Week 8 Calcium Flashcards
Intracellular Ca2+ concentration and function
very low concentration (1microM)
reversible increase of Ca2+ can bind proteins -> cell processes
Extracellular Ca2+ concentration and function
High concentration (1mM)
1. bone mineralisation
2. maintain activity of excitable tissue
2 main types of Calcium in plasma
- ionised Ca2+ (free)
- albumin-bound Ca2+ (inactive)
which type of calcium is actively regulated
ionised calcium:
Its concentration is constant
which organs contribute to calcium balance
GI, Kidney, Bone
negative calcium balance leads to….
decrease in bone density
osteocytes
mechanosensor cells for bones
stimulates bone growth
may become osteoblasts
osteoclasts
bone resorption
osteoblasts
make bone
osteoblast - bone formation process - osteoid (bone matrix)
- osteoblast precursor
- osteoblast
- osteoid
- calcified osteoid
how long does it take for osteoid to mineralise
several days
how long for full mineralisation
several months
mineralisation main component
hydroxyapatite(calcium phosphate)
what is hydroxyapatite
calcium phosphate (& OH)
tiny crystals around collagen fibres, provides rigidity
what does mineralisation depend on?
calcitriol (active form of Vitamin D)
calcitriol deficiency leads to??
osteomalacia
rickets (kids)
alkaline phosphate (ALP) and mineralisation
An enzyme expressed by osteoblasts:
1. hydrolysis and releases inorganic phosphate ions
2. hydrolyses pyrophosphate (2 phosphate - inhibitor of mineralisation
osteoclast and bone resorption
multinucleate:
border adjacent to bone releases H+ and enzymes
enzyme:
carbonic anhydrase II, H+ generation.
which cells have RANK ligand
bone marrow stromal cells
which cells have RANK (receptor)
precursor osteoclasts
Characteristics of osteopetrosis
Increased bone density/mass
Increased fragility due to brittle structure.
cause of osteopetrosis
failure of matrix degradation by osteoclasts.
most common cause of osteoporosis
oestrogen drop after menopause
main cause of osteoporosis
increased bone resorption
what is Paget’s disease
overactive osteoclasts
calcitriol comes from?
steroid hormone -> from vitamin D
what does PTH regulate/how fast
-regulate ionised calcium levels
-minute-by-minute
increased in response to falling Ca2+
what controls PTH secretion
calcium receptors on cell -> senses calcium concentration
what receptor is the calcium receptor
G protein coupled receptors
PTH biochemical effects and what organs:
- calcium efflux from bone
- Ca2+ reabsorption (distal)
- bicarbonate and phosphate loss (proximal)
- Ca2+ absorption (intestinal)
what stimulates/suppresses PTH system
(urinary calcium loss, decreased bone resorption, decreased calcitriol) will stimulate PTH release -> to reverse this action.
principal function of calcitonin
to reduce osteoclast activity, treat high serum calcium.
calcitonin as a biomarker(where is it secreted)
Secreted from thyroid gland:
1. medullary cancer of the thyroid
2. will increase when serum Ca2+ increases
cholecalciferol (Vitamin D) to calcitriol production pathway
- Has a precursor on skin, converted through sunlight UV
- cholecalciferol is converted to calcitriol in the liver and kidney
calcitriol synthesis pathway
- 25 hydroxylase adds OH to cholecalciferol (Liver)
- 25-OH vitamin D functions constitutively
- 1alpha-hydroxylse adds another OH to 25-OH vit D. (Kidney)
- 1,25 (OH)2 vitamin D is stimulated by PTH, calcium can affect its activity.
calcitriol effect, and affect what organs
Maintain calcium and phosphate levels:
By itself:
- increase Ca2+ and PO4- absorption (GI)
with PTH:
- Increases bone resorption and stimulate osteoclast (RANKL).
