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Growth hormone treatment enhances nutrition and growth in children with cystic fibrosis receiving enteral nutrition
GROWTH HORMONE TREATMENT ENHANCES NUTRITION AND GROWTH IN CHILDREN WITH CYSTIC FIBROSIS RECEIVING ENTERAL NUTRITION DANA S. HARDIN, MD, JULIE RICE, RN, CHUL AHN, PHD, THOMAS FERKOL, MD, MICHELLE HOWENSTINE, MD, STACEY SPEARS, RD, CLAUDE PRESTIDGE, MD, DAN K. SEILHEIMER, MD, AND ROSS SHEPHERD, MD
Objectives Impaired longitudinal growth and poor weight gain are common and important problems in children with cystic fibrosis. This study evaluates the hypothesis that adjunctive growth hormone (GH) therapy augments the growth response to nutritional supplementation. Study design We recruited 18 prepubertal children who received enteral nutritional supplementation for at least 2 years before enrollment. Nine were randomly assigned to receive no GH for 1 year, followed by 1 year of GH. Nine were randomly assigned to receive 1 year of GH followed by a second year of GH. Measurements included height, weight, pulmonary function, lean tissue mass, bone mineral content, hospitalizations, outpatient antibiotic use, and caloric intake. Results Growth hormone resulted in significant improvement in height, weight, bone mineral content, lean tissue mass, and number of hospitalizations. Pulmonary function was similar at baseline. Absolute forced vital capacity and forced expiratory volume in 1 minute significantly increased in GH treatment, but there was no significant change in percent predicted pulmonary function. Caloric intake was similar in both groups during both years. Conclusions These results suggest that GH is a useful for enhancing growth in children with cystic fibrosis receiving enteral nutritional supplementation. (J Pediatr 2005;146:324-8)
he first consensus conference on Nutrition was held by the North American Cystic Fibrosis Foundation in 1990.1 This group strongly emphasized the importance of achieving optimal nutrition and growth. Their conclusions were based on multiple publications documenting the association between malnutrition and worsened morbidity and mortality in both children and adults with cystic fibrosis (CF).2,3 Since that time, it is recommended that patients treated at Cystic Fibrosis Foundation accredited sites have a thorough dietary evaluation at least annually. Those identified as malnourished are counseled on appropriate measures to improve caloric intake. For many, in whom oral nutritional supplements are unsuccessful, placement of a gastrostomy tube for nocturnal enteral nutritional supplementation is the current standard of care.4 Despite this approach, malnutrition and poor linear growth are frequent problems in children with CF. The most recent annual report from the Cystic Fibrosis Foundation documents5 that 30% of children are below the 10th percentile for height and 26% are below the 10th percentile for weight. In a recent analysis,6 we demonstrated a poor association between weight velocity and height velocity, suggesting that improved height may need to be addressed by separate means than simply by nutritional augmentation alone. Studies by our group7,8 and others9-11 have documented significant improvement in both height and weight in children with CF treated with recombinant human growth hormone (GH). We undertook this study to test the hypothesis that GH improves growth and pulmonary function in children receiving nutritional supplementation by overnight enteral feedings through a gastrostomy tube.
T
BMC CF FVC FEV1
324
Bone mineral content Cystic fibrosis Forced vital capacity Forced expiratory volume in 1 second
GH GHTX IGF LTM
Growth hormone GH treatment Insulin-like growth factor Lean tissue mass
See editorial, p 303.
From the University of Texas-Southwestern Medical School, Department of Pediatrics, Dallas, Texas; the University of Texas-Houston, Departments of Biostatistics and Internal Medicine, Houston, Texas; Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics; Washington University, St Louis, Department of Pediatrics, St Louis, Missouri; Children’s Medical Center, Cystic Fibrosis Center, Dallas, Texas; and Baylor College of Medicine, Department of Pediatrics, Houston, Texas. Supported in part by the Genentech Center for Clinical Research. Submitted for publication Aug 19, 2003; revision received Aug 9, 2004; accepted Oct 5, 2004. Reprint requests: Dana S. Hardin, MD, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, G2.220, Dallas, TX 75390-9063. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.10.037
Table I. Characteristics of subjects in each study group at baseline GHTX (n = 9) Age (y) Height (cm) Height Z score Weight (kg) Weight Z score
11.6 129.6 21.71 26.1 22.01
± ± ± ± ±
2.2 9.2 1.03 6.2 1.71
Non-TX (n = 9) 11.1 133.1 21.65 27.5 21.89
± 1.9 ± 6.7 ± 0.97 ± 6.7 ± 0.76
GH, growth hormone; TX, treatment. There are no statistically significant differences.
METHODS Subjects We recruited 18 prepubertal children from four institutions. All were naive to GH therapy and each had received enteral nutritional supplementation for at least 2 years before study enrollment. Nine of these subjects were randomly assigned to receive no GH for 1 year (NonTX), followed by 1 year of GH treatment (GHYr2). Nine were randomly assigned to receive 1 year of GH treatment (GHTX) and each elected to continue GH for a second year (ContGH). All subjects signed written informed consent approved by the local institutional review board. Random assignment was performed through the use of a computer-generated assignment. The baseline inclusion criteria were height and weight less than the 10th percentile for age, Tanner stage 1 pubertal maturation, and adherence to nutritional therapy, as assessed by repeated dietary evaluation. Exclusion criteria were treatment with sustained systemic corticosteroid therapy within 6 weeks of study and colonization with Burkholderia cepacia. There was no statistical difference between any of the groups at baseline (Table I). Every 3 months, subjects underwent a physical examination, including Tanner staging (breasts for girls and testes for boys) and were queried for adverse events.
Anthropometric Measures Height was measured on a calibrated stadiometer using the mean of 3 readings. Weight was measured in kilograms, using a calibrated scale. Each was measured every 3 months. Subjects were weighed in lightweight street clothing after emptying their pockets and removing shoes. Lean tissue mass (LTM) and bone mineral content (BMC) were measured by using Dual Energy X-ray absorptiometry (DXA, Lunar Prodigy) every 6 months.
