INVITED COMMENTARIES
Nonalcoholic Fatty Liver Disease and Dyslipidemia: The Beleagured Hepatocyte W. Daniel Jackson and Linda S. Book See ‘‘Improvement in Liver Histology Is Associated With Reduction in Dyslipidemia in Children With Nonalcoholic Fatty Liver Disease’’ by Corey et al on page 360.
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n this issue of the Journal of Pediatric Gastroenterology and Nutrition, Corey and colleagues present a retrospective investigation in children and adolescents of the relation between the histologic status of nonalcoholic fatty liver disease (NAFLD) and alteration in serum lipoproteins and triglycerides (TG) considered risk factors for cardiovascular disease (CVD) in adults (1). The data for this investigation were obtained in the TONIC study, which was designed to compare the therapeutic efficacies of vitamin E and metformin with placebo and consists of subject information, lipid profiles, and histology at the beginning and termination of a 96-week treatment period (2). The study aims were to describe the frequency of dyslipidemia in children meeting criteria for nonalcoholic steatohepatitis (NASH), discern a relation between liver histology and lipoprotein levels, including the derived variables of non–high-density lipoprotein-cholesterol (HDL-C) and TG/HDL, and to evaluate the changes in lipoprotein levels associated with resolution of NASH and improved histologic score (NAS). The study results both validate the relation between NASH and certain lipoprotein parameters associated with CVD risk, especially non–HDL-C, and support the hypothesis that improved histologic evidence of inflammation, that is, resolved NASH and improved NAS histologic score, is associated with improved lipid CVD risk profile in children. Although the focus of this investigation was on describing the altered lipoprotein profile risk factors for CVD in patients with NASH or NAFLD, it is intriguing to consider that the observed lipid profile changes may include metabolic markers of the pathophysiology of NAFLD and NASH. Steatosis in the liver is the consequence of net accumulation of fatty acids in the hepatocytes, exceeding the hepatocyte’s mechanisms to maintain homeostasis and defend itself from the oxidative risk of fatty acids. There is increased hepatocyte influx of fatty acids resulting from the uptake of the triglyceride-rich intermediate density lipoproteins (IDLs), free fatty acids liberated from adipocytes, and fatty acids generated in the hepatocyte by de novo lipogenesis from excessive carbohydrate, especially fructose, consumption. Fat accumulation occurs when this influx exceeds the rate of hepatocyte mitochondrial and peroxisomal oxidation of fatty Received December 11, 2014; accepted December 23, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City. Address correspondence and reprint requests to W. Daniel Jackson, MD, Primary Children’s Medical Center, 81 Mario Capecchi Dr, Salt Lake City, UT 84113 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000706
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acids and the rate of reesterification of fatty acids as nonreactive triglycerides packaged and exported as very low-density lipoprotein (VLDL). The consequence of this imbalance of influx and oxidation or export is the accumulation of triglycerides stored in cytoplasmic vacuoles and potentially toxic free fatty acids; thus, steatosis is the pathologic result of genetic and behavioral factors resulting in fat and carbohydrate consumption exceeding acute metabolic needs, associated with elevated insulin, which limits fatty acid oxidation and promotes net lipid storage (3–5). The TG accumulation in hepatocytes and increased exposure to free fatty acids with oxidative membrane damage with an immunologic and inflammatory response is the path to hepatocyte injury or steatohepatitis (NASH) (5). It is possible that peripheral blood lipid profile changes may be biomarkers of these phenomena, reflecting altered lipoprotein metabolism by the hepatocyte. In this study of lipoprotein changes in NASH, Corey et al found at baseline that HDL was lower and TG/HDL 3 higher in subjects with NASH, although these parameters did not change significantly during the 96-week treatment period. They did observe, however, that the lipid profile markers of improvement in histologic status of NASH were total cholesterol, LDL, and non–HDL-C, which includes IDL, TG (as VLDL and chylomicrons—if nonfasting or not clearing), lipoprotein (a), and LDL. LDL and total cholesterol were also significantly decreased in subjects with improved histology and probably are best considered covariates as components of non–HDL-C. It is perhaps illuminating that the other components of non–HDL-C are related to TG transport as IDL, VLDL, and chylomicrons/chylomicron remnants. IDL is the residual particle formed after VLDL-TG is hydrolyzed and chylomicron remnant the residual particle after chylomicron triglycerides are partially hydrolyzed by endothelial lipoprotein lipase in the muscle and adipose tissue, which are then taken up by the liver. Lipoprotein (a) is a hepatocyte-derived LDL-like particle bound to apolipoprotein (a) with a proinflammatory role implicated in coronary and cerebrovascular disease in adults. Although total TG and TG/HDL ratio did not seem to be significant independent markers for histologic improvement, the actual levels of IDL, VLDL, and chylomicron/remnants as well as lipoprotein (a), all components of non–HDL-C, were not measured or reported. Thus, one may consider a hypothesis that changes in their circulating levels may be markers for disturbed fatty acid economy in the hepatocyte, for example, an increased ratio of imported lipoproteins relative to exported VLDL triglyceride-rich particles by hepatocytes or increased lipoprotein (a). Certainly, the complexity of the metabolic pathophysiology of fatty liver disease with genetic, immunologic, endocrine, and nutritional influences will not yield to a simple hypothesis, but the lipoprotein data provided by Corey et al suggest a path for further study.
REFERENCES 1. Corey K, Vuppalanchi R, Vos M, et al. Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2015;60:360–7. 2. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305:1659–68. 3. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519–23. 4. Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease. J Biomed Res 2013;27:1–13. 5. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006;290:G852–8.
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Evidence-Based Diagnosis and Treatment of Functional Constipation: ‘‘Are We There Yet?’’ Manu R. Sood See ‘‘Practice Patterns of Pediatricians and Trainees for the Management of Functional Constipation Compared With 2006 NASPGHAN Guidelines’’ by Yang and Punati on page 308.
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rofessional organizations develop clinical practice guidelines with the hope that they will help improve quality of care, reduce variation of practice, and ensure that evidence is actually used in clinical practice whenever possible. Despite the existence of guidelines and protocols, a gap between recommended care and clinical practice often exists (1). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Yang and Punati (2) report findings of a survey study conducted in California involving pediatric attending physicians and trainees at 7 academic centers. Trainee physicians who were on the American Academy of Pediatrics section e-mail list were also invited to participate. A questionnaire designed to evaluate the diagnostic and therapeutic approaches for functional constipation (FC) with and without fecal incontinence (FI) was e-mailed to 8223 individuals. Nine hundred sixty-seven completed responses were included in the data analysis; 80% were trainees and 20% were attending physicians. Eighty-four percent of the pediatric attending physicians and trainees reported that they were unfamiliar or slightly familiar with 2006 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) FC guidelines. Similar findings have been reported in a survey study evaluating the awareness of pediatric Rome criteria for the diagnosis of functional gastrointestinal disorders (FGIDs), in which only 28% of the surveyed general pediatricians were aware of the Rome criteria compared with 99% of pediatric gastroenterologists (3). Although the 2006 NASPGHAN FC guidelines have since been revised (4), updated guidelines were not published when the Yang and Punati study was conducted. The lack of awareness of FC guidelines and Rome criteria among general pediatricians raises a few questions. The methods for dissemination of guidelines may be ineffective. It also makes one wonder whether the guidelines are perceived as cumbersome to implement in clinical practice. Because the 2006 NASPGHAN guidelines were mostly based on expert opinion, pediatricians may not agree with some of the recommendations and are therefore reluctant to adopt them into clinical practice. Unfortunately, the Received October 21, 2014; accepted December 18, 2014. From the Division of Pediatric Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee. Address correspondence and reprint requests to Manu R. Sood, Division of Pediatric Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000687
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updated joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and NASPGHAN FC guidelines published in 2014 are also predominantly based on expert opinion because of lack of good published evidence for the diagnosis and treatment of FC. For example, the recommendation regarding the role of digital rectal examination was based on 1 study alone. There were no studies evaluating the prevalence of hypothyroidism, celiac disease, and hypercalcemia in children with FC that met the guidelines’ inclusion criteria. The level of evidence for role of fiber and fluid in childhood constipation was graded as ‘‘low.’’ Similarly, evidence for the role of polyethylene glycol for disimpaction and the efficacy of maintenance therapy with polyethylene glycol, lactulose, and milk of magnesia was graded ‘‘very low.’’ The expert committee working on FC guidelines has done a tremendous job despite major challenges they must have faced because of lack of good published evidence in the field. A wide variability in the diagnosis and treatment of FC exists, and guidelines are meant to reduce this variability. A study evaluating the care of FC in Italy, the Netherlands, and the United States surveyed 383 primary care physicians in these countries (5). Sixty-three percent of surveyed physicians were convinced that hard stool could be softened by drinking more water. Abdominal x-ray was used by 49% to diagnose FC. Only 11% of physicians in the Netherlands used digital examination during evaluation of FC compared with 54% in the United States. Almost 60% of the surveyed attending physicians and trainees in the Yang and Punati (2) study reported using digital examination rarely or never in the evaluation of children with FC. The joint ESPGHAN and NASPGHAN FC guidelines recommend that digital rectal examination is not necessary in patients presenting with a typical history and in the absence of red flags (4). It is important to emphasize, however, that judicious use of digital rectal examination in patients presenting with an atypical history with onset of symptoms in early infancy, delayed passage of meconium, and alarm symptoms can be helpful. Inspection of the perianal region without digital examination can be easily performed in most children and can help to identify a malpositioned anal opening, the absence of anal wink (which can suggest spinal abnormalities), and the presence of anal fissure (which points toward FC with passage of large-caliber stools). Published data regarding the role of abdominal x-ray to diagnose FC are controversial. One reason for this could be the lack of a standardized scoring system to evaluate colon stool burden and severity of rectal impaction. The updated joint FC guidelines identified 5 studies that met their inclusion criteria, but only 1 study specifically evaluated the value of abdominal x-ray to discriminate children with constipation from those without (6). This study found that abdominal x-ray has poor discriminative value in differentiating children with FC from those without. Current evidence does not support the use of abdominal x-ray to diagnose FC (4). In the Yang and Punati (2) study, the majority of the surveyed pediatricians acknowledged using abdominal x-ray sometimes or often to diagnose FC. FI is a common problem in children with FC and up to 80% of children with FI have associated FC (7). In the Yang and Punati study, 75% of the surveyed pediatricians reported that only 0% to 10% of their patients with FC had FI, suggesting that they may underestimate the association of FC and FI. Fecal soiling is a distressing symptom and difficult to conceal because of the odor associated with stool leakage. Soiling accidents at school can lead to stigmatization, peer rejection, and bullying (8,9). Children with constipation and FI commonly demonstrate social withdrawal and school avoidance behavior and have poor health-related quality of www.jpgn.org
