Nutrition and Growth

J Clin Res Ped Endo 2009;1(4):157–163 ISSN: 1308-5727 DOI: 10.4274/jcrpe.v1i4.39 Online ISSN: 1308-5735

Fima Lifshitz

President, Pediatric Sunshine Academics, Inc; Director of Pediatrics & Senior Nutrition Scientist, Sansum Medical Research Institute, Santa Barbara, CA, USA and Professor of Pediatrics, Emeritus, Downstate Medical Center, State University of New York, Brooklyn, NY, USA; Former Professor of Pediatrics, Cornell University Medical College, New York, NY & University of Miami, Miami, FL, USA

Keywords: ABSTRACT Nutritional growth retardation (NGR), nutrient intake, short stature, growth retardation, Nutrition plays a fundamental role in determining the growth of individuals. An appropri- metabolic rates, erythrocyte ate growth progression is considered a harbinger of adequate nutrient intake and good Na+,K+- ATPase activity. health. On the other hand growth deceleration with or without short stature may indicate inadequate nutrition, even when there is no body weight deficit for height. Nutritional growth Received: 11 November, 2008 Accepted: 04 December, 2008 retardation (NGR) is most prevalent in populations at risk of poverty. However in affluent com- munities patients with NGR are often referred to the specialist because of short stature and Corresponding Author: delayed sexual development. The diagnosis may be overlooked and/or be established after Fima Lifshitz exhaustive evaluations, if the pattern of weight progression over time is not considered. Pediatric Sunshine Academics, Inc. Director of Pediatrics & Patients with so-called idiopathic short stature may present diminished nutrient intake and Senior Nutrition Scientist decreased IGF-I levels, however their nutritional status and body weight progression patterns Sansum Medical Research are usually not addressed by pediatric endocrinologists. NGR patients may cease to gain Institute Santa Barbara, CA, appropriate weight and fail to grow in height, even without exhibiting body weight deficits USA Tel: +805-687 8038 for height. They adapt to decreased nutrient intake by decreasing growth progression and Fax: +805-682 3332 thereby achieve equilibrium by decreasing the nutrient demands. This occurs by diminishing E-mail: [email protected] their metabolic rates and erythrocyte Na+,K+- ATPase activity, however they may not present alterations in other clinical biochemical markers of malnutrition. Therefore accurate weights and heights plotted on the growth chart over time are necessary to detect NGR. Nutritional rehabilitation is accompanied with catch up growth, though it may be difficult to change the dietary habits of adolescents who exhibit NGR.

Conflict of interest: None declared

Growth is the fundamental physiologic time and compares it to expected norms. process that characterizes childhood. It The norms are usually provided by the gen- should be closely monitored by pediatri- eral population as depicted in growth charts cians and families alike as a benchmark of (www.cdc.gov/growthcharts).2 Short stature a child’s health. Similarly, secular trends in and growth failure frequently, but not growth patterns are followed as indicators always, occur together. For example, a of children’s health on a population level. healthy child of short parents will have Growth can be worrisome along two vari- short stature but not growth failure; he or ables: height (short stature) and velocity she will grow at normal velocity towards a (growth failure).1 Height involves a meas- lower genetic potential. Conversely, a REVIEW urement of linear stature at a single point in child of very tall parents can have growth

© 2008 Journal of Turkish Pediatric Endocrinology and Diabetes Society This is an open-access article distributed under the terms of the 157 Pubbiz/Probiz Ltd. ﬁti. Creative Commons Attiribution License which permits unrestricted use distribution and reprodiction in any medium prov ided the original work is prope rly cited Nutrition and Growth

