Startseite Correlation between serum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D in response to analytical procedures; a systematic review and meta-analysis
Artikel Open Access

Correlation between serum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D in response to analytical procedures; a systematic review and meta-analysis

  • Muhittin Abdulkadir Serdar ORCID logo , Fatma Demet Arslan ORCID logo EMAIL logo , Neslihan Yıldırım Saral ORCID logo und Doğan Yücel ORCID logo
Veröffentlicht/Copyright: 13. Mai 2024
Artikel downloaden (PDF)
Turkish Journal of Biochemistry
Aus der Zeitschrift Turkish Journal of Biochemistry Band 49 Heft 3

Abstract

Objectives

In this study, the aim is to provide a more detailed understanding of vitamin D metabolism by evaluating the correlation between 1,25-dihydroxyvitamin D (1,25(OH)2D) and 25-hydroxyvitamin D (25(OH)D) according to the variations in measurement methods and clinical conditions.

Methods

We searched PubMed, Embase, and Web of Science for studies reporting correlation results between 1,25(OH)2D and 25(OH)D. We performed a meta-analysis based on the correlation results of 1,25(OH)2D and 25(OH)D in different clinical conditions. We included a total of 63 studies and our laboratory’s results in the meta-analysis. The studies were categorized into high-quality methods group (HQMG), medium-quality methods group (MQMG), and low-quality methods group (LQMG) based on the 25(OH)D and 1,25(OH)2D measurement.

Results

In the healthy, renal disease, and other disease groups, the highest correlation values were observed in the studies categorized as HQMG, with values of 0.35 (95 % CI; 0.23–0.48), 0.36 (95 % CI; 0.26–0.42), and 0.36 (95 % CI; 0.22–0.48), respectively. Significant statistical heterogeneity was observed in the healthy, renal disease, and other disease groups, with I2 values of 92.4 , 82.7, and 90.7 %, respectively (p<0.001). Both Funnel plots and the results of Egger’s and Begg’s tests indicated no statistically significant bias across all studies.

Conclusions

A significantly low correlation was found between 25(OH)D and 1,25(OH)2D. However, higher correlations were found in the studies categorized as HQMG. Various factors, including methodological inadequacies and disparities, might contribute to this. In the future, with more accurate and reproducible measurements of 1,25(OH)2D, a clearer understanding of vitamin D metabolism will be achieved.

Keywords: 1,25-dihydroxyvitamin D; 25-hydroxyvitamin D; analytical chemistry methods; correlation study; healthy subjects; renal disease

Introduction

Vitamin D deficiency (VDD) is the most common worldwide, and more than 1 billion people are known to have a deficiency [1]. Although VDD was known long ago, rickets and osteomalacia were first distinctly described in 1645 [2]. The experimental animal studies have clarified its synthesis, mechanism, and treatments for its deficiencies [3], [4], [5], [6]. It has been stated that there has been a considerable increase in the number of individuals affected by VDD in recent years, especially common in the elderly and those who stay indoors for longer periods, people with pigmented skin, pregnant women, vegans, and children of developmental age.

The regulation of vitamin D metabolism

Vitamin D metabolism and regulation are very complex (Figure 1). Vitamin D3 is produced in the skin by ultraviolet-B (290–315 nm) irradiation of 7-dehydrocholesterol (7-DHC). Irradiation of 7-DHC produces pre-D3 (which later becomes vitamin D3), lumisterol, and tachysterol [7]. Melanin in the skin absorbs UV radiation, potentially reducing the skin’s ability to produce vitamin D from sunlight. This could be a key factor contributing to lower 25-hydroxyvitamin D (25(OH)D) levels (which is a well-established indicator of vitamin D levels) in Black and Hispanic individuals living in regions with less direct sunlight [8]. The 25(OH)D levels can exhibit significant seasonal fluctuations, with elevated concentrations in the summer and decreased levels in the winter.

Figure 1: Vitamin D metabolism and regulation.
Figure 1:

Vitamin D metabolism and regulation.

Vitamin D is initially metabolized to 25(OH)D, predominantly in the liver, and then further converted to 1,25-dihydroxyvitamin D (1,25(OH)2D), mainly in the kidney. This final form, 1,25(OH)2D, is the primary active form responsible for most of vitamin D’s effects in the body [9].

The 25-hydroxylase-CYP2R1 is highly controlled by a variety of diseases (obesity, diabetes mellitus, starvation, infection, inflammation, cancer, etc.), and although many regulatory factors have now been identified, significant gaps remain. Genetic silencing mutations in CYP2R1 can cause rickets, osteomalacia, or other clinical conditions. Serum 25(OH)D may not reflect only the vitamin D produced by diet and skin. In particular, hepatic 25(OH)D synthesis has a complex regulation involving many possible hormones and factors.

The enzyme 1,25-dihydroxylase CYP27B1 is mainly present in the renal proximal tubule, and its production is influenced by changes in parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 1,25(OH)2D, calcium, and phosphate levels [10]. A specific region in the enhancer region of renal CYP27B1 is responsible for responding to PTH, FGF23, and 1,25(OH)2D regulation [11]. However, this region is not open to such regulation in non-kidney tissues like skin, immune cells, and adipose tissue. In non-renal tissues, a different enhancer region of CYP27B1 is regulated by various factors such as interferon-γ (IFN-γ), cytokines like tumor necrosis factor-α (TNF-α), or leptin [12, 13]. These feedback loops play a vital role in regulating 1,25(OH)2D production in the kidney, which differs from CYP27B1 in other cell types, including distal renal tubular cells that are minimally affected by PTH [14]. CYP24A1 regulates 1,25(OH)2D levels in other tissues and is stimulated by TNF-α and IFN-γ. However, in some conditions like sarcoidosis, where macrophages produce excess 1,25(OH)2D without proper CYP24A1 regulation, it can lead to hypercalcemia and hypercalciuria [15], [16], [17].

25(OH)D and 1,25(OH)2D are carried in the bloodstream by a protein called vitamin D-binding protein (DBP). This protein safeguards them from degradation and allows for their storage. About 85–90 % of the 25(OH)D/1,25(OH)2D pool is bound to DBP in the serum. The remaining 10–15 % is loosely attached to serum albumin and lipoproteins. Only a tiny fraction (less than 0.1 % of 25(OH)D and about 0.4 % of 1,25(OH)2D) is freely available [9]. Total 25(OH)D or 1,25(OH)2D includes three fractions: DBP-bound, weakly bound to albumin (also called bioavailable, as they can easily dissociate from albumin), and free compounds. Changes in DBP levels due to genetic factors, hormonal status, or liver and kidney conditions can impact the accuracy of 25(OH)D levels as a marker of vitamin D status, especially in pregnancy, estrogen-containing contraceptives, and liver or kidney diseases. Through the measurement of total 25(OH)D, DBP, and albumin by the principles of protein-ligand binding kinetics, it is possible to calculate both the 25(OH)D/1,25(OH)2D-DBP and 25(OH)D/1,25(OH)2D-albumin affinities [9, 18]. However, these are used limitedly due to their impracticality and complexity.

The clinical decision limits for vitamin D

Determining the clinical decision limits of 25(OH)D is complicated. In 1997, the Food and Nutrition Board of the Institute of Medicine identified serum 25(OH)D as a good marker for evaluating vitamin D status [19]. However, there was not enough data at that time to fully understand its normal range in the body. Estimated values were insufficient, and it has since become evident that vitamin D deficiency is more prevalent than previously thought. It is affected by various factors such as seasons, diet, medications, and inaccurate measurement methods. Studies have investigated the relationship between serum PTH levels and 25(OH)D levels. It is known that PTH levels increase at low levels of 25(OH)D values but decrease at 75–110 nmol/L levels [20], [21], [22]. In this context, high PTH levels suggest the body is adapting to lower calcium intake. However, whether this adaptation indicates better health is still uncertain [23]. To date, no definitive functional change in 25(OH)D levels is known at the point where PTH stabilizes at the lower end of the healthy reference value (or clinical decision threshold level) of 25(OH)D. Vitamin D significantly increases circulating 1,25(OH)2D concentrations, but in vitamin D users, this increase is suppressed by calcium co-administration.

Measuring 25(OH)D levels is crucial in assessing human vitamin D status. Cut-off values for various status categories are established based on correlations between circulating 25(OH)D concentrations and physiological/clinical changes in the body [24], [25], [26]:

  1. Increased risk of deficiency status (<30 nmol/L, <12 ng/mL)

  2. Increased risk of inadequacy (<40 nmol/L, <16 ng/mL)

  3. Adequacy (>50 nmol/L, >20 ng/mL)

  4. Increased risk of excess (or potentially harmful effects) (>125 nmol/L, >50 ng/mL).

The relationship between 25(OH)D and 1,25(OH)2D

Circulating 1,25(OH)2D level is generally not a good indicator of vitamin D status. 1,25(OH)2D has a short half-life; PTH, Ca, and PO4 tightly regulate serum levels and do not decrease until severe vitamin D deficiency. Additionally, the limitations of commercial measurement kits for 1,25(OH)2D have necessitated the development of new methods and the use of alternative reference ranges [27, 28].

The relationship between 25(OH)D and 1,25(OH)2D is multifaceted and complex. In this study, we planned to conduct a meta-analysis and systematic review to elucidate the relationship between 25(OH)D and 1,25(OH)2D, aiming to gain a better understanding of vitamin D metabolism. This correlation was designed considering two different scenarios. In the first scenario, the measurement methods for 25(OH)D and 1,25(OH)2D, along with the analytical limitations associated with these methods, were considered. In the second scenario, various clinical conditions, such as in healthy individuals, kidney diseases (where 1,25(OH)2D synthesis takes place), and systemic diseases, were individually evaluated by considering their specific effects on vitamin D metabolism.

Materials and methods

This meta-analysis was conducted following the guidelines recommended by the PRISMA statement [29].

The strategy of publication search

In this meta-analysis study, comprehensive search strategies were created to identify publications. Articles published between 2005 and 2023 without language restrictions are in MEDLINE (via PubMed), Embase, and Web of Science. Using the keywords “(25-hydroxy D OR 25-hydroxycholecalciferol OR 25OHD OR 25-OH vitamin D OR calcidiol) AND (1,25-dihydroxy vitamin D OR 1,25-dihydroxycholecalciferol OR 1,25-dihydroxy vitamin D OR calcitriol)) NOT (animal)) NOT (review)) NOT (case report)) AND (correlation)).”

The selection and extraction criteria of publications

Four independent reviewers, who were blinded to the study details, read the titles and abstracts of all reports found through electronic searches (MAS, FDA, NYS, DY). For studies that seemed to fulfill the inclusion criteria, or when the title and abstract provided insufficient data for a definitive decision, the complete report was acquired. The reliability between reviewers was assessed using Cohen’s kappa test, setting an acceptable threshold at 0.74. Discussions among the reviewers resolved disagreements about whether to include or exclude certain studies. The relationship between 1,25(OH)2D and 25(OH)D levels was analyzed using various clinical conditions and analytical techniques.

For this meta-analysis, studies were included if they reported correlation test results (such as Pearson correlation without or with log transformation, Spearman correlation, or regression analysis) conducted in serum or plasma, were published in English, had accessible full texts, and were conducted on human subjects. Studies were excluded if they lacked correlation values but provided interpretations, were animal studies, or involved other biological samples (such as cord blood, cerebrospinal fluid, etc.).

The classification of analytical methods

High-quality methods group (HQMG): Automated and traceable 25(OH)D and 1,25(OH)2D measurements, commercial liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) measurement (ImmuTube® LC-MS/MS assay), in-house LC-MS/MS measurement, and automated repeatable immunoassay (like LIASON) methods were used and given analytical performance for both tests (limit of detection, limit of quantification, repeatability, linearity, etc.).

Medium-quality methods group (MQMG): This group contains non-automated 25(OH)D and 1,25(OH)2D radioimmunoassay (RIA), enzyme immunoassay (EIA), enzyme-linked immunosorbent assay (ELISA), and limited analytical performance information.

