Published online July 1, 2005
PEDIATRICS Vol. 116 No. 1 July 2005, pp. 68-72 (doi:10.1542/peds.2004-1129)
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Effect of Nutrition on Growth in Short Stature Before and During Growth-Hormone Therapy

Zvi Zadik, MD*,{ddagger}, Tali Sinai, MSc{ddagger}, Amnon Zung, MD* and Ram Reifen, MD, MSc{ddagger}

* Pediatric Endocrine Unit, Kaplan Medical Center, Rehovot, Israel
{ddagger} School of Nutritional Sciences, Hebrew University of Jerusalem, Jerusalem, Israel


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Although nutritional counseling is an integral part of the management of rapidly growing children, few studies have focused on the importance of nutritional supervision during growth-hormone (GH) therapy. The objective of this study was to study the effect of caloric intake on growth before and during GH therapy.

Methods. A total of 115 short normal prepubertal children who were 7.4 ± 1.2 years of age (mean ± SD) and had height SD score (SDS) of –2.5 ± 0.6 were treated with a GH dose range of 0.13 to 0.52 mg/kg per week for 1 year. A 3-day nutritional recall and blood chemistry analysis were repeated every 3 months.

Results. Caloric intake (expressed as % recommended dietary allowance) was positively correlated with the pretreatment growth velocity (SDS) and the increment in growth velocity SDS during the first year of GH therapy (r = 0.363 and 0.493). By stepwise regression analysis, we identified 4 parameters that could predict the 1-year increment in growth velocity SDS: the contribution of each factor (% variability) was pretreatment growth velocity SDS 36%, GH dose (27%), caloric intake 4%, and the integrated concentration of GH 2% (r2 = 0.689). GH therapy induced an alkaline phosphatase increment of 59 ± 49 IU/mL, an insulin-like growth factor-I increment of 32.6 ± 11.9 nmol/L, and a GH binding protein increment of 10.2 ± 2.7%. During GH therapy, an increase in serum transferrin (56.5 ± 35.2 mg/dL) and a decrease in serum iron (20.5.5 ± 20.2 µg/dL) were noted. These changes could not be detected through hemoglobin levels or hematopoietic indexes. Dietary iron supplementation reversed this phenomenon.

Conclusions. The nutritional status of GH-treated patients before and throughout the course of GH treatment should be monitored closely to improve the growth response and prevent nutritional deficiencies. Special emphasis should be placed on iron nurture.

Key Words: growth-hormone therapy • growth-hormone–binding protein • nutrition • iron

Abbreviations: GH, growth hormone • SDS, SD score • RDA, recommended dietary allowance • IGF-I, insulin-like growth factor-I • GHBP, growth-hormone–binding protein

Adequate nutrition is a prerequisite for normal growth. Nutrients are assimilated, transported, and synthesized into the newly produced tissue. In a rapidly growing child, there is an increased need for "building materials" to be incorporated into de novo–synthesized tissues. Because growth-hormone (GH) therapy induces a rapid acceleration in growth, it is expected that a child who does not increase accordingly is experiencing compromised nutritional intake or a deficiency in some essential nutrients.

The present study was undertaken to evaluate the interrelationship between caloric intake and growth and the effect of GH therapy on iron status. Indeed, other nutrients may play an important role as well, yet we focused on iron's being the most abandoned variable in children's diet. Iron is tested on a regular basis in children through blood counts, and it is supplemented often in the pediatric population.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
A total of 115 prepubertal children (86 boys) who had been referred to the pediatric endocrine clinic for short stature were included in the study. The children were of normal birth weight for gestational age; free of chronic diseases, nutritional or gastrointestinal problems, or dysmorphic syndromes; and exhibited a maximal GH response to provocative test (>10 µg/L). The calculated final height prediction was not significantly different from target height (–2.3 ± 0.3 vs –2.5 ± 0.3 SD score [SDS], respectively).

SDS units were calculated as (observation – mean)/SD, where mean is the population mean for age and gender, SD is the SD for this mean, and observation is the actual parameter measured on this patient. Height was measured using a Harpenden Stadiometer. The height SDS was determined according to National Center for Health Statistics growth charts.1 Pubertal status was evaluated according to Tanner.2 The participation of all children conformed to institutional standards and approved protocols for research involving human subjects. Informed written consent was obtained for each participant from his or her legal guardian. Pertinent clinical and laboratory data are given in Table 1.