Growth Hormone Therapy Growth hormone was given by daily subcutaneous injection in a dose of 0.3 mg/kg per week (Nutropin AQ, Genentech Inc; San Francisco, Calif). Subjects were trained in injection technique by the research nurse. Compliance was assessed by questionnaire and by having patients return empty vials of GH. The dose was adjusted every 3 months for weight gain. We did not measure GH response to secretagogue Growth Hormone Treatment Enhances Nutrition And Growth In Children With Cystic Fibrosis Receiving Enteral Nutrition
Figure 1. Comparison of height and weight velocity in the subjects receiving GH the first year (GHTX) and those not receiving GH (NonTX). The GHTX group demonstrates significant improvement for both height and weight.
testing; however, insulin-like growth factor (IGF)-1 levels were assessed at baseline, then yearly.
Pulmonary and Clinical Status We assessed clinical status of the study subjects by measuring absolute and percent predicted forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) every 3 months. Hospitalizations and outpatient intravenous antibiotic use were quantified and detailed on each case report form and confirmed by review of the medical record.
Glucose Tolerance Casual blood glucose levels (CBG) were measured at every study visit in all subjects. Fasting blood glucose (FBG) levels, as well as blood sugar measures during nighttime enteral feedings, were measured in 12 subjects.
Nutritional Status Nutritional intake was measured by a 3-day food record every 6 months. Nutritional composition and caloric intake were calculated by the same dietician using Diet Master Pro software (Lifestyle Technologies, Phoenix, Ariz). Compliance with gastrostomy feedings was assessed by patient response to the physician, by annual clinic dietary assessment, and by the food journal information. Levels of Vitamins D, E, and A, as well as electrolytes and calcium, were obtained from the medical record for 75% of the study participants.
Statistics A paired Student t test was used to determine statistical significance of each study end point by comparing NonTX with GHTX. Similarly, a paired test was used to compare GHTX and GHYr2 and ContGH with GHTX. Significance was defined as P < .05.
RESULTS Subjects Throughout the study, all subjects required pancreatic enzyme treatment, none received systemic steroid treatment 325
Table II. Growth rates, lean tissue mass, pulmonary function, hospital admissions, and bone mineral content in study subjects GHY2 (n = 9) Height velocity (cm/y) Weight velocity (kg/y) DLTM (kg) DFVC (L) DFEV1 (L/s) D Hospitalizations DBMC (g/y)
5.9 ± 6.0 ± 3.9 ± 1.1 ± 0.6 ± 2.1 ± 177 ±
ContGH (n = 9)
2.1 1.7 1.4 0.2 0.3 2.1 69
6.2 ± 4.6 ± 4.1 ± 1.6 ± 0.5 ± 0.8 ± 163 ±
1.2 3.1 2.0 0.1 0.4 0.4 75
LTM, lean tissue mass; BMC, bone mineral content; GHY2, children who were originally randomly assigned to no treatment, then received GH during the second year; ContGH, children who elected to continue GH for a second year after the first year of treatment.
and none were colonized with B cepacia. The boys remained Tanner 1 throughout the study, as did the girls during the first year. During the second year, one girl (ContGH) developed Tanner stage 2 breasts. No subject reported adverse events, and none were found on physical examination.
Anthropometric Data At the end of 1 year, height and weight velocity were significantly greater in the GHTX group (Figure 1). The GHTX group also had significantly greater height and weight Z scores (HtZ: NonTX = 21.73 ± 1.0, GHTX = 21.08 ± 1.0, P = 0.04; WtZ: NonTX = 21.95 ± 1.4, GHTX = 20.73 ± 2.4, P = .01). Body mass index also increased in the GHTX (11.2 ± 0.8) but decreased slightly in the NonTX (20.4 ± 0.6). There was significant increase in LTM in the GHTX compared with the NonTX (LTM kg/y: NonTX = 2.4 ± 1.1, GHTX= 3.8 ± 1.0, P = .04). Evaluation at the end of the second year revealed similar improvement in height, weight, and LTM in GHYr2 to GHTX and ContGH (Table II). Those patients who continued GH for the second year (ContGH) demonstrated an increase in growth similar to GHTXYr2 (Table II). There was no difference between the total body BMC of GHTX and NonTX at baseline. BMC was consistent with osteopenia12 (mean Z score = 21.76 ± 0.78, calculated from age/sex-matched normative data using the Children’s Nutrition Center Web site13). At the end of the first year, BMC was higher in the GHTX (change in BMC, g/y: NonTX = 34 ± 15, GHTX = 176 ± 22, P = .02). At the end of the second year, GHYr2 had a change in BMC similar to GHTX, and ContGH demonstrated continued improvement of BMC (Table II).
Pulmonary Function and Clinical Status At baseline there was no difference in absolute FVC and FEV1 between the groups. At the end of 1 year, GHTX demonstrated significantly higher absolute FVC and FEV1 (Figure 2). At the end of the second year, the improvement in 326
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Figure 2. Absolute forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at baseline and after 1 year in children with CF receiving GH therapy (GHTX) compared with nontreated control subjects.
absolute FVC and FEV1 in the GHYr2 group was similar to GHTX, and there was continued improvement in ContGH (Table II). At baseline, percent predicted (%) pulmonary function was similar between the groups (GHTX: %FEV1 = 68 ± 15, %FVC = 78 ± 17; NonTX: %FEV1 = 66 ± 22, %FVC = 80 ± 14). After 1 year, there was no statistical difference in percent predicted pulmonary function between the groups; however, the GHTX group increased modestly and the NonTX decreased (% predicted FVC: GHTX = 81 ± 21, NonTX = 78 ± 19, P = NS, % predicted FEV1: GHTX = 70 ± 22, NonTX = 66 ± 22, P = NS). The groups had similar numbers of hospitalizations the year before the study. However, at the end of year 1, the GHTX had fewer hospitalizations (NonTX = 3.0 ± 2.0, GHTX = 1.1 ± 1.0, P = .003). There was no statistical difference in outpatient antibiotic use (NonTX = 0.85 ± 0.8, GHTX = 0.57 ± 0.51, P = .05). At the end of the second year, hospitalizations in GHYr2 demonstrated a decrease similar to GHTX, and there was further decrease in those continuing GH for a second year (Table II).