Low-quality methods group (LQMG): The methods have no or insufficient information regarding 25(OH)D and 1,25(OH)2D measurements.

The classification of clinical conditions

The clinical conditions were evaluated in three groups: healthy, kidney diseases, and other illnesses.

The results of 1,25(OH)2D and 25(OH)D in our laboratory

In addition to the studies, the total of 25.457 results of 5424 patients who applied for various reasons between 2015 and 2023 and had measurements of 1,25(OH)2D and 25(OH)D in the Acıbadem Labmed Laboratory have also been included. Patients have been presented in three groups, like the other groups, based on their ICD codes, diagnoses, clinical information, and other laboratory test results.

Presentation of data

Data extraction was achieved by the four authors of the meta-analysis (MAS, DY, NSY, FDA). Detailed data from 63 articles, along with our laboratory results, are included in this meta-analysis. The following information was extracted from the studies: the year of the research, place where it was conducted, study design, sample size, gender, age, diseases, analytical measurement procedures, sample size, gender, correlation results between 25(OH)2D and 25(OH)D, and analytical quality considerations. Data were compiled into evidence tables, and a descriptive summary was formulated to assess the volume of data, various study characteristics, and outcomes (Table 1).

Table 1:

Detailed data from 63 articles and our laboratory results are included in this meta-analysis. These data consist of the year of the research, place where it was conducted, study design, sample size, gender, age, diseases, analytical measurement procedures, sample size, gender, correlation results between 25(OH)2D and 25(OH)D, and analytical quality performances.

No. Study Study type Country Population n Age group Female/male 25 (OH)D measurement 25 (OH)D brand/procedure 1,25 (OH)2D measurement type 1,25 (OH)2D brand/procedure Analytical performance Correlation, r p-Value Analytical quality
1 Salle, 1983 [30] Non-RCT France Premature infants supplemented with vitamin D 61 Children Radioligand assay Sigma Chemicals, MO, USA Specific receptor assay In-house/no data CVinterassay 0.79 (LR) <0.001 LQMG
CVintraassay
Analytical sensitivity
2 Shany, 1984 [31] Cross-sectional Israel Women in normal labor-serum 20 Adult 20/0 Chromatographic competitive protein binding assays In-house RIA In-house/no data No data 0.22 (LR) >0.05 LQMG
3 Mosekilde, 1989 [32] Case-control Denmark Primary hyperparathyroidism and controls 75 Adult PTH 24/10-H 28/12 RIA In house RIA In-house CVinterassay 0.39 (MR) <0.05 LQMG
CVintraassay
Analytical sensitivity
Cross reaction
4 Bettica, 1999 [33] Cross-sectional Italy Postmenopausal women 570 Adult 23/0 RIA After extraction (Nichols Institute Diagnostics, CA) RIA Nichols Institute Diagnostics, CA CVinterassay 0.49 (P) <0.03 MQMG
CVintraassay
5 Panidis, 2005 [34] Case-control Greece PCOS and healthy control 228 Adult 228/0 RIA BioSource Europe, Nivelles, Belgium RIA BioSource Europe, Nivelles, Belgium No data 0.204 (P) 0.013 MQMG
6 Malavolta, 2005 [35] Cross sectional Italy Postmenopausal women 156 Adult 156/0 RIA Nichols Institute Diagnostics, Paris, France RIA DiaSorin, Stillwater, MN, USA IVD 0.177 (P) 0.027 MQMG
No data
7 Li, 2007 [36] RCT United States Prostate cancer and control group 480 Adult 0/480 RIA No data RIA No data CVintraassay 0.17 (S) <0.001 LQMG
8 London, 2007 [37] Cross-sectional France ESRD 40 Adult CLIA LAISON, DiaSorin, MN, USA RIA DiaSorin, MN, USA No data 0.365 (P) <0.05 HQMG
9 Moosgaard, 2007 [38] Cross-sectional Denmark Primary hyperparathyroidism 252 Adult 215/37 RIA DiaSorin, MN, USA RIA Nichols Institute, California, USA IVD 0.15 (LR) <0.05 MQMG
CVinterassay
CVintraassay
Cross reaction
10 Jean, 2008 [39] Non-RCT France CKD stage 5 43 Adult 17/26 CLIA LAISON, DiaSorin, MN, USA RIA DiaSorin, MN, USA CVinterassay 0.283 (LR) 0.02 HQMG
Analytical sensitivity
11 Matias, 2008 [40] Cross-sectional Portugal ESRD 223 Adult 107/116 RIA IDS Ltd, Boldon, UK RIA IDS Ltd, Boldon, UK IVD 0.25 (S) <0.001 MQMG
CVinterassay
CVintraassay
12 Need, 2008 [41] Cross-sectional Australia Osteoporosis 319 Adult 8/311 Competitive protein binding assay In house-No data HPLC and RIA In house-no data CVinterassay 0.115 (no data) <0.05 LQMG
Analytical sensitivity
13 Shroff, 2008 [42] Cross-sectional UK CKD and health control 101 Adult Patients; 24/37, controls; 18/22 EIA IDS Ltd, Boldon, UK RIA DiaSorin, MN, USA No data 0.11 (no data) 0.4 MQMG
14 Inoue, 2008 [43] Cross-sectional Japan Postmenopausal primary hyperparathyroidism 30 Adult 30/0 Competitive protein binding assay In house Radioreceptor assay In house No data −0.401 (P) 0.0462 LQMG
15 Zittermann, 2009 [44] Prospective cohort Germany End-stage heart failure and health control 510 Adult 98/190 RIA DiaSorin. MN, USA EIA IDS Ltd, Boldon, UK CVinterassay 0.218 (P) <0.001 MQMG
213/69 CVintraassay
Analytical sensitivity
Cross reaction
16 Marcen, 2009 [45] Cross-sectional Spain Renal transplant (12. months) 509 Adult 214/295 EIA IDS, Boldon, UK RIA Biosource Europe, Nivelles, Belgium IVD 0.138 (Log, P) 0.008 MQMG
No data
17 Boudville, 2010 [46] Cross-sectional Australia CKD (stage 5) with pre-dialysis 25 Adult 5/20 RIA DiaSorin, MN, USA RIA after extraction DiaSorin, MN, USA IVD 0.54 (S) 0.005 MQMG
CVinterassay
18 Nguyen, 2010 [47] Cross-sectional France Idiopathic hypercalcemia and hypercalciuria 20 Adult 45,150 Chromatographic competitive protein binding assays In house-no data Chromatographic competitive protein binding assays and HPLC In house No data 0.434 (LR) 0.0383 LQMG
No data
19 Christensen, 2010 [48] Cross-sectional Norway Healthy subjects 3484 Adult 1551/1933 RIA IDS, Boldon, UK RIA IDS, Boldon, UK IVD 0.14 (P) <0.001 MQMG
CVinterassay
Analytical sensitivity
Cross reaction
20 Zhou, 2010 [49] Cross-sectional United States Osteoarthritis 27 Adult 13/14 RIA DiaSorin, MN, USA RIA DiaSorin, MN, USA CVinterassay 0.016 (S) 0.94 MQMG
Analytical sensitivity
21 Thrailkill, 2011 [50] Prospective cohort United States Healthy subjects 55 Adult 31/24 Competitive immunoluminometry No data, ARUP Laboratories RIA No data, ARUP Laboratories No data 0.451 (S) <0.001 MQMG
Type 1 DM without proteinuria 99 Adult 53/46 0.19 (S) 0.062 MQMG
Type 1 DM with proteinuria 16 Adult 8/8. 0.096 (S) 0.744 MQMG
22 Walker, 2011 [51] Case-control United States Healthy subjects 44 Adult 35/9 RIA In-house RIA In-house CVinterassay 0.02 (no data) 0.89 LQMG
CVintraassay
Analytical sensitivity
Cross reaction
23 Stein, 2012 [52] Cross-sectional United States Children with CKD (1–5) 100 Adult 40/60 RIA DiaSorin, MN, USA Column chromatography, RIA, and kinetic methods Laboratory Corporation of America CVinterassay 0.38 (P) <0.001 MQMG
CVintraassay
24 Moen, 2012 [53] Case-control Norway Multiple sclerosis 99 Adult 71/28 RIA DiaSorin, MN, USA RIA DiaSorin, MN, USA CVinterassay 0.342 (no data) 0.001 MQMG
Healthy subjects 159 Adult 117/42 CVintraassay 0.255 (no data) 0.001 MQMG
25 Jovanovich, 2012 [54] RCT CKD is not yet on dialysis and ESRD 1497 Adult White 17/856 CLIA LAISON, DiaSorin, MN, USA RIA DiaSorin, MN, USA CVinterassay 0.33 (S) <0.001 HQMG
Black 12/612 CVintraassay
Analytical sensitivity
26 Kox, 2012 [55] Non-RCT The Netherlands Young, healthy, non-smoking male 112 Adult 0/112 ECLIA Roche Diagnostics, Burgess Hill, UK RIA IDS Ltd, Boldon, UK No data 0.23 (S) 0.02 HQMG
27 Carpenter, 2012 [56] Cross-sectional Connecticut, US Healthy infants and toddlers 715 Adult 25(OH)D group; 401/352, 1,25(OH)2D group; 379/355 RIA DiaSorin, MN, USA RIA DiaSorin, MN, USA IVD 0.15 (P) <0.001 MQMG
CVinterassay
CVintraassay
28 Denburg, 2013 [57] Prospective cohort United States Children with CKD (stage 2–5) 171 Adult 70/101 RIA DiaSorin, MN, USA RIA DiaSorin, MN, USA CVintraassay 0.47 (S) <0.001 MQMG
29 Muindi, 2013 [58] Non-RCT United States Colorectal cancer 313 Adult 147/116 LC-MS/MS TSQ Quantum ULTRA Mass Spectrometer RIA DiaSorin, MN, USA IDMS 0.308 (S) <0.05 HQMG
IVD
Analytical sensitivity
30 Viapiana, 2013 [59] Cross-sectional Italy Postmenopausal women affected by primary hyperparathyroidism and healthy postmenopausal women 63 Adult 63/0 EIA IDS Ltd, Boldon, UK EIA IDS Ltd, Boldon, UK CVinterassay −0.46 (MR) <0.01 MQMG
CVintraassay
Analytical sensitivity
31 Camargo, 2014 [60] Cross-sectional Sao Paulo, Brazil Postmenopausal women 50 Adult 50/0 CLIA LAISON, DiaSorin.Inc, Stillwater, MN RIA IDS Ltd, Boldon, UK CVinterassay 0.584 (P) <0.01 HQMG
CVintraassay
32 Swanson, 2014 [61] Cross-sectional United States Osteoporotic fractures in men 679 Adult 0/679 LC-MS/MS In-house LC-MS/MS In-house CVinterassay 0.5 (S) <0.001 HQMG
CVintraassay
Analytical sensitivity
33 Kamphuis, 2014 [62] Retrospective cohort Netherlands Sarcoidosis patients 172 Adult 174/127 RIA IDS Ltd, Boldon, UK RIA IDS Ltd, Boldon, UK No data 0.36 (P) <0.001 MQMG
34 Pasquali, 2015 [63] Case-control Italy Renal transplant 135 Adult 79/56 RIA DiaSorin, MN, USA RIA IDS Ltd, Boldon, UK IVD 0.45 (S) <0.001 HQMG
Haemodialysis 76 Adult 43/34 CVinterassay 0.51 (S) <0.001 HQMG
CKD stage 2–5 111 Adult 72/39 CVintraassay 0.51 (S) <0.001 HQMG
Healthy subjects 290 Adult 146/141 0.25 (S) 0.003 HQMG
Primary hyperparathyroidism 20 Adult 9/11 0.51 (S) 0.042 HQMG
35 Kondo, 2016 [64] Cross-sectional Japan Diabetic nephropathy (low risk) 151 Adult 43/108 CLIA Abbott Laboratories, Chicago, USA RIA DiaSorin, Saluggia, Italy Automated 0.31 (P) >0.05 HQMG
Diabetic nephropathy (moderate risk) 102 Adult 37/65 IVD 0.06 (P) >0.05 HQMG
Diabetic nephropathy (high risk) 113 Adult 40/73 No data 0.44 (P) <0.05 HQMG
Diabetic nephropathy (Vert high risk) 78 Adult 33/45 0.1 (P) <0.05 HQMG
36 Zhang, 2016 [65] Prospective cohort United States HIV-infected man 640 Adult 0/640 Immunoaffinity LC-MS/MS In-house Immunoaffinity LC-MS/MS In-house IDMS 0.32 (no data) 0.001 HQMG
Healthy adults, HIV-uninfected men 99 Adult 0/99 CV
Analytical sensitivity 0.09 (no data) 0.623 HQMG
37 Souberbielle, 2016 [66] Cross sectional France Healthy subjects 892 Adult 429/463 CLIA LIASON XL, DiaSorin, MN, USA CLIA LIASON XL, DiaSorin, MN, USA CVinterassay 0.21 0.001 HQMG
CVintraassay
Analytical sensitivity
38 Ter Horst, 2016 [67] Prospective cohort The Netherlands Morbidly obese women 37 Adult 37/0 Isotope dilution LC-MS/MS In-house Isotope dilution LC-MS/MS In-house No data 0.2 (P) 0.25 HQMG
39 Doyon, 2016 [68] Cross-sectional 12 European countries Children with CKD (stage 3–5) 500 Children 179/321 LC-MS/MS In-house LC-MS/MS In-house CVinterassay 0.56 (LR) <0.001 HQMG
CVintraassay
Analytical sensitivity
40 Valcour, 2016 [69] Cross-sectional United States Newborn infants 78 Children No data No data CLIA LAISON XL, DiaSorin, MN, USA CVinterassay 0.15 (P) 0.18 MQMG
CVintraassay
Analytical sensitivity
Cross reaction
41 Ghazi, 2016 [70] RCT Iran Children 210 Children 105/105 EIA IDS Ltd, Boldon, UK ELISA Cusabio Biotech Co. CVinterassay −0.111 (S) 0.126 MQMG
CVintraassay
Analytical sensitivity
42 Bima, 2017 [71] Cross-sectional Australia Healthy subjects 322 Adult 145/177 Solid-phase extraction and LC-MS/MS Qu Lab, University, Buffalo, New York Solid-phase extraction LC-MS/MS Qu Lab, University, Buffalo, New York IDMS 0.53 (Log, P) <0.0001 HQMG
Accuracy
CVinterassay
CVintraassay
Analytical sensitivity
43 Marques Vidigal, 2017 [72] Case-control Brazil Healthy subjects 321 Adult %50.8 male HPLC No data HPLC No data No data 0.35 (P) <0.001 MQMG
Colorectal cancer 152 Adult %53.3 male 0.09 (P) >0.05 MQMG
44 Yadav, 2017 [73] Cross-sectional India Nephrotic syndrome and healthy controls 141 Adult 42/59 EIA IDS Ltd, Boldon, UK EIA IDS Ltd, Boldon, UK Accuracy 0.321 (S) 0.001 HQMG
15/25 CVinterassay
CVintraassay
Analytical sensitivity
45 Pauwels, 2017 [74] Case-control Belgium CKD and healthy 121 Adult Healthy (7/13) RIA DiaSorin, MN, USA LC-MS/MS In-house IDMS 0.24 (P) 0.09 HQMG
Patients (51/50) Accuracy
CVinterassay
Analytical sensitivity
46 Chung, 2017 [75] Cross-sectional Korea Isolated haematuria, proteinuria, or renal dysfunction of unexplained cause. 199 Adult 0/94 No data No data No data No data No data 0.179 (LR) 0.02 LQMG
47 Best, 2018 [76] Prospective cohort United States Pregnant women 58 Adult 58/0 LC-MS/MS In-house LC-MS/MS In-house CVinterassay 0.14 (P) >0.05 HQMG
CVintraassay
48 Havens, 2018 [77] Cross-sectional United States Youth without HIV, Group 2 209 Adult 33/176 No data No data No data No data No data 0.319 (S) <0.0001 LQMG
Youth without HIV (before of prophylaxis), Group 1 99 Adult 0/99 0.189 (S) >0.05 LQMG
Youth without HIV (12 weeks of prophylaxis), Group 2 77 Adult 0/77 0.041 (S) >0.05 LQMG
49 Ouma, 2018 [78] Case-control Japan Alzheimer’s disease 108 Adult 69/39 RIA DiaSorin, MN, USA RIA IDS Ltd, Boldon, UK No data 0.301 (P) 0.372 MQMG
Mild cognitive impairment 61 Adult 31/30 0.254 (P) 0.05 MQMG
Healthy subjects 61 Adult 28/31 0.162 (P) 0.221 MQMG
50 Baumann, 2018 [79] Cross-sectional Switzerland Early breast cancer 310 Adult 310/0 HPLC Chromsystems, Gräflingen, Germany RIA IDS Ltd, Boldon, UK No data 0.21 (S) <0.001 HQMG
51 Zittermann, 2018 [80] RCT Germany Heart failure 165 Adult Vitamin D group 64 (male) CLIA DiaSorin, MN, USA CLIA LAISON, DiaSorin. MN, USA No data 0.205 (S) <0.01 HQMG
Placebo group 71 (male)
52 Evenepoel, 2019 [81] Prospective cohort Belgium Renal transplant 518 Adult 202/316 RIA No data RIA No data No data 0.49 (S) <0.0001 LQMG
53 Albahlol, 2020 [82] Cross-sectional Saudi Arabia Pregnant women (preeclampsia, GDM, undisturbed ectopic pregnancy abortion, premature rupture of membranes) and control 322 Adult 322/0 ELISA Sunlong Biotech Co. Ltd., Zhejiang, China ELISA Sunlong Biotech Co. Ltd., Zhejiang, China No data 0.157 (S) <0.05 LQMG
54 Martin, 2020 [83] Cross-sectional United States Early onset Preeclampsia-EOP -S 7 Adult 7/0 EIA IDS Ltd, Scottsdale, AZ EIA IDS Ltd, Scottsdale, AZ IVD 0.542 (LR) 0.03 HQMG
Early onset controls- EOC -S 5 Adult 5/0 0.324 (LR) 0.221 HQMG
CVinterassay
CVintraassay
Analytical sensitivity
Cross reaction
55 Harmon, 2020 [84] Prospective cohort Western New York Healthy subjects 86 Adult 86/0 ELISA BioVendor R&D, Asheville, NC EIA IDS Ltd, Scottsdale, AZ CVinterassay 0.41 (P) <0.001 MQMG
Late onset Controls-LOC-S 9 Adult 9/0 CVintraassay 0.133 (P) 0.61 MQMG
Late onset Controls- LOC -S 10 Adult 10/0 −0.11 (P) 0.673 MQMG
56 Ismail, 2021 [85] Case-control Saudi Arabia Acute coronary syndrome and controls 123 Adult ACS 57/16 UPLC-MS In house UPLC-MS In house No data 0.88 (P) <0.001 HQMG
Control 38/12
57 Meza-Meza, 2021 [86] Cross-sectional United States SLE with renal disease 88 Adult 0/88 ELISA Cusabio, China ELISA Eagle Biosciences, USA Analytical sensitivity −0.26 (S) 0.001 LQMG
58 Tsuprykov, 2021 [87] Prospective cohort Germany Pregnant healthy women 427 Adult 427/0 CMIA Architect i2000 (Abbott Laboratories, Wiesbaden, Germany) CLIA IDS GmbH, Frankfurt am main, Germany Cross reaction 0.572 (S) <0.001 HQMG
59 Ogura, 2021 [88] Case-control Japan Parkinson’s disease 27 Adult 10/9 RIA DiaSorin, MN, USA RIA IDS Ltd, Boldon, UK No data 0.423 (S) 0.028 MQMG
Multiple system atrophy 19 Adult 10/9 0.356 (S) 0.039 MQMG
Healthy subjects 61 Adult 28/33 −0.234 (S) 0.069 MQMG
60 Saghir Afifeh, 2021 [89] Prospective cohort Italy Acute coronary syndrome 228 Adult %76.6 (male) CLIA LAISON XL, DiaSorin, MN, USA CLIA LAISON, DiaSorin, MN, USA No data 0.175 (LR) 0.035 HQMG
%69.2 (male)
61 Lotfollahi, 2021 [90] Cross-sectional Iran ESRD 156 Adult 52/104 HPLC Chrom Abzar Parse Co, Iran EIA ZellBio GmbH, Germany Analytical sensitivity 0.12 (P) >0.05 LQMG
62 Meng, 2021 [91] Case-control United States Primary hyperparathyroidism and healthy 60 Adult 60/0 RIA No data No data No data No data 0.11 (LR) >0.05 LQMG
63 Bacanakgil, 2022 [92] Prospective cohort Istanbul, Turkey Infertile women (before with vitamin D replacement) 62 Adult 62/0 ECLIA Roche Cobas 6000, Germany ELISA No data No data 0.164 (P) 0.202 MQMG
Infertile women (after with vitamin D replacement) 62 Adult 62/0 0.508 (P) <0.001 MQMG
64 Our results, 2023 Cross-sectional Istanbul, Turkey Healthy subjects 485 Adult 308/177 CLIA Advia Centaur (Siemens Healthineers, USA) EIA IDS Ltd, Boldon, UK 0.5 (P) <0.001 HQMG
Other diseases 4544 Adult 250/142 0.26 (P) <0.001 HQMG
Renal diseases 395 Adult 3128/1416 0.26 (P) <0.001 HQMG

