Nutrition has become an integral part of care for people with cystic fibrosis (CF). Over the past 30 years, advances have been made in the quest to improve nutritional status, clinical outcomes, and survival in this population.^1-3 The Cystic Fibrosis Foundation (CFF) has developed guidelines and recommendations for many aspects of nutrition therapy.^2-5 While these recommendations are based on currently available information, in this dynamic arena new data is constantly presented. Evaluating new options and approaches for nutrition therapy can provide the practitioner with additional means to improve care and clinical outcomes.

One area of CF care that has evolved over time is the recommendation that all individuals with CF aim to achieve a body mass index (BMI) ≥ 50%.³ There is a documented association between BMI and pulmonary function, measured as forced expiratory volume 1 second (FEV₁) percent predicted.⁶ Others have looked at the impact of short stature, weight at age two, and recovery of birth weight z score as related to later lung function.^7-9 Yen and colleagues evaluated data from the CF Patient Registry (reviewed in this issue). Their study reported an association between the weight for age percentile (WAP) at age four and FEV₁ and survival. They also found that a higher WAP at age four was associated with better linear growth, decreased hospital days, and decreased number of acute exacerbations. This work highlights the critical importance of early and aggressive nutrition therapy.

With the adoption of newborn screening (NBS) as standard practice in the United States, CF care can begin shortly after birth. Since many infants are asymptomatic at diagnosis, the decision about when (or whether) to start pancreatic enzyme replacement therapy (PERT) is not always clear.⁴ O’Sullivan’s group reports serial fecal elastase values of
61 infants from birth to one year (reviewed in this issue). They found that levels vary throughout the first year of life and that taking only one measurement is not always sufficient. Patients with an initial value < 50 μg/g continued to be pancreatic insufficient (PI) at one year, but some patients with an initial value above 50 μg/g were pancreatic sufficient (PS) by the end of the study. Although this is not a common occurrence, the authors recommend checking fecal elastase at diagnosis and again at one year if the initial value is > 50 μg/g. Genetic testing for mutation analysis may also be helpful, but not all genotypes have a documented PI or PS designation. Clinical judgment should be used in conjunction with test results.

Since the CFTR gene was identified in 1989, CF mutation analysis has become common practice in the CF population.¹⁰ Mutation analysis can provide additional clues about disease progression, but it does not tell the whole story. Bradley and colleagues looked at genetic modifiers of nutritional status in cystic fibrosis to try to determine what other genetic factors are involved in nutritional status. In the study reviewed herein, the authors looked at twins and siblings enrolled in the CFF Twin-Sibling study to try to elucidate other genes that are involved in nutritional outcomes and identified regions on chromosomes 1 and 5 that appear to have an effect on nutritional status. While this information will not change clinical practices now, it is possible that in the future we will be able to target specific interventions based on identified genetic modifiers.

Another area of research that is evolving is fatty acid status in CF. Current CFF guidelines provide recommendations for the amount of fat for individuals with CF to consume but do not specify the type because there is not sufficient data to determine an optimal fat source.³ The fat recommendation is related to weight gain and prevention of essential fatty acid deficiency. It has been documented that people with CF have serum fatty acid (FA) abnormalities.¹¹ Maqbool’s group looked at the relation between dietary fat intake type and serum fatty acid status in children with CF; they found that the kinds of fat that impact serum levels include LA (linoleic acid), DHA (docosahexaoic acid), triene:tetraene (T:T), and arachadonic acid (AA):DHA (reviewed in this issue). They suggest that these serum markers can be improved by increasing alpha linoleic acid (ALA) and LA in the diet. The additions of foods such as flaxseed oil, canned tuna, walnuts, canola, safflower, or sunflower oil may be a noninvasive way to improve fatty acid profiles. The promotion of “heart healthy” fats in CF has not been well studied, but these data suggest these types of diet changes provide a benefit.

Bone disease and vitamin D insufficiency in people with CF have been well documented.^16-18 Vitamin D’s role outside of the bones, specifically as related to inflammation, is an area of increasing interest.¹⁹ Grossman and colleagues looked at a novel method for vitamin D repletion during hospitalization for pulmonary exacerbation. In a randomized, controlled pilot study, they gave 250,000 IU of vitamin D₃ to adults admitted for pulmonary exacerbation. The treatment and placebo groups were followed for 12 months posttreatment, and clinically relevant outcomes were evaluated. In the treatment group there was an increase in serum vitamin D, a decrease in the number of hospital days and days on antibiotics, and an improved FEV₁ and survival. In a separate arm of the study (reviewed in this issue) they looked at inflammatory markers in the same groups, finding that in the vitamin D treatment group, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), both markers of inflammation, were decreased and antimicrobial peptide LL-37 was increased. These results suggest that vitamin D could potentially decrease inflammation in CF. As vitamin D plays a major role in people with CF, its impact likely extends beyond the bones.

As the world of CF nutrition continues to evolve, the focus is shifting to include more than just weight gain and preventing micronutrient deficiencies. Nutrition can be used as a tool to improve overall health. Nutrition interventions can affect relevant clinical outcomes through early intervention and individualized care.

