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

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

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

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.

Fat Soluble Vitamins

Vitamin A

Normal vision,

epithelial cell

integrity,

regulation of cell

growth,

and immune

function Beef liver

Herring

Eggs

Vitamin D

Bone health,

regulation of cell

growth,

neuromuscular

and immune

functionSalmon

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.

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)

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.

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

Screening/Recruitment

Inclusion ExclusionPatient 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

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

Study Procedures

Assessment Baseline 3 Months

Anthropometry

HeightWeight

√

√

√

√

Serum

Vitamin A (retinol)Vitamin E (alpha- & gamma-tocopherol)

√

√

√

√

Diet & Adherence

3-Day Weighed FoodRecord CollectedVitamin SupplementationAdherence to Treatment

√

√

√

√

√

√

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

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

Results- Serum Vitamin Concentrations

American N=7 Italian N=15Before

KalydecoAfter

KalydecoBefore

KalydecoAfter

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 groupbSignificantly different from American at p<0.01 between group

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 NAaSignificantly different from American at p<0.001 between groupbSignificantly different from American at p<0.01 between group

Results- Dietary Intake of Energy and Fat

American N=7 Italian N=15Before

KalydecoAfter

KalydecoBefore

KalydecoAfter

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, g80.8±18.9 80.2±19.0 84.6±31.1 102.3±24.8d

Fat, % kcal36.8±3.8 38.4±4.9 34.8±5.0 36.8±5.4

aSignificantly different from American at p<0.001 between groupcSignificantly different from baseline at p<0.05 within groupdSignificantly different from baseline at p<0.01 within group

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±601.1aSignificantly different from American at p<0.001 between group

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 groupcSignificantly different from baseline at p<0.05 within groupdSignificantly different from baseline at p<0.01 within groupeSignificantly different from baseline at p<0.001 within groupfSignificantly different from American at p<0.05 between group

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

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

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

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