Glucose Tolerance Casual blood glucose levels were similar at baseline in both groups. At 1 year, there was a slight but not statistically significant increase in CBG in GHTX (baseline = 87 ± 11, 1 year of GH = 92 ± 9 mg/dL, P = NS). Fasting blood glucose levels were similar throughout the 2 years of study. Patients with mid-nocturnal feeding glucose levels measured had no significant increase with GH (baseline =116 ± 17, 1 year of GH = 119 ± 20). IGF-1 levels (ng/mL) were lower than published values for age, sex, and Tanner stage at baseline (119 ± 42), and there was no difference between the GHTX and NonTX. After 1 year, IGF-1 levels increased significantly in the GHTX (286 ± 91) but did not change in the NonTX (125 ± 27). After the second year, the ContGH demonstrated slightly higher The Journal of Pediatrics March 2005
IGF-1 levels (324 ± 29), and results from the GHYr2 (319 ± 25) were similar to those treated the first year.
Nutritional Status Nutritional supplementation through gastrostomy tube accounted for 75% of the calories consumed by the children in our study. The most common supplemental feeding was Nutren Two Cal (Nestle, Deerfield, Ill) (70%), followed by Tolerex (Novaritis Nutrition, Minneapolis, Minn) (10%). Other supplements included Peptomen Junior (Nestle, Deerfield, Ill), Nutren, and KinderCare (Mead Johnson, Evansville, In). All patients enrolled in our study were receiving caloric intake commensurate with the recommendations of the National Cystic Fibrosis Foundation4 (mean calorie/kg = 137 ± 26). The average protein intake was 12% of the total daily caloric intake (range, 8% to 17%), fat intake was 33% of the daily total (range, 8% to 40%), and carbohydrate intake was 55% of the total (range, 40% to 68%). There was no significant difference in caloric intake or in percentage of carbohydrate, fat, and protein between the groups at 1 year, nor was there any difference from baseline. Routine measurement of vitamin levels E, A, and D did not indicate a deficiency. Similarly, routine calcium and electrolyte panels were collected yearly and were normal throughout the study (data not shown).
DISCUSSION
necrosis factor-a and catabolism.17 In our current study, the improvement in LTM with GH suggests lowering of protein catabolism. Negative protein balance contributes to worsened clinical status by decreasing body muscle mass and possibly by contributing to worsened immune function.14 Thus improvement in protein kinetics with GH is potentially quite important and may not be accomplished by nutritional supplementation of protein. Another mechanism by which GH may improve growth is by increasing IGF-1 levels. Most of the anabolic actions of GH are mediated through IGF-1, and low levels lead to poor growth and muscle development. Similar to our previous reports,7,17 we found low baseline IGF-1 levels with a significant increase after GH. Poor nutrition can cause lower IGF-1 levels; however, the children in our current study had low IGF-1 levels despite good nutritional supplementation. This indicates that IGF-1 levels are low in CF for reasons besides poor nutrition. One possibility is the interference of hepatic production of IGF-1 by proinflammatory cytokines.14 GH directly increases IGF-1.15 Lowering of cytokine levels with GH17 may indirectly increase IGF-1 as well.
Bone Mineral Content Recent reports document a high prevalence of osteoporosis in patients with CF,12 and malnutrition has been cited as a major risk factor.18,19 Despite this association, studies of nutritional supplementation have not evaluated potential benefits to bone. Our subjects have osteopenia, yet intake of calcium, vitamin D, and calories is appropriate according to CF Foundation recommendations. Low BMC in these subjects with CF suggests that poor longitudinal growth is an important risk factor for osteoporosis. Growth hormone treatment resulted in a greater increase in total BMC. One reason for improvement may be the increase in LTM and growth velocity. Previous studies in both normal children20 and CF21,22 have demonstrated a close correlation between LTM and BMC. Furthermore, normal growth velocity is important for the normal accumulation of BMC.23 Another possible reason for increased BMC with GH may be the lowering of cytokine levels, since cytokines stimulate osteoclast activity.
Our study presents new information on the role of GH as an adjunct to nutritional supplementation in achieving optimal nutrition and growth. Our results suggest that GH also improves clinical status. We have reported the results separately for those receiving GH the first year or the second year. The similar response suggests our findings are not secondary to study enrollment alone, and the continued improvement in the children who received GH for a second year indicates benefit of ongoing therapy. Most of the previous work in the field of nutrition in CF has been conducted with enteral or parenteral feedings given for 6 months or less. The short-term weight gain documented by these studies is similar to the weight gain we describe with the addition of GH. Only one previous study has been conducted over a longer period of time. Dalzell et al23 followed a cohort of patients treated with nighttime enteral feedings for 4 years. They documented significant decline in rate of weight gain during each year of study, with final results similar to those of our NonTX subjects. The decline in weight with ongoing enteral nutrition suggests a plateau of effectiveness; however, the reason for this is not clear. The potential mechanism(s) by which GH may enhance response to nutritional supplementation in CF deserves comment. Protein catabolism has been described,3,24,25 even in non–acutely ill subjects with CF.17,26,27 Studies in subjects without CF15,16 and with CF17 have documented improved whole-body protein kinetics with GH. We have also demonstrated lowering of cytokine tumor necrosis factor-a in CF patients treated with GH and the correlation of tumor
This study provides further support to our previous findings of improved absolute pulmonary function after treatment with GH. Some of this effect is expected, since lung capacity should improve with linear growth. Additionally, GH resulted in lack of decline in %FEV1. Although the difference from NonTX was not statistically significant, previous studies demonstrate a decline in %FEV1 of 3% to 5% per year. Thus this may be clinically relevant. Our data demonstrate a reduction in the number of hospitalizations with GH. These findings support our previous report.7 Unlike our previous study, we did not find a significant difference in the number of outpatient intravenous antibiotic courses. It is possible that our subject number was too small to demonstrate the effect.