failure, but still be taller than the cut-off for be over-emphasized, carefully assessing the short stature of the general population. progression of body weight is equally rele- Multiple diseases can present solely with vant to be able to recognize NGR. growth failure, not necessarily with short Longitudinal assessment of both height and stature. Included are non-endocrine diseases weight is required.6-9 i.e. as celiac disease, cystic fibrosis, renal An increasing number of children on disease and HIV infection.1 These alterations stimulant medications are being referred to share a common pathophysiological process the pediatric endocrinologist for short stature in regards to growth failure, namely malnu- evaluation. Stimulant medication for the trition. Non organic causes leading to treatment of attention deficit hyperactivity decreased food intake may also result in disorder (ADHD) has long been suspected of poor growth and short stature. Failure to adversely affecting linear growth, since it is asses a patients’ nutritional intake can lead well known that these medications produce to unnecessarily delayed or missed NGR anorexia and poor nutrient intake. A cooper- diagnoses. The clinical outcome of many ative growth paper reviewed 29 cohort stud- nutritional alterations depends on the timeli- ies of children treated with methylphenidate ness of diagnosis and treatment.3,4 or dexamphetamine.10 The most sensitive The single most important cause of studies measured growth progression before growth retardation worldwide is poverty- and after the period of treatment, and eight related malnutrition. When suboptimal nutri- of these 16 studies showed an attenuation of tion is continued for prolonged periods of growth on stimulants. In the most rigorous time, growth stunting occurs as the main study, 540 children, 7-9 yr old, with ADHD clinical phenotype.3,4 However nutritional were randomly assigned to different treat- growth retardation (NGR) is a frequently ment groups for up to 24 months. The under-appreciated entity in pediatric behavioral effectiveness of medication use endocrine practices in the United States. was greatest among children who ingested Poverty-related malnutrition is less common medications throughout the 24-month obser- than in developing nations, and if anything, vation period. Those who stopped taking the current major health crisis is the obesity their medication and those who did not epidemic. Partly in response to the obesity ingest them consistently showed increasing around them, a subset of American youths, behavioral problems. However, there was many from suburban upper middle class, significant growth deterioration among chil- restrict their nutrient intake and develop dren who took the medication for the NGR and delayed sexual development.1 This longest periods. After 2 years’ treatment, decreased intake is on the continuum of height was suppressed by a mean of –1.94 weight gain problems; it is insufficient to cm and deficits in weight gain were even support normal growth but it does not larger. The authors concluded that consistent include a distorted body image as occurs in treatment with stimulant medication was eating disorders.5 associated with maintenance of behavioral Children with NGR are generally referred effectiveness but continued growth suppres- to the pediatric endocrinologist because of sion.11 The somewhat larger deterioration short stature or delayed puberty. Therefore, observed in body weight may be due to the pediatricians and pediatric endocrinologists anorexic effects of these medications. need to recognize NGR and become familiar Suboptimal nutrition appears to be an under- with its causes and treatment. Although the lying cause of stimulant-mediated growth fal- importance of evaluating the pattern of tering. stature increments throughout life in the The classic anthropometric criteria for differential diagnosis of short stature cannot NGR stipulate low weight for age with min-