  1. UPLC-MS, ultra-performance liquid chromatography-mass spectrometry; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-mass spectrometry/mass spectrometry; RIA, radioimmunoassay; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; CLIA, chemiluminescence immunoassay; RCT, randomized controlled trial; MR, multiple regression; LR, linear regression; P, Pearson correlation; S, Spearman correlation; Log, logarithmic transformation; HQMG, high-quality methods group; MQMG, medium-quality methods group; LQMG, low-quality methods group; IVD, invitro diagnostic device; CVinterassay, interassay coefficient of variation; CVintraassay, intraassay coefficient of variation; IDMS, isotope dilution tandem mass spectrometry.

For measurements of 25(OH)D and 1,25(OH)2D in this study, information about the manufacturers, methods, sample types, analytical performances, and interferences belonging to the most commonly preferred brands are provided in Supplemental Table 1 (for 25(OH)D) and Supplemental Table 2 (for 1,25(OH)2D).

Statistical analysis

Meta-analysis was achieved on the correlation between 25(OH)D and 1,25(OH)2D. These analyses were done using Stata MP17 4.6.241 (Stata Corp LLC, Texas, USA). Random effects meta-analyses were performed using the DerSimonian–Laird method. The χ2 and I2 statistics were used to assess the statistical heterogeneity among the included studies. Forest plots were drawn to describe the weighted correlation with 95 % confidence intervals (CI). In addition, the Funnel plot and Egger and Beggs tests were applied to explore the sources of bias.

Results

The flowchart of the study, according to the PRISMA statement, is presented in Figure 2. Initially, the search strategy retrieved 1388 references. After screening the titles and abstracts, 1325 articles were excluded due to unrelated topics. The entire texts of the remaining 264 articles were assessed, and 63 studies were included in the meta-analysis. In this meta-analysis, correlation analysis results of a total of 25.147 people, consisting of 63 studies and our laboratory data, were evaluated. The meta-analysis outcomes are represented according to clinical conditions in Figures 3–5.

Figure 2: The flowchart of the study is based on the PRISMA* statement. *PRISMA (preferred reporting items for systematic reviews and meta-analyses). From: Page et al. [29].
Figure 2:

The flowchart of the study is based on the PRISMA* statement. *PRISMA (preferred reporting items for systematic reviews and meta-analyses). From: Page et al. [29].

