The effects of a Cystic Fibrosis drug (Kalydeco) and associated changes in a variety of outcomes including, anthropometric measures , serum vitamin levels and energy intake.

1. Fat Soluble Vitamin
Status in Subjects with
Cystic Fibrosis
Brianna Higgins, B.S., LEND Nutrition Fellow
Virginia Stallings, MD, Joan Schall, Ph.D., Carolyn Mcanlis, B.S., RD, Nina Sainath,
MD, Chaira Bertolaso, MD

2. Cystic Fibrosis (CF)
 Autosomal recessive genetic disorder
 Mutation in Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) gene
 Reduces the number of CFTR channels at the cell surface (synthesis
or processing mutations) or impairs channel function (gating or
conductance mutations)
 Channel transports chloride ions into and out of cells
 Movement of water in tissues
 Production of thin, freely flowing mucus in lungs and gut
https://ghr.nlm.nih.gov/condition/cystic-fibrosis#definition

4. CF Signs & Symptoms
• Fatigue
• Chronic cough
• Recurrent URIs
• Chronic Hypoxia
• Clubbing, Barrel Chest
• Digestive enzymes
• Absorption of some fatty
acids and vitamins
• Abdominal Distention
• Rectal Prolapse
• Fatty, smelly stools
(Steatorrhea)
• Meconium Ileus in newborn

5. CF Signs & Symptoms
 In pancreas
 Ducts of the pancreas blocked, preventing the release of digestive
enzymes that break down food and to allow absorption of vital
nutrients
 Difficulty absorbing fat and fat soluble vitamins
 Difficulty growing normally and maintaining healthy body
weight and body mass index (BMI)
 Patients with CF are prescribed pancreatic enzymes and
vitamins to combat risk for growth failure and vitamin
deficiencies
Cystic Fibrosis Foundation Patient Registry. 2011 Annual Data Report. Bethesda, MD: Cystic Fibrosis Foundation; 2012.

6. Fat Soluble Vitamins
Vitamin A
Normal vision,
epithelial cell
integrity,
regulation of cell
growth,
and immune
functionBeef liver
Herring
Eggs
Vitamin D
Bone health,
regulation of cell
growth,
neuromuscular
and immune
function
Salmon
Fortified
Milk & OJ
Egg yolk
Vitamin E
Prevents cell
membrane
oxidation and
maintains
neurological
functionsNuts
Sunflower
Seeds
Vegetable
Oil
Vitamin K
Coagulation,
bone
calcification,
energy
metabolism,
modulation of
inflammationSpinach
Broccoli
Soybeans
Institute of Medicine. National Academy Press; 2001; Institute of Medicine. National Academy Press; 2011; Holick MF. Mayo Clin Proc. 2006; Institute of Medicine.
National Academy Press; 2000; Koscik RL et al. Pediatrics. 2004; Booth SL. Annu Rev Nutr. 2009; 5.Institute of Medicine. Food and Nutrition Board. Dietary Reference
Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC:
National Academy Press; 2001.

7. Recommended Intake for Fat
Soluble Vitamins
Vit A (IU) Vit D (IU) Vit E (IU) Vit K (µg)
Non-CF (1-50+
years)
1000-3000 600-800 6-22 30-120*
CF Patients
0 to 12 months 1500 400-500 40-50 300-500
1 to 3 years 5000 800-1000 80-150 300-500
4 to 8 years 5000-10000 800-2000 100-200 300-500
9+ years 10000 800-2000 200-400 300-500
Borowitz et al. J Pediatric Gastroenterology and Nutrition. 2002; J. Clin Endo and Metabol. 2012; Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K,
arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001.; Institute of
Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.; 6.Institute of Medicine. Food
and Nutrition Board. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoidsexternal link disclaimer. Washington, DC: National Academy Press, 2000.
*Adequate Intake (AI)

8. Kalydeco (Ivacaftor)
 New, FDA approved prescription medication ≥ 2 years of age
 Addresses CFTR gating mutations in patients with CF (G551D,
G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or
S549R)
 Treatment has resulted in clinically significantly improvements
in pulmonary function, weight and body mass index (BMI)
 Effect on serum fat-soluble vitamin absorption and dietary
intake has not been determined
Ramsey et al., N Engl J Med 2011;365(18):1663-1672.; Vertex Parmaceuticals I. KALYDECO (Ivacaftor): Highlights of
Prescribing Information. 2012. Cambridge, MA.