Growth Hormone Treatment Enhances Nutrition And Growth In Children With Cystic Fibrosis Receiving Enteral Nutrition
327
Pulmonary and Clinical Status
Nutritional Status The patients who participated in our studies received standard of care in line with current Cystic Fibrosis Foundation nutrition guidelines. Critics of GH use in the CF population have suggested that children would gain height normally if they received enough calories. Our subjects demonstrate that despite good nutritional intake, short stature still occurs. Although previous guidelines in CF nutrition have focused on improving weight, the most recent North American Consensus Conference on Nutrition also stressed the importance of normalizing linear growth.4 This new focus was developed by using recent information from Becker et al28 and Konstan et al29 documenting the association between poor linear growth and future worsened lung function. The typical approach to improving linear growth has been to improve nutritional intake. However, only a few studies of nutritional supplementation have documented significant improvement in linear growth. The most improvement was noted in a small study of malnourished (mean weight Z score, 21.23) and stunted (mean height Z score, 20.91) children with CF.24 Enteral feeding for 1 year resulted in a growth velocity of 7.6 cm/y. This change is less than reported in the current study and is less than in previous studies of GH alone.6,7 The study also found lack of sustained effect once feedings were discontinued. Long-term studies of GH treated children with CF should help clarify whether improving linear growth will result in future better lung function.
Glucose Tolerance Previous studies have indicated that enteral feedings result in increased problems with glucose intolerance. The children participating in our study did not have evidence of glucose intolerance, although we did not perform glucose tolerance tests.
Summary Our current findings support our previous studies and suggest that GH provides safe adjunctive therapy to optimal nutritional support for helping patients with CF improve growth and clinical status.
REFERENCES 1. Cystic Fibrosis Foundation. Nutritional Assessment and Management in Cystic Fibrosis. Consensus Conferences 1990, Bethesda, Maryland;1:1-15. 2. Kraemer, Rudeberg A, Hadorn B, Rossi E. Relative underweight in cystic fibrosis and its prognostic value. Acta Paediatr Scand 1978;67:33-5. 3. Holt TL, Ward LC, Francis PJ, Isles A, Cooksley WGE, Shepherd RW. Whole body protein turnover in malnourished cystic fibrosis patients and its relationship to pulmonary disease. Am J Clin Nutr 1985;41:1061-6. 4. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Pediatr Gastroenterol Nutr 2002;35: 246-59. 5. Cystic Fibrosis Foundation. Cystic fibrosis foundation patient registry annual data report. Cystic Fibrosis Foundation; 2000. 6. Hardin DS. Growth problems and growth hormone treatment in children with cystic fibrosis. Journal of Pediatric Endocrinology and Metabolism 2002;15:731-5.
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7. Hardin DS, Ellis K, Dyson M, McConnel R, Rice J, Seilheimer DK. Growth hormone improves clinical status in children with cystic fibrosisresults of a randomized controlled trial. J Pediatr 2001;139:636-42. 8. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in children with cystic fibrosis. Horm Metab Res 1998;30:636-41. 9. Schnabel D, Schonau E, Staab D, Tacke A, Felsenberg D, Wahn U, et al. Effects of growth hormone therapy on bone metabolism in patients with cystic fibrosis (CF). Paediatr Osteol 1998;10:209-17. 10. Sackey AH, Taylor CJ, Barraclough M, Wales JKH, Pickering M. Growth hormone as a nutritional adjunct in cystic fibrosis: results of a pilot study. J Hum Nutr Diet 1995;8:185-91. 11. Alemzadeh R, Upchurch L, McCarthy V. Anabolic effects of growth hormone treatment in young children with cystic fibrosis. J Am Coll Clin Nutr 2001;17:419-24. 12. Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, et al. Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 1998;128:186-93. 13. http://www.bcm.tmc.edu/bodycomplab. 14. Chang HR, Bistrian B. The role of cytokines in the catabolic consequences of infection and injury. Journal of Pediatric Endocrinology and Metabolism 1998;22:156-66. 15. Mauras N, George D, Evans J, Milov D, Abrams S, Rini A, et al. Growth hormone has anabolic effects in glucocorticoid-steroid-dependent children with inflammatory bowel disease: a pilot study treatment of chronic bowel disease with GH. Metabolism 2002;51:127-35. 16. Copeland KC, Nair KS. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab 1994;78:1040-7. 17. Hardin DS, Dyson M, Rice J, Seilheimer DK, Ellis KJ. Growth hormone improves protein catabolism in children with cystic fibrosis. J Clin Endocrinol Metab 2001;85:4424-8. 18. Gibbens DT, Gilsanz V, Boechat MI, Dufer D, Carlson ME, Wang CI. Osteoporosis in cystic fibrosis. J Pediatr 1988;113:295-300. 19. Bhudhikanok GS, Lim J, Marcus R, Harkins A, Moss R, Bachrach LK. Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 1996;97: 103-11. 20. Ellis KJ. Body composition of a young, multiethnic, male population. Am J Clin Nutr 1997;66:1323-31. 21. Ellis KJ, Shypailo RJ, Hardin DS, Perez MD, Motil KJ, Wong WW. Z Score prediction model for assessment of bone mineral content in pediatric diseases. J Bone Min Res 2000;16:1658-63. 22. Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A, Ellis KJ. Normal bone mineral density in cystic fibrosis. Arch Dis Child 2001;84: 363-8. 23. Trotter M, Hixon BB. Sequential changes in weight, density, and percentage ash weight of human skeletons from an early fetal period through old age. Anat Rec 1973;179:1-8. 24. Dalzell AM, Shepherd RW, Dean B, Cleghorn GJ, Holt TL, Francis PJ. Nutritional Rehabilitation in Cystic Fibrosis: a 5-year follow-up study. J Pediatr Gastroenterol Nutr 1992;15:141-5. 25. Shepherd RW, Thomas BJ, Bennett D, Cooksley WGE, Ward LC. changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis. J Pediatr Gastroenterol Nutr 1983;2:439-46. 26. Miller M, Ward L, Thomas BJ, Cooksley WGE, Shepherd RW. Altered body composition and muscle protein degradation in nutritionally growth-retarded children with cystic fibrosis. Am J Clin Nutr 1982;36: 492-9. 27. Hardin DS, LeBlanc A, Lukenbaugh S, Para L, Seilheimer DK. Increased rates of proteolysis associated with insulin resistance in cystic fibrosis. Pediatrics 1998;101:948-56. 28. Becker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis survival. J Am Dietetic Assoc 2001;101:438-42. 29. Konstan MW, Butler SM, Johnson CA, Wagener JS, Lai HC, Morgan WJ. The relationship between nutritional status in early life and pulmonary function in cystic fibrosis. J Pediatr 2003;142:624-30.
