Vitamin D3 1,25-Dihydroxyvitamin D
Updated: Nov 19, 2019
Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Sridevi Devaraj, PhD, DABCC, FAACC, FRSC, CCRP
more...
Reference Range
The biologically active form of vitamin D is 1,25-dihydroxyvitamin D (1,25(OH)2 D). Measurement
of serum levels of 1,25(OH)2 D should be considered upon suspicion of deficiency or excess of this
form of the vitamin.
Reference ranges for 1,25(OH)2 D may be reported as either pg/mL or pmol/L. The molecular weight
of 1,25(OH)2 D is approximately 416.7, yielding the following conversion factors: 1 pmol/L = 0.42
pg/mL; conversely, 1 pg/mL = 2.4 pmol/L.
Reference ranges for 1,25(OH) D are as follows [1]
2 :
Males: 18-64 pg/mL
Females: 18-78 pg/mL
Interpretation
Plasma 1,25-dihydroxyvitamin D (1,25(OH)2 D) is tightly controlled by plasma parathyroid hormone
(PTH), serum calcium, serum phosphate, and fibroblast-like growth factor 23 (FGF-23).
Decreased 1,25-dihydroxyvitamin D levels
Decreased levels of 1,25(OH)2 D can result from chronic kidney disease, various heritable disorders,
tumor-induced osteomalacia, the use of HIV protease inhibitors, or severe vitamin D deficiency.
Chronic kidney disease: Low 1,25(OH)2 D levels have been shown to present even in early stages of
kidney failure. The decrease of 1,25(OH)2 D level is more prominent when kidney failure progresses. In
a study by Levin et al (2007), 13% of patients with an estimated glomerular filtration rate (eGFR)
greater than 80 mL/min and more than 60% of patients with an eGFR of less than 30 mL/min had low
serum levels of 1,25(OH) D. [2]
2 Impaired production of the enzyme 1α-hydroxylase in kidney failure
was thought to be the main mechanism. However, phosphate retention and FGF-23 also contribute to
the decreased synthesis of 1,25(OH) 2 D.[3]
, Heritable disorders associated with low 1,25(OH)2 D levels include vitamin D–dependent rickets type 1
(inactivating mutation in the 1-hydroxylase gene), [4] autosomal-dominant hypophosphatemic rickets
(mutation of the gene coding for FGF-23, which prevents its breakdown), [5] and X-linked
hypophosphatemic rickets (mutations that elevate levels of FGF-23). [6]
In tumor-induced osteomalacia, tumor-secreted FGF-23 inhibits enzyme 1α-hydroxylase and
subsequently results in decreased 1,25(OH) D synthesis. [7]
2
HIV protease inhibitors have been reported to markedly suppress the activities of 25- and 1α-
hydroxylase and thus affect 1,25(OH) 2D synth esis. [8] In a cohort study including 671 patients,
progression to bone demineralization was observed in 28% of the patients over a median of 2.5 years.
Patients who were concurrently using protease inhibitors were at greater risk for worsening bone
demineralization than those who were not using protease inhibitors (OR 1.64; 95% CI, 1.35-2.04; P<
0.0001). [9]
Severe vitamin D deficiency: 25(OH)D is the main substrate of 1,25(OH)2 D. Vitamin D deficiency can
affect the production of 1,25(OH)2 D owing to the lack of substrate. A positive correlation between
serum levels of 25(OH)D and 1,25(OH)2 D was observed during seasonal changes. Treatment with
25(OH)D can normalize 1,25(OH)2 D concentrations in patients with vitamin D deficiency. [10]
Increased 1,25-dihydroxyvitamin D levels
Increased 1,25(OH)2 D levels can result from extrarenal 1α-hydroxylation or hereditary vitamin D–
resistant rickets.
In granulomatous disease such as lymphoproliferative disorders, sarcoidosis, tuberculosis, and
inflammatory bowel disease, 1α-hydroxylase enzyme activity was found in macrophages as the
extrarenal source of 1,25(OH)2 D. When 1α-hydroxylase is activated, it converts 25(OH)D to 1,25(OH)2
D, just as what occurs under physiologic conditions in the kidneys. [11] However, unlike the kidney, the
1α-hydroxylase in the macrophages in granulomatous diseases is not controlled by the usual
physiologic regulators. Moreover, not all conditions or all patients with increased macrophage activity
manifest increases in 1α-hydroxylase activity. In vitro studies of monocytes/macrophages indicate
that gamma interferon is an important regulator of 1α-hydroxylase but only when other key signaling
pathways are also activated (eg, JAK-STAT and MAP-Kinase). [12]
Hereditary vitamin D-resistant rickets is a very rare autosomal recessive disorder in which mutations
of vitamin D receptor (VDR) coding genes cause failure or abnormal binding of vitamin D to VDRs. [13,
14]
Patients usually present with hypocalcemia, early-onset rickets, alopecia, and other ectodermal
anomalies.
Collection and Panels
Specimen: Blood (0.25 mL room-temperature serum)
Container: Red-top tube, serum separator tube (also acceptable: lavender [EDTA] or pink [K2 EDTA])
Collection method: Routine venipuncture
Updated: Nov 19, 2019
Author: Ha Cam Thuy Nguyen, MD; Chief Editor: Sridevi Devaraj, PhD, DABCC, FAACC, FRSC, CCRP
more...
