Calcium lectures 19/20

What is the difference between intracellular and extracellular calcium

Intracellular calcium is maintained at v low concentrations

Extracellular calcium is present much higher concentrations

functions of extracellular calcium

allows bone mineralisation

maintains normal activity of excitable tissues

normal range for calcium

2.1-2.6 mmol/L

exists in ionised calcium and as albumin-bound calcium

what can cause low or high albumin

low albumin - by infection, malignancy, malnutrition

high albumin - by dehydration

Calcium balance changes throughout life

growth = needs +ve calcium balance

adulthood = neutral balance

ageing = slow negative calcium balance esp in menopause

What do osteoblasts do

responsible for bone matrix mineralisation

sit close to each other and work together to respond

What happens in bone matrix mineralisation

takes several months - usually a delay of several days before osteoid is mineralised

mineralisation of osteoid depend on calcitriol

What provides rigidity and resistance to compression in bone

tiny crystals surrounding collagen fibres

what happens in vitamin D deficiency

failure to mineralise = rickets in children and osteomalacia in adults

Alkaline phophatase (ALP) mineralisation

ALP expressed on surface of differentiated osteoblasts

released ino ECF

releases inorganic phosphate ions via hydrolysis

how does ALP promote mineralisation

increases local concentration of inorganic phosphate ions

hydrolyses pyrophosphatase (key inhibitor of mineralisation) to 2 phosphate ions 

What are osteoclasts

responsible for bone resorption

multinucleated, motile cells

secrete H+ ions and enzymes in their ruffled border

express lots of carbonic anhydrase II (for H+ generation)

What is RANK-RANKL?

A pathway essential for osteoclast differentiation and activation

RANKL (on osteoblasts) binds to RANK receptors (on osteoclast precursors) to promote maturation and activation

How do osteoclasts resorb bone

they demineralise and chew through bone via secretion of an acid and enzymes that break down bone matrix components

What is osteopetrosis

Failure of matrix degradation by osteoclasts

occurs due to proton pump failure » chloride channel defects 

= abnormally dense bones that are brittle

What are bone functions

Spport the body and protext organs

leverage system for movement

site of hematopoiesis (new blood cell formation)

endocrine function

mineral homeostasis

What are osteocytes

Most abundant cell type in bone - mechanosensors

What is the bone remodelling cycle

1. quiescence - no active bone turnover occuring

2. resorption - osteoclasts activate and resorb bone (small cavity)

3. Reversal - osteoclasts apoptose and replaced by osteoblasts

4. formation - osteoblasts secrete osteoid which mineralises = new tissue

5. mineralisation - 

How is ionised calcium regulated

PTH and calcitriol in endoccrine feedback loops

PTH physiology

Regulated calcium

In low Ca2+ » PTH increases

high Ca2+ feeds back to Parathyroid to suppress PTH in negative feedback

tightly contrlled

Calcium-sensing receptors on cell surfaces detect Ca2+ levels to regulate secretion

Ca2+ binding activations G-protein coupled receptors

What does PTH do

stimulates effluc of Ca2+ from bone

stimualtes renal tubule reabsorption of calcium

promotes phosphate and bicarb loss from kidney

indirectlt stimulats intensinal absorption of Ca2+

Calcitonin

secreted by thyroid C cells

hormone

lowers plasma calcium by inhibition of bone resorption and increasing calcium deposition in bone

Vitamin D metabolism action in liver

Skin: Uv light » 7-dehydrocholesterol converted to cholecalciferol (vitaminD3)

Liver: 25 -hydroxylase converts VitD3 to 25-hydroxycholecalciferol (calcidiol)

Kidney: 1-alpha-hydroxylase converts calcidiol » 1,25(OH)2 D (calcitriol (active form)

PTH stimulates 1alpha-hydroxylase in low Ca2_

where does Vit D come from in diet

Oily fish, butter, eggs, margarine

Cholecalciferol present in foods are activated by liver and kidney to form calcitriol (1,25-dihydroxycholecalciferol) - active form

What is calcitriol needed for

long-term maintenance of calcium levels, normal bone growth, mineralisation

Mechanism of calcitriol Action

Calcitriol binds to vitamin D receptor = VDR-calcitriol complex (VDRC)

VDRC » acts to regulate calcium and phosphate metabolism

Stimulates osteoclasts = ^^ Ca2+ efflux from bone (^^renal Ca2+ reabsoprtion

Phosphate regulation

calcium balance and mineralisation

PTH and vit D interact to maintain phosphate levels
Kidney: acts with PTH to conserve calcium

PTH secretion

Increased blood Ca2+ = decreased PTH secretion

maintains normal Ca2+ homeostasis in negative feedbacl

What does PTH act to do

increase bone resorption, decrease urinary calcium loss, increase calcitriol production in kidney

Effects of 25(OH)D deficiency on Ca2+ metabolism

• ↓ intestinal Ca²⁺ absorption → ↓ blood Ca²⁺.

• ↓ Ca²⁺ → ↑ PTH (secretion ↑).

• ↑ PTH → phosphate wasting in kidneys.