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life (9,10). When treating children with FC-associated FI, achieving social continence is critical, especially in middle- and high school– age children. If the standard therapeutic modalities are not successful, referral to a pediatric gastroenterologist or a pediatric motility center for further evaluation and management should be considered. Cecostomy for antegrade enemas can help achieve social continence in a select group of children (11). Long-term data regarding success of sacral neuromodulation in treating constipation and FI are lacking, but promising results have been reported from the Netherlands (12). FC and FGIDs are common problems for which parents seek medical advice. The average health care cost in the United States for the management of children with constipation is estimated to be approximately $3430/year compared with $1099/year for children without constipation (13). This amounts to an additional health care expenditure of $3.9 billion/year. Despite the high prevalence and significant health care expenditure associated with the diagnosis and treatment of FC, there have been no organized public health awareness campaigns. Our professional organizations need to prioritize issues regarding better dissemination of published guidelines and evidence, consider a public awareness campaign that includes general pediatricians, and provide support to help generate better evidence for the diagnosis and treatment of FC.
REFERENCES 1. Ebben RH, Vloet LC, Verhofstad MH, et al. Adherence to guidelines and protocols in the prehospital and emergency care setting: a systematic review. Scand J Trauma Resusc Emerg Med 2013;21:9. 2. Yang CH, Punati J. Practice patterns of pediatricians and trainees for the management of functional constipation compared with 2006 NASPGHAN guidelines. J Pediatr Gastroenterol Nutr 2015;60:308–11. 3. Sood MR, Di Lorenzo C, Hyams J, et al. Beliefs and attitudes of general pediatricians and pediatric gastroenterologists regarding functional gastrointestinal disorders: a survey study. Clin Pediatr 2011;50:891–6. 4. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr 2014;58:258–74. 5. Burgers R, Bonanno E, Madarena E, et al. The care of constipated children in primary care in different countries. Acta Paediatr 2012;101:677–80. 6. de Lorijn F, van Rijn RR, Heijmans J, et al. The Leech method for diagnosing constipation: intra- and interobserver variability and accuracy. Pediatr Radiol 2006;36:43–9. 7. Rajindrajith S, Devanarayana NM, Benninga MA. Review article: faecal incontinence in children: epidemiology, pathophysiology, clinical evaluation and management. Aliment Pharmacol Ther 2013; 37:37–48. 8. Joinson C, Heron J, Butler U, et al., Avon Longitudinal Study of Parents and Children Study Team. Psychological differences between children with and without soiling problems. Pediatrics 2006;117:1575– 84. 9. Bongers ME, van Dijk M, Benninga MA, et al. Health related quality of life in children with constipation-associated fecal incontinence. J Pediatr 2009;154:749–53. 10. Kaugars AS, Silverman A, Kinservik M, et al. Families’ perspectives on the effect of constipation and fecal incontinence on quality of life. J Pediatr Gastroenterol Nutr 2010;51:747–52. 11. Har AF, Rescorla FJ, Croffie JM. Quality of life in pediatric patients with unremitting constipation pre and post Malone Antegrade Continence Enema (MACE) procedure. J Pediatr Surg 2013;48: 1733–7. 12. van Wunnik BP, Peeters B, Govaert B, et al. Sacral neuromodulation therapy: a promising treatment for adolescents with refractory functional constipation. Dis Colon Rectum 2012;55:278–85. 13. Liem O, Harman J, Benninga M, et al. Health utilization and cost impact of childhood constipation in the United States. J Pediatr 2009;154:258– 62.
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Invited Commentaries
Use of WHO Growth Curves for Patients With Cystic Fibrosis May Provide a False Sense of Security Jacob Robson and Elizabeth H. Yen See ‘‘Comparison of WHO and CDC Growth Charts in Predicting Pulmonary Outcomes in Cystic Fibrosis’’ by Goday et al on page 378.
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ith vast improvements in newborn screening techniques (1) and heightened clinical awareness from general practitioners, cystic fibrosis (CF) is frequently diagnosed early in life, before the onset of pulmonary symptoms (2). Because several longitudinal studies have linked early nutritional status to improved pulmonary function and respiratory symptoms later in childhood (3,4), aggressive recommendations have been made to optimize nutritional status immediately after diagnosis. In a 2008 report (5), the Cystic Fibrosis Foundation’s Subcommittee on Growth and Nutrition released their recommendation that infants and toddlers diagnosed early as having CF attain weight-for-length (WFL) status of 50th percentile, based on the Centers for Disease Control and Prevention (CDC) growth references, by age 2. Subsequent studies have shown that children who maintain above-average growth in early childhood are more likely to have normal lung function into adulthood and have a survival advantage over those who are in lower growth percentiles (6). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Goday et al (7) present the first analysis examining pulmonary function outcomes based on anthropometric measurements from early childhood using the World Health Organization (WHO) growth standards. This study assesses whether CDC-based growth recommendations can be applied directly to patients measured using WHO standards and begins an important discussion on how best to measure growth and nutritional status in children with CF. Since their release in 2006, WHO growth standards have been widely adopted for assessment of growth in pediatric clinics worldwide. Because of their rigorous methodological development in a sampling of predominantly breast-fed infants across 6 countries (Norway, India, Ghana, Oman, Brazil, and the United States) (8), the CDC recommends use of the WHO growth standards for plotting anthropometric weight and length measurements in US children between birth and age 2; however, the transition to following growth of children with CF on the WHO growth curves is not trivial. Although the CDC and WHO
Received September 19, 2014; accepted October 8, 2014. From the Department of Pediatrics, Division of Gastroenterology and Nutrition, UCSF Benioff Children’s Hospital, San Francisco, CA. Address correspondence and reprint requests to Elizabeth H. Yen, MD, 500 Parnassus Ave, MU-4E Box 0136, San Francisco, CA 94143-0136 (e-mail: [email protected]). E.H.Y. is supported by a grant from the Cystic Fibrosis Foundation. J.R. is supported by a grant from the National Institutes of Health, T-32 Training grant. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000603
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Invited Commentaries growth curves follow similar patterns for the first 6 months of age, the rate of increase in weight-for-age is steeper on the CDC curves from age 6 months to 2 years. Via review of the Cystic Fibrosis Foundation’s registry data, Goday et al showed that WFL measurements at age 2 were significantly higher based on WHO curves (median 65th percentile vs 48th percentile on CDC curves). Furthermore, almost half (43%) of those who were in the 10th to 50th percentile WFL on the CDC growth charts were 50th percentile using WHO standards. This finding presents important implications for infants and toddlers with CF, most of whom, along with their parents, fight daily battles to take pancreatic replacement enzymes and a variety of nutritional supplements to meet guidelines for growth. Children with CF struggle with multiple barriers to digestion and absorption of nutrients beyond pancreatic insufficiency, which, coupled with increased metabolic demands, often leads to gastrostomy tube placement for nutritional supplementation (9). If pulmonary outcomes for those reaching 50th percentile WFL on the WHO curves alone were equivalent to those reaching 50th percentile on the CDC curves, it would allow for more modest caloric intake and growth goals, likely a welcome change for patients and families. Data presented by Goday et al, however, show that pulmonary function, based on FEV1% predicted at age 6, was significantly better in those attaining 50th percentile WFL at age 2 on both the WHO and CDC curves, versus those who met 50th percentile on the WHO curve alone. Although the difference between the 2 groups was modest clinically (median FEV1% predicted differed by only 4 points between the 2 groups), the difference in pulmonary function and overall respiratory status may become more pronounced later in childhood and into early adulthood. It will be critical to pursue further longitudinal studies to better understand whether growth recommendations using the WHO standards may need to be increased to confer the same longer-term benefits that are seen with CDC-based growth recommendations. Furthermore, there are interesting theoretical implications to the finding by Goday et al that maintenance of weight 50th percentile, on both CDC and WHO curves, between ages 2 and 6 years, correlated with improved pulmonary function. Although better nutritional status and growth early in life are associated with better pulmonary function and outcomes later in life, the nature of the relation is not well explained. During the past 20 years, significant improvements in the medical management of pulmonary manifestations of CF have led to overall improvements in lung function in childhood (10); however, the maintenance of adequate nutritional status has continued to be a struggle for patients with CF and has lasting consequences for their overall health. Longitudinal outcomes data based on growth status early in childhood can be used to provide patients, families, and providers important goals for nutritional supplementation. Novel treatments such as those that potentiate defective cystic fibrosis transmembrane conductance regulator (CFTR) channels are already helping patients with CFTR gating mutations, improving lung function and also leading to more robust nutritional status (11); however, until similar treatments have been developed for patients with CF with nongating CFTR mutations, who are the vast majority, it will be important to continue to refine and publicize nutritional recommendations that are easily interpretable for families and practitioners and can be clearly linked to improved pulmonary function and extended expected survival rates. The WHO growth standards are now the recommended tool for tracking anthropometric growth in children from birth to age 2—therefore, it is necessary to establish how early growth on WHO growth charts correlates with pulmonary function and survival into adulthood.