9. Purpose
 To identify and compare differences in serum Vitamin A and E,
dietary intake, and anthropometric measures in North
American and Italian children and adult subjects with CF,
before and after a three month treatment with Kalydeco®
 Within and between population groups

10. Screening/Recruitment
Inclusion Exclusion
Patient with one or two CFTR
gating mutations
FEV1 < 40% predicted
≥ 5 years of age Use of any inhibitors or inducers
of cytochrome P450 (CYP) 3A
From the United States, Canada
and Italy
Pregnant or breast feeding
Clinical decision has been made
for subject to start Ivacaftor
treatment
Receiving parenteral nutrition
Other chronic illness affecting
growth or nutritional status

11. Study Procedures
Visit 1: Baseline study
visit at CHOP
• Three day
assessment in
CTRC and NGL
Treatment begins at
home
Visit 2: Follow-up visit
(3 months post-
treatment start) at
CHOP
• Three day
assessment in CTRC
and NGL

12. Study Procedures
Assessment Baseline 3 Months
Anthropometry
Height
Weight
√
√
√
√
Serum
Vitamin A (retinol)
Vitamin E (alpha- &
gamma-tocopherol)
√
√
√
√
Diet & Adherence
3-Day Weighed Food
Record Collected
Vitamin Supplementation
Adherence to Treatment
√
√
√
√
√
√

13. Methodology- Diet Analysis
 Subjects and parents/guardians asked to weigh and
record descriptions and amounts of all foods and
beverages consumed a 3-day period
 Completed diet records reviewed and analyzed by skilled
research bionutritionists
 Nutrition Data System (NDS) database
 American diet records
 Meta Dieta database
 Italian diet records

14. Results- Descriptive Data
All N=22 American N=7 Italian N=15
Before Kalydeco Before Kalydeco Before Kalydeco
Age 17.8±13.0 17.0±20.1 18.2±9.0
Sex, %-F 64 43 73
Race, % C 95 85 100
Pancreatic
Insufficient, % 73 71 73

15. Results- Serum Vitamin
Concentrations
American N=7 Italian N=15
Before
Kalydeco
After
Kalydeco
Before
Kalydeco
After
Kalydeco
Vitamin A-
retinol (µg/dL)
35.8±10.4 39.7±10.2 37.0±11.0 36.4±8.3
Vitamin E-
alpha-tocopherol
(µg/mL)
11.5±3.7 10.9±2.0 9.5±3.3 8.9±2.6
Vitamin E-
gamma-tocopherol
(µg/mL)
1.0±0.5 0.9±0.5 0.4±0.2a 0.4±0.2b
aSignificantly different from American at p<0.001 between group
bSignificantly different from American at p<0.01 between group

16. Results- Dietary Intake of
Vitamins
American N=7 Italian N=15
Before Kalydeco After Kalydeco Before Kalydeco After Kalydeco
Vitamin A, total eq 807.2±518.02 678.8±450.8 780.6±491.5 759.2±381.6
Vitamin A,% RDA 192.5±126.8 175.4±138.0 120.1±79.0 115.9±61.9
Vitamin D, mcg 4.3±2.0 5.7±4.3 1.6±1.7b 1.5±1.1b
Vitamin D, % RDA 28.7±13.6 38.3±28.7 10.5±11.2a 9.7±7.3a
Vitamin E, mg 12.8±5.9 12.6±3.5 8.5±5.4 9.9±5.6
Vitamin E, % RDA 132.1±71.1 135.5±63.5 66.2±35.6a 79.3±51.9a
Vitamin K, mcg 86.6±85.4 112.6±143.6 NA
Vitamin K, % AI 122.5±86.6 155.7±149.1 NA
aSignificantly different from American at p<0.001 between group
bSignificantly different from American at p<0.01 between group