Figure 3: Forest plot depicting the correlation between 25(OH)D and 1,25(OH)2D in the healthy group.
Figure 3:

Forest plot depicting the correlation between 25(OH)D and 1,25(OH)2D in the healthy group.

Figure 4: Forest graph of the correlation between 25(OH)D and 1,25(OH)2D in the renal diseases group.
Figure 4:

Forest graph of the correlation between 25(OH)D and 1,25(OH)2D in the renal diseases group.

Figure 5: Forest graph of the correlation between 25(OH)D and 1,25(OH)2D in other disease groups.
Figure 5:

Forest graph of the correlation between 25(OH)D and 1,25(OH)2D in other disease groups.

Accordingly, in the healthy group, a total of 24 studies were evaluated. Among these, ten were classified as HQMG, eleven as MQMG, and three as LQMG. The correlation values were calculated as 0.35 (95 % CI, 0.23–0.48) with 91.2 % of heterogeneity (I2) for HQMG, 0.21 (95 % CI, 0.10–0.31) with 91.3 % for MQMG, and as 0.22 (95 % CI, 0.03–0.42) with 38.0 % for LQMG. The correlation value was determined in the total healthy group as 0.26 (95 % CI, 0.18–0.34) with 92.4 % of I2. It was observed that the correlation value was the highest in HQMG, followed by MQMG, and lastly, LQMG. Significant heterogeneity was detected in all groups except for the LQMG group and in the overall evaluation of the study.

In the case of renal diseases, a total of 19 studies were assessed. Among these, nine were categorized as HQMG, seven as MQMG, and three as LQMG. The correlation values were calculated as 0.34 (95 % CI, 0.26–0.42) with 78.6 % of I2 for HQMG, 0.28 (95 % CI, 0.17–0.38) with 75.0 % for MQMG, and 0.27 (95 % CI, 0.25–0.37) with 92.6 % for LQMG. In the overall analysis, encompassing both healthy and renal disease groups, the correlation value was determined to be 0.31 (95 % CI; 0.25–0.37) with 82.7 % of I2. It was observed that the correlation value was the highest in HQMG, followed by MQMG, and lastly, LQMG. Notably, significant heterogeneity was detected in all groups except for the LQMG group and in the comprehensive study assessment.

In the context of other diseases, 36 studies were examined. Among these, 12 were classified as HQMG, 13 as MQMG, and 11 as LQMG. The correlation values were calculated as 0.36 (95 % CI; 0.22–0.48) with 94.8 % of I2 for HQMG, as 0.19 (95 % CI; 0.09–0.30) with 71.6 % for MQMG, and as 0.16 (95 % CI; 0.01–0.32) with 89.6 % for LQMG. The correlation value was determined to be 0.25 (95 % CI; 0.17–0.32) with 90.7 % of I2 in the comprehensive analysis covering healthy and disease groups. It was observed that the correlation value was the highest in HQMG, followed by MQMG, and lastly, LQMG. Importantly, significant heterogeneity was detected in all groups.

As a result, the correlation values obtained from measurements conducted with HQMG are higher than those of MQMG and LQMG.

The results of the assessment for publication bias in the conducted study are presented in Figure 6. According to both the Funnel plots and the results of Egger and Begg’s tests, it was determined that there was no statistically significant bias.

Figure 6: Funnel plots, Egger’s and Begg’s test results of all groups.
Figure 6:

Funnel plots, Egger’s and Begg’s test results of all groups.

Discussion

The relationship between 25(OH)D and 1,25(OH)2D is quite complex. In addition to the different reasons mentioned above, it is especially related to the measurement of 1,25(OH)2D. The characteristics of 25(OH)D and 1,25(OH)2D methods are presented in Supplemental Tables 1 and 2.

Since 2010, the U.S. National Institutes of Health, Office of Dietary Supplements (NIH-ODS), through the Vitamin D Standardization Program (VDSP), has been working to standardize the measurement of serum total 25(OH)D, which is the primary indicator of vitamin D levels. Studies have shown that the results of assays used to determine serum total 25(OH)D, comprising both 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3], may vary depending on the specific assay method employed [93–95].

The VDSP is a cooperative venture involving the National Institutes of Health, National Institute of Standards and Technology (NIST), Office of Dietary Supplements (NIH-ODS) [96], Centers for Disease Control and Prevention (CDC), as well as the national survey laboratories in multiple countries, and vitamin D investigators worldwide [97].

The VDSP has enforced a reference measurement system that includes reference measurement procedures conducted at NIST and CDC, along with NIST Standard Reference Materials [98–102]. Additionally, it comprises the CDC Vitamin D Standardization Certification Program and partnerships with the College of American Pathologists and Vitamin D external quality assessment scheme [103–105]. The VDSP has set strict criteria for assay performance, ensuring that measurement variability and bias meet the standards of a coefficient of variation (CV) of ≤10 % and a mean bias of ≤ 5 % [106, 107].

Despite highly successful standardization efforts in 25(OH)D measurements, the issues still need to be solved. In the VDSP’s Intra-laboratory Study for the Assessment study, 12 assays were compared, and 9 out of the 12 assays demonstrated a mean bias within ≤ 5 %. Samples with high levels of 25(OH)D2 were essential in evaluating the effectiveness of the immunoassays, highlighting possible differences in response or recovery between 25(OH)D2 and 25(OH)D3 in various assays [108].

Serious problems were also encountered in the LC-MS/MS method, which was presented as a better method. Only 53 % of the LC-MS/MS assays met the VDSP criterion of mean %bias ≤5 %. Four assays showed a mean %bias between 12 % and 21 % among those that did not. A regression study using the concentrations of four vitamin D metabolites in 50 single donor samples found that implementing several LC-MS/MS assays was affected by the presence of 3-epi-25(OH)D3 [109]. Significant correlation discrepancies and high bias values have also been reported for 25(OH)D measurements by immunoassay, chromatography, and mass spectrometry [110–112].

It has been observed that the analytical measurement difficulties are much greater in 1,25(OH)2D measurements compared to 25(OH)D. 1,25(OH)2D is a compound found in very low concentrations (pmol/L) in circulation and is highly lipophilic. Furthermore, the structurally similar metabolic precursor 25(OH)D circulates at nmol/L concentrations, making assay specificity an analytical concern. Significant advancements have been made in measuring 1,25(OH)2D. In 1974, a radioreceptor assay (RRA) was developed, utilizing the competitive binding of 1,25(OH)2D and a tritiated tracer to its nuclear receptor isolated from the calf thymus [113]. The first RIA that measured 1,25(OH)2 D was introduced in 1978 [114]. RIA for 1,25(OH)2 D using a radio iodinated (125 I) tracer was invented [115]. The assay involves acetonitrile extraction and purification of endogenous 1,25(OH)2 D by solid phase chromatography and quantification by RIA.

Kissmeyer and Sonne developed an LC-MS/MS method that quantified the ammonium adduct of 1,25‐(OH)2D3 in rat and pig serum [116]. Later, methods utilizing 4dd-phenyl-1,2,4-triazoline-3,5-dione (PTAD) as a derivatizing reagent were developed, further lowering the limit of quality (LOQ) values. In recent years, methods incorporating a single step of immunoaffinity extraction were developed, and assay kits were commercialized [117–124]. It has been specially done using Immunoaffinity extraction with ImmunoTube® 1,25(OH)2 Vitamin D LC-MS/MS Kit (Immunodiagnostic GmbH, Germany) or Immunodiagnostic Systems (IDS, UK) antibody. These commercially available kits can be applied to different brands of LC-MS/MS systems.

In this study, our laboratory results are particularly crucial. According to the correlation results obtained with automated systems in a quite extensive patient group, 1,25(OH)2D and 25(OH)D measurements were found to be significantly higher in healthy individuals compared to the groups with renal and other diseases, with correlation coefficients of 0.50 (0.42–0.58), 0.26 (0.16–0.36), and 0.26 (0.23–0.29) respectively. A moderately significant correlation was observed in the healthy group. We believe that these results, obtained through the use of the same systems across all groups and with a sufficient amount of data, represent the best data currently available that demonstrates the current relationship.

Exacerbating the issue of low concentration is the poor ionization of the analyte, coupled with the potential complications arising from the derivatization required for sufficient analytical sensitivity. Additionally, poor sample preparation techniques can have a significant adverse impact on clinical performance in LC-MS/MS-based methods [125]. It is worth noting that LC-MS/MS is a complex and specialized technique that requires advanced equipment and trained personnel, making it relatively expensive compared to some other testing methods. Despite these considerations, LC-MS/MS is recognized as the gold standard for accurate and reliable measurement of 1,25(OH)2D3 in biological samples.

The development of fully automated chemiluminescence immunoassays has indeed contributed to significant progress in accurately and efficiently measuring 1.25(OH)2D. Two notable products in this category are produced by IDS-iSYS, 1,25-dihydroxy vitamin D (Immunodiagnostic Systems, UK) and LIAISON® XL 1,25 dihydroxyvitamin D (DiaSorin Inc, USA). These assays represent a notable step forward in the accuracy and efficiency of measuring 1,25(OH)2D levels.

Under standardized conditions, a recently introduced automated immunoassay demonstrates strong agreement with measurements obtained using a liquid chromatography-tandem mass spectrometry reference method (LC-MS/MS) [126]. Nonetheless, recent findings from DEQAS reveal that coefficients of variation within specific tests and mean 1,25(OH)2D levels between different test procedures can exhibit fluctuations of over 20 % [127].

According to a study conducted by Zittermann and colleagues, the measurement of circulating 1,25(OH)2D was carried out using two different methods: an LC-MS/MS method provided by Immundiagnostik and an automated immunoassay test provided by DiaSorin. The study found a correlation (r=0.534) and an agreement (62 %) between the two methods and highlighted the need for additional standardization studies [128]. A recent meta-analysis has also revealed that the measurement procedure can significantly impact circulating 1,25(OH)2D levels. These differences in measurement make it challenging to compare results between labs and establish consistent reference values for circulating 1,25(OH)2D levels. Consequently, automation and standardization are crucial for improving the reliability of testing procedures [129]. It is worth noting that 80.8 % of the 1,25(OH)2D assays included in the meta-analysis were RIA and radioreceptor assays.

Upon closer examination, it is observed that there is a statistically insignificant or low correlation between 25(OH)D and 1,25(OH)2D in general. However, as can be seen in our results, the highest correlation in all three disease groups is found in HQMG. The highest correlations in the HQMG group are observed in all groups. The results in the renal diseases group are exciting. This may be due to this patient group taking Vitamin D supplements. However, the lower correlation in other diseases suggests that the relationship is highly complex and disrupted by different mechanisms in various diseases.

Even though the HQMG shows the highest correlation values in the healthy group, this is still a weak correlation. However, vastly different and heterogeneous results are present. The most significant factors here are methodological challenges, the short half-life of 1,25(OH)2D, and its complex regulations. While there is a direct enzymatic transformation of 25(OH)D into 1,25(OH)2D, a relationship between their serum levels may be noted. 1,25(OH)2D can directly suppress the production of 1α-hydroxylase and indirectly by reducing PTH levels and promoting FGF23 production. This feedback mechanism is crucial for preventing hypercalcemia. As a result, the level of 1,25(OH)2D is not influenced by the circulating amount of 25(OH)D [130, 131]. We anticipate that with improved methodologies, the correlation value could increase in the future.

This study has notable limitations. In the search that was carried out, the term ‘correlation’ was explicitly looked for in the title, keywords, and abstract. There might be studies that do not mention the term “correlation” but discuss it within the text. While some studies may have used successful measurement procedures, they may not have been explicitly stated or may have been inadequately presented. Another significant limitation is that we did not consider age and gender differences in our analysis. We refrained from making distinctions based on age and gender as we believed it might reduce the number of studies in each group. In the studies included in this meta-analysis, different correlation analyses (Pearson correlation without or with log transformation, Spearman correlation, or regression analysis) were used. We included all of these correlation analyses in our study.