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  		TABLE 1. Clinical and Laboratory Data of Children at Initiation of Study

 
Study Protocol
The procedure for determination of spontaneous GH secretion was performed at the Endocrine Diagnostic Unit of the Kaplan Hospital (Rehovot, Israel), as previously described,3–5 Blood was collected using a continuous withdrawal pump and a nonthrombogenic constant blood withdrawal system (Cormed, Kent City, MI). The blood collection tubes were replaced every 30 minutes. After plasma separation, samples were kept frozen at –20°C until assayed. Mean 24-hour GH concentration was calculated in each case. The provocative stimuli tested were clonidine and arginine, or insulin, as previously described.3–5 Bone age was determined according to Greulich and Pyle.6 Patients were randomly allocated to a treatment protocol of 0.13 mg/kg per week divided into 7 daily injections, 0.26 mg/kg per week divided into 2 weekly injections, 0.26 mg/kg per week divided into seven daily injections, 0.26 mg/kg per week divided into 2 daily injections, or 0.52 mg/kg per week divided into 7 daily injections. Because there were no differences in any of the parameters measured between the 0.26-mg/kg per week dose given once or twice daily, the results of the 2 groups were combined for the purpose of analysis. All participants were seen at the clinic at 3-month intervals.

Nutritional Evaluation
The participants underwent nutritional evaluation by a dietitian before and during the year of GH therapy. The individual nutritional needs of each patient were calculated, and the appropriate recommendations were made at each visit for all patients after the third month of GH therapy. The actual dietary intake was analyzed on the basis of detailed food records kept for 3 days before each of the trimonthly clinical visits. An in-house computer program based on local food tables analyzed the composition of all individual food components. The results of the analyses are reported as percentage of recommended dietary allowance (RDA).7

Laboratory Methods
The level of GH was assayed with a double-antibody radioimmunoassay kit (Sorin HGHK-2, Vercelli, Italy) with a sensitivity of 0.5 µg/L; the intra- and interassay coefficients of variation were 12%, 10%, and 11% for low-, medium-, and high-concentration quality control, respectively. Insulin-like growth factor-I–binding protein-3 (IGF-BP3) was assayed with an immunoradiometric kit (Diagnostic System Laboratories, Webster, TX) with assay sensitivity of 0.05 mg/L; the intra- and interassay coefficients of variation were 2% and 4.5%, respectively. The IGF-I RIA kit (Incstar RIA kit, Stillwater, MN) consisted of acid separation on microcolumns; assay sensitivity was 2.6, and the intra- and interassay coefficients of variation were 2.5% and 9.5%, respectively. GH-binding protein (GHBP) activity was performed as previously described.8 Binding results were corrected for endogenous GH bound to plasma GHBP, based on the plasma GH level in each sample. GHBP results were given as percentage of a normal adult control pool; assay sensitivity was 1.5% nmol/L, and the intra- and interassay coefficients of variation were 2.5% and 5.5%, respectively. Serum iron was measured by a colorimetric method on the Hitachi-912 auto analyzer (Boehringer-Mannheim, Mannheim, Germany); assay sensitivity was 1.5 µg/L, and the intra- and interassay coefficients of variation were 1.5% and 2.5%, respectively. Transferrin was measured by a immunoturbidimetric assay (Boehringer-Mannheim); assay sensitivity was 15 µg/L, and the intra- and interassay coefficients of variation were 0.8% and 2.5%, respectively.

Statistical Methods
Student’s t test, least-squares linear regression, multiple linear regression, stepwise regression, and analysis of variance were performed using the Sigmastat program.9 Data are given as mean ± SD.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical and laboratory data are presented in Table 1.

