Vitamin D

What is 1,25-Dihydroxycholecalciferol

The active form of vitamin D

Effect of vitamin D₃ on plasma Ca²⁺ & phosphate

Increases both

What mineral is vit D synthesis dependant on

Ca²⁺

What hormones boost vit D

Prolactin, Parathyroid Hormone, Oestrogens

Where do we get vit D from

Diet / Supplements

UV on light skin

Once vitamin D enters the body what organs does it get processed in (& what happens in each organ)

Liver & Kidney

Fate of inactive metabolite (24,25-dihydroxyvitamin D)

We get rid of the inactive metabolite.

The amount of this increases when we take in too much vitamin D or in hypercalcaemia

Where is the major site of action for vit D

Intestine

Role of vit D in intestines

Increase Ca²⁺ and phosphate (indirectly) absorption

How does vit D increase Ca²⁺ absorption

Vit D induces the synthesis of calbindin D-28K.

Calbindin D-28K binds 4 Ca²⁺ and shuttles the Ca²⁺ across the cells of the small intestine from the lumen to the blood

Where is the Ca2+ channel TRPV6

In lumen of intestines

Role of Vit D in kidneys

Minor effect
Reabsorption of both Ca2+ and phosphate

Role of Vit D in bone

Minor effect
Acts with PTH to ↑ osteoclast activity and (old) bone resorption
Increase plasma Ca2+ and phosphate
Stimulate (new) bone mineralisation due to high Ca2+ levels

Calcitonin

Produced by parafollicular C cells of the thyroid gland

What stimulates calcitonin secretion

↑ plasma Ca²⁺

Half life of calcitonin

10 mins

(little long term effect)

Role of calcitonin

Inhibits osteoclast bone resorption (primary action)

Decreases plasma Ca2+

Decreases Ca2+ and phosphate reabsorption in kidney

What does a lack of calcitonin cause

No pathophysiological consequences of deficiency
Possibly important in infant, pregnancy and lactation

How is an imbalance in blood Ca2+ levels rectified

What hormones (other than PTH & Calcitonin) affect bone turnover

Oestrogen & Androgens: Decreases bone re-absorption
Cortisol: Increases re-absorption of bone
Thyroxine - Necessary for foetal bone development

How does the effect of thyroxine change in children & adults

Anabolic during growth to stimulate peak bone mass accrual (increase)
Catabolic effects in adult that increase bone turnover

Name 4 local factors that have an effect on bone turnover (role?)

GF 1 - increased osteoblast proliferation
TGF - increased osteoblast activity

BMP - bone formation

PG’s - increased bone turnover

What level of serum calcium & serum ionised calcium is considered hypocalcaemia

< 8.8 mg/dL (< 2.20 mmol/L) when plasma protein concentration normal

Serum ionized Calcium concentration < 4.7 mg/dL (< 1.17 mmol/L)

Symptoms of hypocalcaemia

Hyper-reflexia - spontaneous twitching, muscle cramps
• Reduced threshold potential, hyperexcitability of cells
• Tingling and Numbness - effect on sensory nerves
• Muscle twitching – effect on motor neurons and muscle
• Trousseau (hand) and Chvostek (face) sign

(Chvostek sign is when a twitch is caused touching the face)

How do you provoke Trousseau’s sign

Inflate a sphygmomanometer cuff above systolic blood pressure

Carpopedal spasms of the hand will be visible

Occlusion of the brachial artery causes flexion of the wrist and metacarpophalangeal joints, hyper-extension of the fingers, and flexion of the thumb on the palm

Hypocalcaemia induced excitability of the nerves in the arm and forearm results in spontaneous firing of nerves fire when subjected to Ischemia after inflating the cuff

What would cause a vit D deficiency

Dietary Lacking

Inability to Absorb Vit D

Inability to metabolise inactive Vit D - Kidney or Liver disorder

Vit D resistance: Kidney unable to produce 1,25 hydroxycholecalciferol because of a congenital absence of 1α- hydroxylase or chronic renal failure

What can a lack of vitamin D cause

Hypocalcaemia

In children: Rickets

In adults: Osteomalacia

How does vit D deficiency cause rickets

Osteomalacia symptoms

Bending and soft weight baring bones

Causes of hypoparathyroidism

Complications in thyroid/parathyroid surgery

Radioactive iodine therapy (thyroid radioactive I₂ ablation)

Autoimmune

Congenital

Low PTH (causes hypocalcaemia, hyperphosphatemia)

Treatment of hypoparathyroidism

Hormone replacement

Oral Ca2+

Vitamin D

What causes Pseudohypoparathyroidism

Inherited autosomal dominant disorder – defective PTH receptor

2 types hypercalcaemia (based on cause)

PTH-Mediated

Not PTH-Mediated

Causes of PTH-Mediated hypercalcaemia

primary hyperparathyroidism

tertiary hyperparathyroidism

familial hypocalciuric hypercalcaemia

ectopic PTH secretion

2 types of not PTH-Mediated hypercalcaemia (causes)

Vitamin D mediated

Not Vitamin D mediated

Causes of vitamin D mediated Hypercalcaemia

Excess vitamin D ingestion

Calcitriol excess

Causes of not vitamin D mediated Hypercalcaemia

A tumour secreting PTH related protein

A tumour secreting/stimulating calcitriol

Bone destruction (+ calcium release) caused by bone metastases/infiltration

2 types of hyperparathyroidism

Primary & secondary hyperparathyroidism

What does Primary hyperparathyroidism cause

Hypercalcaemia (↑ bone resorption, ↑ renal Ca²⁺ reabsorption and ↑ intestinal reabsorption)

Hypophosphatemia (↓ renal phosphate reabsorption, high Ca2+ excreted in urine (hypercalcemia), Ca2+ Phosphate stones in kidney)

Treatment for Primary hyperparathyroidism

surgical removal of parathyroid glands

Cause of Secondary Hyperparathyroidism

hypocalcaemia caused by Vit D deficiency or chronic renal failure

What does the PTH receptor family include

PTH1 & PTH2 receptors
Three Ligands: PTH, PTH-related protein (PTHrP), tuberoinfundibular peptide of 39 residues (TIP39)

Most common cause of elevated serum calcium in hospitalized patients

Hypercalcemia of malignancy (HCM)

(found with varying frequency in patients with various types of cancer)

What is Malignancy Associated Hypercalcaemia

a condition where high calcium levels (hypercalcemia) occur due to cancer

How does Malignancy Associated Hypercalcaemia work

Tumours secrete substances that mimic hormones

What hormones do tumours in Malignancy Associated Hypercalcaemia secrete

Effect of tumour secreting each hormone

What are the tumours associated with each hormone-mimicking-substance

What is osteopenia

poverty of bone

Compare osteoporosis, osteomalacia & hyperparathyroidism on the basis of matrix deficiency and mineralisation deficiency

What is osteoporosis

Decrease total bone mass

Causes of osteoporosis (5)

Long term dietary Ca2+ or Vit D deficiency
Vit C deficiency – required for collagen synthesis
Immobilization, ↓ mechanical stress
Menopause (↓ oestrogen)
Certain drugs: anticonvlusants, glucocorticoids