ZINC HOMEOSTASIS AND KINETICS IN CHILDREN WITH CYSTIC FIBROSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Zinc is essential for normal growth, developmental and immune function. Pancreatic insufficiency is known to impair zinc absorption and overt zinc deficiency (acrodermatitis enteropathica) is well described in CF. However the importance of less severe forms of zinc deficiency is unclear due to the lack of a good measure of zinc status. The most widely used test, plasma zinc concentration, has poor specificity and sensitivity, and may be falsely depressed in CF due to co-existing infection or hypoproteinemia. We have previously shown that changes in zinc kinetics (multi-compartmental models) can identify adaptation in zinc deficiency before the plasma zinc concentration becomes abnormal. The specific objectives of this study are to compare zinc absorption, endogenous fecal zinc excretion, zinc balance and zinc status in children with CF, with and without supplementary zinc, and healthy age-matched controls. Twenty-four children with CF and pancreatic insufficiency, aged 8-14y, will be randomized to receive 20 mg/d zinc as zinc acetate or an identical placebo for 2 months. After this they will be admitted for a 6-day in-patient stay when zinc stable isotopes will be administered orally and intravenously, a complete 6-day urine and fecal collection carried out, and multiple blood samples taken after isotope administration. This data will be used to assess zinc absorption, endogenous fecal zinc excretion, zinc balance and zinc kinetics (a novel measure of zinc status). Data from the two groups of CF children will be compared to data from 12 age-matched controls consuming the current recommended daily allowance for zinc. We hypothesize that the placebo-treated CF children will have significantly lower zinc absorption, higher endogenous fecal zinc excretion, poorer zinc balance, and worse zinc status than the controls; and that the zinc-treated CF children will have similar zinc balance and zinc status to the controls. We further hypothesize that zinc supplementation will not lead to any adverse effects of iron status (hemoglobin, ferritin, transferin receptors) or copper status (serum copper, ceruloplasmin and copper- zinc superoxide dismutase). Finally, we hypothesize that fat malabsorption will be positively correlated with endogenous fecal zinc excretion, and negatively correlated with zinc absorption and zinc balance. HYPOTHESES We hypothesize that, 1. Children with CF will have worse zinc status, lower fractional zinc absorption, increased endogenous fecal zinc excretion, and poorer zinc balance, than age-matched controls. 2. After two months of zinc supplementation with 20 mg/d zinc as zinc acetate children with CF will have similar zinc status, fractional zinc absorption, endogenous fecal zinc excretion, and zinc balance to age-matched controls. 3. Two months of zinc supplementation will not affect iron status (Hemoglobin, serum ferritin, serum transferin receptors) or copper status (serum copper, ceruloplasmin, copper/ zinc superoxide dismutase). 4. Zinc absorption, endogenous fecal zinc excretion and zinc balance will be positively correlated with the degree of fat malabsorption. SPECIFIC AIMS The aims of this study are to use stable isotope-based multicompartmental modeling techniques to evaluate zinc balance, zinc status, zinc absorption, endogenous fecal zinc excretion and urinary zinc excretion in children with cystic fibrosis (CF,) with or without additional zinc supplementation and compared them to healthy age-matched controls. Specifically, we will randomize 24 children with CF and pancreatic insufficiency to receive 2 months of zinc supplementation (20 mg/d) or placebo. At the end of the intervention we will use stable isotope techniques to assess zinc absorption, endogenous fecal zinc excretion, zinc balance, and zinc kinetics (using a multi-compartmental model). We will also assess the effect of zinc supplementation (or placebo) on iron and copper status. Comparisons will be made between the two randomized groups of CF children and 12 healthy age- gender- and ethnicity-matched controls.