Predictors of Growth Velocity
Pretreatment Growth Velocity
Analysis of food intake revealed that caloric intake (%RDA) but not protein intake (%RDA) was significantly correlated with the pretreatment growth velocity, expressed in SDS units (r = 0.363, P < .001; and r = 0.154, P = .099, respectively). The mean 24-hour GH levels but not the maximal GH response to stimulation were positively correlated with the pretreatment growth velocity (SDS) of the normal short children (r = 0.431, P < .01), as previously reported.10 GHBP was positively correlated with BMI (kg/m2) and caloric intake before the initiation of GH therapy (r = 0.456, P < .01; and r = 0.368, P < .01, respectively). IGF-I was positively correlated with caloric (r = 0.396, P < .01) but not protein intake. IGF-BP3 levels were significantly correlated with IGF-I levels and caloric intake (r = 0.320, P < .001; and r = 0.317, P < .001, respectively). With the use of linear regression, no correlation was found between the pretreatment growth velocity (SDS) and IGF-I levels.

Posttreatment Growth Velocity
Analysis of food intake revealed that caloric intake (expressed as %RDA) but not protein intake (expressed as %RDA) was positively correlated with the increment in growth velocity SDS during the first year of GH therapy (r = 0.363, P < .001; and r = 0.493, P < .001). The 24-hour GH levels but not the maximal GH response to stimulation were negatively correlated to the 1-year increment in growth velocity (SDS) after GH therapy in normal short children (r = –0.570, P < .01), and the pretreatment growth velocity, expressed in SDS, was negatively correlated with the 1-year growth velocity in GH-treated normal short children (r = –0.598, P < .001), as previously reported.10 The increment in IGF-I was positively correlated with GH dose (r = 0.553, P < .001) and with caloric (r = 0.511, P < .01) but not protein intake.

Effect of GH Therapy
By stepwise regression analysis, we identified 4 parameters that could predict the 1-year increment in growth velocity SDS: the contribution of each factor (% variability) was pretreatment growth velocity SDS (36%), GH dose (27%), caloric intake (4%), and the integrated concentration of GH (2%; r2 = 0.689, P < .001). Stepwise regression analysis within the 0.26-mg/kg per week group (n = 68) demonstrated that caloric intake accounted for 27% of the variability in GH response to stimulation, and integrated concentration of growth hormone accounted for 11% and 10%, respectively, and pretreatment growth velocity for 7%. The overall r2 of the model was 0.544 (P < .001). Participant number in the other dose groups (0.13 mg/kg per week, n = 25; and 0.52 mg/kg per week, n = 22) was too small for repeating stepwise regression analysis within each group. GH therapy induced an alkaline phosphatase increment of 59 ± 49 IU/mL (P < .001), an IGF-I increment of 32.6 ± 11.9 nmol/L, and a GHBP increment of 10.2 ± 2.7% (P < .01; Table 2). During GH therapy, an increase in serum transferrin (56.5 ± 35.2 mg/dL) and a decrease in serum iron (20.5.5 ± 20.2 µg/dL) were noted (P < .01; Table 3). The changes in iron and transferrin were not correlated with GH dose or growth velocity. These changes could not be detected through hemoglobin levels or hematopoietic indexes. Iron supplementation at 3 months of GH therapy reversed the changes in iron and transferrin blood levels (Table 3). Although the study design did not allow segregation of the dietary protein from caloric intake, our results suggest the greater importance of suboptimal caloric and iron intake.


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  		TABLE 2. Changes in Growth Velocity, IGF-I, GHBP, and AP During 1 Year of GH Therapy in 115 Short Normal Children

 

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  		TABLE 3. Changes in Hemoglobin, Hematocrit, Red Cell Distribution Width (RDW), Iron, and Transferrin During 1 Year of GH Therapy (4 Different Schedules) in 115 Short Normal Children

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
By closely monitoring nutrition, we demonstrated a correlation between caloric intake and growth velocity, both before and during GH therapy, in short normal children. Nutritional status is known to have an effect on the levels of GH, IGF-I, and GHBP.

In extreme cases such as anorexia nervosa, as was summarized recently,11 marked derangements in GH axis can be found in some of the patients, such as increased basal and stimulated GH secretion12,13 and increased spontaneous GH secretion in a part of these patients.14 Recuperation of at least 10% of initial weight in anorexia nervosa resulted in normalization of the spontaneous GH secretion.14 Serum GHBP is reduced in patients with anorexia nervosa, possibly reflecting the decrease in the number of somatic GH receptors. Weight recovery results in normalization of GHBP levels.15,16 Some of our patients had a subnormal dietary intake but far from anorexia nervosa. Despite that the patients were supervised closely with respect to their dietary needs (by RDA), repeated monitoring at each trimonthly visit disclosed that some of the patients were unable to comply with the dietary instructions and needed repeated encouragement and supervision.

