National Health and Nutrition Examination Survey 1999–2002 data for the fifth percentile (<30 μg/dL). 25D was determined using a radioimmunoassay with a radioiodinated tracer (Hollis Laboratory, Medical University of South Carolina, Charleston, SC) (19) and by CHOP clinical laboratory using liquid chromatography-tandem mass spectrometry. Levels of 25D <30 ng/mL were considered low based on the present literature related to non–bone health outcomes (20–25). α-Tocopherol was assessed by quantitative high-performance liquid chromatography (ARUP Laboratories, Salt Lake City, UT). Total cholesterol was assessed by standard methods at CHOP clinical laboratory. Low levels of α-tocopherol were defined from clinical laboratory reference ranges as <3 mg/L for children ages 1 to 12 years and <6 mg/L for 13 to 19 years (26–28). When using α-tocopherol:cholesterol ratio, the cutoff point of <5.4 mg/g was used to define low levels in children based on CF-specific results (29). For vitamin K, serum concentrations of total osteocalcin and ucOC were determined using a hydroxyapatite-binding radioimmunoassay and expressed as the percentage not bound (undercarboxylated osteocalcin [%ucOC]) and normalized to total osteocalcin (Gundberg Laboratory, Yale School of Medicine, New Haven, CT) (30). PIVKA II was determined using an enzyme-linked immunoassay (Booth Laboratory, Tufts University, Boston, MA) (31). For vitamin K status using %ucOC, >50% was defined as low, and for PIVKA II, >2.0 ng/mL was defined as low (32–34).

Weight was measured to the nearest 0.1 kg using an electronic scale (Scaletronix, White Plains, NY) and height to the nearest 0.1 cm using a stadiometer (Holtain, Crymych, UK). Age- and sex-specific standard deviation (SD) scores, that is, z scores for weight, z scores for height, and z scores for body mass index were calculated (35).

Descriptive statistics were calculated for the study sample using means, SDs, medians, and ranges (as appropriate) for continuous variables, and frequency distributions for categorical variables. Vitamin intake and serum levels were analyzed for each group (LXS and placebo comparison group) separately and then for the total sample. Differences in serum vitamin levels between LXS and placebo comparison groups at baseline and at 12 months were assessed with unpaired t tests or Mann-Whitney U tests, as appropriate for skewness. For longitudinal changes in growth status from baseline to 12 months, paired t tests were used. Significant changes from baseline in serum vitamin status was explored for each vitamin outcome variable separately, using longitudinal mixed effects (LME) models adjusting for both dietary and supplemental vitamin intake as %RDA or %AI (depending upon the vitamin), with time as the coefficient for the 12-month change. LME models were run separately by group (LXS and placebo comparison group) and then for the total sample. An interaction term for group × time was also explored to determine whether time trends in vitamin status differed by supplementation group. All of the statistical analyses were performed with STATA 12.0 (STATA Corp, College Station, TX) and significance was defined as P < 0.05. The data are presented as mean ± SD, unless otherwise indicated.

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RESULTS

A total of 58 subjects (32 boys, age 10.3 ± 2.9 years, range 5.1–17.8) had baseline and 12-month serum vitamin, diet, and supplemental vitamin intake results. Dietary and supplemental vitamin intakes at baseline and 12 months are presented in Table 1 for the total sample and by group as %RDA and %AI. For the total sample, caloric intake increased from a mean of 2569 ± 752 kcal/day at baseline to a mean of 2653 ± 660 kcal/day at 12 months, resulting in a net increase of 83 ± 666 kcal/day. The baseline mean of the percentage of estimated energy requirement was 126% ± 33% and was similar for each group. The growth status improved significantly during the 12 months: z scores for height from −0.49 ± 0.93 to −0.42 ± 0.92 (P = 0.019) and (z scores for weight from −0.38 ± 0.70 to −0.29 ± 0.83 (P = 0.043). Median supplemental intake vitamin A was high, approximately 5 times the RDA. Dietary intake of vitamin D was <50% RDA, and supplemental vitamin D was approximately 2 times the RDA. The total vitamin E was primarily from supplemental intake and this was 13 to 16 times the RDA. Dietary intake of vitamin K was similar to the AI, whereas supplemental intake was 5 times the AI at baseline and 13 times the AI at 12 months. The placebo comparison group had a higher supplemental vitamin K intake at 12 months.