When all the results are evaluated, this study is the first meta-analysis conducted considering differences in methodological and health situations between 25(OH)D and 1,25(OH)2D. Both in the examination of Vitamin D metabolism and the relationship between 25(OH)D and 1,25(OH)2D, differences in methodological and health situations are crucial and must be considered.

Corresponding Author: Fatma Demet Arslan, Department of Medical Biochemistry, Faculty of Medicine, Bakırçay University, Gazi Mustafa Kemal Mah., Kaynaklar Cd., Seyrek, 35665, Menemen, Izmir, Türkiye, E-mail:

  1. Research ethics: This study was approved by the Bakırçay University Local Ethics Board with 1303 of decide number on 08.11.2023.

  2. Informed consent: Not applicable.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: None declared.

  6. Data availability: Not applicable.

References

1. Sahota, O. Understanding vitamin D deficiency. Age Ageing 2014;43:589–91. https://doi.org/10.1093/ageing/afu104.Suche in Google Scholar PubMed PubMed Central

2. Whistler, D. De morbo puerli anglorum, quem patrio ideiomate indigenae vocant “the rickets”. Hist Med 1645;5:397–415.Suche in Google Scholar

3. Mellanby, E An experimental investigation on rickets. 1919. Nutrition 1989;5:81–7.Suche in Google Scholar

4. McCollum, EV, Pitz, W, Simmonds, N, Becker, JE, Shipley, PG, Bunting, RW. The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin that promotes calcium deposition. 1922. The effect of additions of fluorine to the diet of the rat on the quality of the teeth. 1925. J Biol Chem 2002;277:E8.Suche in Google Scholar

5. Steenbock, H, Black, A. Fat-soluble vitamins: XVII. The induction of growth-promoting and calcifying properties in a ration by exposure to ultraviolet light. J Biol Chem;61:405–22. https://doi.org/10.1016/s0021-9258(18)85139-0.Suche in Google Scholar

6. Hess AF ULF. Cure of infantile rickets by sunlight. J Am Med Assoc 1921;77:39.10.1001/jama.1921.02630270037013Suche in Google Scholar

7. Holick, MF, MacLaughlin, JA, Doppelt, SH. Regulation of cutaneous pre-vitamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 1981;211:590–3. https://doi.org/10.1126/science.6256855.Suche in Google Scholar PubMed

8. Bell, NH, Greene, A, Epstein, S, Oexmann, MJ, Shaw, S, Shary, J. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 1985;76:470–3. https://doi.org/10.1172/jci111995.Suche in Google Scholar PubMed PubMed Central

9. Bikle, D, Bouillon, R, Thadhani, R, Schoenmakers, I. Vitamin D metabolites in captivity? Should we measure free or total 25(OH)D to assess vitamin D status? J Steroid Biochem Mol Biol 2017;173:105–16. https://doi.org/10.1016/j.jsbmb.2017.01.007.Suche in Google Scholar PubMed PubMed Central

10. Jones, G, Prosser, DE, Kaufmann, M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 2014;55:13–31. https://doi.org/10.1194/jlr.r031534.Suche in Google Scholar

11. Meyer, MB, Benkusky, NA, Kaufmann, M, Lee, SM, Onal, M, Jones, G, et al.. A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation. J Biol Chem 2017;292:17541–58. https://doi.org/10.1074/jbc.m117.806901.Suche in Google Scholar

12. Tsuji, K, Maeda, T, Kawane, T, Matsunuma, A, Horiuchi, N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J Bone Miner Res 2010;25:1711–23. https://doi.org/10.1002/jbmr.65.Suche in Google Scholar PubMed

13. Bouillon, R, Decallonne, B. The white adipose tissue connection with calcium and bone homeostasis. J Bone Miner Res 2010;25:1707–10. https://doi.org/10.1002/jbmr.175.Suche in Google Scholar PubMed

14. Bajwa, A, Forster, MN, Maiti, A, Woolbright, BL, Beckman, MJ. Specific regulation of CYP27B1 and VDR in proximal versus distal renal cells. Arch Biochem Biophys 2008;477:33–42. https://doi.org/10.1016/j.abb.2008.06.006.Suche in Google Scholar PubMed

15. Hollis, BW, Wagner, CL. New insights into the vitamin D requirements during pregnancy. Bone Res 2017;5:17030. https://doi.org/10.1038/boneres.2017.30.Suche in Google Scholar PubMed PubMed Central

16. Caprio, M, Infante, M, Calanchini, M, Mammi, C, Fabbri, A. Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord 2017;22:27–41. https://doi.org/10.1007/s40519-016-0312-6.Suche in Google Scholar PubMed

17. Adams, JS, Hewison, M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys 2012;523:95–102. https://doi.org/10.1016/j.abb.2012.02.016.Suche in Google Scholar PubMed PubMed Central

18. Kim, HJ, Ji, M, Song, J, Moon, HW, Hur, M, Yun, YM. Clinical utility of measurement of vitamin D-binding protein and calculation of bioavailable vitamin D in the assessment of vitamin D status. Ann Lab Med 2017;37:34–8. https://doi.org/10.3343/alm.2017.37.1.34.Suche in Google Scholar PubMed PubMed Central

19. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academies Press; 1997.Suche in Google Scholar

20. Chapuy, MC, Preziosi, P, Maamer, M, Arnaud, S, Galan, P, Hercberg, S, et al.. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997;7:439–43. https://doi.org/10.1007/s001980050030.Suche in Google Scholar PubMed

21. Thomas, MK, Lloyd-Jones, DM, Thadhani, RI, Shaw, AC, Deraska, DJ, Kitch, BT, et al.. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777–83. https://doi.org/10.1056/nejm199803193381201.Suche in Google Scholar

22. Dawson-Hughes, B, Harris, S, Dallal, G. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr 1997;65:67–71. https://doi.org/10.1093/ajcn/65.1.67.Suche in Google Scholar PubMed

23. Holick, MF, Siris, ES, Binkley, N, Beard, MK, Khan, A, Katzer, JT, et al.. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215–24. https://doi.org/10.1210/jc.2004-2364.Suche in Google Scholar PubMed

24. Institute of Medicine (US). Committee to review dietary reference intakes for vitamin D and calcium. In: Ross, AC, Taylor, CL, Valle, HBD, editors. Dietary reference intakes for calcium and vitamin D. Washington (DC): National Academies Press (US); 2011.Suche in Google Scholar

25. Bischoff-Ferrari, HA, Giovannucci, E, Willett, WC, Dietrich, T, Dawson-Hughes, B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18–28. https://doi.org/10.1093/ajcn/84.1.18.Suche in Google Scholar PubMed

26. Aloia, JF. Clinical Review: the 2011 report on dietary reference intake for vitamin D: where do we go from here? J Clin Endocrinol Metab 2011;96:2987–96. https://doi.org/10.1210/jc.2011-0090.Suche in Google Scholar PubMed

27. Tang, JCY, Nicholls, H, Piec, I, Washbourne, CJ, Dutton, JJ, Jackson, S, et al.. Reference intervals for serum 24,25-dihydroxyvitamin D and the ratio with 25-hydroxyvitamin D established using a newly developed LC-MS/MS method. J Nutr Biochem 2017;46:21–9. https://doi.org/10.1016/j.jnutbio.2017.04.005.Suche in Google Scholar PubMed

28. Moreira, CA, Ferreira, CEDS, Madeira, M, Silva, BCC, Maeda, SS, Batista, MC, et al.. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab 2020;64:462–78. https://doi.org/10.20945/2359-3997000000258.Suche in Google Scholar PubMed PubMed Central

29. Page, MJ, McKenzie, JE, Bossuyt, PM, Boutron, I, Hoffmann, TC, Mulrow, CD, et al.. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71.Suche in Google Scholar PubMed PubMed Central

30. Salle, BL, Glorieux, FH, Delvin, EE, David, LS, Meunier, G, Salle, A, et al.. Vitamin D metabolism in preterm infants: serial serum calcitriol values during the first four days of life. Acta Pcediatr Scand 1983;72:203–6. https://doi.org/10.1111/j.1651-2227.1983.tb09697.x.Suche in Google Scholar PubMed

31. Shany, S, Biale, Y, Zuili, I, Yankowitz, N, Berry, JL, Mawer, EB. Feto-maternal relationships between vitamin D metabolites in Israeli Bedouins and Jews. Am J Clin Nutr 1984;40:1290–4. https://doi.org/10.1093/ajcn/40.6.1290.Suche in Google Scholar PubMed

32. Mosekilde, L, Charles, P, Lindegreen, P. Determinants for serum 1,25-dihydroxycholecalciferol in primary hyperparathyroidism. Bone Miner 1989;5:279–90. https://doi.org/10.1016/0169-6009(89)90006-8.Suche in Google Scholar PubMed

33. Bettica, P, Bevilacqua, M, Vago, T, Norbiato, G. High prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in northern Italy for initial screening. Osteoporos Int 1999;9:226–9. https://doi.org/10.1007/s001980050141.Suche in Google Scholar PubMed

34. Panidis, D, Balaris, C, Farmakiotis, D, Rousso, D, Kourtis, A, Balaris, V, et al.. Serum parathyroid hormone concentrations are increased in women with polycystic ovary syndrome. Clin Chem 2005;51:1691–7. https://doi.org/10.1373/clinchem.2005.052761.Suche in Google Scholar PubMed

35. Malavolta, N, Pratelli, L, Frigato, M, Mulè, R, Mascia, ML, Gnudi, S. The relationship of vitamin D status to bone mineral density in an Italian population of postmenopausal women. Osteoporos Int 2005;16:1691–7. https://doi.org/10.1007/s00198-005-1883-7.Suche in Google Scholar PubMed

36. Li, H, Stampfer, MJ, Bruce, J, Hollis, W, Mucci, LA, Gaziano, JM, et al.. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer. PLoS Med 2007;4:e103. https://doi.org/10.1371/journal.pmed.0040103.Suche in Google Scholar PubMed PubMed Central

37. London, GM, Guérin, AP, Verbeke, FH, Pannier, B, Boutouyrie, P, Marchais, SJ, et al.. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol 2007;18:613–20. https://doi.org/10.1681/asn.2006060573.Suche in Google Scholar

38. Moosgaard, B, Vestergaard, P, Heickendorff, L, Mosekilde, L. Plasma 1,25-dihydroxy vitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate, and renal function. Clin Endocrinol 2007;66:35–42. https://doi.org/10.1111/j.1365-2265.2006.02680.x.Suche in Google Scholar PubMed

39. Jean, G, Terrat, JC, Vanel, T, Hurot, JM, Lorriaux, C, Mayor, B, et al.. Evidence for persistent vitamin D 1-alpha-hydroxylation in hemodialysis patients: evolution of serum 1,25-dihydroxycholecalciferol after 6 months of 25-hydroxycholecalciferol treatment. Nephron Clin Pract 2008;110:c58–5. https://doi.org/10.1159/000151534.Suche in Google Scholar PubMed

40. Matias, PJ, Ferreira, C, Jorge, C, Borges, M, Aires, I, Amaral, T, et al.. 25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients. Nephrol Dial Transplant 2009;24:611–8. https://doi.org/10.1093/ndt/gfn502.Suche in Google Scholar PubMed

41. Need, AG, O’Loughlin, PD, Morris, HA, Coates, PS, Horowitz, M, Nordin, BEC. Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res 2008;23:1859–63. https://doi.org/10.1359/jbmr.080607.Suche in Google Scholar PubMed

42. Shroff, R, Egerton, M, Bridel, M, Shah, V, Donald, AE, Cole, TJ, et al.. A bimodal association of vitamin D levels and vascular disease in children on dialysis. J Am Soc Nephrol 2008;19:1239–46. https://doi.org/10.1681/asn.2007090993.Suche in Google Scholar

43. Inoue, Y, Kaji, H, Hisa, I, Tobimatsu, T, Naito, J, Iu, MF, et al.. Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism. Endocr J 2008;55:57–65. https://doi.org/10.1507/endocrj.k07-102.Suche in Google Scholar PubMed