In this study, we focused on iron's being the most abandoned variable in children's diet. Indeed, other nutrients may play an important role as well, yet iron is tested on a regular basis in children through blood counts, and it is supplemented often in the pediatric population.

Iron is found in myriad enzymes that are crucial to metabolism. These enzymes include oxidases, catalases, reductases, peroxidases, and dehydrogenases. Each enzyme plays an important role as a reversible donor or acceptor of electrolytes during cellular metabolism; many of these actions are involved in de novo protein synthesis and, hence, new tissue generation. All of the iron needed to execute these diverse tasks comes from the diet.

During periods of rapid growth, for example in puberty, the massive increase in body mass and the physiologic increase in hemoglobin concentration require a great deal of iron. If the increasing need for iron is not met by proper supply, then iron deficiency may develop. Borderline iron stores may result in iron deficiency when an increase in demand is produced by the rapid incorporation of iron into newly built tissue, as seen in puberty.

It is difficult to assess iron stores when homeostasis is rapidly changing. Anttila and Siimes17 followed 60 prepubertal children, testing them at 6-month intervals for 24 months. A significant increase in mean hemoglobin was first seen at genital stage G4, whereas changes in transferrin and ferritin blood levels were noted much earlier. Ferritin decreased and mean transferrin increased slightly between stages G1 and G3 of pubertal development in these boys. After iron supplementation, the authors observed improvements in the levels of parameters representing iron status. GH therapy induces a rapid change in growth velocity as a result of newly built body mass. This mass accumulation is explained mainly by de novo protein and carbohydrate synthesis. This rapid change in growth is similar in extent to that seen during normal puberty.

Dietary iron may have an effect on growth. It has been shown18 that during rapid growth in children, iron levels are depleted. Iron either has a direct metabolic effect on the child or exerts an indirect effect by increasing appetite, a known bonus of therapy at all ages. During GH therapy, an increase in the prevalence of iron deficiency from 17% to 54% was noted by Vihervuoru et al19 in a group of 35 children.

The uniqueness of our study lies in the range of GH doses used (from 0.13 to 0.52 mg/kg per week), which allowed us to test the effect of growth velocity on iron homeostasis, because the greater the GH dose, the greater the growth velocity. This model differs from the pubertal growth period in that there was no involvement of sex steroids in our patients, who remained prepubertal throughout the study.

From our results, it is obvious that rapid consumption induces changes in iron stores, which are not reflected in the hemoglobin levels but are expressed in ferritin and transferrin levels. Iron-poor diets may also be hypocaloric. Because the patients' nutritional intake followed their preferences rather than an experimental design, it is difficult to separate the effect of suboptimal caloric intake from that of suboptimal iron intake. Despite that the patients were supervised closely with respect to their dietary needs as suggested in the literature, repeated monitoring at each trimonthly visit disclosed that some of the patients were unable to comply with the dietary instructions. This may have had an effect on growth, because caloric intake seemed to be correlated positively with the 1-year growth velocity.

It seems from this work that adequate nutritional support is important in GH-treated patients, not only under basal conditions but also during the therapy itself. Lack of adequate nutrition affects these patients' growth response.

We suggest that nutritional evaluation be an integral part of care in rapidly growing children, especially when growth is artificially accelerated. During rapid periods of growth, dietary supplements may be needed.


   ACKNOWLEDGMENTS
 
We are indebted to Bio-Technology General Israel for the generous supply of growth hormone. We are grateful for the expert technical work of R. Dovev, RN.


   FOOTNOTES
 
Accepted Oct 21, 2004.

Reprint requests to (Z.Z.) Pediatric Endocrine Unit, Kaplan Hospital, Rehovot 76100, Israel. E-mail zvizadik{at}012.net.il

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  6. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of Hand and Wrist. Stanford, CA: Stanford University Press; 1959
  7. National Research Council. RDA. 10th ed. Washington, DC: National Academy Press; 1989
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics




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