TABLE 1

TABLE 1

Serum vitamin levels at baseline and 12 months are presented for the total sample and separately by supplementation group in Table 2. The LME models show that vitamin A status improved significantly from baseline to 12 months by 3.0 ± 1.4 μg/dL (adjusted R2 = 0.02, P = 0.03), as did serum vitamin K status, as indicated by a decline in %ucOC of −6.0% ± 1.6% by 12 months (adjusted R2 = 0.15, P < 0.001). Serum vitamins D and E status did not change for 12 months, and vitamin K indicated by PIVKA II (subsample n = 42) also did not change. The improvements in vitamins A (retinol) and K (%ucOC) status for 12 months were evident in both supplementation groups, although serum retinol was lower at both time points in the comparison group. The α-tocopherol:cholesterol ratio was lower in the comparison group at 12 months. Supplemental intake of vitamins D, E, and K, but not A, significantly predicted serum vitamin status, whereas dietary vitamin intake was not predictive of serum status for any vitamin.

TABLE 2

TABLE 2

Table 3 provides a comparison of serum vitamin status for the present CF Avanti study sample with previous samples of children and young adults with CF and PI who participated in 2 CHOP nutrition studies for 12 years, the CF Nutrition (1998–2000) (11,12) and the CF Bones (2000–2002) studies (10,13,14). There are a greater proportion of subjects with low serum retinol status in the present study (20%) than in the past studies (4% and 0%). In contrast, vitamin K status improved, with only 5% in the present study having low vitamin K status based upon %ucOC compared with 19% in the past, and 19% in the present study based upon PIVKA II compared with 50% in the past. Vitamin D status was low in 50% of subjects in the present study, an improvement from 90% in the CF Bones study. For vitamin E status, 13% were low with little change from the past.

TABLE 3

TABLE 3

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DISCUSSION

The aim of this study was to assess the impact on fat-soluble vitamin absorption of LXS and a placebo comparison group with similar calorie and fat composition in children with CF and PI. Serum vitamins A and K status, adjusted for dietary and supplemental intakes, improved overall, whereas vitamins D and E were unchanged. A randomized placebo-controlled trial by Lepage et al (15) with first-generation LXS in children ages 6 to 17 years reported an improvement in serum vitamin E in the LXS group only and no changes in serum vitamins A, D, and K (PIVKA II). In the present study the improvements in vitamins A and K status occurred in both LXS and placebo comparison groups. These improvements may be related to the sustained increase in caloric intake, or better adherence to CF care while enrolled in this research study or other unidentified factors. Vitamin A status improvement is not explained by dietary or supplemental intake. Vitamin K status improvement may be related to the greater use of higher dose supplemental vitamin K with increasing participant age (2 vitamins per day in older patients) and with increased vitamin K content of commercially available CF-specific vitamin products (ie, SourceCF, AquADEKS, Aptalis Pharma US, Vandalia, OH).

Changes in recent years in vitamin status in CF can be considered by comparing the present study with 2 older studies conducted with similar populations and methods as summarized in Table 3. Serum vitamin status and both dietary and supplemental vitamin intakes were assessed using similar methods. The intake from supplements was consistently higher than dietary intake in each vitamin evaluated. In the CF Avanti study, dietary intakes of vitamins were similar to those found in the CF Nutrition and CF Bones studies, with the exception of dietary vitamin D intake, which was lower in the present study than in CF Bones (median 264 vs 329 IU/day) (14). The mean supplemental intake of vitamins A and E were similar to those found in previous studies, whereas intakes of D and K were somewhat higher in the present study compared with the CF Bones study (13,14), likely because of increased D and K dose per pill in the CF-specific vitamin products.

Mean baseline serum retinol (Table 3) was lower in the present study than in the CF Nutrition (11) and CF Bones studies (10). In the present sample, 20% had low serum retinol levels compared with 4% and 0% in the CF Nutrition and CF Bones studies. The decrease in serum retinol in the present study compared with previous studies was likely because of vitamin A changes in CF-specific vitamin formulation during the last 10 years. Preformed vitamin A content has decreased and carotenoids content has increased. Carotenoids are inefficiently converted into serum retinol (2). Mean baseline serum retinol in the present study was similar to retinol levels reported by Brei et al (36) in a 2011 observational study in Germany in subjects ages 4 to 27 years (39 μg/dL) and higher than those reported in 2007 by Hakim et al (37) in Israel in subjects ages 1.5 to 27 years (24 μg/dL).