17. Results- Dietary Intake of Energy
and Fat
American N=7 Italian N=15
Before
Kalydeco
After
Kalydeco
Before
Kalydeco
After
Kalydeco
Energy intake,
kcal
1914±401 1847±342 2163±590 2508±552a,c
Estimated
Energy
Requirements
(EER), %
97.3±14.7 92.2±6.0 90.4±21.0 103.3±23.4c
Fat, g
80.8±18.9 80.2±19.0 84.6±31.1 102.3±24.8d
Fat, % kcal
36.8±3.8 38.4±4.9 34.8±5.0 36.8±5.4
aSignificantly different from American at p<0.001 between group
cSignificantly different from baseline at p<0.05 within group
dSignificantly different from baseline at p<0.01 within group

18. Results- Vitamin Supplementation
American N=7 Italian N=15
Before Kalydeco After Kalydeco Before Kalydeco After Kalydeco
Vitamin A, retinol eq 2715.0±1784.7 2715.0±1784.7 3126.9±1535.9 3054±1376.1
Vitamin A,% RDA 558.8±406.8 558.8±406.8 492.7±262.3 480.5±234.8
Vitamin D, IU 4694.3±4663.9 4568.6±4757.1 1613.3±145.4a
1586.7±531.7a
Vitamin D, % RDA 782.4±777.3 761.4±792.8 268.9±93.8a
264.4±88.6a
Vitamin E, IU 524.3±1095.1 524.3±1095.1 430.5±466.4 447.3±192.9
Vitamin E, % RDA 4798.3±10508.7 4798.3±10508.7 2238.5±828.5 2313.2±907.1
Vitamin K, µg 612.9±799.9 612.9±799.9 1178.7±383.0 1216.0±441.4
Vitamin K, % AI 1060.8±1426.0 1060.8±1426.0 1602.0±572.6 1643.5±601.1
aSignificantly different from American at p<0.001 between group

19. Results- Anthropometrics
American N=7 Italian N=15
Before
Kalydeco After Kalydeco
Before
Kalydeco After Kalydeco
Weight, kg 33.8±17.7 35.6±17.1d 50.5±11.4f 53.4±11.2b,e
Height, cm 136.7±19.3 138.2±18.3c 158.0±12.2 b 159.4±11.7b,d
BMI 16.9±3.5 17.6±3.3c 20.0±3.1f 20.8±3.2d,f
bSignificantly different from American at p<0.01 between group
cSignificantly different from baseline at p<0.05 within group
dSignificantly different from baseline at p<0.01 within group
eSignificantly different from baseline at p<0.001 within group
fSignificantly different from American at p<0.05 between group

20. Limitations
 Small sample size
 Not enough funding to assess Vitamin D & K serum
concentrations
 Two different diet analysis databases used
 RDA based on Dietary Guidelines for Americans, 2010

21. Conclusion
 Compared to Italian subjects, American subjects had greater
 Vitamin E gamma-tocopherol serum concentrations
 Consumption of Vitamin D and E from diet and Vitamin D from
supplements
 Three months of Kalydeco treatment associated with
 Increased intake of energy, percentage of estimated energy
requirements, and grams of fat in Italian subjects
 Increased height, weight and BMI in both the American and Italian
subjects
 No changes with treatment were found for serum fat soluble
vitamin levels or fat soluble vitamin consumption from the
subjects’ diet

22. Conclusion
 Kalydeco treatment does not reduce need for fat soluble
vitamin supplementation in patients with CF
 Treatments to aid in the improvement of fat soluble vitamin
absorption in patients with CF should continue to be studied
 Patients with CF should receive an increase in nutrition
education on how to consume more foods with larger
quantities of fat soluble vitamins
 Especially Italian patients

23. Acknowledgements
 “Energy Balance and Weight Gain with Ivacaftor Treatment of
CFTR Gating Mutations” study team
 Funding provided by Vertex Pharmaceutical and CHOP Research
Institute and Nutrition Center
 This project was supported by project #T73MC00051 from the
Maternal and Child Health Bureau, Health Resources and
Services Administration, Department of Health and Human
Services