1,25-dihydroxyvitamin D

Calcidiol vs calcitriol

Calcitriol = 1,25-dihydroxyvitamin D - the active hormone; a secosteroid acting through the nuclear VDR
Calcidiol = 25-hydroxyvitamin D - the storage form, and the one you measure

	25-OH-D (calcidiol)	1,25-(OH)2-D (calcitriol)
Half-life	2-3 weeks	4-6 hours
Concentration	nmol/L	pmol/L (~1000x lower)
Reflects	Total body vitamin D stores	PTH and FGF-23 activity
Measure it to	Assess vitamin D status	Investigate hypercalcaemia, rickets subtypes, CKD

*Never order 1,25-D to assess vitamin D deficiency - it is normal or even high* in deficiency, because secondary hyperparathyroidism drives 1-alpha-hydroxylase
- This is the commonest vitamin D ordering error
~20-25% of Australian adults have 25-OH-D <50 nmol/L; higher in winter, southern latitudes, dark skin, veiling, institutionalised and housebound people
~80-90% of vitamin D comes from cutaneous synthesis, not diet

The activation pathway

Skin: 7-dehydrocholesterol + UVB (290-315 nm) -> pre-vitamin D3 -> cholecalciferol (D3)
- UVB does not penetrate glass; sunscreen, melanin, latitude, season and age all reduce synthesis
Diet: D3 (animal), D2 ergocalciferol (plant/fungal, less potent)
Liver: 25-hydroxylase (CYP2R1) -> 25-OH-D (substrate-driven, essentially unregulated)
Kidney (proximal tubule): 1-alpha-hydroxylase (CYP27B1) -> calcitriol
- *This is the regulated step*
Inactivation: 24-hydroxylase (CYP24A1) -> 24,25-(OH)2-D and calcitroic acid

Stimulates	Inhibits
PTH (dominant)	FGF-23 (also induces 24-hydroxylase)
Hypophosphataemia	Hyperphosphataemia
Hypocalcaemia (indirectly, via PTH)	Calcitriol itself (negative feedback)
	Calcitonin, low PTH

FGF-23 and PTH act in the same direction on phosphate (both phosphaturic) and in opposite directions on calcitriol

Site	Action
Intestine (duodenum)	inc calcium absorption via apical TRPV6 + calbindin-D9k + basolateral PMCA1b. The dominant physiological action
Intestine	inc phosphate absorption (NaPi-2b)
Kidney - distal tubule	inc calcium reabsorption via TRPV5, with accompanying phosphate reabsorption
Bone	inc osteoclast-mediated resorption (inc RANKL on osteoblasts); mechanism incompletely defined
Parathyroid	dec PTH gene transcription - negative feedback
Bone (osteocyte)	inc FGF-23
Immune	Macrophage cathelicidin; modulates T cells (the basis of extrarenal 1-alpha-hydroxylase in granulomas)

*Net effect: raise serum calcium AND phosphate - which is how it differs from PTH (calcium up, phosphate down*)

Activated macrophages in granulomas express CYP27B1 that is not suppressed by calcium or negative feedback
-> unregulated calcitriol -> PTH-independent hypercalcaemia in sarcoidosis, TB, lymphoma, berylliosis, granulomatosis with polyangiitis, fungal disease

25-OH-D	Category
>=50 nmol/L (at end of winter)	Sufficient
30-49	Mild deficiency
12.5-29	Moderate deficiency
<12.5 nmol/L	Severe - risk of rickets/osteomalacia

*Do not screen the general population* - test only those with risk factors, malabsorption, osteoporosis, unexplained hypocalcaemia or raised ALP, or before starting an antiresorptive

PTH-independent hypercalcaemia (suppressed PTH, no obvious malignancy) -> high 1,25-D points to granulomatous disease or lymphoma
Rickets subtyping:

	Ca	PO4	PTH	ALP	25-D	1,25-D
Nutritional (vitamin D deficient)	dec/normal	dec	inc	inc	dec	normal or inc
Vitamin D-dependent rickets type 1 (CYP27B1 loss)	dec	dec	inc	inc	normal	*dec*
Type 2 (VDR resistance)	dec	dec	inc	inc	normal	*very inc* (+ alopecia)
X-linked hypophosphataemia (PHEX -> inc FGF-23)	normal	very dec	normal	inc	normal	inappropriately normal/low
Tumour-induced osteomalacia (FGF-23)	normal	very dec	normal	inc	normal	low/normal

Idiopathic infantile hypercalcaemia - CYP24A1 loss of function -> failure to inactivate calcitriol -> hypercalcaemia, hypercalciuria, nephrocalcinosis, suppressed PTH; presents after vitamin D supplementation
CKD: 1,25-D falls early (dec renal mass, inc FGF-23) before 25-OH-D or calcium change

Colecalciferol (D3) is the standard - 1,000-2,000 IU daily for maintenance; 3,000-5,000 IU daily for 6-12 weeks in moderate-severe deficiency, then maintenance
Ensure adequate calcium intake (~1,000-1,300 mg/day, dietary preferred)
Recheck 25-OH-D at ~3 months if it matters; not routinely thereafter
Malabsorption/bariatric surgery -> higher doses, or parenteral

*Avoid annual mega-dosing*

A single annual 500,000 IU dose of colecalciferol paradoxically increased falls and fractures in older women
- -> *use daily or monthly dosing, not annual bolus*
The same signal has appeared with large intermittent doses generally

When to use calcitriol (or alfacalcidol) instead of colecalciferol

Only where the 1-alpha-hydroxylation step is missing or bypassed

Hypoparathyroidism / pseudohypoparathyroidism (no PTH to drive the enzyme)
CKD stage 4-5 and dialysis
Vitamin D-dependent rickets type 1
Severe symptomatic hypocalcaemia needing rapid effect
*Narrow therapeutic index - short half-life, no storage, and hypercalcaemia/hypercalciuria develop quickly. Monitor calcium and urinary calcium*

Balance against skin cancer risk: a few minutes of mid-morning or mid-afternoon exposure to arms and hands most days in summer; 2-3 hours per week in winter in southern states
Do not recommend deliberate sun exposure when the UV index is >=3 without protection

Hypercalcaemia from vitamin D

Toxicity is from 25-OH-D excess (usually >375-500 nmol/L) displacing calcitriol from binding protein - not from calcitriol itself in supplement form
Treat: stop supplements, low-calcium diet, fluids, glucocorticoids (reduce intestinal absorption and extrarenal 1-alpha-hydroxylase), avoid sun
Granulomatous hypercalcaemia responds to glucocorticoids - the diagnostic-therapeutic clue

Rickets and osteomalacia; proximal myopathy; secondary hyperparathyroidism
Osteoporosis - replete before starting a bisphosphonate or denosumab (hypocalcaemia risk otherwise)
Granulomatous disease - sarcoidosis, TB, fungal, berylliosis; and lymphoma -> 1,25-D-mediated hypercalcaemia
CKD-MBD - low calcitriol drives secondary hyperparathyroidism
Malabsorption - coeliac, IBD, pancreatic insufficiency, bariatric surgery, cholestasis
Enzyme-inducing drugs - phenytoin, carbamazepine, rifampicin (inc 24-hydroxylase -> accelerated catabolism)
CYP24A1 loss of function - idiopathic infantile hypercalcaemia
Dark skin, veiling, institutional care, obesity (sequestration in adipose tissue)
Deficiency is usually asymptomatic until severe; then bone pain, proximal myopathy, waddling gait, and fracture
Children: rickets - bowed legs, rachitic rosary, widened wrists, delayed fontanelle closure, craniotabes; hypocalcaemic seizures in infancy
Adults: osteomalacia - Looser zones (pseudofractures), raised ALP, raised PTH, low/low-normal calcium and phosphate
Repletion improves bone mineralisation, PTH and myopathy over months
Correcting deficiency prevents rickets and osteomalacia. Supplementing people who are already replete has not shown benefit for fractures, falls, cancer or cardiovascular disease in large randomised trials - a reason to test and treat, not to supplement everyone

11 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.