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REFERENCES 1. Farrell P, Kosorok M, Rock M, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107:1–13. 2. Assael B, Casazza G, Iansa P, et al. Growth and long-term lung function in cystic fibrosis: a longitudinal study of patients diagnosed by neonatal screening. Pediatr Pulmonol 2009;44:209–15. 3. Konstan M, Butler S, Wohl M, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr 2003;142:624–30. 4. Peterson M, Jacobs D, Milla C. Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis. Pediatrics 2003;112:588–92. 5. Stallings V, Stark L, Robinson K, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc 2008;108:832–9. 6. Yen E, Quinton H, Borowitz D. Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis. J Pediatr 2013;162:530–5. 7. Machogu E, Cao Y, Miller T, et al. Comparison of WHO and CDC growth charts in predicting pulmonary outcomes in cystic fibrosis. J Pediatr Gastroenterol Nutr 2015;60:378–83. 8. de Onis M, Garza C, Onyango AW, et al. Comparison of the WHO child growth standards and the CDC 2000 growth charts. J Nutr 2007; 137:144–8. 9. Bradley G, Carson K, Leonard A, et al. Nutritional outcomes following gastrostomy in children with cystic fibrosis. Pediatr Pulmonol 2012; 47:743–8. 10. McPhail G, Acton J, Fenchel M, et al. Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic Pseudomonas aeruginosa infections, and dornase alfa use. J Pediatr 2008;153:752–7. 11. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–72.
Milk Fat Globule Membrane: A Case of Throwing the Baby Out With the Bathwater? Mary S. Fewtrell See ‘‘Infections in Infants Fed Formula Supplemented With Bovine Milk Fat Globule Membranes’’ by Domello¨f et al on page 384.
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or many years, the goal in the design of infant formulas has been to narrow the gap in performance and outcomes between breast-fed infants and those fed infant formulas. This has involved Received December 3, 2014; accepted December 18, 2014. From the University College London Institute of Child Health, London, UK. Address correspondence and reprint requests to Mary S. Fewtrell, MD, University College London Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000685
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modifications to the macro- and micronutrient content of formulas, but also the addition of various specific components hypothesised to be causally related to observed differences in outcome, such as longchain polyunsaturated fatty acids, nucleotides, and pre- and probiotics. Randomised trials testing these interventions have often failed to consistently demonstrate the anticipated outcome effects, even when differences are sometimes observed at a biochemical level. The failure of ‘‘single-component’’ supplementation to produce hypothesised effects on outcome may reflect a number of issues, including the manner in which components are added (eg, free as opposed to bound), difficulty in establishing the optimal amounts given variability in the composition of human milk between mothers and populations and within mothers depending on stage of lactation or diet, unphysiological formulations, and the possibility that outcome effects may result from complex interactions between components, which cannot easily be mimicked in a formula. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Domello¨f et al (1) report data from a randomised trial in healthy term Swedish infants using infant formula supplemented with a bovine milk fat globule membrane (MFGM)–enriched whey protein concentrate. The intervention resulted in a significantly reduced risk of acute otitis media (AOM) and decreased use of antipyretics compared with a standard term formula. These findings are secondary outcomes from this trial that has already reported significant beneficial effects of the intervention on cognitive function at 12 months (2) and on serum cholesterol concentrations (3); for all of these outcomes, the results of the MFGM-supplemented infants were closer to those of a breast-fed reference group. Although this is the only trial testing infant formula supplemented with MFGM, and further trials are required together with longer term follow-up, the apparent effects of this intervention on several important outcomes are remarkable in the context of existing research aiming to optimise infant formulas. The MFGM, which has historically been discarded with the milk fat during the production of infant formulas, is a triple membrane resulting from the mammary secretory cell that surrounds the triglyceride core of the milk fat globule, enabling fat to be conveyed in an aqueous environment. Interestingly, the genes associated with the production of the milk fat globule and MFGM are the most greatly conserved lactation genes throughout evolution (4), supporting the likely functional importance of this structure. The MFGM contains numerous lipids such as sphingomyelin, gangliosides, sialic acid, and cholesterol, but also a small (1%–2%) proportion of the total milk protein, which includes a large number of bioactive components such as mucin (MUC1), lactadherin, and lactoferrin. Both lipid and protein fractions of the MFGM have been shown to exert a range of antimicrobial effects, and previous clinical trials have shown preventive effects of MFGM-enriched complementary foods against diarrhoea in 6- to 12-month-old Peruvian infants (5) and a reduction in febrile episodes in 2.5- to 6-year-old Belgian children who received MFGM-enriched milk (6). A higher incidence of infection, notably gastroenteritis and AOM, is the most consistent and accepted outcome difference for infants fed formula instead of human milk, even amongst those living in high-income countries (7–9). In the study by Domello¨f et al, the intervention resulted in a lower cumulative incidence of AOM, which was already uncommon in this healthy population, most of whom were vaccinated against pneumococcal disease (1 case [1%] vs 7 cases [9%] in control infants, P ¼ 0.03). There was no effect on other bacterial infections treated with antibiotics or on hospitalisation for viral infections including gastroenteritis, perhaps because of the even lower incidence of these infections (1 in the intervention group vs 4 in the control group and 1 in the breast-fed reference group). Although symptoms were self-reported by parents, cases of AOM were verified from the medical notes and diagnosed by otoscopy. www.jpgn.org
Invited Commentaries As discussed in the article, there are a number of potential mechanisms for these findings, including effects on the humeral immune system, or alterations in the composition or function of the microbiota in the oral cavity or gut resulting from antimicrobial factors in MFGM. It also seems plausible, as previously highlighted by the group, that the observed effects of supplementation with MFGM on different outcomes could be the result of single or multiple factors, with the possibility that different factors are limiting in individual infants. In combination with data previously published from this trial, the results of Domello¨f et al suggest that, although further research is clearly required, supplementation of infant formulas with MFGM has potential in achieving the goal of narrowing the gap in performance between breast-fed and formula-fed infants. Although this intervention is perhaps scientifically less satisfactory than using single-component interventions, in that it does not enable determination of the precise component(s) responsible for a given outcome, it is arguably a more pragmatic and physiological approach.
