ZINC HOMEOSTASIS AND KINETICS IN CHILDREN WITH CYSTIC FIBROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要 锌对正常生长、发育和免疫功能是必不可少的。众所周知，胰腺功能不全会损害锌的吸收，而明显的锌缺乏(肠性肢端皮炎)在慢性萎缩性胰腺炎中有很好的描述。然而，由于缺乏良好的锌状况衡量标准，不太严重的锌缺乏症的重要性尚不清楚。最广泛使用的检测方法是血浆锌浓度，其特异性和敏感度较差，可能由于同时存在感染或低蛋白血症而在CF中被假性抑制。我们以前已经证明，锌动力学的变化(多室模型)可以在血浆锌浓度变得异常之前识别锌缺乏的适应性。本研究的具体目标是比较补锌和不补锌的CF儿童和年龄匹配的健康对照组儿童的锌吸收、内源性粪便锌排出、锌平衡和锌状况。24名患有慢性胰腺炎和胰腺功能不全的儿童，年龄8-14岁，将随机接受20 mg/d的锌作为醋酸锌或相同的安慰剂，为期2个月。在此之后，他们将住院6天，届时将口服和静脉注射锌稳定同位素，进行为期6天的完整尿液和粪便收集，并在注射同位素后采集多份血液样本。这些数据将被用来评估锌的吸收、内源性粪便锌的排泄、锌的平衡和锌的动力学(一种新的衡量锌状态的指标)。来自两组CF儿童的数据将与12名年龄匹配的对照组的数据进行比较，这些对照组的儿童摄入目前推荐的每日锌摄入量。我们假设，与对照组相比，服用安慰剂的CF儿童的锌吸收显著降低，内源性锌排泄增加，锌平衡更差，锌状况更差；而锌治疗的CF儿童将具有与对照组相似的锌平衡和锌状况。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、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儿童的锌营养状况更差，锌吸收分数更低，内源性粪锌排泄增加，锌平衡更差。 2.与醋酸锌一样补充锌20 mg/d两个月后，CF患儿的锌营养状况、锌吸收分数、内源性粪锌排泄和锌平衡与年龄匹配的对照组相似。 3.补锌两个月不影响铁状态(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 本研究的目的是利用稳定同位素多室模拟技术评估囊性纤维化(CF)患儿补充或不补充锌前后的锌平衡、锌状况、锌吸收、内源性粪锌排泄和尿锌排泄，并与年龄匹配的健康对照组进行比较。 具体地说，我们将随机选择24名患有CF和胰腺功能不全的儿童，接受2个月的锌补充(20 mg/d)或安慰剂治疗。在干预结束时，我们将使用稳定同位素技术来评估锌的吸收、内源性粪便锌的排泄、锌的平衡和锌的动力学(使用多室模型)。我们还将评估补锌(或安慰剂)对铁和铜状态的影响。 将在两个随机分组的CF儿童和12个年龄、性别和种族匹配的健康对照组之间进行比较。

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.