The Journal of Pediatrics March 2005
Objectives Impaired longitudinal growth and poor weight gain are common and important problems in children with cystic fibrosis. This study evaluates the hypothesis that adjunctive growth hormone (GH) therapy augments the growth response to nutritional supplementation. Study design We recruited 18 prepubertal children who received enteral nutritional supplementation for at least 2 years before enrollment. Nine were randomly assigned to receive no GH for 1 year, followed by 1 year of GH. Nine were randomly assigned to receive 1 year of GH followed by a second year of GH. Measurements included height, weight, pulmonary function, lean tissue mass, bone mineral content, hospitalizations, outpatient antibiotic use, and caloric intake. Results Growth hormone resulted in significant improvement in height, weight, bone mineral content, lean tissue mass, and number of hospitalizations. Pulmonary function was similar at baseline. Absolute forced vital capacity and forced expiratory volume in 1 minute significantly increased in GH treatment, but there was no significant change in percent predicted pulmonary function. Caloric intake was similar in both groups during both years. Conclusions These results suggest that GH is a useful for enhancing growth in children with cystic fibrosis receiving enteral nutritional supplementation. (J Pediatr 2005;146:324-8)
he first consensus conference on Nutrition was held by the North American Cystic Fibrosis Foundation in 1990.1 This group strongly emphasized the importance of achieving optimal nutrition and growth. Their conclusions were based on multiple publications documenting the association between malnutrition and worsened morbidity and mortality in both children and adults with cystic fibrosis (CF).2,3 Since that time, it is recommended that patients treated at Cystic Fibrosis Foundation accredited sites have a thorough dietary evaluation at least annually. Those identified as malnourished are counseled on appropriate measures to improve caloric intake. For many, in whom oral nutritional supplements are unsuccessful, placement of a gastrostomy tube for nocturnal enteral nutritional supplementation is the current standard of care.4 Despite this approach, malnutrition and poor linear growth are frequent problems in children with CF. The most recent annual report from the Cystic Fibrosis Foundation documents5 that 30% of children are below the 10th percentile for height and 26% are below the 10th percentile for weight. In a recent analysis,6 we demonstrated a poor association between weight velocity and height velocity, suggesting that improved height may need to be addressed by separate means than simply by nutritional augmentation alone. Studies by our group7,8 and others9-11 have documented significant improvement in both height and weight in children with CF treated with recombinant human growth hormone (GH). We undertook this study to test the hypothesis that GH improves growth and pulmonary function in children receiving nutritional supplementation by overnight enteral feedings through a gastrostomy tube.
T
BMC CF FVC FEV1
324
Bone mineral content Cystic fibrosis Forced vital capacity Forced expiratory volume in 1 second
GH GHTX IGF LTM
Growth hormone GH treatment Insulin-like growth factor Lean tissue mass
See editorial, p 303.
From the University of Texas-Southwestern Medical School, Department of Pediatrics, Dallas, Texas; the University of Texas-Houston, Departments of Biostatistics and Internal Medicine, Houston, Texas; Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics; Washington University, St Louis, Department of Pediatrics, St Louis, Missouri; Children’s Medical Center, Cystic Fibrosis Center, Dallas, Texas; and Baylor College of Medicine, Department of Pediatrics, Houston, Texas. Supported in part by the Genentech Center for Clinical Research. Submitted for publication Aug 19, 2003; revision received Aug 9, 2004; accepted Oct 5, 2004. Reprint requests: Dana S. Hardin, MD, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, G2.220, Dallas, TX 75390-9063. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2004.10.037
Table I. Characteristics of subjects in each study group at baseline GHTX (n = 9) Age (y) Height (cm) Height Z score Weight (kg) Weight Z score
11.6 129.6 21.71 26.1 22.01
± ± ± ± ±
2.2 9.2 1.03 6.2 1.71
Non-TX (n = 9) 11.1 133.1 21.65 27.5 21.89
± 1.9 ± 6.7 ± 0.97 ± 6.7 ± 0.76
GH, growth hormone; TX, treatment. There are no statistically significant differences.
METHODS Subjects We recruited 18 prepubertal children from four institutions. All were naive to GH therapy and each had received enteral nutritional supplementation for at least 2 years before study enrollment. Nine of these subjects were randomly assigned to receive no GH for 1 year (NonTX), followed by 1 year of GH treatment (GHYr2). Nine were randomly assigned to receive 1 year of GH treatment (GHTX) and each elected to continue GH for a second year (ContGH). All subjects signed written informed consent approved by the local institutional review board. Random assignment was performed through the use of a computer-generated assignment. The baseline inclusion criteria were height and weight less than the 10th percentile for age, Tanner stage 1 pubertal maturation, and adherence to nutritional therapy, as assessed by repeated dietary evaluation. Exclusion criteria were treatment with sustained systemic corticosteroid therapy within 6 weeks of study and colonization with Burkholderia cepacia. There was no statistical difference between any of the groups at baseline (Table I). Every 3 months, subjects underwent a physical examination, including Tanner staging (breasts for girls and testes for boys) and were queried for adverse events.
Anthropometric Measures Height was measured on a calibrated stadiometer using the mean of 3 readings. Weight was measured in kilograms, using a calibrated scale. Each was measured every 3 months. Subjects were weighed in lightweight street clothing after emptying their pockets and removing shoes. Lean tissue mass (LTM) and bone mineral content (BMC) were measured by using Dual Energy X-ray absorptiometry (DXA, Lunar Prodigy) every 6 months.
Growth Hormone Therapy Growth hormone was given by daily subcutaneous injection in a dose of 0.3 mg/kg per week (Nutropin AQ, Genentech Inc; San Francisco, Calif). Subjects were trained in injection technique by the research nurse. Compliance was assessed by questionnaire and by having patients return empty vials of GH. The dose was adjusted every 3 months for weight gain. We did not measure GH response to secretagogue Growth Hormone Treatment Enhances Nutrition And Growth In Children With Cystic Fibrosis Receiving Enteral Nutrition
Figure 1. Comparison of height and weight velocity in the subjects receiving GH the first year (GHTX) and those not receiving GH (NonTX). The GHTX group demonstrates significant improvement for both height and weight.
testing; however, insulin-like growth factor (IGF)-1 levels were assessed at baseline, then yearly.