REFERENCES 1. Timby N, Hernell O, Vaarala O, et al. Infections in infants fed formula supplemented with bovine milk fat globule membranes. J Pediatr Gastroenterol Nutr 2015;60:384–9. 2. Timby N, Domellof E, Hernell O, et al. Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial. Am J Clin Nutr 2014;99:860–8. 3. Timby N, Lonnerdal B, Hernell O, et al. Cardiovascular risk markers until 12 mo of age in infants fed a formula supplemented with bovine milk fat globule membranes. Pediatr Res 2014;76:394–400. 4. German JB. Dietary lipids from an evolutionary perspective: sources, structures and functions. Matern Child Nutr 2011;7 (s2):2–16. 5. Zavaleta N, Kvistgaard AS, Graverholt G, et al. Efficacy of an MFGM-enriched complementary food in diarrhea, anemia and micronutrient status in infants. J Pediatr Gastroenterol Nutr 2011;53:561–8. 6. Veereman-Wauters G, Staelens S, Rombaut R, et al. Milk fat globule membrane (INPULSE) enriched formula milk decreases febrile episodes and may improve behavioural regulation in young children. Nutrition 2012;28:749–52. 7. Dutch State Institute for Nutrition and Health, Van Rossum CMT, Buchner FL, et al. Quantification of health effects of breastfeeding. Review of the literature and model situation. RIVM Report 350040001/2005. 8. Ip S, Chung M, Raman G, et al. Breastfeeding and Maternal and Infant Health Outcomes in Developed Countries. Evidence Report/Technology Assessment no. 153. Rockville, MD: Agency for Healthcare Research and Quality; 2007. 9. Kramer MS, Chalmers B, Hodnett ED. Promotion of Breastfeeding Intervention Trial (PROBIT): a randomized trial in the Republic of Belarus. JAMA 2001;285:413–20.
The Vitamin D Controversy Patrika Tsai See ‘‘Relation Between Vitamin D Status and Nonalcoholic Fatty Liver Disease in Children’’ by Hourigan et al on page 396.
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itamin D has generated widespread interest with growing evidence of its importance in several physiologic mechanisms. Vitamin D status is linked to a wide range of conditions including mental health, fertility, osteoporosis, cancers,
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Invited Commentaries autoimmune disorders, and liver disease. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Hourigan et al (1) show no significant associations between vitamin D level and histology or severity of nonalcoholic fatty liver disease (NAFLD) in contrast to adult studies that show lower vitamin D levels correlating with NAFLD severity. The number of children who could, however, be included in the analysis is 102, and the study may not have been powered enough to show significant differences in the histology. Also, the evolution of pediatric NAFLD to adult NAFLD is still unknown. It is possible that repeat biopsies on the patients in this study as they get older would yield similar results to adult studies. Just as acanthosis nigricans and elevated fasting insulin levels may precede the onset of type 2 diabetes mellitus for many years, so may the development of low vitamin D levels precede severe NAFLD. The study’s lack of association between vitamin D level and NAFLD severity may simply reflect shorter duration of NAFLD. Hourigan et al found that vitamin D–deficient and –insufficient children showed higher triglyceride levels and higher total cholesterol levels with a trend to higher LDL levels compared with vitamin D–sufficient children. The study, therefore, does show some concerning metabolic differences in children with sufficient vitamin D levels compared with those without. Future studies with larger sample sizes conducted for a longer period are needed to truly understand the relation between vitamin D status and NAFLD. In the interim, what are we to recommend to NAFLD patients about nutritional supplements such as vitamin D? Hourigan et al found a high number of children to have low vitamin D levels, with 35% (36/102) having insufficiency and 43% (44/102) having deficiency, for a total of 78% who were low in vitamin D. They noted that the average intake of vitamin D was less than the 600 IU presently recommended. There has been significant controversy regarding the cutoff for the blood level of vitamin D at which to define deficiency, as well as the appropriate dose of vitamin D. The Endocrine Society guidelines released in 2011 recommend screening for vitamin D deficiency with a 25-hydroxyvitamin D [25(OH)D] level in populations at risk for deficiency, which includes obese individuals and defines deficiency as 30 ng/mL. For obese children and adults, the Endocrine Society also recommends that the usual daily dose be doubled or tripled. The Endocrine Society and the Institute of Medicine (IOM), in their 2011 report, both recommend 600 IU daily for children 1 to 18 years (2,3); however, the IOM states that almost everyone is vitamin D sufficient with a blood level of 20 ng/mL and blood levels >30 ng/mL do not demonstrate consistent increased benefit (3). Although little harm in the form of vitamin D toxicity has been reported, the IOM cites that the Endocrine Society guidelines may result in unnecessary cost of laboratory testing Received November 18, 2014; accepted November 25, 2015. From the University of California, San Francisco. Address correspondence and reprint requests to Patrika Tsai, MD, MPH, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco, Mail Code 0136, 550 16th St, 5th Floor, San Francisco, CA 94158 (e-mail: tsaip@peds. ucsf.edu). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000655
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and classification of populations at risk of vitamin D deficiency that may not truly be at risk (4). With regard to obese individuals, the IOM states that there is no evidence yet to recommend higher doses of vitamin D than for nonobese individuals. Of note, both the Endocrine Society guidelines and the IOM report focus primarily on vitamin D in relation to bone health and other organ systems and disease processes but not the liver or NAFLD. The level of vitamin D needed for optimal liver health remains unknown and warrants further investigation. Pediatric NAFLD patients, who are typically obese or overweight, often have risk factors for low vitamin D levels, including poor diet and limited sun exposure. Although the data for vitamin D in relation to liver health are still under investigation, vitamin D is clearly important in bone health, which should also be of concern to us as pediatric gastroenterologists in our efforts to promote optimal growth and development, as well as prevent future medical problems such as falls and fractures. Bischoff-Ferrari et al (5) performed a meta-analysis suggesting optimal health benefits with vitamin D levels at a minimum of 30 ng/mL with little risk and with doses of 1800 to 4000 IU/day needed to reach these levels. These doses are much higher than present IOM recommendations and appear more in line with the Endocrine Society guidelines for obese individuals. As physicians, our goal should be optimal health, not just sufficient health for our patients.
REFERENCES 1. Hourigan SK, Abrams S, Yates K, et al. Relation between vitamin D status and nonalcoholic fatty liver disease in children. J Pediatr Gastroenterol Nutr 2015;60:396–404. 2. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. 3. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011. 4. Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab 2012;97:1146–52. 5. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, et al. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21: 1121–32.
Protected Time: A Vital Ingredient for Research Career Development John A. Barnard
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ature þ Nurture ¼ Success. This simple equation is true in most areas of professional life, including academic medicine. One of the most important types of nurture is ‘‘protected time’’ for research. For the purposes of this brief commentary, the focus is on protected time for original research with potential for
Received December 10, 2014; accepted December 22, 2014. From the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio. Address correspondence and reprint requests to John A. Barnard, 700 Children’s Dr, W177, Columbus, OH 43205 (e-mail: john.barnard@ nationwidechildrens.org). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000693
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funding by the National Institutes of Health (NIH) or an equivalent peer-reviewed funding agency. In the present hypercompetitive funding climate, protection of junior research–intensive faculty members from clinical, teaching, and administrative duties is vitally important. Research-intensive faculty members must have time to read and understand the literature, attend classes and lectures, confer with colleagues, perform and supervise experiments, manage regulatory requirements, write manuscripts, and write compelling grant applications, among many other important duties. Junior physician scientists must complete the equivalent of a graduate student and postdoctoral education in a few short years to compete with more traditionally trained PhD colleagues for funding. This can only be accomplished with adequate protected time. How much protected time is enough? No published evidence exists that supports a specific level of effort. Historically, many institutions have followed the 80:20 rule, that is, 80% research time and 20% clinical, teaching, and administrative time. Similarly, NIH K awards and many other young investigator grants, such as North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Foundation young investigator development awards, require commitment of 70% to 80% protected time. For example, a K23 career development award from the NIH supports patient-oriented research and requires a commitment of 75% protected research time. So does a K08 award, which funds laboratory research. More important, most experienced research leaders agree that all research disciplines, whether they are clinical, translational, or basic research, require 70% to 80% protected time.
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Invited Commentaries Clinical work constitutes the remaining 20% effort. For pediatric gastroenterologists, this is usually 1 half-day of patientrelated activity, such as a clinic or procedure session, per week and 1 to 2 months annually on an inpatient or consult service. Logically, though, caveats and nuances exist. For example, how many hours per week will one work? Twenty percent of a 70-hour work week is very different from 20% of a 40-hour work week. These considerations must be discussed and clearly understood mutually with program directors, division chiefs, and others in leadership roles. Research-intensive junior physician scientists should minimize teaching and administrative responsibilities. There will be time later in one’s career to develop these skills. Protected time is not a lifelong commitment. At some point, protected time must transition to externally funded time. The reason for this is simple: protected time is expensive. It requires one’s institution to forgo clinical revenue, directly support research salary and supplies, and assume indirect costs, which are usually 50% to 80% of direct costs. Transition of young clinician scientists to externally funded time is best facilitated by NIH K awards, which partially fund protected time and are less competitive than R series grants. Some departments require acquisition of a K award during the final year of fellowship. More typically, 2 to 5 years of protected time are permitted for those junior faculty members with a promising aptitude and work ethic required of a research career. Acquisition of a K award will extend this interval for research career development. Thereafter, transition to independent funding such as an R01 will be required for ongoing support. It is then that the personal and institutional rewards of protected time is realized.
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Nonalcoholic Fatty Liver Disease and Dyslipidemia: The Beleagured Hepatocyte W. Daniel Jackson and Linda S. Book See ‘‘Improvement in Liver Histology Is Associated With Reduction in Dyslipidemia in Children With Nonalcoholic Fatty Liver Disease’’ by Corey et al on page 360.
