Vitamin D Insufficiency Prevalent in CF Children Up to Age 3, Study Says

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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In contrast to vitamins A and E, the early and sustained use of supplements of vitamin D in young children with cystic fibrosis (CF) led to later and variable responses, a study found.

Nearly one-fifth (17%) of these children continued to have low vitamin D levels at age 3 despite receiving high doses of supplements.

“Our study demonstrated that infants with CF diagnosed through [newborn screening] responded to vitamins A and E supplementation quickly and almost universally ([more than] 90% achieved sufficiency status by 1 years of age), while response to vitamin D supplementation occurred more slowly ([less than] 50% in infancy) and variably (17% failed to respond by age 3 years) despite early and sustained supplementation,” the researchers wrote.

According to the team, the factors that may help predict vitamin D insufficiency up to age 3 include the supplement dose and the season. The human body creates vitamin D from direct sunlight, so people have higher levels during warmer months. Here, the study found that the vitamin levels were significantly higher in summer months — June to August — as compared with the winter months from December through February.

Blood levels of a form of vitamin E called alpha-tocopherol, pancreatic insufficiency, respiratory infections, and blood levels of interleukin (IL)-10, a signaling molecule that maintains the balance of the immune response, were identified as other factors for predicting a vitamin D deficiency.

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The study, “Vitamins A, D, E status as related to supplementation and lung disease markers in young children with cystic fibrosis,” was published in the journal Pediatric Pulmonology.

Besides impaired lung function, mutations in the CFTR gene — the cause of CF — can lead to exocrine pancreatic insufficiency, a condition in which the pancreas is unable to release digestive enzymes to break down food in the intestines. This causes insufficient nutrient absorption.

As a result, CF patients are at risk of fat-soluble vitamin deficiencies, including vitamins A, D, and E. For that reason, the Cystic Fibrosis Foundation (CFF) recommends daily supplements of these vitamins specifically for CF children.

While the supplements aid in the control of vitamins A and E, the levels of vitamin D vary largely, even in the cases of large daily doses of supplements.

However, the factors contributing to this variable response remain poorly investigated in young children with CF.

Now, researchers at the University of Wisconsin-Madison assessed if the recommended supplement doses are able to normalize the blood levels of vitamin A, D, and E in CF children during the first three years of life. Moreover, they aimed to identify factors associated with vitamin D deficiency.

The team evaluated data from 144 infants, born between 2012 and 2017, who received their CF diagnosis via newborn screening. These infants were part of the U.S. multi-center FIRST study —Feeding Infants Right… from the Start — which was designed to determine the potential benefits and risks of breastfeeding for CF infants.

At about 4 months of age and then yearly thereafter, the team collected blood samples to measure the concentrations of retinol (vitamin A), 25-hydroxy-vitamin D or 25OHD, the most accurate way to measure vitamin D in the body, and alpha-tocopherol . They also accounted for any vitamin supplements.

Vitamin A deficiency was defined as a concentration of retinol below 200 nanograms per milliliter (ng/mL), while vitamin D insufficiency was noted when 25OHD was below 30 ng/mL, and vitamin E deficiency when alpha-tocopherol was below 5 micrograms (mcg)/mL.

The analysis also included data regarding respiratory infections and hospitalizations, as well as the levels of inflammation markers.

Around half of the children (74 patients, 51%) carried F508del, the most common CF-causing mutation, in both copies of the CFTR gene. Pancreatic insufficiency was present in 72% (103) of the participants.

Results revealed that the blood levels of retinol and 25OHD increased significantly until age 3, but alpha-tocopherol did not.

Data combined from all ages showed that the prevalence of vitamin D insufficiency was significantly higher at 22% than the insufficiency of vitamin A, at 3%, and vitamin E, at 5%.

The need for supplements increased with age for all three vitamins. Those with pancreatic insufficiency also had a higher demand for vitamin supplements — 88% of these children met the CFF guidelines for vitamin A and D supplement intakes.

Children whose parents had a higher educational level also had a higher intake of vitamin supplements. No correlation was seen for household income level or type of health insurance.

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All children were vitamin A sufficient by 2 years of age and 94% were vitamin E sufficient by age 3. More than 80% of participants achieved vitamins A and E sufficiency in early infancy, in contrast with only 42% of patients reaching vitamin D sufficiency at the same age period. Also, 17% remained deficient despite high supplement intakes, responding to supplements either temporarily or never.

Vitamin A and vitamin D insufficiencies were significantly lower in children with no respiratory infections. No such link was seen for vitamin E insufficiency.

Also, higher blood levels of three cytokines — molecules that mediate and regulate immune and inflammatory response — called interleukin (IL)-8, IL-10 and TNF-alpha, showed a negative correlation with retinol and 25OHD levels. That means that higher levels of the cytokines correlated with lower amounts of the vitamins.

For vitamin E, only IL-10 showed a negative correlation with alpha-tocopherol.

A statistical analysis revealed that vitamin D supplement dose, season, blood levels of alpha-tocopherol, pancreatic insufficiency, respiratory infections, and IL-10 blood levels were significant predictors of 25OHD levels in the first three years of life for CF children. Notably, as the scientists expected, vitamin D levels showed seasonal variation, in that they were significantly higher in warm weather compared with those months with colder weather, when time outdoors often is limited.

Overall, while supplements normalized the levels of vitamin A and E, those of vitamin D remained insufficient in a proportion of children.

“Vitamin D insufficiency in CF is unique compared to fat-soluble vitamins A and E because it develops early but is resistant to correction with sustained supplementation,” the researchers wrote.

“Elucidation of the causes of this abnormality and its impact will require further longitudinal studies,” they added.

Strategies to minimize factors that may affect vitamin D levels in the bloodstream could include optimization of pancreatic enzyme replacement therapy, a strategy to help digest food and absorb nutrients, the team concluded, adding that close monitoring of vitamin levels is important.