ZINC HOMEOSTASIS AND KINETICS IN CHILDREN WITH CYSTIC FIBROSIS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 摘要 锌对正常生长、发育和免疫功能至关重要。已知胰腺功能不全会损害锌的吸收，并且在CF中充分描述了明显的锌缺乏（肠病性肢端皮炎）。然而，由于缺乏一个很好的衡量锌状态的方法，不太严重形式的缺锌的重要性尚不清楚。最广泛使用的测试，血浆锌浓度，具有较低的特异性和敏感性，并可能在CF由于共存感染或低蛋白血症而被假性抑制。我们以前已经表明，锌动力学的变化（多房室模型）可以识别适应锌缺乏之前，血浆锌浓度变得异常。本研究的具体目的是比较CF儿童（有和没有补充锌）和健康年龄匹配对照组的锌吸收、内源性粪便锌排泄、锌平衡和锌状态。24名CF和胰腺功能不全儿童，年龄8- 14岁，将随机接受20 mg/d醋酸锌锌或相同的安慰剂治疗2个月。之后，他们将住院6天，口服和静脉注射锌稳定同位素，进行完整的6天尿液和粪便采集，并在同位素给药后采集多份血样。该数据将用于评估锌吸收、内源性粪便锌排泄、锌平衡和锌动力学（锌状态的新指标）。来自两组CF儿童的数据将与来自12名年龄匹配的对照组的数据进行比较，这些对照组摄入目前推荐的每日锌摄入量。我们假设安慰剂治疗的CF儿童与对照组相比，锌吸收显著降低，内源性粪便锌排泄增加，锌平衡较差，锌状态较差;锌治疗的CF儿童与对照组相比，锌平衡和锌状态相似。我们进一步假设，补锌不会导致铁状态（血红蛋白、铁蛋白、转铁蛋白受体）或铜状态（血清铜、血浆铜蓝蛋白和铜锌超氧化物歧化酶）的任何不良影响。最后，我们假设脂肪吸收不良与内源性粪便锌排泄呈正相关，与锌吸收和锌平衡呈负相关。 假设 我们假设， 1. 与年龄匹配的对照组相比，CF儿童的锌状态更差，锌吸收分数更低，内源性粪便锌排泄增加，锌平衡更差。 2. 在两个月后，以20 mg/d的醋酸锌形式补充锌，CF儿童的锌状态、锌吸收分数、内源性粪便锌排泄和锌平衡与年龄匹配的对照组相似。 3. 两个月的锌补充不会影响铁状态（血红蛋白，血清铁蛋白，血清转铁蛋白受体）或铜状态（血清铜，铜蓝蛋白，铜/锌超氧化物歧化酶）。 4. 锌吸收、内源性粪锌排泄和锌平衡与脂肪吸收不良程度呈正相关。 具体目标 本研究的目的是使用稳定的同位素为基础的多房室模型技术，以评估锌平衡，锌的状态，锌吸收，内源性粪便锌排泄和尿锌排泄的囊性纤维化（CF）的儿童有或没有额外的锌补充，并将其与健康的年龄匹配的控制。 具体来说，我们将24名CF和胰腺功能不全的儿童随机接受2个月的补锌（20 mg/d）或安慰剂。在干预结束时，我们将使用稳定同位素技术评估锌吸收、内源性粪便锌排泄、锌平衡和锌动力学（使用多房室模型）。我们还将评估锌补充剂（或安慰剂）对铁和铜状态的影响。 将对CF儿童的两个随机分组和12名年龄、性别和种族匹配的健康对照组进行比较。

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.