44. Zittermann, A, Schleithoff, SS, Frisch, S, Götting, C, Kuhn, J, Koertke, H, et al.. Circulating calcitriol concentrations and total mortality. Clin Chem 2009;55:1163–70. https://doi.org/10.1373/clinchem.2008.120006.Suche in Google Scholar PubMed

45. Marcén, R, Ponte, B, Rodríguez-Mendiola, N, Fernández-Rodriguez, A, Galeano, C, Villafruela, JJ, et al.. Vitamin D deficiency in kidney transplant recipients: risk factors and effects of vitamin D3 supplements. Transplant Proc 2009;41:2388–90. https://doi.org/10.1016/j.transproceed.2009.06.050.Suche in Google Scholar PubMed

46. Boudville, N, Inderjeeth, C, Elder, GJ, Glendenning, P. Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure. Clin Endocrinol 2010;73:299–304. https://doi.org/10.1111/j.1365-2265.2010.03821.x.Suche in Google Scholar PubMed

47. Nguyen, M, Boutignon, H, Mallet, E, Linglart, A, Guillozo, H, Jehan, F, et al.. Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment. J Pediatr 2010;157:296–302. https://doi.org/10.1016/j.jpeds.2010.02.025.Suche in Google Scholar PubMed

48. Christensen, MHE, Lien, EA, Hustad, S, Almås, B. Seasonal and age-related differences in serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone in patients from Western Norway. Scand J Clin Lab Invest 2010;70:281–6. https://doi.org/10.3109/00365511003797172.Suche in Google Scholar PubMed

49. Zhou, S, LeBoff, MS, Glowacki, J. Vitamin D metabolism and action in human bone marrow stromal cells. Endocrinology 2010;151:14–22. https://doi.org/10.1210/en.2009-0969.Suche in Google Scholar PubMed PubMed Central

50. Thrailkill, KM, Jo, CH, Cockrell, GE, Moreau, CS, Fowlkes, JL. Enhanced excretion of vitamin D binding protein in type 1 diabetes: a role in vitamin D deficiency? J Clin Endocrinol Metab 2011;96:142–9. https://doi.org/10.1210/jc.2010-0980.Suche in Google Scholar PubMed PubMed Central

51. Walker, VP, Zhang, X, Rastegar, I, Liu, PT, Hollis, BW, Adams, JS, et al.. Cord blood vitamin D status impacts innate immune responses. J Clin Endocrinol Metab 2011;96:1835–43. https://doi.org/10.1210/jc.2010-1559.Suche in Google Scholar PubMed PubMed Central

52. Stein, DR, Feldman, HA, Gordon, CM. Vitamin D status in children with chronic kidney disease. Pediatr Nephrol 2012;27:1341–50. https://doi.org/10.1007/s00467-012-2143-7.Suche in Google Scholar PubMed PubMed Central

53. Moen, SM, Celius, EG, Sandvik, L, Brustad, M, Nordsletten, L, Eriksen, EF, et al.. Bone turnover and metabolism in patients with early multiple sclerosis and prevalent bone mass deficit: a population-based case-control study. PLoS One 2012;7:e45703. https://doi.org/10.1371/journal.pone.0045703.Suche in Google Scholar PubMed PubMed Central

54. Jovanovich, A, Chonchol, M, Cheung, AK, Kaufman, JS, Greene, T, Roberts, WL, et al.. Racial differences in markers of mineral metabolism in advanced chronic kidney disease. Clin J Am Soc Nephrol 2012;7:640–7. https://doi.org/10.2215/cjn.07020711.Suche in Google Scholar PubMed PubMed Central

55. Kox, M, van den Berg, MJW, van der Hoeven, JG, Wielders, JPM, van der Ven, AJ, Pickkers, P. Vitamin D status is not associated with inflammatory cytokine levels during experimental human endotoxaemia. Clin Exp Immunol 2013;171:231–6. https://doi.org/10.1111/cei.12006.Suche in Google Scholar PubMed PubMed Central

56. Carpenter, TO, Herreros, F, Zhang, JH, Ellis, BK, Simpson, C, Torrealba-Fox, E, et al.. Demographic, dietary, and biochemical determinants of vitamin D status in inner-city children. Am J Clin Nutr 2012;95:137–46. https://doi.org/10.3945/ajcn.111.018721.Suche in Google Scholar PubMed PubMed Central

57. Denburg, MR, Tsampalieros, AK, de Boer, IH, Shults, J, Kalkwarf, HJ, Zemel, BS, et al.. Mineral metabolism and cortical volumetric bone mineral density in childhood chronic kidney disease. J Clin Endocrinol Metab 2013;98:1930–8. https://doi.org/10.1210/jc.2012-4188.Suche in Google Scholar PubMed PubMed Central

58. Muindi, JR, Adjei, AA, Wu, ZR, Olson, I, Huang, H, Groman, A, et al.. Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes. Horm Cancer 2013;4:242–50. https://doi.org/10.1007/s12672-013-0139-9.Suche in Google Scholar PubMed PubMed Central

59. Viapiana, O, Fracassi, E, Troplini, S, Idolazzi, L, Rossini, M, Adami, S, et al.. Sclerostin and DKK1 in primary hyperparathyroidism. Calcif Tissue Int 2013;92:324–9. https://doi.org/10.1007/s00223-012-9665-7.Suche in Google Scholar PubMed

60. Camargo, MBR, Vilaça, T, Hayashi, LF, Rocha, OGF, Lazaretti-Castro, M. 25-Hydroxyvitamin D level does not reflect intestinal calcium absorption: an assay using strontium as a surrogate marker. J Bone Miner Metabol 2015;33:319–28. https://doi.org/10.1007/s00774-014-0592-8.Suche in Google Scholar PubMed

61. Swanson, CM, Nielson, CM, Shrestha, S, Lee, CG, Barrett-Connor, E, Jans, I, et al.. Higher 25(OH)D2 is associated with lower 25(OH)D3 and 1,25(OH)2D3. J Clin Endocrinol Metab 2014;99:2736–44. https://doi.org/10.1210/jc.2014-1069.Suche in Google Scholar PubMed PubMed Central

62. Kamphuis, LS, Bonte-Mineur, F, Van Laar, JA, Van Hagen, PM, Van Daele, PL. Calcium and vitamin D in sarcoidosis: is supplementation safe? J Bone Miner Res 2014;29:2498–503. https://doi.org/10.1002/jbmr.2262.Suche in Google Scholar PubMed

63. Pasquali, M, Tartaglione, L, Rotondi, S, Muci, ML, Mandanici, G, Farcomeni, A, et al.. Calcitriol/calcifediol ratio: an indicator of vitamin D hydroxylation efficiency? BBA Clin 2015;3:251–6. https://doi.org/10.1016/j.bbacli.2015.03.004.Suche in Google Scholar PubMed PubMed Central

64. Kondo, M, Toyoda, M, Miyatake, H, Tanaka, E, Koizumi, M, Komaba, H, et al.. The prevalence of 25-hydroxyvitamin D deficiency in Japanese patients with diabetic nephropathy. Intern Med 2016;55:2555–62. https://doi.org/10.2169/internalmedicine.55.6346.Suche in Google Scholar PubMed

65. Zhang, L, Tin, A, Brown, TT, Margolick, JB, Witt, MD, Palella, FJ, et al.. Vitamin D deficiency and metabolism in HIV-infected and HIV-uninfected men in the multicenter AIDS cohort study. AIDS Res Hum Retrovir 2017;33:261–70. https://doi.org/10.1089/aid.2016.0144.Suche in Google Scholar PubMed PubMed Central

66. Souberbielle, JC, Massart, C, Brailly-Tabard, S, Cavalier, E, Chanson, P. Prevalence and determinants of vitamin D deficiency in healthy French adults: the VARIETE study. Endocrine 2016;53:543–50. https://doi.org/10.1007/s12020-016-0960-3.Suche in Google Scholar PubMed

67. Ter Horst, KW, Versteeg, RI, Gilijamse, PW, Ackermans, MT, Heijboer, AC, Romijn, JA, et al.. The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women. Diabetes Metab 2016;42:416–23. https://doi.org/10.1016/j.diabet.2016.04.011.Suche in Google Scholar PubMed

68. Doyon, A, Schmiedchen, B, Sander, A, Bayazit, A, Duzova, A, Canpolat, N, et al.. Genetic, environmental, and disease-associated correlates of vitamin D status in children with CKD. Clin J Am Soc Nephrol 2016;11:1145–53. https://doi.org/10.2215/cjn.10210915.Suche in Google Scholar

69. Valcour, A, Zierold, C, Podgorski, AL, Olson, GT, Wall, JV, DeLuca, HF, et al.. A novel, fully-automated, chemiluminescent assay for the detection of 1,25-dihydroxyvitamin D in biological samples. J Steroid Biochem Mol Biol 2016;164:120–6. https://doi.org/10.1016/j.jsbmb.2015.08.005.Suche in Google Scholar PubMed

70. Ghazi, AA, Hosseinpanah, F, Abdi, H, Hedayati, M, Hasheminia, M, Ghazi, S, et al.. Effect of different doses of oral cholecalciferol on serum 1,25(OH)2D in vitamin D deficient schoolchildren. Horm Metab Res 2016;48:394–8. https://doi.org/10.1055/s-0042-101029.Suche in Google Scholar PubMed

71. Bima, A, Pezic, A, Sun, C, Cameron, FJ, Rodda, C, Van Der Mei, I, et al.. Environmental and genetic determinants of two vitamin D metabolites in healthy Australian children. J Pediatr Endocrinol Metab 2017;30:531–41. https://doi.org/10.1515/jpem-2016-0088.Suche in Google Scholar PubMed

72. Marques Vidigal, V, Aguiar Junior, PN, Donizetti Silva, T, de Oliveira, J, Marques Pimenta, CA, Vitor Felipe, A, et al.. Genetic polymorphisms of vitamin D metabolism genes and serum level of vitamin D in colorectal cancer. Int J Biol Markers 2017;32:e441–6. https://doi.org/10.5301/ijbm.5000282.Suche in Google Scholar PubMed

73. Yadav, AK, Ramachandran, R, Aggarwal, A, Kumar, V, Gupta, KL, Jha, V. Fibroblast growth factor 23 in untreated nephrotic syndrome. Nephrology 2018;23:362–5. https://doi.org/10.1111/nep.13001.Suche in Google Scholar PubMed

74. Pauwels, S, Jans, I, Billen, J, Heijboer, A, Verstuyf, A, Carmeliet, G, et al.. 1β,25-Dihydroxyvitamin D3: a new vitamin D metabolite in human serum. J Steroid Biochem Mol Biol 2017;173:341–8. https://doi.org/10.1016/j.jsbmb.2017.02.004.Suche in Google Scholar PubMed

75. Chung, S, Kim, M, Koh, ES, Hwang, HS, Chang, YK, Park, CW, et al.. Serum 1,25-dihydroxy vitamin D better reflects renal parameters than 25-hydroxyvitamin D in patients with glomerular diseases. Int J Med Sci 2017;14:1080–7. https://doi.org/10.7150/ijms.20452.Suche in Google Scholar PubMed PubMed Central

76. Best, CM, Pressman, EK, Queenan, RA, Cooper, E, O’Brien, KO. Longitudinal changes in serum vitamin D binding protein and free 25-hydroxyvitamin D in a multiracial cohort of pregnant adolescents. J Steroid Biochem Mol Biol 2019;186:79–88. https://doi.org/10.1016/j.jsbmb.2018.09.019.Suche in Google Scholar PubMed PubMed Central

77. Havens, PL, Long, D, Schuster, GU, Gordon, CM, Price, G, Wilson, CM, et al.. Tenofovir disoproxil fumarate appears to disrupt the relationship of Vitamin D and parathyroid hormone. Antivir Ther 2018;23:623–8. https://doi.org/10.3851/imp3269.Suche in Google Scholar