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n this issue of the Journal of Pediatric Gastroenterology and Nutrition, Corey and colleagues present a retrospective investigation in children and adolescents of the relation between the histologic status of nonalcoholic fatty liver disease (NAFLD) and alteration in serum lipoproteins and triglycerides (TG) considered risk factors for cardiovascular disease (CVD) in adults (1). The data for this investigation were obtained in the TONIC study, which was designed to compare the therapeutic efficacies of vitamin E and metformin with placebo and consists of subject information, lipid profiles, and histology at the beginning and termination of a 96-week treatment period (2). The study aims were to describe the frequency of dyslipidemia in children meeting criteria for nonalcoholic steatohepatitis (NASH), discern a relation between liver histology and lipoprotein levels, including the derived variables of non–high-density lipoprotein-cholesterol (HDL-C) and TG/HDL, and to evaluate the changes in lipoprotein levels associated with resolution of NASH and improved histologic score (NAS). The study results both validate the relation between NASH and certain lipoprotein parameters associated with CVD risk, especially non–HDL-C, and support the hypothesis that improved histologic evidence of inflammation, that is, resolved NASH and improved NAS histologic score, is associated with improved lipid CVD risk profile in children. Although the focus of this investigation was on describing the altered lipoprotein profile risk factors for CVD in patients with NASH or NAFLD, it is intriguing to consider that the observed lipid profile changes may include metabolic markers of the pathophysiology of NAFLD and NASH. Steatosis in the liver is the consequence of net accumulation of fatty acids in the hepatocytes, exceeding the hepatocyte’s mechanisms to maintain homeostasis and defend itself from the oxidative risk of fatty acids. There is increased hepatocyte influx of fatty acids resulting from the uptake of the triglyceride-rich intermediate density lipoproteins (IDLs), free fatty acids liberated from adipocytes, and fatty acids generated in the hepatocyte by de novo lipogenesis from excessive carbohydrate, especially fructose, consumption. Fat accumulation occurs when this influx exceeds the rate of hepatocyte mitochondrial and peroxisomal oxidation of fatty Received December 11, 2014; accepted December 23, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City. Address correspondence and reprint requests to W. Daniel Jackson, MD, Primary Children’s Medical Center, 81 Mario Capecchi Dr, Salt Lake City, UT 84113 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000706
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acids and the rate of reesterification of fatty acids as nonreactive triglycerides packaged and exported as very low-density lipoprotein (VLDL). The consequence of this imbalance of influx and oxidation or export is the accumulation of triglycerides stored in cytoplasmic vacuoles and potentially toxic free fatty acids; thus, steatosis is the pathologic result of genetic and behavioral factors resulting in fat and carbohydrate consumption exceeding acute metabolic needs, associated with elevated insulin, which limits fatty acid oxidation and promotes net lipid storage (3–5). The TG accumulation in hepatocytes and increased exposure to free fatty acids with oxidative membrane damage with an immunologic and inflammatory response is the path to hepatocyte injury or steatohepatitis (NASH) (5). It is possible that peripheral blood lipid profile changes may be biomarkers of these phenomena, reflecting altered lipoprotein metabolism by the hepatocyte. In this study of lipoprotein changes in NASH, Corey et al found at baseline that HDL was lower and TG/HDL 3 higher in subjects with NASH, although these parameters did not change significantly during the 96-week treatment period. They did observe, however, that the lipid profile markers of improvement in histologic status of NASH were total cholesterol, LDL, and non–HDL-C, which includes IDL, TG (as VLDL and chylomicrons—if nonfasting or not clearing), lipoprotein (a), and LDL. LDL and total cholesterol were also significantly decreased in subjects with improved histology and probably are best considered covariates as components of non–HDL-C. It is perhaps illuminating that the other components of non–HDL-C are related to TG transport as IDL, VLDL, and chylomicrons/chylomicron remnants. IDL is the residual particle formed after VLDL-TG is hydrolyzed and chylomicron remnant the residual particle after chylomicron triglycerides are partially hydrolyzed by endothelial lipoprotein lipase in the muscle and adipose tissue, which are then taken up by the liver. Lipoprotein (a) is a hepatocyte-derived LDL-like particle bound to apolipoprotein (a) with a proinflammatory role implicated in coronary and cerebrovascular disease in adults. Although total TG and TG/HDL ratio did not seem to be significant independent markers for histologic improvement, the actual levels of IDL, VLDL, and chylomicron/remnants as well as lipoprotein (a), all components of non–HDL-C, were not measured or reported. Thus, one may consider a hypothesis that changes in their circulating levels may be markers for disturbed fatty acid economy in the hepatocyte, for example, an increased ratio of imported lipoproteins relative to exported VLDL triglyceride-rich particles by hepatocytes or increased lipoprotein (a). Certainly, the complexity of the metabolic pathophysiology of fatty liver disease with genetic, immunologic, endocrine, and nutritional influences will not yield to a simple hypothesis, but the lipoprotein data provided by Corey et al suggest a path for further study.
REFERENCES 1. Corey K, Vuppalanchi R, Vos M, et al. Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2015;60:360–7. 2. Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305:1659–68. 3. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519–23. 4. Jiang ZG, Robson SC, Yao Z. Lipoprotein metabolism in nonalcoholic fatty liver disease. J Biomed Res 2013;27:1–13. 5. Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 2006;290:G852–8.
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Evidence-Based Diagnosis and Treatment of Functional Constipation: ‘‘Are We There Yet?’’ Manu R. Sood See ‘‘Practice Patterns of Pediatricians and Trainees for the Management of Functional Constipation Compared With 2006 NASPGHAN Guidelines’’ by Yang and Punati on page 308.
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rofessional organizations develop clinical practice guidelines with the hope that they will help improve quality of care, reduce variation of practice, and ensure that evidence is actually used in clinical practice whenever possible. Despite the existence of guidelines and protocols, a gap between recommended care and clinical practice often exists (1). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Yang and Punati (2) report findings of a survey study conducted in California involving pediatric attending physicians and trainees at 7 academic centers. Trainee physicians who were on the American Academy of Pediatrics section e-mail list were also invited to participate. A questionnaire designed to evaluate the diagnostic and therapeutic approaches for functional constipation (FC) with and without fecal incontinence (FI) was e-mailed to 8223 individuals. Nine hundred sixty-seven completed responses were included in the data analysis; 80% were trainees and 20% were attending physicians. Eighty-four percent of the pediatric attending physicians and trainees reported that they were unfamiliar or slightly familiar with 2006 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) FC guidelines. Similar findings have been reported in a survey study evaluating the awareness of pediatric Rome criteria for the diagnosis of functional gastrointestinal disorders (FGIDs), in which only 28% of the surveyed general pediatricians were aware of the Rome criteria compared with 99% of pediatric gastroenterologists (3). Although the 2006 NASPGHAN FC guidelines have since been revised (4), updated guidelines were not published when the Yang and Punati study was conducted. The lack of awareness of FC guidelines and Rome criteria among general pediatricians raises a few questions. The methods for dissemination of guidelines may be ineffective. It also makes one wonder whether the guidelines are perceived as cumbersome to implement in clinical practice. Because the 2006 NASPGHAN guidelines were mostly based on expert opinion, pediatricians may not agree with some of the recommendations and are therefore reluctant to adopt them into clinical practice. Unfortunately, the Received October 21, 2014; accepted December 18, 2014. From the Division of Pediatric Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee. Address correspondence and reprint requests to Manu R. Sood, Division of Pediatric Gastroenterology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000687
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updated joint European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and NASPGHAN FC guidelines published in 2014 are also predominantly based on expert opinion because of lack of good published evidence for the diagnosis and treatment of FC. For example, the recommendation regarding the role of digital rectal examination was based on 1 study alone. There were no studies evaluating the prevalence of hypothyroidism, celiac disease, and hypercalcemia in children with FC that met the guidelines’ inclusion criteria. The level of evidence for role of fiber and fluid in childhood constipation was graded as ‘‘low.’’ Similarly, evidence for the role of polyethylene glycol for disimpaction and the efficacy of maintenance therapy with polyethylene glycol, lactulose, and milk of magnesia was graded ‘‘very low.’’ The expert committee working on FC guidelines has done a tremendous job despite major challenges they must have faced because of lack of good published evidence in the field. A wide variability in the diagnosis and treatment of FC exists, and guidelines are meant to reduce this variability. A study evaluating the care of FC in Italy, the Netherlands, and the United States surveyed 383 primary care physicians in these countries (5). Sixty-three percent of surveyed physicians were convinced that hard stool could be softened by drinking more water. Abdominal x-ray was used by 49% to diagnose FC. Only 11% of physicians in the Netherlands used digital examination during evaluation of FC compared with 54% in the United States. Almost 60% of the surveyed attending physicians and trainees in the Yang and Punati (2) study reported using digital examination rarely or never in the evaluation of children with FC. The joint ESPGHAN and NASPGHAN FC guidelines recommend that digital rectal examination is not necessary in patients presenting with a typical history and in the absence of red flags (4). It is important to emphasize, however, that judicious use of digital rectal examination in patients presenting with an atypical history with onset of symptoms in early infancy, delayed passage of meconium, and alarm symptoms can be helpful. Inspection of the perianal region without digital examination can be easily performed in most children and can help to identify a malpositioned anal opening, the absence of anal wink (which can suggest spinal abnormalities), and the presence of anal fissure (which points toward FC with passage of large-caliber stools). Published data regarding the role of abdominal x-ray to diagnose FC are controversial. One reason for this could be the lack of a standardized scoring system to evaluate colon stool burden and severity of rectal impaction. The updated joint FC guidelines identified 5 studies that met their inclusion criteria, but only 1 study specifically evaluated the value of abdominal x-ray to discriminate children with constipation from those without (6). This study found that abdominal x-ray has poor discriminative value in differentiating children with FC from those without. Current evidence does not support the use of abdominal x-ray to diagnose FC (4). In the Yang and Punati (2) study, the majority of the surveyed pediatricians acknowledged using abdominal x-ray sometimes or often to diagnose FC. FI is a common problem in children with FC and up to 80% of children with FI have associated FC (7). In the Yang and Punati study, 75% of the surveyed pediatricians reported that only 0% to 10% of their patients with FC had FI, suggesting that they may underestimate the association of FC and FI. Fecal soiling is a distressing symptom and difficult to conceal because of the odor associated with stool leakage. Soiling accidents at school can lead to stigmatization, peer rejection, and bullying (8,9). Children with constipation and FI commonly demonstrate social withdrawal and school avoidance behavior and have poor health-related quality of www.jpgn.org