imal deficits in weight for height. By these retinol-binding protein, pre-albumin, albu- cross-sectional criteria, it may be difficult to min, transferrin, and triiodothyronine (T3) differentiate NGR children from those with levels, do not differentiate NGR patients familial short stature or constitutional from those with familial or constitutional growth delay.6-9 Only the longitudinal pro- short stature. Other indices of malnutrition, gression of body weight and height can such as the urinary creatine-height index or more clearly reveal NGR, which may occur urinary nitrogen/creatinine ratio, do not usu- even when there is weight-for-height ally demonstrate abnormalities. The reason excess.12 The distinguishing feature is a is that NGR patients have adapted to their delay in linear growth and puberty resulting suboptimal nutritional intake and they main- from inadequate weight gain. Thus, tain homeostasis by decreasing growth, although concern is intensified when weight thereby reaching equilibrium with preserva- or height measurements fall below the 5th tion of biochemical nutritional markers.13 percentile, growth failure expressed as dete- Although fasting and protein-calorie mal- rioration across percentiles of weight and nutrition have been shown to lower circulat- height may also indicate NGR even when ing IGF-I levels in humans and rodents, the child is still above the 5th percentile. IGF-I levels may not differentiate NGR With nutritional rehabilitation, catch-up patients from those with familial and/or con- growth is usually achieved.1,7-9 stitutional short stature. The degree of nutri- Analysis of body weight progression may tional insufficiency in NGR is not as severe be the most important clue for diagnosing as that observed in protein-calorie mal- NGR in patients with short stature. nutrition or fasting, and may impair growth Calculation of theoretical weights and by altering other cellular mechanisms with- heights based on previous growth per- out affecting the serum IGF-I levels as dis- centiles may be used to quantitatively com- cussed below. Because the energy restriction pare current anthropometric indices with is mild, and NGR children consume suffi- previously established patterns of weight cient dietary protein, IGF-I concentrations and height progression.1,7-9 Theoretical may be preserved within a range appropri- weight is defined as the weight the patient ate for bone age development. Likewise, rats should have had at the time of the examina- consuming diets containing 15% protein and tion, if the patient had continued to gain 90% of the total energy requirements, main- weight along the percentile previously tained the IGF-I concentrations within nor- established during the pre-morbid growth mal ranges.14 period. Body weight-for-height deficits are We reported that NGR patients show not common in NGR, but the body weight is decreased activity of erythrocyte Na+,K+- often deficient relative to the theoretical ATPase compared with familial and/or con- weight. In contrast, short patients without stitutional short stature patients.13 This NGR, such as those with constitutional enzyme is involved in the active transport of growth delay, continue to gain weight along sugars and amino acids and in cellular ther- established percentiles and the body weight mogenesis, normally accounting for approx- at the time of assessment is equal to the the- imately one-third of the basal energy oretical body weight. A fall in growth asso- requirements. Reduced energy intake lowers ciated with a poor rate of weight gain indi- the basal metabolic rate and decreases Na+, cates NGR, even without an appreciable K+-ATPase activity. Because anthropometric weight-for-height deficit.1,9,12 parameters may be lacking or inaccurate and Patients with NGR do not appear wasted, usual biochemical markers may not be suffi- and the usual biochemical parameters of nu- cient to detect NGR, a more sensitive test is tritional status, including serum levels of required for the diagnosis of NGR.

J Clin Res Ped Endo 2009;1(4):157–163 159 Nutrition and Growth

Erythrocyte Na+, K+-ATPase activity may changes occur during chronic suboptimal offer such a diagnostic tool. However, to nutrition. date, this assay has not been widely avail- We have shown that diminished energy able for clinical purposes, is cumbersome, intake resulting in NGR reduces metabolic and has only been applied on a research rate even before there is a loss of body basis.13,14 weight.19 The rate of protein synthesis may Growth deceleration is the adaptive decrease in response to a reduction in en- response to suboptimal nutrition, so patients ergy intake, because this process is energy with NGR have achieved equilibrium expensive and accounts for 10–15% of the between their genetic growth potential and basal metabolic rate.20 It has long been their nutritional intake. Diminished growth known that protein catabolism is also sensi- brings the nutrient demands into balance tive to energy deprivation, such that reduced with the nutritional intake, without adverse- dietary energy sources may lead to increased ly affecting biochemical or functional home- nitrogen fiuxes in which protein breakdown ostatic measures. Of course, there are limits is accelerated to provide energy.21,22 Nitrogen to these adaptive possibilities. If nutritional retention markedly increases during nutri- deprivation becomes more severe, or when tional rehabilitation;23 nutritional recovery acute malnutrition is superimposed on the also normalizes the excretion of amino acids chronic suboptimal state, there will be and increases the rate of protein synthesis.24 altered anthropometric measurements, such In NGR, the result of the altered rates of pro- as weight and skin fold thickness, and bio- tein turnover and nitrogen retention may be chemical indices reflecting malnutrition. the cessation of normal growth, as an adap- The biochemical and hormonal changes tive response to the decreased intake. In associated with chronic suboptimal nutrition addition to suboptimal energy intake, vari- have been studied utilizing a rodent model. ous mineral and vitamin deficiencies have Sodium-potassium ATPase activity was been implicated in the etiology of NGR.1,25 reduced in rats fed less than 80% of ad-libi- More recently we studied the changes in tum energy intake.14 Body weight gain was the 24-hr metabolic and physical activity preserved in sub optimally fed rats treated profile of rodents undergoing chronic sub- with recombinant human GH.15,16 optimal nutrition to assess if the metabolic Furthermore, simultaneous restriction of adaptations contribute to the preservation of both energy and zinc did not augment the body weight gain and growth.26 We utilized growth deterioration of chronic suboptimal the rodent EMTAC to conduct accurate nutrition.17 Substitution of fat for carbohy- measurements of continuous energy expen- drates led to greater body weight gains, diture and physical activity in rats restricted through reduced energy expenditure and to 80, 70 or 60% of ad-libitum energy con- possibly decreased leptin secretion.18 Other sumed by controls. Rats that were restricted changes due to chronic suboptimal nutrition to only 80% of their ad-libitum energy intake included a reduction of liver weight with an grew at lower rates than those of the ad-libi- increase in percent total polyunsaturates, n- tum fed controls. Furthermore, they pre- 6 polyunsaturates and total unsaturates in served fat-free mass, but had reduced ener- mitochondrial lipids. Suboptimal nutrition gy expenditure and physical activity, along also reduced mandibular and femur bone with increased respiratory quotients, during growth. Finally, rats sub optimally fed for the dark period at night. Thus, these rats uti- three weeks showed decreased T-cell num- lized their body fat and reduced their physi- bers in the thymus that may alter the cal activity to conserve energy to preserve immune system. All these studies suggest lean body mass and to allow some growth. that minor biochemical and physiological However, rats fed only 70% of ad-libitum