78. Ouma, S, Suenaga, M, Bölükbaşı Hatip, FF, Hatip-Al-Khatib, I, Tsuboi, Y, Matsunaga, Y. Serum vitamin D in patients with mild cognitive impairment and Alzheimer’s disease. Brain Behav 2018;8:e00936. https://doi.org/10.1002/brb3.936.Suche in Google Scholar PubMed PubMed Central

79. Michael, B, Dani, SU, Daniel, D, Andreas, H, Dirk, K, Mark, MT, et al.. Vitamin D levels in Swiss breast cancer survivors. Swiss Med Wkly 2018;148:w14576. https://doi.org/10.4414/smw.2018.14576.Suche in Google Scholar PubMed

80. Zittermann, A, Ernst, JB, Prokop, S, Fuchs, U, Dreier, J, Kuhn, J, et al.. Effects of vitamin D supplementation on renin and aldosterone concentrations in patients with advanced heart failure: the EVITA trial. Internet J Endocrinol 2018;2018:5015417. https://doi.org/10.1155/2018/5015417.Suche in Google Scholar PubMed PubMed Central

81. Evenepoel, P, Claes, K, Meijers, B, Laurent, MR, Bammens, B, Naesens, M, et al.. Bone mineral density, bone turnover markers, and incident fractures in de novo kidney transplant recipients. Kidney Int 2019;95:1461–70. https://doi.org/10.1016/j.kint.2018.12.024.Suche in Google Scholar PubMed

82. Albahlol, IA, Almaeen, AH, Alduraywish, AA, Dar, UF, El-Metwally, TH. Vitamin D status and pregnancy complications: serum 1, 25-di-hydroxyl-vitamin D, and its ratio to 25-hydroxy-vitamin D are superior biomarkers than 25-hydroxy-vitamin D. Int J Med Sci 2020;17:3039–48. https://doi.org/10.7150/ijms.47807.Suche in Google Scholar PubMed PubMed Central

83. Martin, CB, Oshiro, BT, Sands, LAD, Kabir, S, Thorpe, D, Clark, TC, et al.. Vitamin-D dysregulation in early- and late-onset preeclampsia: a gestational-age matched study. J Steroid Biochem Mol Biol 2020;203:105729. https://doi.org/10.1016/j.jsbmb.2020.105729.Suche in Google Scholar PubMed

84. Harmon, QE, Kissell, K, Jukic, AMZ, Kim, K, Sjaarda, L, Perkins, NJ, et al.. Vitamin D and reproductive hormones across the menstrual cycle. Hum Reprod 2020;35:413–23. https://doi.org/10.1093/humrep/dez283.Suche in Google Scholar PubMed PubMed Central

85. Ismail, HM, Algrafi, AS, Amoudi, O, Ahmed, S, Al-Thagfan, SS, Shora, H, et al.. Vitamin D and its metabolites deficiency in acute coronary syndrome patients undergoing coronary angiography: a case-control study. Vasc Health Risk Manag 2021;17:471–80. https://doi.org/10.2147/vhrm.s312376.Suche in Google Scholar

86. Meza-Meza, MR, Muñoz-Valle, JF, Ruiz-Ballesteros, AI, Vizmanos-Lamotte, B, Parra-Rojas, I, Martínez-López, E, et al.. Association of high calcitriol serum levels and its hydroxylation efficiency ratio with disease risk in SLE patients with vitamin D deficiency. J Immunol Res 2021;2021:2808613. https://doi.org/10.1155/2021/2808613.Suche in Google Scholar PubMed PubMed Central

87. Tsuprykov, O, Elitok, S, Buse, C, Chu, C, Krämer, BK, Hocher, B. Opposite correlation of 25-hydroxy-vitamin D- and 1,25-dihydroxy-vitamin D-metabolites with gestational age, bone- and lipid-biomarkers in pregnant women. Sci Rep 2021;11:1923. https://doi.org/10.1038/s41598-021-81452-9.Suche in Google Scholar PubMed PubMed Central

88. Ogura, H, Hatip-Al-Khatib, I, Suenaga, M, Hatip, FB, Mishima, T, Fujioka, S, et al.. Circulatory 25(OH)D and 1,25(OH)2D as differential biomarkers between multiple system atrophy and Parkinson’s disease patients. eNeurologicalSci 2021;25:100369. https://doi.org/10.1016/j.ensci.2021.100369.Suche in Google Scholar PubMed PubMed Central

89. Saghir Afifeh, AM, Verdoia, M, Nardin, M, Negro, F, Viglione, F, Rolla, R, et al.. Determinants of vitamin D activation in patients with acute coronary syndromes and its correlation with inflammatory markers. Nutr Metabol Cardiovasc Dis 2021;31:36–43. https://doi.org/10.1016/j.numecd.2020.09.021.Suche in Google Scholar PubMed PubMed Central

90. Lotfollahi, L, Ossareh, S, Neyestani, TR. Evaluation of 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D levels in maintenance hemodialysis patients. Iran J Kidney Dis 2021;1:31–7.Suche in Google Scholar

91. Meng, L, Su, C, Shapses, SA, Wang, X. Total and free vitamin D metabolites in patients with primary hyperparathyroidism. J Endocrinol Invest 2022;45:301–7. https://doi.org/10.1007/s40618-021-01633-1.Suche in Google Scholar PubMed

92. Bacanakgil, BH, İlhan, G, Ohanoǧlu, K. Effects of vitamin D supplementation on ovarian reserve markers in infertile women with diminished ovarian reserve. Medicine (Baltim) 2022;101:e28796. https://doi.org/10.1097/md.0000000000028796.Suche in Google Scholar PubMed PubMed Central

93. Sempos, CT, Binkley, N. 25-Hydroxyvitamin D assay standardisation and vitamin D guidelines paralysis. Publ Health Nutr 2020;23:1153–64. https://doi.org/10.1017/s1368980019005251.Suche in Google Scholar PubMed PubMed Central

94. Binkley, N, Dawson-Hughes, B, Durazo-Arvizu, R, Thamm, M, Tian, L, Merkel, JM, et al.. Vitamin D measurement standardization: the way out of the chaos. J Steroid Biochem Mol Biol 2017;173:117–21. https://doi.org/10.1016/j.jsbmb.2016.12.002.Suche in Google Scholar PubMed

95. Wise, SA, Phinney, KW, Tai, SSC, Camara, JE, Myers, GL, Durazo-Arvizu, R, et al.. Baseline assessment of 25-hydroxyvitamin D assay performance: a Vitamin D Standardization Program (VDSP) interlaboratory comparison study. J AOAC Int 2017;100:1244–52. https://doi.org/10.5740/jaoacint.17-0258.Suche in Google Scholar PubMed

96. Wise, SA, Tai, SSC, Burdette, CQ, Camara, JE, Bedner, M, Lippa, KA, et al.. Role of the National Institute of Standards and Technology (NIST) in support of the vitamin D initiative of the National Institutes of Health, Office of Dietary Supplements. J AOAC Int 2017;100:1260–76. https://doi.org/10.5740/jaoacint.17-0305.Suche in Google Scholar PubMed

97. Sempos, CT, Vesper, HW, Phinney, KW, Thienpont, LM, Coates, PM, Vitamin D Standardization Program (VDSP). Vitamin D status as an international issue: national surveys and the problem of standardization. Scand J Clin Lab Invest Suppl 2012;243:32–40. https://doi.org/10.3109/00365513.2012.681935.Suche in Google Scholar PubMed

98. Mineva, EM, Schleicher, RL, Chaudhary-Webb, M, Maw, KL, Botelho, JC, Vesper, HW, et al.. A candidate reference measurement procedure for quantifying serum concentrations of 25-hydroxyvitamin D₃ and 25-hydroxyvitamin D₂ using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2015;407:5615–24. https://doi.org/10.1007/s00216-015-8733-z.Suche in Google Scholar PubMed PubMed Central

99. Phinney, KW, Bedner, M, Tai, SSC, Vamathevan, VV, Sander, LC, Sharpless, KE, et al.. Development and certification of a standard reference material for vitamin D metabolites in human serum. Anal Chem 2012;84:956–62. https://doi.org/10.1021/ac202047n.Suche in Google Scholar PubMed PubMed Central

100. Tai, SSC, Bedner, M, Phinney, KW. Development of a candidate reference measurement procedure for the determination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum using isotope-dilution liquid chromatography-tandem mass spectrometry. Anal Chem 2010;82:1942–8. https://doi.org/10.1021/ac9026862.Suche in Google Scholar PubMed PubMed Central

101. Stepman, HCM, Vanderroost, A, Van Uytfanghe, K, Thienpont, LM. Candidate reference measurement procedures for serum 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 by using isotope-dilution liquid chromatography-tandem mass spectrometry. Clin Chem 2011;57:441–8. https://doi.org/10.1373/clinchem.2010.152553.Suche in Google Scholar PubMed

102. Phinney, KW, Tai, SSC, Bedner, M, Camara, JE, Chia, RRC, Sander, LC, et al.. Development of an improved standard reference material for Vitamin D metabolites in human serum. Anal Chem 2017;89:4907–13. https://doi.org/10.1021/acs.analchem.6b05168.Suche in Google Scholar PubMed PubMed Central

103. Burdette, CQ, Camara, JE, Nalin, F, Pritchett, J, Sander, LC, Carter, GD, et al.. Establishing an accuracy basis for the Vitamin D External Quality Assessment Scheme (DEQAS). J AOAC Int 2017;100:1277–87. https://doi.org/10.5740/jaoacint.17-0306.Suche in Google Scholar PubMed

104. Erdman, P, Palmer-Toy, DE, Horowitz, G, Hoofnagle, A. Accuracy-based vitamin D survey: six years of quality improvement guided by proficiency testing. Arch Pathol Lab Med 2019;143:1531–8. https://doi.org/10.5858/arpa.2018-0625-cp.Suche in Google Scholar

105. Centers for Disease Control and Prevention (CDC). Vitamin D standardization – certification Program. Available at: https://www.cdc.gov/labstandards/vdscp.html.Suche in Google Scholar

106. Stöckl, D, Sluss, PM, Thienpont, LM. Specifications for trueness and precision of a reference measurement system for serum/plasma 25-hydroxyvitamin D analysis. Clin Chim Acta 2009;408:8–13. https://doi.org/10.1016/j.cca.2009.06.027.Suche in Google Scholar PubMed

107. Binkley, N, Sempos, CT. Vitamin D Standardization Program (VDSP). Standardizing vitamin D assays: the way forward. J Bone Miner Res 2014;29:1709–14. https://doi.org/10.1002/jbmr.2252.Suche in Google Scholar PubMed PubMed Central

108. Wise, SA, Camara, JE, Sempos, CT, Lukas, P, Le Goff, C, Peeters, S, et al.. Vitamin D Standardization Program (VDSP) intralaboratory study for the assessment of 25-hydroxyvitamin D assay variability and bias. J Steroid Biochem Mol Biol 2021;212:105917. https://doi.org/10.1016/j.jsbmb.2021.105917.Suche in Google Scholar PubMed PubMed Central

109. Wise, SA, Camara, JE, Burdette, CQ, Hahm, G, Nalin, F, Kuszak, AJ, et al.. Interlaboratory comparison of 25-hydroxyvitamin D assays: vitamin D Standardization Program (VDSP) Intercomparison Study 2 – part 1 liquid chromatography – tandem mass spectrometry (LC-MS/MS) assays – impact of 3-epi-25-hydroxyvitamin D3 on assay performance. Anal Bioanal Chem 2022;414:333–49. https://doi.org/10.1007/s00216-021-03576-1.Suche in Google Scholar PubMed

110. Berry, DJ, Dutton, J, Fraser, WD, Järvelin, MR, Hyppönen, E. Harmonization study between LC-MS/MS and Diasorin RIA for measurement of 25-hydroxyvitamin D concentrations in a large population survey. J Clin Lab Anal 2017;31:e22049. https://doi.org/10.1002/jcla.22049.Suche in Google Scholar PubMed PubMed Central