Pulmonary and Clinical Status We assessed clinical status of the study subjects by measuring absolute and percent predicted forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) every 3 months. Hospitalizations and outpatient intravenous antibiotic use were quantified and detailed on each case report form and confirmed by review of the medical record.
Glucose Tolerance Casual blood glucose levels (CBG) were measured at every study visit in all subjects. Fasting blood glucose (FBG) levels, as well as blood sugar measures during nighttime enteral feedings, were measured in 12 subjects.
Nutritional Status Nutritional intake was measured by a 3-day food record every 6 months. Nutritional composition and caloric intake were calculated by the same dietician using Diet Master Pro software (Lifestyle Technologies, Phoenix, Ariz). Compliance with gastrostomy feedings was assessed by patient response to the physician, by annual clinic dietary assessment, and by the food journal information. Levels of Vitamins D, E, and A, as well as electrolytes and calcium, were obtained from the medical record for 75% of the study participants.
Statistics A paired Student t test was used to determine statistical significance of each study end point by comparing NonTX with GHTX. Similarly, a paired test was used to compare GHTX and GHYr2 and ContGH with GHTX. Significance was defined as P < .05.
RESULTS Subjects Throughout the study, all subjects required pancreatic enzyme treatment, none received systemic steroid treatment 325
Table II. Growth rates, lean tissue mass, pulmonary function, hospital admissions, and bone mineral content in study subjects GHY2 (n = 9) Height velocity (cm/y) Weight velocity (kg/y) DLTM (kg) DFVC (L) DFEV1 (L/s) D Hospitalizations DBMC (g/y)
5.9 ± 6.0 ± 3.9 ± 1.1 ± 0.6 ± 2.1 ± 177 ±
ContGH (n = 9)
2.1 1.7 1.4 0.2 0.3 2.1 69
6.2 ± 4.6 ± 4.1 ± 1.6 ± 0.5 ± 0.8 ± 163 ±
1.2 3.1 2.0 0.1 0.4 0.4 75
LTM, lean tissue mass; BMC, bone mineral content; GHY2, children who were originally randomly assigned to no treatment, then received GH during the second year; ContGH, children who elected to continue GH for a second year after the first year of treatment.
and none were colonized with B cepacia. The boys remained Tanner 1 throughout the study, as did the girls during the first year. During the second year, one girl (ContGH) developed Tanner stage 2 breasts. No subject reported adverse events, and none were found on physical examination.
Anthropometric Data At the end of 1 year, height and weight velocity were significantly greater in the GHTX group (Figure 1). The GHTX group also had significantly greater height and weight Z scores (HtZ: NonTX = 21.73 ± 1.0, GHTX = 21.08 ± 1.0, P = 0.04; WtZ: NonTX = 21.95 ± 1.4, GHTX = 20.73 ± 2.4, P = .01). Body mass index also increased in the GHTX (11.2 ± 0.8) but decreased slightly in the NonTX (20.4 ± 0.6). There was significant increase in LTM in the GHTX compared with the NonTX (LTM kg/y: NonTX = 2.4 ± 1.1, GHTX= 3.8 ± 1.0, P = .04). Evaluation at the end of the second year revealed similar improvement in height, weight, and LTM in GHYr2 to GHTX and ContGH (Table II). Those patients who continued GH for the second year (ContGH) demonstrated an increase in growth similar to GHTXYr2 (Table II). There was no difference between the total body BMC of GHTX and NonTX at baseline. BMC was consistent with osteopenia12 (mean Z score = 21.76 ± 0.78, calculated from age/sex-matched normative data using the Children’s Nutrition Center Web site13). At the end of the first year, BMC was higher in the GHTX (change in BMC, g/y: NonTX = 34 ± 15, GHTX = 176 ± 22, P = .02). At the end of the second year, GHYr2 had a change in BMC similar to GHTX, and ContGH demonstrated continued improvement of BMC (Table II).
Pulmonary Function and Clinical Status At baseline there was no difference in absolute FVC and FEV1 between the groups. At the end of 1 year, GHTX demonstrated significantly higher absolute FVC and FEV1 (Figure 2). At the end of the second year, the improvement in 326
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Figure 2. Absolute forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) at baseline and after 1 year in children with CF receiving GH therapy (GHTX) compared with nontreated control subjects.
absolute FVC and FEV1 in the GHYr2 group was similar to GHTX, and there was continued improvement in ContGH (Table II). At baseline, percent predicted (%) pulmonary function was similar between the groups (GHTX: %FEV1 = 68 ± 15, %FVC = 78 ± 17; NonTX: %FEV1 = 66 ± 22, %FVC = 80 ± 14). After 1 year, there was no statistical difference in percent predicted pulmonary function between the groups; however, the GHTX group increased modestly and the NonTX decreased (% predicted FVC: GHTX = 81 ± 21, NonTX = 78 ± 19, P = NS, % predicted FEV1: GHTX = 70 ± 22, NonTX = 66 ± 22, P = NS). The groups had similar numbers of hospitalizations the year before the study. However, at the end of year 1, the GHTX had fewer hospitalizations (NonTX = 3.0 ± 2.0, GHTX = 1.1 ± 1.0, P = .003). There was no statistical difference in outpatient antibiotic use (NonTX = 0.85 ± 0.8, GHTX = 0.57 ± 0.51, P = .05). At the end of the second year, hospitalizations in GHYr2 demonstrated a decrease similar to GHTX, and there was further decrease in those continuing GH for a second year (Table II).