energy intake had reductions in both growth capacity and learning ability that may also and lean body mass and had a greater mag- be compromised. Decreased growth velocity nitude in the reduction of energy expendi- nevertheless constitutes a functional com- ture and physical activity. Rats subjected to promise per se, which should be detected even greater amounts of energy restriction, and treated as early as possible.1,29-31 such as those fed 60% of ad-libitum energy Nutritional rehabilitation for NGR of intake, had even greater detrimental effects nonorganic origin requires providing the such as reduced growth, loss of lean body patient with adequate caloric and nutrient and fat mass along with further decreases in intake for the restoration of previous growth energy expenditure and physical activity. patterns. Initially, estimation of energy Despite consuming only 60% of their ad-libi- requirements should be based on the age- tum energy intake, these rats still preserved and gender-specific RDA based on the 26% of their body weight gain as compared patient’s theoretical weight. Adequate intake to ad-libitum fed controls. This suggests that of protein usually accompanies sufficient over the course of the experiment, some caloric intake, but care should be taken that essential needs of metabolism were still micronutrient intakes meet the RDA and being met and a minimal amount of energy specific deficiencies, such as iron or zinc, was still available for growth.26 should be treated.30,31 Some patients may not Other physiological adaptations may be willing or able to consume a completely contribute to the maintenance of health and balanced diet and may require a multivita- body weight gain during chronic suboptimal min and mineral supplement. A careful diet nutrition. For example, a reduction of body history can elucidate food preferences and temperature might be another mechanism eating patterns that need to be considered in for energy conservation, since changes in devising an appropriate dietary plan. Our energy expenditure are directly related to experience has been to offer general dietary body temperature.27 It is possible that other suggestions rather than to prescribe a specif- factors might also contribute to the preserva- ic diet. Frequent follow-up visits provide an tion of metabolic homeostasis, such as alter- opportunity to revise and update dietary rec- ations in erythrocyte sodium-potassium- ommendations and to assess weight and ATPase activity.14 Nonetheless, it remains height improvements. Although the appro- controversial whether decreased body size is priate diet can be easily determined, suc- an advantageous adaptation to a limited cessful intervention requires a change in food supply or whether adverse health and dietary behaviors and possibly health beliefs functional impairments result. Mild energy as well.32 Increasing the caloric density of the restriction in rodents has been repeatedly child’s diet often involves raising the dietary shown to extend life span.28 fat and providing nutrient dense foods that However it is difficult to conceive an the patient and the family may not accept. appropriate homeostasis that will allow opti- The assurance that an appropriate nutrition- mal health and prolongation of life with lev- al intake will result in normal growth, with- els of energy restriction that are associated out producing obesity, is necessary support- with poor growth and degradation of lean ive therapy. This is of particular concern in body mass. Physical activity is decreased the initial stages of the treatment, when with a 20% decrease in energy consumption, weight increases rapidly before any notice- and as mentioned above, energy expendi- able effect on height is observed.29-31 tures in rats promptly decrease with a rela- The USDA guidelines for dietary intake tively mild energy restriction.14,18,26 Moreover were released, September 24 2004.33 The DRIs there are other functional impairments that are evidence-based recommendations for are more difficult to assess, such as mental planning and assessing dietary intake of

