VITAMIN D and Pathologies

vitamin D 2 (diet) 1,25(OH) 2 D 3 calcitriol Synthesis of active vitamin D 10%, 90%, Bile Salts Tightly regulated 25-hydroxylase 1  -hydroxylase calcidiol

Vitamin D pathway Cholesterol 7-dehydrocholesterol UVB rays (skin) Inactive Vit D 3 (cholecalciferol) 25 hydroxylase (liver) Calcidiol (25-hydroxycholecalciferol) 1α-hydroxylase (kidney) Calcitriol (1,25-dihydroxycholecalciferol) Active Vitamin D

Hypercalcaemia vs Hypocalcaemia Symptoms Hypercalcaemia neuromuscular irritability muscle cramps/tetany Seizures Hypercalcaemia nausea/vomiting/constipation/anorexia tiredness, confusion, depression, headaches muscle weakness kidney stones/ectopic calcification loss of bone polyuria/polydipsia

Treatment for hyper/hypocalcaemia Hypercalcaemia (>3-3.5mmol/l must treat as emergency) fluids (normal saline) loop diuretic (furosemide) calcitonin bisphosphonates oral phosphate long term ? parathyroid gland surgery Hypocalcaemia acute (neuromuscular symptoms) IV calcium gluconate chronic –oral calcium –vitamin D (form will depend on where the defect is)

What is tetany? Tetany – as E.C. [Ca 2+ ] falls, peripheral nerve fibres discharge spontaneously, leading to muscle contractions – Freq observed in the wrist, pulled into flexed position – carpopedal spasm

What do they look like on an ECG? Normal Hypocalcaemia Hypercalcaemia

Renal osteodystrophy – aka renal bone disease Variety of metabolic bone diseases – High turnover Osteitis fibrosa – Low turnover Osteomalacia Adynamic bone disease – Amyloidosis

Osteitis fibrosa (2 o hyperparathyroidism ) – High rate of turnover associated with persistently high PTH » 2 o hyperparathyroidism – Increased bone resorption » Increased number/activity OB and OC » Increased Howship’s lacunae (resorption pits) – Deposition of fibrous tissue – As bone turnover rapid they make disorganized, woven type bone, no strength (similar to that of Paget’s)

Osteomalacia similar to Rickets but in adults – Don’t have high PTH (often low/normal) – Low rate bone formation (undetectable) and turnover – Bone doesn’t buffer Ca 2+ well – effectively locked in bone

Adynamic bone disease – nothing happening to bone, static – Becoming most common form of renal bone disease – Normal/decreased osteoid – No tissue fibrosis – Decreased osteoblasts and osteoclasts – Low or unmeasurable rates of bone formation – >50% dialysis patients – More commoin in DM/ESRF – Hard to distinguish from OP » Are patients old/postmenopausal? – Symptomatic control, can’t cure

Amyloidosis Deposition of β 2 -microglobulin Takes 7-10 years to develop; not a problem for diabetics, often die before this develops

Low calcium PTH Reabsorb bone In tubules: reabsorb calcium In mitochondria Activate Vit D Absorb more from gut High calcium Negative feedback Hyperparathyroidism 1ry – extra secretion of PTH 2ry – kidney disease: reduced active Vit D production 3ry – after chronic high PTH levels, PT glands become desensitised and produce constitutively high levels of PTH Calcium regulation

↓Vitamin D metabolism or action = Reduced bone matrix mineralisation. Deficiency of Vit D (sunlight, diet)/ Malabsorption (eg coeliac’s)/ Renal disease (eg CRF) Rickets (children) – Bow legs – Deformities of ribcage, long bones and spine Osteomalacia (adults) – Bone pain – Pathological fractures – Waddling gait (prox myopathy) Investigations – Bloods - ↑Alkaline Phosphatase (due to increased osteoblastic activity) – x-ray – may show some changes (demineralisation) Treatments – Vitamin D supplements depending on what the condition is. Calcitriol supplements should only be given to patients with chronic renal failure. If the cause is dietary deficiency or inadequate sunlight exposure then these can be treated without medication.

Hyperparathyroidism 1 o hyperparathyroidism – Affects PTH gland directly – 90% of all hypercalcaemia – Often due to a tumour – High plasma Ca 2+

2 o hyperparathyroidism – Vitamin D deficiency – usually renal disease – Low plasma Ca 2+ (hypocalcaemia) - stimulates PTH production from glands – No increase in vitamin D production, no increase in Ca 2+ absorption, no –ve feedback on parathyroids – Sustained PTH secretion – PTH can only act on bone – Ca 2+ loss from bone – Renal bone disease

3 o hyperparathyroidism – Long-term problem associated with renal failure – PTH glands become desensitised to Ca 2+ and vitamin D (lose receptors); no negative feedback – Even if Ca 2+ and vitamin D levels corrected PTH still produced – Glands often hyperplastic – High plasma Ca 2+

Vascular calcification In dialysis patients – Calcium not deposited in bone – Instead is deposited with hydroxyapatite in blood vessels causing calcification Often seen in coronary arteries and in x-rays without angiography – Within 1 year of dialysis, have BVs of an 80 year old due to calcification