Augustine Marianne V, Leonard Mary B, Thayu Meena, Baldassano Robert N, de Boer Ian H, Shults Justine, Denson Lee A, DeBoer Mark D, Herskovitz Rita, Denburg Michelle R
The Children's Hospital of Philadelphia (M.V.A., M.B.L., M.T., R.N.B., J.S., R.H., M.R.D.), Perelman School of Medicine at the University of Pennsylvania (M.B.L., R.N.B., J.S., M.R.D.), Philadelphia, Pennsylvania 19104; Kidney Research Institute, University of Washington (I.H.d.B.), Seattle, Washington 98104; Department of Pediatrics, Cincinnati Children's Hospital Medical Center (L.A.D.), Cincinnati, Ohio 45229; and Department of Pediatrics, University of Virginia Health System (M.D.D.), Charlottesville, Virginia 22908.
J Clin Endocrinol Metab. 2014 Jun;99(6):E991-8. doi: 10.1210/jc.2013-3846. Epub 2014 Mar 11.
Preclinical studies suggest that TNF-α suppresses PTH synthesis, inhibits renal 1α-hydroxylase activity, and impairs fibroblast growth factor 23 (FGF23) degradation. The impact of inflammation on vitamin D and mineral metabolism has not been well-characterized in Crohn's disease (CD).
The objective of the study was to assess short-term changes in vitamin D-related mineral metabolism in CD after anti-TNF-α induction therapy.
DESIGN/PARTICIPANTS: Eighty-seven CD participants, aged 5-39 years, were assessed at the initiation of anti-TNF-α therapy and 10 weeks later.
Indices of clinical disease activity and serum concentrations of vitamin D metabolites, vitamin D-binding protein (DBP), calcium, PTH, FGF23, IL-6, and TNF-α were measured at each visit. A multivariable generalized estimating equation (GEE) regression analysis was used to examine the correlates of PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations at each visit.
After anti-TNF-α therapy, cytokines and inflammatory markers [IL-6, TNF-α, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)] concentrations decreased (all P < .0001), and PTH and 1,25(OH)2D concentrations increased (median 21 vs 30 pg/mL, P < .0001, and median 41.7 vs 48.1 pg/mL, P = .014, respectively). Levels of 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D, DBP, and FGF23 did not change. In GEE analyses, higher IL-6, TNF-α, ESR, and CRP were associated with lower PTH concentrations (all P < .001), adjusted for corrected calcium and 25(OH)D levels. Higher PTH was associated with higher 1,25(OH)2D concentrations (P < .001) at each visit, independent of 25(OH)D concentrations. Higher levels of all inflammatory markers were associated with lower 1,25(OH)2D concentrations (all P < .05). However, when PTH was added to these models, the inflammatory markers (with the exception of CRP) were no longer significantly associated with 1,25(OH)2D.
Greater inflammation was associated with lower PTH and 1,25(OH)2D concentrations. After anti-TNF-α induction, PTH and 1,25(OH)2D concentrations increased without concomitant changes in 25(OH)D and FGF23, consistent with effects of inflammation on PTH and thereby renal conversion of 25(OH)D to 1,25(OH)2D.
临床前研究表明，肿瘤坏死因子-α（TNF-α）可抑制甲状旁腺激素（PTH）合成，抑制肾脏1α-羟化酶活性，并损害成纤维细胞生长因子23（FGF23）的降解。炎症对维生素D和矿物质代谢的影响在克罗恩病（CD）中尚未得到充分表征。
本研究的目的是评估抗TNF-α诱导治疗后CD患者维生素D相关矿物质代谢的短期变化。
设计/参与者：87名年龄在5至39岁之间的CD参与者在开始抗TNF-α治疗时及10周后接受评估。
每次就诊时测量临床疾病活动指标以及维生素D代谢产物、维生素D结合蛋白（DBP）、钙、PTH、FGF23、白细胞介素-6（IL-6）和TNF-α的血清浓度。采用多变量广义估计方程（GEE）回归分析来检查每次就诊时PTH和1,25-二羟基维生素D [1,25(OH)2D]浓度的相关性。
抗TNF-α治疗后，细胞因子和炎症标志物[IL-6、TNF-α、红细胞沉降率（ESR）和C反应蛋白（CRP）]浓度降低（均P <.0001），PTH和1,25(OH)2D浓度升高（中位数分别为21 vs 30 pg/mL，P <.0001；中位数分别为41.7 vs 48.1 pg/mL，P =.014）。25-羟基维生素D [25(OH)D]、24,25-二羟基维生素D、DBP和FGF23水平未发生变化。在GEE分析中，校正钙和25(OH)D水平后，较高的IL-6、TNF-α、ESR和CRP与较低的PTH浓度相关（均P <.001）。每次就诊时，较高的PTH与较高的1,25(OH)2D浓度相关（P <.001），与25(OH)D浓度无关。所有炎症标志物水平较高均与较低的1,25(OH)2D浓度相关（均P <.05）。然而，当将PTH添加到这些模型中时，炎症标志物（CRP除外）与1,25(OH)2D不再显著相关。
炎症越严重，PTH和1,25(OH)2D浓度越低。抗TNF-α诱导治疗后，PTH和1,25(OH)2D浓度升高，而25(OH)D和FGF23无相应变化，这与炎症对PTH的影响以及由此导致的肾脏将25(OH)D转化为1,25(OH)2D的作用一致。
