Parathyroid hormone
Structure
- 84-aa peptide from chief cells of 4 parathyroid glands
- Secreted as pre-pro-PTH -> pro-PTH -> PTH(1-84)
- Biological activity resides in PTH(1-34) - the basis of teriparatide
- Plasma half-life 2-4 minutes -> intraoperative PTH monitoring works
- Acts through PTH1R (Gs/Gq GPCR) on osteoblasts and renal tubule
The one-line summary
- PTH raises calcium and lowers phosphate. Everything else follows
Interpretation basics
- Secretion is pulsatile with a circadian rhythm (nocturnal peak)
- Reference interval assay- and generation-dependent
- PTH must always be interpreted against a simultaneous calcium - a 'normal' PTH with a high calcium is pathological
Regulation of secretion
- Calcium-sensing receptor (CaSR) on chief cells - a Gq/Gi GPCR sensing ionised calcium
- dec ionised Ca -> dec CaSR signalling -> inc PTH release (the receptor is inhibitory - occupancy switches PTH off)
- Extremely steep sigmoidal curve -> minute-to-minute control
- Calcitriol -> VDR on chief cells -> dec PTH gene transcription (negative feedback)
- FGF-23 -> dec PTH secretion
- Magnesium
- Moderate hypoMg -> stimulates PTH
- *Severe hypoMg -> paradoxically blocks PTH secretion AND causes end-organ resistance* - hypocalcaemia refractory until Mg replaced
- Phosphate - hyperphosphataemia raises PTH (directly and by lowering ionised Ca)
Actions - three organs
| Organ | Action | Mediator |
|---|---|---|
| Bone | inc resorption -> Ca + PO4 released | PTH1R on osteoblasts/osteocytes -> inc RANKL, dec OPG -> osteoclast recruitment. Osteoclasts have no PTH receptor |
| Kidney - distal tubule | inc Ca reabsorption | TRPV5 channel |
| Kidney - proximal tubule | dec PO4 reabsorption (phosphaturia) | Internalises NaPi-2a/2c cotransporters |
| Kidney - proximal tubule | inc 1-alpha-hydroxylase -> inc calcitriol | -> indirect inc intestinal Ca absorption via TRPV6 |
- PTH has no direct intestinal action - gut absorption is entirely via calcitriol
Continuous vs intermittent - the therapeutic paradox
- Continuous exposure (hyperparathyroidism) -> net catabolic, cortical bone loss
- Intermittent daily exposure (teriparatide, abaloparatide) -> net anabolic, favours osteoblast survival
Phosphate axis
- Two phosphaturic hormones: PTH and FGF-23 (osteocyte-derived, needs Klotho as co-receptor)
- FGF-23 also suppresses 1-alpha-hydroxylase and induces 24-hydroxylase -> lowers calcitriol
- Opposite of PTH on vitamin D, same direction on phosphate
Interpreting a PTH result
| Ca | PTH | Interpretation |
|---|---|---|
| inc | inc / inappropriately normal | Primary or tertiary hyperparathyroidism, FHH, lithium |
| inc | suppressed | PTH-independent: malignancy (PTHrP, osteolysis), vitamin D excess, granulomatous |
| dec | low/normal | Hypoparathyroidism, hypomagnesaemia |
| dec | inc | Vitamin D deficiency, CKD, pseudohypoparathyroidism, malabsorption |
Assay pitfalls
- Generation matters: 1st-generation C-terminal assays read 50-500x higher than the intact hormone, because C-terminal fragments are renally cleared and accumulate
- A recognised trap in renal impairment; modern labs use 2nd (intact) or 3rd (whole/bio-intact 1-84) generation assays
- 2nd-generation intact assays still cross-react with the inhibitory PTH(7-84) fragment
- Biotin supplements interfere with immunoassays
- Ionised calcium is the physiological driver - use it when albumin, pH or paraproteins distort total calcium
- Sample handling: PTH is unstable - separate promptly, keep cold
PTH as a drug
- Teriparatide PTH(1-34) SC daily - anabolic, for severe/very-high-risk osteoporosis
- Build bone then lock it in - must be followed by an antiresorptive or gains are lost within ~12 months
- Abaloparatide - PTHrP analogue, same principle
- Palopegteriparatide - long-acting PTH(1-34) prodrug giving continuous physiological levels, for chronic hypoparathyroidism
Drugs acting on the PTH axis
- Cinacalcet / etelcalcetide - calcimimetics; allosteric CaSR activators -> dec PTH
- Secondary HPT of dialysis, parathyroid carcinoma, inoperable primary HPT
- Calcitriol / alfacalcidol - bypass the 1-alpha-hydroxylase step in CKD and hypoparathyroidism
- Burosumab - anti-FGF-23 antibody for X-linked hypophosphataemia and tumour-induced osteomalacia
Genetic disorders of the axis
- CaSR loss-of-function -> familial hypocalciuric hypercalcaemia (heterozygous) / neonatal severe hyperparathyroidism (homozygous)
- CaSR gain-of-function -> autosomal dominant hypocalcaemia (hypercalciuric - treating it causes nephrocalcinosis)
- GNAS -> pseudohypoparathyroidism (PTH resistance: low Ca, high PO4, high PTH)
- AIRE -> APS-1 autoimmune hypoparathyroidism
- CDC73/HRPT2 -> hyperparathyroidism-jaw tumour syndrome, parathyroid carcinoma
- MEN1, RET (MEN2A), CDKN1B (MEN4) -> multiglandular hyperplasia
- PTHrP -> humoral hypercalcaemia of malignancy
Consequences of excess and deficiency
- Sustained PTH excess -> cortical bone loss (distal radius, hip), osteitis fibrosa cystica, brown tumours, nephrolithiasis, nephrocalcinosis
- Sustained PTH deficiency -> hypocalcaemia, hyperphosphataemia, basal ganglia calcification, cataract, and (from treatment) hypercalciuria and CKD
- CKD: dec calcitriol + PO4 retention + inc FGF-23 -> secondary -> then autonomous tertiary hyperparathyroidism
- Over-suppression of PTH in dialysis causes adynamic bone disease - target PTH ~2-9x ULN, do not normalise
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