Reference Range
The biologically active form of vitamin D is 1,25-dihydroxyvitamin D (1,25(OH)2 D). Measurement
of serum levels of 1,25(OH)2 D should be considered upon suspicion of deficiency or excess of this
form of the vitamin.
Reference ranges for 1,25(OH)2 D may be reported as either pg/mL or pmol/L. The molecular weight
of 1,25(OH)2 D is approximately 416.7, yielding the following conversion factors: 1 pmol/L = 0.42
pg/mL; conversely, 1 pg/mL = 2.4 pmol/L.
Reference ranges for 1,25(OH) D are as follows [1]
2 :
Males: 18-64 pg/mL
Females: 18-78 pg/mL
Interpretation
Plasma 1,25-dihydroxyvitamin D (1,25(OH)2 D) is tightly controlled by plasma parathyroid hormone
(PTH), serum calcium, serum phosphate, and fibroblast-like growth factor 23 (FGF-23).
Decreased 1,25-dihydroxyvitamin D levels
Decreased levels of 1,25(OH)2 D can result from chronic kidney disease, various heritable disorders,
tumor-induced osteomalacia, the use of HIV protease inhibitors, or severe vitamin D deficiency.
Chronic kidney disease: Low 1,25(OH)2 D levels have been shown to present even in early stages of
kidney failure. The decrease of 1,25(OH)2 D level is more prominent when kidney failure progresses. In
a study by Levin et al (2007), 13% of patients with an estimated glomerular filtration rate (eGFR)
greater than 80 mL/min and more than 60% of patients with an eGFR of less than 30 mL/min had low
serum levels of 1,25(OH) D. [2]
2 Impaired production of the enzyme 1α-hydroxylase in kidney failure
was thought to be the main mechanism. However, phosphate retention and FGF-23 also contribute to
the decreased synthesis of 1,25(OH) 2 D.[3]
, Heritable disorders associated with low 1,25(OH)2 D levels include vitamin D–dependent rickets type 1
(inactivating mutation in the 1-hydroxylase gene), [4] autosomal-dominant hypophosphatemic rickets
(mutation of the gene coding for FGF-23, which prevents its breakdown), [5] and X-linked
hypophosphatemic rickets (mutations that elevate levels of FGF-23). [6]
In tumor-induced osteomalacia, tumor-secreted FGF-23 inhibits enzyme 1α-hydroxylase and
subsequently results in decreased 1,25(OH) D synthesis. [7]
2
HIV protease inhibitors have been reported to markedly suppress the activities of 25- and 1α-
hydroxylase and thus affect 1,25(OH) 2D synth esis. [8] In a cohort study including 671 patients,
progression to bone demineralization was observed in 28% of the patients over a median of 2.5 years.
Patients who were concurrently using protease inhibitors were at greater risk for worsening bone
demineralization than those who were not using protease inhibitors (OR 1.64; 95% CI, 1.35-2.04; P<
0.0001). [9]
Severe vitamin D deficiency: 25(OH)D is the main substrate of 1,25(OH)2 D. Vitamin D deficiency can
affect the production of 1,25(OH)2 D owing to the lack of substrate. A positive correlation between
serum levels of 25(OH)D and 1,25(OH)2 D was observed during seasonal changes. Treatment with
25(OH)D can normalize 1,25(OH)2 D concentrations in patients with vitamin D deficiency. [10]
Increased 1,25-dihydroxyvitamin D levels
Increased 1,25(OH)2 D levels can result from extrarenal 1α-hydroxylation or hereditary vitamin D–
resistant rickets.
In granulomatous disease such as lymphoproliferative disorders, sarcoidosis, tuberculosis, and
inflammatory bowel disease, 1α-hydroxylase enzyme activity was found in macrophages as the
extrarenal source of 1,25(OH)2 D. When 1α-hydroxylase is activated, it converts 25(OH)D to 1,25(OH)2
D, just as what occurs under physiologic conditions in the kidneys. [11] However, unlike the kidney, the
1α-hydroxylase in the macrophages in granulomatous diseases is not controlled by the usual
physiologic regulators. Moreover, not all conditions or all patients with increased macrophage activity
manifest increases in 1α-hydroxylase activity. In vitro studies of monocytes/macrophages indicate
that gamma interferon is an important regulator of 1α-hydroxylase but only when other key signaling
pathways are also activated (eg, JAK-STAT and MAP-Kinase). [12]
Hereditary vitamin D-resistant rickets is a very rare autosomal recessive disorder in which mutations
of vitamin D receptor (VDR) coding genes cause failure or abnormal binding of vitamin D to VDRs. [13,
14]
Patients usually present with hypocalcemia, early-onset rickets, alopecia, and other ectodermal
anomalies.
Collection and Panels
Specimen: Blood (0.25 mL room-temperature serum)
Container: Red-top tube, serum separator tube (also acceptable: lavender [EDTA] or pink [K2 EDTA])
Collection method: Routine venipuncture