Glucose Tolerance Casual blood glucose levels were similar at baseline in both groups. At 1 year, there was a slight but not statistically significant increase in CBG in GHTX (baseline = 87 ± 11, 1 year of GH = 92 ± 9 mg/dL, P = NS). Fasting blood glucose levels were similar throughout the 2 years of study. Patients with mid-nocturnal feeding glucose levels measured had no significant increase with GH (baseline =116 ± 17, 1 year of GH = 119 ± 20). IGF-1 levels (ng/mL) were lower than published values for age, sex, and Tanner stage at baseline (119 ± 42), and there was no difference between the GHTX and NonTX. After 1 year, IGF-1 levels increased significantly in the GHTX (286 ± 91) but did not change in the NonTX (125 ± 27). After the second year, the ContGH demonstrated slightly higher The Journal of Pediatrics March 2005
IGF-1 levels (324 ± 29), and results from the GHYr2 (319 ± 25) were similar to those treated the first year.
Nutritional Status Nutritional supplementation through gastrostomy tube accounted for 75% of the calories consumed by the children in our study. The most common supplemental feeding was Nutren Two Cal (Nestle, Deerfield, Ill) (70%), followed by Tolerex (Novaritis Nutrition, Minneapolis, Minn) (10%). Other supplements included Peptomen Junior (Nestle, Deerfield, Ill), Nutren, and KinderCare (Mead Johnson, Evansville, In). All patients enrolled in our study were receiving caloric intake commensurate with the recommendations of the National Cystic Fibrosis Foundation4 (mean calorie/kg = 137 ± 26). The average protein intake was 12% of the total daily caloric intake (range, 8% to 17%), fat intake was 33% of the daily total (range, 8% to 40%), and carbohydrate intake was 55% of the total (range, 40% to 68%). There was no significant difference in caloric intake or in percentage of carbohydrate, fat, and protein between the groups at 1 year, nor was there any difference from baseline. Routine measurement of vitamin levels E, A, and D did not indicate a deficiency. Similarly, routine calcium and electrolyte panels were collected yearly and were normal throughout the study (data not shown).
DISCUSSION
necrosis factor-a and catabolism.17 In our current study, the improvement in LTM with GH suggests lowering of protein catabolism. Negative protein balance contributes to worsened clinical status by decreasing body muscle mass and possibly by contributing to worsened immune function.14 Thus improvement in protein kinetics with GH is potentially quite important and may not be accomplished by nutritional supplementation of protein. Another mechanism by which GH may improve growth is by increasing IGF-1 levels. Most of the anabolic actions of GH are mediated through IGF-1, and low levels lead to poor growth and muscle development. Similar to our previous reports,7,17 we found low baseline IGF-1 levels with a significant increase after GH. Poor nutrition can cause lower IGF-1 levels; however, the children in our current study had low IGF-1 levels despite good nutritional supplementation. This indicates that IGF-1 levels are low in CF for reasons besides poor nutrition. One possibility is the interference of hepatic production of IGF-1 by proinflammatory cytokines.14 GH directly increases IGF-1.15 Lowering of cytokine levels with GH17 may indirectly increase IGF-1 as well.
Bone Mineral Content Recent reports document a high prevalence of osteoporosis in patients with CF,12 and malnutrition has been cited as a major risk factor.18,19 Despite this association, studies of nutritional supplementation have not evaluated potential benefits to bone. Our subjects have osteopenia, yet intake of calcium, vitamin D, and calories is appropriate according to CF Foundation recommendations. Low BMC in these subjects with CF suggests that poor longitudinal growth is an important risk factor for osteoporosis. Growth hormone treatment resulted in a greater increase in total BMC. One reason for improvement may be the increase in LTM and growth velocity. Previous studies in both normal children20 and CF21,22 have demonstrated a close correlation between LTM and BMC. Furthermore, normal growth velocity is important for the normal accumulation of BMC.23 Another possible reason for increased BMC with GH may be the lowering of cytokine levels, since cytokines stimulate osteoclast activity.
Our study presents new information on the role of GH as an adjunct to nutritional supplementation in achieving optimal nutrition and growth. Our results suggest that GH also improves clinical status. We have reported the results separately for those receiving GH the first year or the second year. The similar response suggests our findings are not secondary to study enrollment alone, and the continued improvement in the children who received GH for a second year indicates benefit of ongoing therapy. Most of the previous work in the field of nutrition in CF has been conducted with enteral or parenteral feedings given for 6 months or less. The short-term weight gain documented by these studies is similar to the weight gain we describe with the addition of GH. Only one previous study has been conducted over a longer period of time. Dalzell et al23 followed a cohort of patients treated with nighttime enteral feedings for 4 years. They documented significant decline in rate of weight gain during each year of study, with final results similar to those of our NonTX subjects. The decline in weight with ongoing enteral nutrition suggests a plateau of effectiveness; however, the reason for this is not clear. The potential mechanism(s) by which GH may enhance response to nutritional supplementation in CF deserves comment. Protein catabolism has been described,3,24,25 even in non–acutely ill subjects with CF.17,26,27 Studies in subjects without CF15,16 and with CF17 have documented improved whole-body protein kinetics with GH. We have also demonstrated lowering of cytokine tumor necrosis factor-a in CF patients treated with GH and the correlation of tumor
This study provides further support to our previous findings of improved absolute pulmonary function after treatment with GH. Some of this effect is expected, since lung capacity should improve with linear growth. Additionally, GH resulted in lack of decline in %FEV1. Although the difference from NonTX was not statistically significant, previous studies demonstrate a decline in %FEV1 of 3% to 5% per year. Thus this may be clinically relevant. Our data demonstrate a reduction in the number of hospitalizations with GH. These findings support our previous report.7 Unlike our previous study, we did not find a significant difference in the number of outpatient intravenous antibiotic courses. It is possible that our subject number was too small to demonstrate the effect.
Growth Hormone Treatment Enhances Nutrition And Growth In Children With Cystic Fibrosis Receiving Enteral Nutrition
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Pulmonary and Clinical Status
Nutritional Status The patients who participated in our studies received standard of care in line with current Cystic Fibrosis Foundation nutrition guidelines. Critics of GH use in the CF population have suggested that children would gain height normally if they received enough calories. Our subjects demonstrate that despite good nutritional intake, short stature still occurs. Although previous guidelines in CF nutrition have focused on improving weight, the most recent North American Consensus Conference on Nutrition also stressed the importance of normalizing linear growth.4 This new focus was developed by using recent information from Becker et al28 and Konstan et al29 documenting the association between poor linear growth and future worsened lung function. The typical approach to improving linear growth has been to improve nutritional intake. However, only a few studies of nutritional supplementation have documented significant improvement in linear growth. The most improvement was noted in a small study of malnourished (mean weight Z score, 21.23) and stunted (mean height Z score, 20.91) children with CF.24 Enteral feeding for 1 year resulted in a growth velocity of 7.6 cm/y. This change is less than reported in the current study and is less than in previous studies of GH alone.6,7 The study also found lack of sustained effect once feedings were discontinued. Long-term studies of GH treated children with CF should help clarify whether improving linear growth will result in future better lung function.