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life (9,10). When treating children with FC-associated FI, achieving social continence is critical, especially in middle- and high school– age children. If the standard therapeutic modalities are not successful, referral to a pediatric gastroenterologist or a pediatric motility center for further evaluation and management should be considered. Cecostomy for antegrade enemas can help achieve social continence in a select group of children (11). Long-term data regarding success of sacral neuromodulation in treating constipation and FI are lacking, but promising results have been reported from the Netherlands (12). FC and FGIDs are common problems for which parents seek medical advice. The average health care cost in the United States for the management of children with constipation is estimated to be approximately $3430/year compared with $1099/year for children without constipation (13). This amounts to an additional health care expenditure of $3.9 billion/year. Despite the high prevalence and significant health care expenditure associated with the diagnosis and treatment of FC, there have been no organized public health awareness campaigns. Our professional organizations need to prioritize issues regarding better dissemination of published guidelines and evidence, consider a public awareness campaign that includes general pediatricians, and provide support to help generate better evidence for the diagnosis and treatment of FC.
REFERENCES 1. Ebben RH, Vloet LC, Verhofstad MH, et al. Adherence to guidelines and protocols in the prehospital and emergency care setting: a systematic review. Scand J Trauma Resusc Emerg Med 2013;21:9. 2. Yang CH, Punati J. Practice patterns of pediatricians and trainees for the management of functional constipation compared with 2006 NASPGHAN guidelines. J Pediatr Gastroenterol Nutr 2015;60:308–11. 3. Sood MR, Di Lorenzo C, Hyams J, et al. Beliefs and attitudes of general pediatricians and pediatric gastroenterologists regarding functional gastrointestinal disorders: a survey study. Clin Pediatr 2011;50:891–6. 4. Tabbers MM, DiLorenzo C, Berger MY, et al. Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr 2014;58:258–74. 5. Burgers R, Bonanno E, Madarena E, et al. The care of constipated children in primary care in different countries. Acta Paediatr 2012;101:677–80. 6. de Lorijn F, van Rijn RR, Heijmans J, et al. The Leech method for diagnosing constipation: intra- and interobserver variability and accuracy. Pediatr Radiol 2006;36:43–9. 7. Rajindrajith S, Devanarayana NM, Benninga MA. Review article: faecal incontinence in children: epidemiology, pathophysiology, clinical evaluation and management. Aliment Pharmacol Ther 2013; 37:37–48. 8. Joinson C, Heron J, Butler U, et al., Avon Longitudinal Study of Parents and Children Study Team. Psychological differences between children with and without soiling problems. Pediatrics 2006;117:1575– 84. 9. Bongers ME, van Dijk M, Benninga MA, et al. Health related quality of life in children with constipation-associated fecal incontinence. J Pediatr 2009;154:749–53. 10. Kaugars AS, Silverman A, Kinservik M, et al. Families’ perspectives on the effect of constipation and fecal incontinence on quality of life. J Pediatr Gastroenterol Nutr 2010;51:747–52. 11. Har AF, Rescorla FJ, Croffie JM. Quality of life in pediatric patients with unremitting constipation pre and post Malone Antegrade Continence Enema (MACE) procedure. J Pediatr Surg 2013;48: 1733–7. 12. van Wunnik BP, Peeters B, Govaert B, et al. Sacral neuromodulation therapy: a promising treatment for adolescents with refractory functional constipation. Dis Colon Rectum 2012;55:278–85. 13. Liem O, Harman J, Benninga M, et al. Health utilization and cost impact of childhood constipation in the United States. J Pediatr 2009;154:258– 62.
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Invited Commentaries
Use of WHO Growth Curves for Patients With Cystic Fibrosis May Provide a False Sense of Security Jacob Robson and Elizabeth H. Yen See ‘‘Comparison of WHO and CDC Growth Charts in Predicting Pulmonary Outcomes in Cystic Fibrosis’’ by Goday et al on page 378.
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ith vast improvements in newborn screening techniques (1) and heightened clinical awareness from general practitioners, cystic fibrosis (CF) is frequently diagnosed early in life, before the onset of pulmonary symptoms (2). Because several longitudinal studies have linked early nutritional status to improved pulmonary function and respiratory symptoms later in childhood (3,4), aggressive recommendations have been made to optimize nutritional status immediately after diagnosis. In a 2008 report (5), the Cystic Fibrosis Foundation’s Subcommittee on Growth and Nutrition released their recommendation that infants and toddlers diagnosed early as having CF attain weight-for-length (WFL) status of 50th percentile, based on the Centers for Disease Control and Prevention (CDC) growth references, by age 2. Subsequent studies have shown that children who maintain above-average growth in early childhood are more likely to have normal lung function into adulthood and have a survival advantage over those who are in lower growth percentiles (6). In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Goday et al (7) present the first analysis examining pulmonary function outcomes based on anthropometric measurements from early childhood using the World Health Organization (WHO) growth standards. This study assesses whether CDC-based growth recommendations can be applied directly to patients measured using WHO standards and begins an important discussion on how best to measure growth and nutritional status in children with CF. Since their release in 2006, WHO growth standards have been widely adopted for assessment of growth in pediatric clinics worldwide. Because of their rigorous methodological development in a sampling of predominantly breast-fed infants across 6 countries (Norway, India, Ghana, Oman, Brazil, and the United States) (8), the CDC recommends use of the WHO growth standards for plotting anthropometric weight and length measurements in US children between birth and age 2; however, the transition to following growth of children with CF on the WHO growth curves is not trivial. Although the CDC and WHO
Received September 19, 2014; accepted October 8, 2014. From the Department of Pediatrics, Division of Gastroenterology and Nutrition, UCSF Benioff Children’s Hospital, San Francisco, CA. Address correspondence and reprint requests to Elizabeth H. Yen, MD, 500 Parnassus Ave, MU-4E Box 0136, San Francisco, CA 94143-0136 (e-mail: [email protected]). E.H.Y. is supported by a grant from the Cystic Fibrosis Foundation. J.R. is supported by a grant from the National Institutes of Health, T-32 Training grant. The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000603
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Invited Commentaries growth curves follow similar patterns for the first 6 months of age, the rate of increase in weight-for-age is steeper on the CDC curves from age 6 months to 2 years. Via review of the Cystic Fibrosis Foundation’s registry data, Goday et al showed that WFL measurements at age 2 were significantly higher based on WHO curves (median 65th percentile vs 48th percentile on CDC curves). Furthermore, almost half (43%) of those who were in the 10th to 50th percentile WFL on the CDC growth charts were 50th percentile using WHO standards. This finding presents important implications for infants and toddlers with CF, most of whom, along with their parents, fight daily battles to take pancreatic replacement enzymes and a variety of nutritional supplements to meet guidelines for growth. Children with CF struggle with multiple barriers to digestion and absorption of nutrients beyond pancreatic insufficiency, which, coupled with increased metabolic demands, often leads to gastrostomy tube placement for nutritional supplementation (9). If pulmonary outcomes for those reaching 50th percentile WFL on the WHO curves alone were equivalent to those reaching 50th percentile on the CDC curves, it would allow for more modest caloric intake and growth goals, likely a welcome change for patients and families. Data presented by Goday et al, however, show that pulmonary function, based on FEV1% predicted at age 6, was significantly better in those attaining 50th percentile WFL at age 2 on both the WHO and CDC curves, versus those who met 50th percentile on the WHO curve alone. Although the difference between the 2 groups was modest clinically (median FEV1% predicted differed by only 4 points between the 2 groups), the difference in pulmonary function and overall respiratory status may become more pronounced later in childhood and into early adulthood. It will be critical to pursue further longitudinal studies to better understand whether growth recommendations using the WHO standards may need to be increased to confer the same longer-term benefits that are seen with CDC-based growth recommendations. Furthermore, there are interesting theoretical implications to the finding by Goday et al that maintenance of weight 50th percentile, on both CDC and WHO curves, between ages 2 and 6 years, correlated with improved pulmonary function. Although better nutritional status and growth early in life are associated with better pulmonary function and outcomes later in life, the nature of the relation is not well explained. During the past 20 years, significant improvements in the medical management of pulmonary manifestations of CF have led to overall improvements in lung function in childhood (10); however, the maintenance of adequate nutritional status has continued to be a struggle for patients with CF and has lasting consequences for their overall health. Longitudinal outcomes data based on growth status early in childhood can be used to provide patients, families, and providers important goals for nutritional supplementation. Novel treatments such as those that potentiate defective cystic fibrosis transmembrane conductance regulator (CFTR) channels are already helping patients with CFTR gating mutations, improving lung function and also leading to more robust nutritional status (11); however, until similar treatments have been developed for patients with CF with nongating CFTR mutations, who are the vast majority, it will be important to continue to refine and publicize nutritional recommendations that are easily interpretable for families and practitioners and can be clearly linked to improved pulmonary function and extended expected survival rates. The WHO growth standards are now the recommended tool for tracking anthropometric growth in children from birth to age 2—therefore, it is necessary to establish how early growth on WHO growth charts correlates with pulmonary function and survival into adulthood.