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apparently healthy people and the reader is Marcel Dekker, 1996:103-120. encouraged to refer to the DRI book or web- 10. MTA Cooperative Group. National Institute site (http://www.nal.usda.gov/fnic/etext/ of Mental Health Multimodal Treatment 000105.html) when evaluating the dietary Study of ADHD Follow-up: changes in intake of a given patient. However the USDA effectiveness and growth after the end of treatment. Pediatrics 2004;113:762-769. food guide is a simpler guideline which 11. Zachor DA, Roberts AW, Hodgens JB, Isaacs should serve the needs of Pediatric JS, Merrick J. Effects of long term Endocrinologists when evaluating the quality psychostimulant medication on growth of of the dietary intake of a short child and to children with ADHD. Res Dev Disabil 2006; provide guidelines for intake to the patients. 27(2):162-174. The consumption of the recommended foods 12. Trowbridge FL, Marks JS, Lopez de Romana from each group is a fairly good indicator of G, Madrid S, Boutton TW, Klein PD. Body the adequacy of the dietary intake, if main- composition of Peruvian children with short tained over time.33 stature and high weight-for-height. II. Impli- cations for the interpretation for weight-for- ACKNOWLEDGEMENT height as an indicator of nutritional status. Am J Clin Nutr 1987;46:411-418. Supported by Pediatric Sunshine Academics Inc. 13. Lifshitz F, Friedman S, Smith MM, Cervantes C, Recker B, O’Connor M. Nutritional dwar- REFERENCES fing: a growth abnormality associated with reduced erythrocyte Na+,K+ ATPase activity. 1. Grimberg A, Lifshitz F, Worrisome Growth. Am J Clin Nutr 1991;54:997-1004. In Pediatric Endocrinology, 5th edition. Vol. 14. Tarim O, Chasalow FI, Murphy J, Rising R, 2, Chapter 1. Ed F. Lifshitz. Informa NY, Carrillo A and Lifshitz F. Evaluation of 2007;1-50. differential effects of carbohydrate and fat 2. Tanner JM, Whitehouse RH. Clinical intake on weight gain, serum IGF-I, and longitudinal standards for height, weight, erythrocyte Na+K+ATPase activity in height velocity, weight velocity and stages of suboptimal nutrition in rats. J Am. Coll Nutr puberty. Arch Dis Child 1976;51:170-179. 1997;16:159-165. 3. Lifshitz F, Tarim O. Nutritional dwarfing. 15. Carrillo A, Rising R, Tverskaya R, Lifshitz F. Ef- Curr Prob Pediatr 1993;23:322-326. fects of Exogenous Recombinant Human 4. Lifshitz F. Nutrition and growth. In: Paige Growth Hormone on an Animal Model of Su- DM, ed. Clinical Nutrition. Nutrition and boptimal Nutrition. J Am Coll Nutr 1998;17: Growth Supplement 4. St Louis: CV Mosby, 276-281. 1985:40-47. 16. Carrillo A, Rising R, Cole C, Tverskaya R, 5. Sanberg DE, Smith MM, Fornari V, Goldstein Lifshitz F. Low dosages of exogenous M, Lifshitz F. Nutritional Dwarfing: Is it a growth hormone and its effect on growth in Consequence of Disturbed Psychosocial an animal model of suboptimal nutrition. Functioning? Pediatr 88:176-933, 1991. Nutrition 2000;16:1074-1078. 6. Tanner JM. Normal growth and techniques 17. Rising R, Scaglia JF, Cole C, Tverskaya R, of growth assessment. Clin Endocrinol Duro D, Lifshitz F. Exogenous recombinant Metab 1986;15:411-451. human growth hormone effects during 7. Lifshitz F, Moses N, Cervantes C, Ginsberg L. suboptimal energy and zinc intake. Nutrition Nutritional dwarfing in adolescents. Semin & Metabolism 2005;2:10. Adolesc Med 1987;3:255-266. 18. Gamba CA, Friedman SM, Rodriquez PN, 8. Lifshitz F, Tarim O. Worrisome growth pat- Macri EV, Vacas MI, Lifshitz F. Metabolic terns in children. Int Pediatr 1994;9:181- status in growing rats fed isocaloric diets 188. with increased carbohydrate-to-fat ratio. 9. Lifshitz F, Tarim O, Smith MM. Nutritional Nutrition 2005;21:249-254. growth retardation. In: Lifshitz F, ed. 19. Friedman SM, Rodriguez PN, Boyer PM, and Pediatric Endocrinology, 3rd ed. New York: Lifshitz F. Decreased energy expenditure-an