Serum vitamin D status is typically low in children and adults with CF and PI. The median baseline serum 25D (31 ng/mL) in this study was comparable with levels observed in children ages 1 to 17 years in the UK in 2010 (median 29 ng/mL), and modestly improved compared with older reports from the United States and United Kingdom from similar populations (21–26 ng/mL) (14,38–41). In the present sample, 50% had low (<30 ng/mL) 25D, which was an improvement from the 90% of children and young adults found insufficient in the CF Bones study. It was similar to the 46% to 56% insufficiency found in more recent studies in the United States, United Kingdom, and Australia (14,38,41–43). The serum 25D improvement over time was likely because of enhanced clinical monitoring and increased vitamin D supplementation in patients with CF and PI.

There has been little change in vitamin E status during this time interval. The median serum α-tocopherol:cholesterol ratio was 7.7 mg/g in the present study, comparable to that found in our previous CF Nutrition study (median 8.2 mg/g) (12) and somewhat improved compared with the results of James et al (29) (median 5.7 mg/g) conducted in the United Kingdom in a similar population 2 decades ago. Using the cutoff value of 5.4 mg/g for vitamin E deficiency, 13% of both our present sample and the previous CF Nutrition sample (12) were deficient.

The proportion of children with low vitamin K status in the present study was only approximately one-fourth that found in CF Bones (5% vs 19%). Subjects ages 8 to 25 years from the recent studies in the United States and Canada have found better vitamin K status (35%–47% ucOC) (13,44,45) than earlier studies of children ages 5 to 18 years in Greece and the United Kingdom (59%–71%) (46,47). Despite this improvement in vitamin K status children in the present study remain suboptimal (74% with >20% ucOC), which was comparable to the 64% to 100% found in other more recent samples of children with CF (13,44,45). Using PIVKA II, the median was 1.2 ng/mL in the present study. These PIVKA II levels were lower than the 2 to 5 ng/mL found in more recent studies of children with CF (13,39), and much lower than the 11 to 23 ng/mL found in earlier studies of children and adults in Canada and the United States (45,48–50). Others have observed higher rates of low vitamin K status than in the present sample based on PIVKA II, from 42% to 80% (13,47,49,50). The improvement in vitamin K status was likely the result of an increased use of CF-specific products and a higher vitamin K dose in the products. From this review of fat-soluble vitamin status in patients with CF and PI, there is evidence that the situation has changed in 12 years. Improvements in both vitamin D and K status are demonstrated, with a possible decline in vitamin A status and little change in vitamin E status.

In summary, the nutritional intervention described in this study provided similar additional calories to both treatment groups and was associated with improvement in growth status. Vitamins A and K status improved in 12 months, whereas vitamins D and E remained unchanged in both the LXS and placebo comparison supplement groups. The vitamin products and age-adjusted dosing approach have not resulted in the optimal fat-soluble vitamin status in CF and PI.

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Acknowledgments

We are grateful to the subjects and their families, and to all the CF Centers that participated in the study: Children's National Medical Center, Washington, DC; The Children's Hospital of Philadelphia, Philadelphia, PA; Monmouth Medical Center, Long Branch, NJ; Pediatric Lung Center, Fairfax, VA; Cystic Fibrosis Center of the University of Virginia, Charlottesville, VA; Children's Hospital of the King's Daughters, Eastern Virginia Medical School, Norfolk, VA; Yale University School of Medicine, New Haven, CT; Cohen Children's Medical Center, New Hyde Park, NY; St Joseph's Children's Hospital, Paterson, NJ, and the Pediatric Specialty Center at Lehigh Valley Hospital, Bethlehem, PA. We thank Drs Caren Gundberg, Yale School of Medicine, and Sarah Booth, Tufts University, for providing the osteocalcin and PIVKA II analyses. We also thank Walter Shaw, PhD, and the Avanti Polar Lipid team for the production of the LXS and placebo products, and Kevin Hommel, PhD, for leading the adherence component of the study. We thank Megan Johnson, Thananya Wooden, Elizabeth Matarrese Friedman, and Nimanee Harris for their valuable contributions to the study.

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Keywords:

children; cystic fibrosis; vitamin A; vitamin D; vitamin E; vitamin K

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,