VITAMIN D and Pathologies

vitamin D2

(diet)

1,25(OH)2D3

calcitriol

Synthesis of active vitamin D

10%,

90%,Bile Salts

Tightly regulated

25-hydroxylase

1a-hydroxylase

calcidiol

Vitamin D pathway

Cholesterol

7-dehydrocholesterol UVB rays (skin)

Inactive Vit D3 (cholecalciferol) 25 hydroxylase (liver)

Calcidiol (25-hydroxycholecalciferol)

1 -hydroxylase α (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. [Ca2+] 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 (2o hyperparathyroidism)

– High rate of turnover associated with persistently high PTH» 2o 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 Ca2+ 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 β2-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

• 1o hyperparathyroidism– Affects PTH gland directly– 90% of all hypercalcaemia– Often due to a tumour– High plasma Ca2+

• 2o hyperparathyroidism– Vitamin D deficiency – usually renal disease– Low plasma Ca2+ (hypocalcaemia) - stimulates PTH production from

glands– No increase in vitamin D production, no increase in Ca2+ absorption,

no –ve feedback on parathyroids– Sustained PTH secretion

• – PTH can only act on bone– Ca2+ loss from bone– Renal bone disease

•

• 3o hyperparathyroidism– Long-term problem associated with renal failure– PTH glands become desensitised to Ca2+ and

vitamin D (lose receptors); no negative feedback– Even if Ca2+ and vitamin D levels corrected PTH still

produced– Glands often hyperplastic– High plasma Ca2+

•

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