adaptive mechanism of nutritional growth 2006;3:11. retardation. Nutr Res 2006; 26:345-349. 27. Rikke BA, Yerg JE, Battaglia ME, Nagy TR, 20. Poehlman F, Melby CL, Badylak SF. Resting Allison DB, Johnson TE. Strain variation in metabolic rate and post-prandial thermoge- the response of body temperature to dietary nesis in highly trained and untrained males. restriction. Mech Ageing Dev 2003 Am J Clin Nutr 1988; 47:793–798. 124:663-678. 33 21. Waterlow JC, Golder M, Picou D. Protein 28. Wang MC, Bohmann D, Jasper H. JNK turnover in man. Am J Clin Nutr 1977;30: extends life span and limits growth by 1333-1339. antagonizing cellular and organism-wide 22. Read WW, McLaren DS, Tchalian M, Nassar responses to insulin signaling. Cell S. Studies with 15N-labeled ammonia and 2005;121:115-125. urea in the malnourished child. J Clin Invest 29. Pugliese MT, Lifshitz F, Grad G, Fort P, 1969;48:1143-1149. Marks-Katz M. Fear of obesity. A cause of 23. Waterlow JC, Golden MH, Garlick PJ. short stature and delayed puberty. N Engl J Protein turnover in man measured with Med 1983;309:513-518. 15N: comparison of end products and dose 30. Lifshitz F, Moses N. Nutritional dwarfing: regimes. Am J Physiol 1978;235:E165-174. growth, dieting and fear of obesity. J Am 24. Golden M, Waterlow JC, Pilou D. The Col Nutr 1988;7:367-376. relationship between dietary intake, weight 31. Lifshitz F. Children on adult diets. Is it harm- change, nitrogen balance, protein turnover ful? Is it healthful? J Am Coll Nutr 1992;11 in man. Am J Clin Nutr 1977;30:1345-1348. Suppl:84S-90S. 25. Cole C, Lifshitz F. Zinc Nutrition and Growth 32. McCann JB, Stein A, Fairburn CG, Dunger Retardation. Ped Endocrinol Rev 2008;5: DB. Eating habits and attitudes of mothers 889-896 of children with non-organic failure to 26. Rising R and Lifshitz F. Energy expenditures thrive. Arch Dis Child 1994;70:234-236. & physical activity in rats with chronic su- 33. www.health.gov/dietaryguidelines/dga2005/ boptimal nutrition. Nutrition & Metabolism report/ HTML/D2

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