Glucose Tolerance Previous studies have indicated that enteral feedings result in increased problems with glucose intolerance. The children participating in our study did not have evidence of glucose intolerance, although we did not perform glucose tolerance tests.
Summary Our current findings support our previous studies and suggest that GH provides safe adjunctive therapy to optimal nutritional support for helping patients with CF improve growth and clinical status.
REFERENCES 1. Cystic Fibrosis Foundation. Nutritional Assessment and Management in Cystic Fibrosis. Consensus Conferences 1990, Bethesda, Maryland;1:1-15. 2. Kraemer, Rudeberg A, Hadorn B, Rossi E. Relative underweight in cystic fibrosis and its prognostic value. Acta Paediatr Scand 1978;67:33-5. 3. Holt TL, Ward LC, Francis PJ, Isles A, Cooksley WGE, Shepherd RW. Whole body protein turnover in malnourished cystic fibrosis patients and its relationship to pulmonary disease. Am J Clin Nutr 1985;41:1061-6. 4. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. Pediatr Gastroenterol Nutr 2002;35: 246-59. 5. Cystic Fibrosis Foundation. Cystic fibrosis foundation patient registry annual data report. Cystic Fibrosis Foundation; 2000. 6. Hardin DS. Growth problems and growth hormone treatment in children with cystic fibrosis. Journal of Pediatric Endocrinology and Metabolism 2002;15:731-5.
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7. Hardin DS, Ellis K, Dyson M, McConnel R, Rice J, Seilheimer DK. Growth hormone improves clinical status in children with cystic fibrosisresults of a randomized controlled trial. J Pediatr 2001;139:636-42. 8. Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in children with cystic fibrosis. Horm Metab Res 1998;30:636-41. 9. Schnabel D, Schonau E, Staab D, Tacke A, Felsenberg D, Wahn U, et al. Effects of growth hormone therapy on bone metabolism in patients with cystic fibrosis (CF). Paediatr Osteol 1998;10:209-17. 10. Sackey AH, Taylor CJ, Barraclough M, Wales JKH, Pickering M. Growth hormone as a nutritional adjunct in cystic fibrosis: results of a pilot study. J Hum Nutr Diet 1995;8:185-91. 11. Alemzadeh R, Upchurch L, McCarthy V. Anabolic effects of growth hormone treatment in young children with cystic fibrosis. J Am Coll Clin Nutr 2001;17:419-24. 12. Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, et al. Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 1998;128:186-93. 13. http://www.bcm.tmc.edu/bodycomplab. 14. Chang HR, Bistrian B. The role of cytokines in the catabolic consequences of infection and injury. Journal of Pediatric Endocrinology and Metabolism 1998;22:156-66. 15. Mauras N, George D, Evans J, Milov D, Abrams S, Rini A, et al. Growth hormone has anabolic effects in glucocorticoid-steroid-dependent children with inflammatory bowel disease: a pilot study treatment of chronic bowel disease with GH. Metabolism 2002;51:127-35. 16. Copeland KC, Nair KS. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab 1994;78:1040-7. 17. Hardin DS, Dyson M, Rice J, Seilheimer DK, Ellis KJ. Growth hormone improves protein catabolism in children with cystic fibrosis. J Clin Endocrinol Metab 2001;85:4424-8. 18. Gibbens DT, Gilsanz V, Boechat MI, Dufer D, Carlson ME, Wang CI. Osteoporosis in cystic fibrosis. J Pediatr 1988;113:295-300. 19. Bhudhikanok GS, Lim J, Marcus R, Harkins A, Moss R, Bachrach LK. Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 1996;97: 103-11. 20. Ellis KJ. Body composition of a young, multiethnic, male population. Am J Clin Nutr 1997;66:1323-31. 21. Ellis KJ, Shypailo RJ, Hardin DS, Perez MD, Motil KJ, Wong WW. Z Score prediction model for assessment of bone mineral content in pediatric diseases. J Bone Min Res 2000;16:1658-63. 22. Hardin DS, Arumugam R, Seilheimer DK, LeBlanc A, Ellis KJ. Normal bone mineral density in cystic fibrosis. Arch Dis Child 2001;84: 363-8. 23. Trotter M, Hixon BB. Sequential changes in weight, density, and percentage ash weight of human skeletons from an early fetal period through old age. Anat Rec 1973;179:1-8. 24. Dalzell AM, Shepherd RW, Dean B, Cleghorn GJ, Holt TL, Francis PJ. Nutritional Rehabilitation in Cystic Fibrosis: a 5-year follow-up study. J Pediatr Gastroenterol Nutr 1992;15:141-5. 25. Shepherd RW, Thomas BJ, Bennett D, Cooksley WGE, Ward LC. changes in body composition and muscle protein degradation during nutritional supplementation in nutritionally growth-retarded children with cystic fibrosis. J Pediatr Gastroenterol Nutr 1983;2:439-46. 26. Miller M, Ward L, Thomas BJ, Cooksley WGE, Shepherd RW. Altered body composition and muscle protein degradation in nutritionally growth-retarded children with cystic fibrosis. Am J Clin Nutr 1982;36: 492-9. 27. Hardin DS, LeBlanc A, Lukenbaugh S, Para L, Seilheimer DK. Increased rates of proteolysis associated with insulin resistance in cystic fibrosis. Pediatrics 1998;101:948-56. 28. Becker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis survival. J Am Dietetic Assoc 2001;101:438-42. 29. Konstan MW, Butler SM, Johnson CA, Wagener JS, Lai HC, Morgan WJ. The relationship between nutritional status in early life and pulmonary function in cystic fibrosis. J Pediatr 2003;142:624-30.
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