Cystic Fibrosis Foundation

Zinc is a vital element in human nutrition. Overt zinc deficiency has been reported in people with cystic fibrosis (CF) where it can lead to poor growth, poor immune function and a characteristic skin rash. Zinc homeostasis is achieved by changes in both zinc absorption and zinc excretion (especially endogenous fecal zinc excretion in to the stool). There are good theoretical reasons to expect that both these adaptive mechanisms may be abnormal in CF. Many children with CF consume additional zinc as part of their routine multivitamins, but it is not known if this additional zinc leads to normal zinc balance in children with CF or prevents more milder forms of zinc deficiency

The importance of less severe forms of zinc deficiency in cystic fibrosis is difficult to determine due to the lack of reliable markers of zinc status. The most widely used marker of zinc status is the plasma (or serum) zinc concentration, although this is and insensitive and non-specific marker. In the past we have used stable-isotope based compartmental models to study zinc metabolism. These involve giving oral and intravenous zinc stable isotopes and taking multiple blood, urine and fecal samples over the next 5-6d. We have studied two different paradigms of zinc deficiency - children on low zinc intakes and children with Crohn's disease (compared to matched controls). In both cases similar changes in compartmental modeling parameters were seen - both increased turnover between the different zinc compartments, and changes in zinc compartmental masses. These changes could beidentifiable before plasma zinc concentrations became abnormal. The changes in compartmental modeling parameters can identify changes due to zinc deficiency before the plasma zinc concentration becomes abnormal. These compartmental modeling studies also allow measurement of zinc absorption, endogenous fecal zinc excretion, and urinary zinc excretion.

Changes in mRNA expression have been described in zinc deficient cell culture systems and in animal models of zinc deficiency. We propose (in other studies) to examine changes in mRNA expression in experimental animals as potential measures of zinc status using micro-array methods. As part of the current proposal we will collect and store mRNA from buccal cells (obtained by cheek swab) for subsequent analysis of potential mRNA markers of zinc status. This later aim will be carried out once other, separate, animal and human studies are completed. We will not be collecting of storing DNA as part of any of these protocols.

The purpose of this study is to use multicompartmental models to assess zinc absorption, excretion, balance and zinc status in children with CF given an additional 20 mg/d of zinc or an identical placebo, and compare them to healthy children.

We hypothesize that children with CF will have poorer zinc status (assessed using multi-compartmental models), reduced zinc absorption, increased endogenous fecal zinc excretion and poorer zinc balance than age-matched controls; and that supplementation with an additional 20 mg/d zinc will normalize zinc balance and zinc status, compared to age-matched controls.

In addition, we will store mRNA (obtained from buccal cells collected using cheek swabs) at the start and end of the zinc supplementation period, to assess changes in mRNA expression in response to zinc supplementation.

Other

There is a small risk of bruising, bleeding and infection associated with the heparin lock catheter and the blood draws. These will be minimized by these procedures only being carried out by people well experienced in them. There are no risks to the urine or fecal collections. The stable isotopes used are safe in any population, non-radioactive, and without know risk. Zinc supplementation is very well tolerated and adults have tolerated 100 mg/d zinc for 18mns without ill effect. There is a small risk of reduced iron or copper absorption with zinc supplementation, but this should not be a concern with the amount and duration of zinc supplementation studies. We will, however, measure zinc and copper status in all subjects at the end of the study. Any subject with iron or copper deficiency will be informed and referred for investigation and treatment. There are no known risks to the consumption of holmium.

There are no direct benefits to subjects.