111. Jafri, L, Khan, AH, Siddiqui, AA, Mushtaq, S, Iqbal, R, Ghani, F, et al.. Comparison of high-performance liquid chromatography, radioimmunoassay, and electrochemiluminescence immunoassay for quantification of serum 25-hydroxy vitamin D. Clin Biochem 2011;44:864–8. https://doi.org/10.1016/j.clinbiochem.2011.04.020.Suche in Google Scholar PubMed

112. Hollis, BW. Comparison of commercially available (125)I-based RIA methods for the determination of circulating 25-hydroxyvitamin D. Clin Chem 2000;46:1657–61. https://doi.org/10.1093/clinchem/46.10.1657.Suche in Google Scholar

113. Brumbaugh, PF, Haussler, DH, Bressler, R, Haussler, MR. Radioreceptor assay for 1 alpha,25-dihydroxyvitamin D3. Science 1974;183:1089–91. https://doi.org/10.1126/science.183.4129.1089.Suche in Google Scholar PubMed

114. Clemens, TL, Hendy, GN, Graham, RF, Baggiolini, EG, Uskokovic, MR, O’Riordan, JL. A radioimmunoassay for 1,25-dihydroxycholecalciferol. Clin Sci Mol Med 1978;54:329–32. https://doi.org/10.1042/cs0540329.Suche in Google Scholar PubMed

115. Hollis, BW, Kamerud, JQ, Kurkowski, A, Beaulieu, J, Napoli, JL. Quantification of circulating 1,25-dihydroxyvitamin D by radioimmunoassay with 125I-labeled tracer. Clin Chem 1996;42:586–92. https://doi.org/10.1093/clinchem/42.4.586.Suche in Google Scholar

116. Kissmeyer, AM, Sonne, K. Sensitive analysis of 1alpha,25-dihydroxyvitamin D3 in biological fluids by liquid chromatography-tandem mass spectrometry. J Chromatogr A 2001;935:93–103. https://doi.org/10.1016/s0021-9673(01)00985-2.Suche in Google Scholar PubMed

117. Yuan, C, Kosewick, J, He, X, Kozak, M, Wang, S. Sensitive measurement of serum 1α,25-dihydroxyvitamin D by liquid chromatography/tandem mass spectrometry after removing interference with immunoaffinity extraction. Rapid Commun Mass Spectrom 2011;25:1241–9. https://doi.org/10.1002/rcm.4988.Suche in Google Scholar PubMed

118. Hedman, CJ, Wiebe, DA, Dey, S, Plath, J, Kemnitz, JW, Ziegler, TE. Development of a sensitive LC/MS/MS method for vitamin D metabolites: 1,25 dihydroxyvitamin D2&3 measurement using a novel derivatization agent. J Chromatogr B 2014;953:62–7. https://doi.org/10.1016/j.jchromb.2014.01.045.Suche in Google Scholar PubMed PubMed Central

119. Duan, X, Weinstock-Guttman, B, Wang, H, Bang, E, Li, J, Ramanathan, M, et al.. Ultrasensitive quantification of serum vitamin D metabolites using selective solid-phase extraction coupled to microflow liquid chromatography and isotope-dilution mass spectrometry. Anal Chem 2010;82:2488–97. https://doi.org/10.1021/ac902869y.Suche in Google Scholar PubMed

120. Hollis, BW. Assay of circulating 1,25-dihydroxyvitamin D involving a novel single-cartridge extraction and purification procedure. Clin Chem 1986;32:2060–3. https://doi.org/10.1093/clinchem/32.11.2060.Suche in Google Scholar

121. Aronov, PA, Hall, LM, Dettmer, K, Stephensen, CB, Hammock, BD. Metabolic profiling of major vitamin D metabolites using Diels-Alder derivatization and ultra-performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem 2008;391:1917–30. https://doi.org/10.1007/s00216-008-2095-8.Suche in Google Scholar PubMed PubMed Central

122. Weiskopf, AS, Vouros, P, Cunniff, J, Binderup, E, Björkling, F, Binderup, L, et al.. Examination of structurally selective derivatization of vitamin D(3) analogues by electrospray mass spectrometry. J Mass Spectrom 2001;36:71–8. https://doi.org/10.1002/jms.105.Suche in Google Scholar PubMed

123. Kissmeyer, AM, Sonne, K. Sensitive analysis of 1alpha,25-dihydroxyvitamin D3 in biological fluids by liquid chromatography-tandem mass spectrometry. J Chromatogr A 2001;935:93–103. https://doi.org/10.1016/s0021-9673(01)00985-2.Suche in Google Scholar PubMed

124. Vreeken, RJ, Honing, M, van Baar, BL, Ghijsen, RT, de Jong, GJ, Brinkman, UA. Online post-column Diels-Alder derivatization for the determination of vitamin D3 and its metabolites by liquid chromatography/thermospray mass spectrometry. Biol Mass Spectrom 1993;22:621–32. https://doi.org/10.1002/bms.1200221102.Suche in Google Scholar PubMed

125. Annesley, TM. Ion suppression in mass spectrometry. Clin Chem 2003;49:1041–4. https://doi.org/10.1373/49.7.1041.Suche in Google Scholar PubMed

126. Van Helden, J, Weiskirchen, R. Experience with the first fully automated chemiluminescence immunoassay for the quantification of 1α, 25-dihydroxy-vitamin D. Clin Chem Lab Med 2015;53:761–70. https://doi.org/10.1515/cclm-2014-0698.Suche in Google Scholar PubMed

127. DEQAS (Vitamin D External Quality Assessment Scheme). Available at: http://deqas.org.Suche in Google Scholar

128. Zittermann, A, Ernst, JB, Becker, T, Dreier, J, Knabbe, C, Gummert, JF, et al.. Measurement of circulating 1,25-dihydroxyvitamin D: comparison of an automated method with a liquid chromatography-tandem mass spectrometry method. Int J Anal Chem 2016;2016:8501435. https://doi.org/10.1155/2016/8501435.Suche in Google Scholar PubMed PubMed Central

129. Zittermann, A, Ernst, JB, Birschmann, I, Dittrich, M. Effect of vitamin D or activated vitamin D on circulating 1,25-dihydroxyvitamin D concentrations: a systematic review and meta-analysis of randomized controlled trials. Clin Chem 2015;61:1484–94. https://doi.org/10.1373/clinchem.2015.244913.Suche in Google Scholar PubMed

130. Armbrecht, HJ, Boltz, MA, Hodam, TL. PTH increases renal 25(OH)D3-1alpha-hydroxylase (CYP1alpha) mRNA but not renal 1,25(OH)2D3 production in adult rats. Am J Physiol Ren Physiol 2003;284:F1032–6. https://doi.org/10.1152/ajprenal.00306.2002.Suche in Google Scholar PubMed

131. Collins, MT, Lindsay, JR, Jain, A, Kelly, MH, Cutler, CM, Weinstein, LS, et al.. Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D. J Bone Miner Res 2005;20:1944–50. https://doi.org/10.1359/jbmr.050718.Suche in Google Scholar

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/tjb-2023-0258).

Received: 2023-12-10
Accepted: 2024-03-20
Published Online: 2024-05-13

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. A brief history of hematology analyzers and recent advancements: the available testing wealth
  4. Research Articles
  5. Correlation between serum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D in response to analytical procedures; a systematic review and meta-analysis
  6. Investigation of CDH1 germline mutations in Turkish patients with Kaposi’s sarcoma
  7. Frequency and pattern of test utilization rate in clinical biochemistry laboratory: two different large hospital examples
  8. High serum angiopoietin-like protein-4 levels are associated with gestational hypertension and preeclampsia: a case-control study
  9. Comparison of efficacy and reliability of six commercial COVID-19 diagnostic PCR kits
  10. Does COVID-19 infection alter serum biochemical and hematological biomarkers in deceased dementia patients?
  11. Activity of protein C, protein S and antithrombin 3 in COVID-19 patients treated with different modalities of oxygen supplementation
  12. Effectiveness after immunization with BNT162b2 and Gam-COVID-Vac for SARS-CoV-2 and neutralizing antibody titers in health care workers
  13. Relationship between methylation pattern of the SYN2 gene and schizophrenia
  14. Revealing distinct DNA methylation patterns in hepatic carcinoma through high-throughput sequencing
  15. 4-h mean lactate clearance as a good predictor of adverse outcome in acute cardiogenic pulmonary edema: a pilot study
  16. Elucidating the role of ZRF1 in monocyte-to-macrophage differentiation, cell proliferation and cell cycle in THP-1 cells
  17. Inflammatory factors secreted from endothelial cells induced by high glucose impair human retinal pigment epithelial cells
  18. Influence of TLR4 signaling on cannabidiol’s antitumor effectiveness in lung adenocarcinoma cells
  19. Renoprotective effect of diacerein in rats with partial unilateral ureteral obstruction model
  20. Cytotoxic and apoptotic effectiveness of Cypriot honeybee (Apis mellifera cypria) venom on various cancer cells
  21. Resveratrol modulates signalling to inhibit vascular smooth muscle cell proliferation induced by angiotensin II and high glucose
  22. Development and production of antibodies against gamma inactivated pathogenic bacterial spores
https://doi.org/10.1515/tjb-2023-0258
Schlagwörter für diesen Artikel
1,25-dihydroxyvitamin D; 25-hydroxyvitamin D; analytical chemistry methods; correlation study; healthy subjects; renal disease
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. A brief history of hematology analyzers and recent advancements: the available testing wealth
  4. Research Articles
  5. Correlation between serum 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D in response to analytical procedures; a systematic review and meta-analysis
  6. Investigation of CDH1 germline mutations in Turkish patients with Kaposi’s sarcoma
  7. Frequency and pattern of test utilization rate in clinical biochemistry laboratory: two different large hospital examples
  8. High serum angiopoietin-like protein-4 levels are associated with gestational hypertension and preeclampsia: a case-control study
  9. Comparison of efficacy and reliability of six commercial COVID-19 diagnostic PCR kits
  10. Does COVID-19 infection alter serum biochemical and hematological biomarkers in deceased dementia patients?
  11. Activity of protein C, protein S and antithrombin 3 in COVID-19 patients treated with different modalities of oxygen supplementation
  12. Effectiveness after immunization with BNT162b2 and Gam-COVID-Vac for SARS-CoV-2 and neutralizing antibody titers in health care workers
  13. Relationship between methylation pattern of the SYN2 gene and schizophrenia
  14. Revealing distinct DNA methylation patterns in hepatic carcinoma through high-throughput sequencing
  15. 4-h mean lactate clearance as a good predictor of adverse outcome in acute cardiogenic pulmonary edema: a pilot study
  16. Elucidating the role of ZRF1 in monocyte-to-macrophage differentiation, cell proliferation and cell cycle in THP-1 cells
  17. Inflammatory factors secreted from endothelial cells induced by high glucose impair human retinal pigment epithelial cells
  18. Influence of TLR4 signaling on cannabidiol’s antitumor effectiveness in lung adenocarcinoma cells
  19. Renoprotective effect of diacerein in rats with partial unilateral ureteral obstruction model
  20. Cytotoxic and apoptotic effectiveness of Cypriot honeybee (Apis mellifera cypria) venom on various cancer cells
  21. Resveratrol modulates signalling to inhibit vascular smooth muscle cell proliferation induced by angiotensin II and high glucose
  22. Development and production of antibodies against gamma inactivated pathogenic bacterial spores
Jetzt anmelden und 20% sparen
Institutioneller Zugang
Wie funktioniert Authentifizierung?
Haben Sie eine Idee, wie wir unsere Website verbessern können?
Bitte schreiben Sie uns.
© 2025 De Gruyter Brill
Heruntergeladen am 8.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/tjb-2023-0258/html?srsltid=AfmBOoqgAYjVvjl5BjYIsIwE5DmAMU_xdSOS9xGtAIHr9pGJjpNPGRWj
Button zum nach oben scrollen