BACKGROUND Serum ferritin concentrations are the most widely used indicator for iron deficiency. WHO determined that insufficient data are available to revise the serum ferritin thresholds of less than 12 μg/L for children and less than 15 μg/L for women, which were developed on the basis of expert opinion, to define iron deficiency. We aimed to derive new physiologically based serum ferritin concentration thresholds for iron deficiency in healthy young children and non-pregnant women using data from the US National Health and Nutrition Examination Survey (NHANES). METHODS In this serial cross-sectional study, we examined the relationship of serum ferritin with two independent indicators of iron-deficient erythropoiesis, haemoglobin and soluble transferrin receptor (sTfR), in children (12-59 months) and non-pregnant women (15-49 years) using cross-sectional NHANES data from 2003-06, 2007-10, and 2015-18. NHANES is a US national stratified multistage probability sample that includes a household interview followed by a standardised physical examination in a mobile examination centre. We excluded individuals with missing serum ferritin, sTfR, haemoglobin, or white blood cell counts measurements; non-pregnant women with missing C-reactive protein (CRP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) data were also excluded. In addition, individuals with infection (white blood cell counts >10·0×109/L) and non-pregnant women with possible liver disease (ALT >70 IU/L or AST >70 IU/L) and inflammation (CRP >5·0 mg/L) were excluded. We examined distributions of haemoglobin and sTfR with serum ferritin and used restricted cubic spline regression models to determine serum ferritin thresholds for iron-deficient erythropoiesis. FINDINGS 5964 children and 10 462 non-pregnant women had physical examinations and were screened for inclusion in the study, of whom 2569 (43·1%) children and 7498 (71·7%) non-pregnant women were included. At lower serum ferritin concentrations, median haemoglobin concentration decreased as sTfR concentration increased, with each varying in a curvilinear manner. Using restricted cubic spline plateau points to determine the onset of iron-deficient erythropoiesis, the serum ferritin thresholds identified by haemoglobin and sTfR concentrations were not different. For children, the haemoglobin identified serum ferritin threshold was 19·9 μg/L (95% CI 18·8-22·6) and the sTfR identified serum ferritin threshold was 20·0 μg/L (19·4-20·9; p=0·89). For women the haemoglobin identified serum ferritin threshold was 25·2 μg/L (24·2-26·2) and the sTfR identified serum ferritin threshold was 24·0 μg/L (23·3-24·6; p=0·05). INTERPRETATION The association between two independent indicators of iron-deficient erythropoiesis, haemoglobin and sTfR, identified serum ferritin concentration thresholds of about 20 μg/L for children and 25 μg/L for non-pregnant women, providing physiological evidence of potential new thresholds for consideration when determining the prevalence and distribution of iron deficiency in populations. In healthy children and non-pregnant women, physiologically based thresholds for iron deficiency might be more clinically and epidemiologically relevant than those based on expert opinion. Validation of this physiologically based approach in non-US populations might help the international harmonisation of serum ferritin thresholds for iron deficiency. FUNDING None.

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儿童和非孕妇缺铁的基于生理学的血清铁蛋白阈值：美国国家健康和营养检查调查 (NHANES) 系列横断面研究。

背景血清铁蛋白浓度是最广泛使用的缺铁指标。世卫组织确定没有足够的数据来修正儿童低于 12 μg/L 和女性低于 15 μg/L 的血清铁蛋白阈值，这些阈值是根据专家意见制定的，以确定缺铁。我们的目的是利用美国国家健康和营养调查 (NHANES) 的数据得出健康幼儿和非孕妇缺铁的新的基于生理学的血清铁蛋白浓度阈值。方法 在这项系列横断面研究中，我们检查了血清铁蛋白与缺铁性红细胞生成的两个独立指标、血红蛋白和可溶性转铁蛋白受体 (sTfR) 的关系，使用 2003-06、2007-10 和 2015-18 的横断面 NHANES 数据在儿童（12-59 个月）和非孕妇（15-49 岁）中进行研究。NHANES 是美国国家分层多阶段概率样本，其中包括家庭访谈，然后是在移动检查中心进行的标准化体检。我们排除了缺少血清铁蛋白、sTfR、血红蛋白或白细胞计数测量的个体；缺少 C 反应蛋白 (CRP)、丙氨酸氨基转移酶 (ALT) 或天冬氨酸氨基转移酶 (AST) 数据的非孕妇也被排除在外。此外，感染者（白细胞计数 >10·0×109/L）和可能患有肝病（ALT >70 IU/L 或 AST >70 IU/L）和炎症（CRP >5）的非孕妇·0 mg/L) 被排除在外。我们检查了血红蛋白和 sTfR 与血清铁蛋白的分布，并使用限制性三次样条回归模型来确定缺铁性红细胞生成的血清铁蛋白阈值。结果 5964名儿童和10462名非孕妇接受了体检并被筛选纳入研究，其中2569名（43·1%）儿童和7498名（71·7%）非孕妇被纳入研究。在较低的血清铁蛋白浓度下，中位血红蛋白浓度随着 sTfR 浓度的增加而降低，并且每种都以曲线方式变化。使用限制性三次样条高原点来确定缺铁性红细胞生成的开始，由血红蛋白和 sTfR 浓度确定的血清铁蛋白阈值没有差异。为儿童，血红蛋白鉴定的血清铁蛋白阈值为 19·9 μg/L (95% CI 18·8-22·6)，sTfR 鉴定的血清铁蛋白阈值为 20·0 μg/L (19·4-20·9; p= 0·89)。对于女性，血红蛋白鉴定的血清铁蛋白阈值为 25·2 μg/L (24·2-26·2)，sTfR 鉴定的血清铁蛋白阈值为 24·0 μg/L (23·3-24·6；p=0 ·05)。解释 缺铁性红细胞生成的两个独立指标血红蛋白和 sTfR 之间的关联确定了儿童的血清铁蛋白浓度阈值约为 20 μg/L，非孕妇的血清铁蛋白浓度阈值为 25 μg/L，为潜在的新阈值提供生理学证据以供考虑在确定人群中缺铁的患病率和分布时。在健康的儿童和非孕妇中，基于生理学的缺铁阈值可能比基于专家意见的阈值更具有临床和流行病学相关性。在非美国人群中验证这种基于生理学的方法可能有助于国际统一针对缺铁的血清铁蛋白阈值。资金 无。