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REFERENCES 1. Farrell P, Kosorok M, Rock M, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107:1–13. 2. Assael B, Casazza G, Iansa P, et al. Growth and long-term lung function in cystic fibrosis: a longitudinal study of patients diagnosed by neonatal screening. Pediatr Pulmonol 2009;44:209–15. 3. Konstan M, Butler S, Wohl M, et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J Pediatr 2003;142:624–30. 4. Peterson M, Jacobs D, Milla C. Longitudinal changes in growth parameters are correlated with changes in pulmonary function in children with cystic fibrosis. Pediatrics 2003;112:588–92. 5. Stallings V, Stark L, Robinson K, et al. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc 2008;108:832–9. 6. Yen E, Quinton H, Borowitz D. Better nutritional status in early childhood is associated with improved clinical outcomes and survival in patients with cystic fibrosis. J Pediatr 2013;162:530–5. 7. Machogu E, Cao Y, Miller T, et al. Comparison of WHO and CDC growth charts in predicting pulmonary outcomes in cystic fibrosis. J Pediatr Gastroenterol Nutr 2015;60:378–83. 8. de Onis M, Garza C, Onyango AW, et al. Comparison of the WHO child growth standards and the CDC 2000 growth charts. J Nutr 2007; 137:144–8. 9. Bradley G, Carson K, Leonard A, et al. Nutritional outcomes following gastrostomy in children with cystic fibrosis. Pediatr Pulmonol 2012; 47:743–8. 10. McPhail G, Acton J, Fenchel M, et al. Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic Pseudomonas aeruginosa infections, and dornase alfa use. J Pediatr 2008;153:752–7. 11. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365:1663–72.
Milk Fat Globule Membrane: A Case of Throwing the Baby Out With the Bathwater? Mary S. Fewtrell See ‘‘Infections in Infants Fed Formula Supplemented With Bovine Milk Fat Globule Membranes’’ by Domello¨f et al on page 384.
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or many years, the goal in the design of infant formulas has been to narrow the gap in performance and outcomes between breast-fed infants and those fed infant formulas. This has involved Received December 3, 2014; accepted December 18, 2014. From the University College London Institute of Child Health, London, UK. Address correspondence and reprint requests to Mary S. Fewtrell, MD, University College London Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000685
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modifications to the macro- and micronutrient content of formulas, but also the addition of various specific components hypothesised to be causally related to observed differences in outcome, such as longchain polyunsaturated fatty acids, nucleotides, and pre- and probiotics. Randomised trials testing these interventions have often failed to consistently demonstrate the anticipated outcome effects, even when differences are sometimes observed at a biochemical level. The failure of ‘‘single-component’’ supplementation to produce hypothesised effects on outcome may reflect a number of issues, including the manner in which components are added (eg, free as opposed to bound), difficulty in establishing the optimal amounts given variability in the composition of human milk between mothers and populations and within mothers depending on stage of lactation or diet, unphysiological formulations, and the possibility that outcome effects may result from complex interactions between components, which cannot easily be mimicked in a formula. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Domello¨f et al (1) report data from a randomised trial in healthy term Swedish infants using infant formula supplemented with a bovine milk fat globule membrane (MFGM)–enriched whey protein concentrate. The intervention resulted in a significantly reduced risk of acute otitis media (AOM) and decreased use of antipyretics compared with a standard term formula. These findings are secondary outcomes from this trial that has already reported significant beneficial effects of the intervention on cognitive function at 12 months (2) and on serum cholesterol concentrations (3); for all of these outcomes, the results of the MFGM-supplemented infants were closer to those of a breast-fed reference group. Although this is the only trial testing infant formula supplemented with MFGM, and further trials are required together with longer term follow-up, the apparent effects of this intervention on several important outcomes are remarkable in the context of existing research aiming to optimise infant formulas. The MFGM, which has historically been discarded with the milk fat during the production of infant formulas, is a triple membrane resulting from the mammary secretory cell that surrounds the triglyceride core of the milk fat globule, enabling fat to be conveyed in an aqueous environment. Interestingly, the genes associated with the production of the milk fat globule and MFGM are the most greatly conserved lactation genes throughout evolution (4), supporting the likely functional importance of this structure. The MFGM contains numerous lipids such as sphingomyelin, gangliosides, sialic acid, and cholesterol, but also a small (1%–2%) proportion of the total milk protein, which includes a large number of bioactive components such as mucin (MUC1), lactadherin, and lactoferrin. Both lipid and protein fractions of the MFGM have been shown to exert a range of antimicrobial effects, and previous clinical trials have shown preventive effects of MFGM-enriched complementary foods against diarrhoea in 6- to 12-month-old Peruvian infants (5) and a reduction in febrile episodes in 2.5- to 6-year-old Belgian children who received MFGM-enriched milk (6). A higher incidence of infection, notably gastroenteritis and AOM, is the most consistent and accepted outcome difference for infants fed formula instead of human milk, even amongst those living in high-income countries (7–9). In the study by Domello¨f et al, the intervention resulted in a lower cumulative incidence of AOM, which was already uncommon in this healthy population, most of whom were vaccinated against pneumococcal disease (1 case [1%] vs 7 cases [9%] in control infants, P ¼ 0.03). There was no effect on other bacterial infections treated with antibiotics or on hospitalisation for viral infections including gastroenteritis, perhaps because of the even lower incidence of these infections (1 in the intervention group vs 4 in the control group and 1 in the breast-fed reference group). Although symptoms were self-reported by parents, cases of AOM were verified from the medical notes and diagnosed by otoscopy. www.jpgn.org
Invited Commentaries As discussed in the article, there are a number of potential mechanisms for these findings, including effects on the humeral immune system, or alterations in the composition or function of the microbiota in the oral cavity or gut resulting from antimicrobial factors in MFGM. It also seems plausible, as previously highlighted by the group, that the observed effects of supplementation with MFGM on different outcomes could be the result of single or multiple factors, with the possibility that different factors are limiting in individual infants. In combination with data previously published from this trial, the results of Domello¨f et al suggest that, although further research is clearly required, supplementation of infant formulas with MFGM has potential in achieving the goal of narrowing the gap in performance between breast-fed and formula-fed infants. Although this intervention is perhaps scientifically less satisfactory than using single-component interventions, in that it does not enable determination of the precise component(s) responsible for a given outcome, it is arguably a more pragmatic and physiological approach.