- Increases renal Ca2+ reabsorption.
difference between calcitriol (VitD) and PTH
PTH leads to phosphate loss (renal - proximal tubule)
Calcitriol leads to phosphate increase (GI absorption)
PTH is short term, calcitriol is long term Ca2+ regulation.
how does PTH affect calcitriol
PTH stimulates 1alpha hydroxylase
how does calcitriol affect PTH
calcitriol deficiency -> impaired PTH signalling
calcitriol can switch off PTH gene transcription via vitamin D receptor.
how does calcitriol promote its own inactivation
activates 24 hydroxylase
hypercalcaemia clinical manifestations
stones: renal stones
bones
muscle weakness: competition with inward Na+ flux.
abdominal moans: pain
psychic groans: depression…
non-pathological hypercalcaemia
Due to high plasma albumin -> raised calcium:
1. dehydration
2. intravenous injection albumin
3. venous stasis
Primary hyperparathyroidism causes
(90%) solitary adenoma
hyperplasia
(rare) carcinoma
Secondary hyperparathyroidism cause
PTH increase due to low calcium. (appropriate)
Tertiary hyperparathyroidism causes
Results from chronic secondary hyperparathyroidism:
secondary gland becomes overactive
1y hyperparathyroidism biochemistry
Increased calcium, Increased PTH
Low bicarbonate and phosphate
normal ALP
moderately elevated ALP when severe
treatment of 1y hyperparathyroidism
Immediate - treat high calcium:
1. rehydration
2. drugs
Definitive:
Remove of adenoma
imaging of hypercalcaemia
renal stones
treatment of hypercalcaemia
- calcitonin - reduce osteoclast activity
- bisphosphonates - inhibits bone resorption and osteoclast activity.
- furosemide - diuretic, inhibit Ca2+ reabsorption
- glucocorticoid: prolong calcitonin effect
why are hypercalcaemias common in malignancies
- Metastasis deposit on bone and directly activate osteoclasts
- release endocrine factors that act on bone
what disease affects calcitriol levels
Hodgkin’s lymphoma and Sarcoidosis
Has 1 hydroxylase activity, so it will contribute to calcitriol synthesis.
solid tumours and endocrine factors
some solid tumours secrete PTH-related peptide
but PTHrP is difference from PTH, PTH level is also suppressed.
name when PTHrP is the cause of hypercalcaemia
humoral hypercalcaemia of malignancy
metastatic breast tumour and hypercalcaemia
locally produce PTHrP
multiple myeloma and hypercalcaemia
activate osteoclasts through cytokines like RANKL
Malignancy biochemistry diagnosis - hypercalcaemia
Raised calcium & ALP
High phosphate
Low PTH
Hypercalcaemia - malignancy vs adenoma - biochemistry
Adenoma will have high PTH, low phosphate
Malignancy will have low PTH, high phosphate.
Adenomas rarely have elevated ALP due to a modest bone turnover.
Whereas malignancy may have very high ALP due to a much less controlled bone turnover.
sarcoidosis and hypercalcaemia
has 1hydroxylase activity, synthesise calcitriol, high calcium, normal PTH.
familial hypocalciuric hypercalcaemia (FHH)
Ca2+ sensing receptors are less sensitive.
PTH and Ca2+ have a higher set point now.
elevated PTH and Ca2+ in blood.
Low urine calcium (excretion) is due to PTH elevation.
factitious hypocalcaemia
low albumin, less calcium:
1. nephrotic syndrome
2. liver disease, less protein synthesis
3. malnutrition
causes of low 1,25 vitamin D
- malabsorption
- inadequate sunlight
- diet factors
- chronic renal disease
rarely enzyme issues
what does calcitriol deficiency lead to (steps)
- low calcium
- high PTH (2ndary hyperp)
- low phosphate
- high bone resorption
- high ALP
osteomalacia and calcitriol
low calcitriol meaning that osteoid cannot be calcified properly
inherited causes of osteomalacia
- deficient 1 hydroxylase (low calcitriol)
- low ALP
- low phosphate
- defective calcitriol receptor
causes of hypoparathyroidism
- surgical damage or removal of parathyroid.
- suppressed secretion (maternal hypercalcaemia)
hypocalcaemia biochemical effects
low Ca2+ and low PTH. Phosphate may be elevated
treatment of hypocalcaemia
doses of calcium and vitamin D or calcitriol
(aging) osteoporosis vs osteomalacia
osteoporosis has a normal histology (less bone density) and relatively normal biochemistry.
osteomalacia has an abnormal histology and biochemistry