Commentary References

1.	Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1998;41:583-91.
2.	Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr.  2002 Sep;35(3):246-59.
3.	Stallings, VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H, Clinical Practice Guidelines on Growth and Nutrition Subcommittee. 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;108:832-839.
4.	Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009 Dec; 155(6 Suppl):S73-93.
5.	V. Tangpricha, A. Kelly, A. Stephenson, K. Maguiness, J. Enders, K. A. Robinson, B. C. Marshall, and D. Borowitz; the Vitamin D Guidelines Committee. An Update on the Screening, Diagnosis, Management, and Treatment of Vitamin D Deficiency in Individuals with Cystic Fibrosis: Evidence-Based Recommendations from the Cystic Fibrosis Foundation J Clin Endocrinol Metab. 2012 Apr;97(4):1082-93
6.	Cystic Fibrosis Patient Registry 2011 Annual Data Report. Bethesda, Maryland; 2012 Jan.
7.	Konstan MW, Butler SM, Wohl MEB, Stoddard M, Matousek R, Wagener JS et al. Growth and nutritional indicies in early life predict pulmonary function in cystic fibrosis. Pediatrics 2003; 112:588-92.
8.	Beker LT, Russek-Cohen E, Fink RJ. Stature as a prognostic factor in cystic fibrosis survival. J Am Diet Assoc 2001;101:438-42.
9.	Lai HJ, Shoff SM, Farrell PM. Recovery of birth weight z-score within two years of diagnosis is positively associated with pulmonary status at 6 years in children with cystic fibrosis.  Pediatrics 2009; 123:714-22.
10.	Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80.
11.	Kuo PT, Huang NN, Bassett R. The fatty acid composition of the serum chylomicrons and adipose tissue of children with cystic fibrosis of the pancreas. J Pediatr 1962;60-394-403.
12.	Maqbool A, Schall JI, Garcia-Espana JF et al. Serum Linoleic acid status as a clinical indicator of essential fatty acid status in children with cystic fibrosis. J Pediatr Gastroenterol Nutr 2008;47:635-44.
13.	Walowiak J, Lisoaska A, Blaszczynski M et al. Polyunsaturated fatty acids in cystic fibrosis are related to nutrition and clinical expression of the disease. J Pediatr Gastroenterol Nutr 2007;45:488-9.
14.	Shoff SM, Ahn HY, Davis L et al. Temporal associations among energy intake, plasma linoleic acid, and growth improvement in response to treatment initiation after diagnosis of cystic fibrosis. Pediatrics 2006;117-391-400.
15.	Freedman SD, Blanco PG, Zaman MM et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-9.
16.	Boyle MP, Noschese ML, Watts SL, Davis ME, Stenner SE, Lechtzin N. Failure of high dose ergocalciferol to correct vitamin D deficiency in adults with cystic fibrosis. Am J Resp Crit Care med 2005;172:212-7.
17.	Wolfenden LL, Judd SE, Shah R, Sanyal R, Zeigler TR, Tangpricha V. Vitamin D and bone health in adults with cystic fibrosis. Clin Endocrinol 2008;69:374-81.
18.	Hall WB, Sparks AA, Aris RM. Vitamin D deficiency in cystic fibrosis. Int J Endocrinol 2010; 2010:218691.
19.	McNally P, Coughlan C, Bergsson G, Doyle M, tagart C, Adorini L et al. Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis. J Cyst Fibros 2011;10:428-434.

O'Sullivan BP, Baker D, Leung KG, Reed G, Baker SS, Borowitz D. Evolution of Pancreatic Function during the First Year in Infants with Cystic Fibrosis. J Pediatr. 2013 Apr;162(4):808-812 (For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)

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In this study, O’Sullivan and colleagues looked at how pancreatic function changes during the first year of life using serial measurements of fecal elastase — a topic of great interest because some infants with cystic fibrosis diagnosed by newborn screening may be pancreatic sufficient (PS) at diagnosis and become pancreatic insufficient (PI) as they grow older. The authors report that the majority of past studies using fecal elastase were cross-sectional with single samples. Their goal was to determine how fecal elastase values change as the babies age by providing a longitudinal evaluation of pancreatic function during the first year of life.

The subjects in this study were part of a larger trial investigating the effect of docosahexanoic acid (DHA) supplementation in infant formula. The subjects were all formula fed and entered into the study by 54 days of life, with data collected for 61 infants. The patients had varied mutations: 28 (46%) homozygous F508del, 10 compound heterozygotes that had genotypes associated with PI, and 5 others with F508del and an unidentified mutation. The infants were grouped based on their initial fecal elastase value (< 50 μg/g, 50-100 μg/g, 100-200 μg/g, and > 200 μg/g). Twenty-nine infants had an initial fecal elastase < 50 μg/g. Although three had a fecal elastase > 200μg/g at some time during the first year of life, all had a value < 200 μg/g at 1 year of age. Seven infants had an initial fecal elastase between 50-100 μg/g: 6 of these had a value >100 μg/g at 1 year of age, and one had a fecal elastase consistent with PS (> 200μg/g) at the end of the study (the mutation for this baby is known to be associated with PS in approximately 40% of cases). Greater variability was seen in the initial fecal elastase in the 100-200 μg/g group, where 48 infants had initial values consistent with PI:4 of these ended up with PS values (> 200 μg/g), while 13 others had at least one value > 200 μg/g during the study period.

The authors note significant variability in the fecal elastase values during the first 12 months of life, with many fecal elastase values not consistent with either their initial or final result. They suggest that infants with low values (< 50 μg/g) are unlikely to become PS, and while an initial level > 50 μg/g but < 200 μg/g may change over time, the majority of infants with an initial fecal elastase <200μg/g will remain PI. Frequent retesting may be confusing and is not recommended unless the initial value is > 50 μg/g, and for those infants, retesting at 1 year of age is recommended. The authors report that genotype is an important determinant of pancreatic function, however, they believe that phenotype (fecal elastase test) is a better indicator: for example, 2 infants with F508del ended the study period above 200 μg/g, which is consistent with PS.

The investigators recommend that management decisions about pancreatic enzyme replacement therapy (PERT) should not be based on a single fecal elastase measurement or genotype determination but should include multiple data points.