• Result = bone de-mineralisation and secondary hyperparathyroidism

PTH vs calcitriol

Function	PTH	Calcitriol (1,25(OH)₂D)
Timescale	Minute-by-minute	Longer-term
Plasma Ca²⁺ effect	Increases ionised Ca²⁺	Maintains plasma Ca²⁺
Phosphate effect	↓ plasma phosphate	↑ plasma phosphate
Major site of action	Kidney + bone	Gut + bone + kidney
Stimulus for secretion	↓ Ca²⁺	↑ PTH or ↓ phosphate

Interaction of PTH and calcitriol

• Co-operative action:

  • PTH promotes 1α-hydroxylase activity → ↑ calcitriol.

  • Both required for osteoclast activation and bone remodelling.

• Feedback inhibition:

  • ^^ calcitriol = ^ 24-hydroxylase → inactivation pathway.

  • Calcitriol can switch off PTH gene transcription via vitamin D receptor (VDR) in parathyroid cells.

Disorders of Calcium (high calcium)

Stones, bones, abdominal moans, psychic groans

• muscle weakness - (competition with Na+ movement)

• CNS (anoerxia, nausea)

• renal, bone, abdominal effects

• ECG changes 

What is false hypercalcaemia

Dehydration = Raised calcium due to high plasma albumin

so must check ionised calcium

What is primary hyperparathyroidism

Autonomous and inappropriate overproduction of PTH

raised calcium » low Phosphate and bicarb

ALP normal or slightly high

imaging of PTH 

Primary hyperparathyroidism causes

Caused by adenoma, hyperplasia, or carcinoma

Treatment of prumary hyperparathyroidism

• Acute management:

• Treat high ionised calcium with rehydration or drugs.

• Definitive treatment:

  • Surgical removal of parathyroid adenoma.

• Mild cases:

  • Managed with follow-up of serum calcium and PTH levels.

• If surgery not possible:

  • Use drugs to lower calcium (e.g. calcimimetics).

 

2ndary vs 3ary hyperparathyroidism

2ndary - appropriate increase in PTH due to  hypocalcaemia caused by renal failure or malabsorption

3rary hyperparathyroidism - overactive hyperPTH gland = v high PTH = hypercalcaemia. caused by worsening of secondary HPT (CKD)

Malignant Disease and hypercalcaemia

20–30% of cancer patients develop hypercalcaemia during their illness.

Mechanisms of tumours leading to hypercalcaemia

1. Tumours secreting PTH-peptide = hypercalcaemia of malignancy (hodgkins ly,phoma synthesis calcitriol

2. metastatic tumour in bone stimulate osteoclast activation (bone resorption) (usually from lung and breast cancer)

what is multiple myeloma

blood cancer from too many plasma cells in bone marrow

plasma cells release cytokine and activate osteoclasts = hypercalcemia from bone resporption

Diagnosing malignant hypercalcaemia

^calcium + suppressed PTH

^ phosphate and ALP 

Hydrate patient or use drugs to lower blood calcium to trwat

Causes of hypercalcaemia

granulomatous disease - affect lung and skin = high calcium normal PTH

»» caused by hydroxylation of vitamin D in granulomas

• Exogenous vitamin D excess.

• Hypocalciuric hypercalcaemia:

  • Calcium-sensing receptor on PT glands less sensitive to calcium.

  • Altered set point for PTH/Ca²⁺ interaction.

  • PTH slightly raised, ionised calcium raised, urine calcium low.

• Drugs (e.g. thiazides, lithium).

• Other endocrine diseases: Addison’s disease, thyrotoxicosis.

• Prolonged immobilisation.

Low blood calcium causes

high neuromuscular excitability

• Neuromuscular symptoms: numbness, anxiety, fatigue, muscle cramps, seizures.

• Mental state changes: personality change, mental confusion, psychoneurosis, impaired intellect.

• ECG changes, eye problems (cataracts, papilloedema).

• Chvostek’s sign: tapping facial nerve → eye/mouth twitch.

• Trousseau’s sign: carpal spasm after BP cuff inflation.

 

Factitious hypocalcaemia

due to low plasma albumin (liver disease, nephrotic syndrome (albumin lost in urine))

dietary lack of protein

treated via IV or oral calcium, close monitoring

what happens if low vitD

↓ Vitamin D → ↓ calcium uptake in gut → triggers PTH secretion → phosphate wasting → weak bones.

or 

Less calcium absorption → secondary hyperparathyroidism → phosphate loss → bone weakening.

i.e low calcium phosphate and high ALP and PTH

= osteomalacia or rickets

What are inheritied cause of rickets

deficient 1-hydroxylase enzyme

defective vitamin D receptor

What is osteomalacia

• Bone disorder associated with vitamin D deficiency.

• Osteoid laid down by osteoblasts is not adequately calcified.

• Osteoid content in bone ↑ at the expense of normal mineralised bone.

• Bones softened, weak, and fracture-prone.

causes of hypoparathydrodism

surfical damage to PT glands

suppressed secretion

genetics

What is osteoporosis

reduced bone mineral density - shows up as normal ca, phosphate, ALP)

Caused by more bone resorption over formation

occurs in age, post-menopause

diagnosed with x-ray (DEXA scan)

Managemne of osteoporosis

life - weight decrease, stop smoking, higher calcium and vit D intake

• Pharmacological:

  • Bisphosphonates (inhibit bone resorption).

  • Selective oestrogen receptor modulators (SERMs).

  • Calcitonin, denosumab, or PTH analogues in severe cases.