REFERENCES 1. Timby N, Hernell O, Vaarala O, et al. Infections in infants fed formula supplemented with bovine milk fat globule membranes. J Pediatr Gastroenterol Nutr 2015;60:384–9. 2. Timby N, Domellof E, Hernell O, et al. Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial. Am J Clin Nutr 2014;99:860–8. 3. Timby N, Lonnerdal B, Hernell O, et al. Cardiovascular risk markers until 12 mo of age in infants fed a formula supplemented with bovine milk fat globule membranes. Pediatr Res 2014;76:394–400. 4. German JB. Dietary lipids from an evolutionary perspective: sources, structures and functions. Matern Child Nutr 2011;7 (s2):2–16. 5. Zavaleta N, Kvistgaard AS, Graverholt G, et al. Efficacy of an MFGM-enriched complementary food in diarrhea, anemia and micronutrient status in infants. J Pediatr Gastroenterol Nutr 2011;53:561–8. 6. Veereman-Wauters G, Staelens S, Rombaut R, et al. Milk fat globule membrane (INPULSE) enriched formula milk decreases febrile episodes and may improve behavioural regulation in young children. Nutrition 2012;28:749–52. 7. Dutch State Institute for Nutrition and Health, Van Rossum CMT, Buchner FL, et al. Quantification of health effects of breastfeeding. Review of the literature and model situation. RIVM Report 350040001/2005. 8. Ip S, Chung M, Raman G, et al. Breastfeeding and Maternal and Infant Health Outcomes in Developed Countries. Evidence Report/Technology Assessment no. 153. Rockville, MD: Agency for Healthcare Research and Quality; 2007. 9. Kramer MS, Chalmers B, Hodnett ED. Promotion of Breastfeeding Intervention Trial (PROBIT): a randomized trial in the Republic of Belarus. JAMA 2001;285:413–20.
The Vitamin D Controversy Patrika Tsai See ‘‘Relation Between Vitamin D Status and Nonalcoholic Fatty Liver Disease in Children’’ by Hourigan et al on page 396.
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itamin D has generated widespread interest with growing evidence of its importance in several physiologic mechanisms. Vitamin D status is linked to a wide range of conditions including mental health, fertility, osteoporosis, cancers,
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Invited Commentaries autoimmune disorders, and liver disease. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Hourigan et al (1) show no significant associations between vitamin D level and histology or severity of nonalcoholic fatty liver disease (NAFLD) in contrast to adult studies that show lower vitamin D levels correlating with NAFLD severity. The number of children who could, however, be included in the analysis is 102, and the study may not have been powered enough to show significant differences in the histology. Also, the evolution of pediatric NAFLD to adult NAFLD is still unknown. It is possible that repeat biopsies on the patients in this study as they get older would yield similar results to adult studies. Just as acanthosis nigricans and elevated fasting insulin levels may precede the onset of type 2 diabetes mellitus for many years, so may the development of low vitamin D levels precede severe NAFLD. The study’s lack of association between vitamin D level and NAFLD severity may simply reflect shorter duration of NAFLD. Hourigan et al found that vitamin D–deficient and –insufficient children showed higher triglyceride levels and higher total cholesterol levels with a trend to higher LDL levels compared with vitamin D–sufficient children. The study, therefore, does show some concerning metabolic differences in children with sufficient vitamin D levels compared with those without. Future studies with larger sample sizes conducted for a longer period are needed to truly understand the relation between vitamin D status and NAFLD. In the interim, what are we to recommend to NAFLD patients about nutritional supplements such as vitamin D? Hourigan et al found a high number of children to have low vitamin D levels, with 35% (36/102) having insufficiency and 43% (44/102) having deficiency, for a total of 78% who were low in vitamin D. They noted that the average intake of vitamin D was less than the 600 IU presently recommended. There has been significant controversy regarding the cutoff for the blood level of vitamin D at which to define deficiency, as well as the appropriate dose of vitamin D. The Endocrine Society guidelines released in 2011 recommend screening for vitamin D deficiency with a 25-hydroxyvitamin D [25(OH)D] level in populations at risk for deficiency, which includes obese individuals and defines deficiency as 30 ng/mL. For obese children and adults, the Endocrine Society also recommends that the usual daily dose be doubled or tripled. The Endocrine Society and the Institute of Medicine (IOM), in their 2011 report, both recommend 600 IU daily for children 1 to 18 years (2,3); however, the IOM states that almost everyone is vitamin D sufficient with a blood level of 20 ng/mL and blood levels >30 ng/mL do not demonstrate consistent increased benefit (3). Although little harm in the form of vitamin D toxicity has been reported, the IOM cites that the Endocrine Society guidelines may result in unnecessary cost of laboratory testing Received November 18, 2014; accepted November 25, 2015. From the University of California, San Francisco. Address correspondence and reprint requests to Patrika Tsai, MD, MPH, Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Francisco, Mail Code 0136, 550 16th St, 5th Floor, San Francisco, CA 94158 (e-mail: tsaip@peds. ucsf.edu). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000655
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and classification of populations at risk of vitamin D deficiency that may not truly be at risk (4). With regard to obese individuals, the IOM states that there is no evidence yet to recommend higher doses of vitamin D than for nonobese individuals. Of note, both the Endocrine Society guidelines and the IOM report focus primarily on vitamin D in relation to bone health and other organ systems and disease processes but not the liver or NAFLD. The level of vitamin D needed for optimal liver health remains unknown and warrants further investigation. Pediatric NAFLD patients, who are typically obese or overweight, often have risk factors for low vitamin D levels, including poor diet and limited sun exposure. Although the data for vitamin D in relation to liver health are still under investigation, vitamin D is clearly important in bone health, which should also be of concern to us as pediatric gastroenterologists in our efforts to promote optimal growth and development, as well as prevent future medical problems such as falls and fractures. Bischoff-Ferrari et al (5) performed a meta-analysis suggesting optimal health benefits with vitamin D levels at a minimum of 30 ng/mL with little risk and with doses of 1800 to 4000 IU/day needed to reach these levels. These doses are much higher than present IOM recommendations and appear more in line with the Endocrine Society guidelines for obese individuals. As physicians, our goal should be optimal health, not just sufficient health for our patients.
REFERENCES 1. Hourigan SK, Abrams S, Yates K, et al. Relation between vitamin D status and nonalcoholic fatty liver disease in children. J Pediatr Gastroenterol Nutr 2015;60:396–404. 2. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. 3. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press; 2011. 4. Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab 2012;97:1146–52. 5. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, et al. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21: 1121–32.
Protected Time: A Vital Ingredient for Research Career Development John A. Barnard
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ature þ Nurture ¼ Success. This simple equation is true in most areas of professional life, including academic medicine. One of the most important types of nurture is ‘‘protected time’’ for research. For the purposes of this brief commentary, the focus is on protected time for original research with potential for
Received December 10, 2014; accepted December 22, 2014. From the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio. Address correspondence and reprint requests to John A. Barnard, 700 Children’s Dr, W177, Columbus, OH 43205 (e-mail: john.barnard@ nationwidechildrens.org). The author reports no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000693
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funding by the National Institutes of Health (NIH) or an equivalent peer-reviewed funding agency. In the present hypercompetitive funding climate, protection of junior research–intensive faculty members from clinical, teaching, and administrative duties is vitally important. Research-intensive faculty members must have time to read and understand the literature, attend classes and lectures, confer with colleagues, perform and supervise experiments, manage regulatory requirements, write manuscripts, and write compelling grant applications, among many other important duties. Junior physician scientists must complete the equivalent of a graduate student and postdoctoral education in a few short years to compete with more traditionally trained PhD colleagues for funding. This can only be accomplished with adequate protected time. How much protected time is enough? No published evidence exists that supports a specific level of effort. Historically, many institutions have followed the 80:20 rule, that is, 80% research time and 20% clinical, teaching, and administrative time. Similarly, NIH K awards and many other young investigator grants, such as North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Foundation young investigator development awards, require commitment of 70% to 80% protected time. For example, a K23 career development award from the NIH supports patient-oriented research and requires a commitment of 75% protected research time. So does a K08 award, which funds laboratory research. More important, most experienced research leaders agree that all research disciplines, whether they are clinical, translational, or basic research, require 70% to 80% protected time.
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Invited Commentaries Clinical work constitutes the remaining 20% effort. For pediatric gastroenterologists, this is usually 1 half-day of patientrelated activity, such as a clinic or procedure session, per week and 1 to 2 months annually on an inpatient or consult service. Logically, though, caveats and nuances exist. For example, how many hours per week will one work? Twenty percent of a 70-hour work week is very different from 20% of a 40-hour work week. These considerations must be discussed and clearly understood mutually with program directors, division chiefs, and others in leadership roles. Research-intensive junior physician scientists should minimize teaching and administrative responsibilities. There will be time later in one’s career to develop these skills. Protected time is not a lifelong commitment. At some point, protected time must transition to externally funded time. The reason for this is simple: protected time is expensive. It requires one’s institution to forgo clinical revenue, directly support research salary and supplies, and assume indirect costs, which are usually 50% to 80% of direct costs. Transition of young clinician scientists to externally funded time is best facilitated by NIH K awards, which partially fund protected time and are less competitive than R series grants. Some departments require acquisition of a K award during the final year of fellowship. More typically, 2 to 5 years of protected time are permitted for those junior faculty members with a promising aptitude and work ethic required of a research career. Acquisition of a K award will extend this interval for research career development. Thereafter, transition to independent funding such as an R01 will be required for ongoing support. It is then that the personal and institutional rewards of protected time is realized.
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