Lecture 22 and tutorial : Calcium Metabolism 1 Flashcards
How does Parathyroid hormone help regulate ECF (serum) Ca2+ levels (and phosphate (Pi) and where is it produced
- PTH is produced in the parathyroid glands by chief cells
- Immediate effects:
a) Stimulates osteoclastic bone reabsorption = release of calcium (and Pi)
b) Renal tubular reabsorption of Ca (but not Pi)
c) Upregulates generation of bioactive form of vitamin D (calcitrol)
This has an indirect delayed effect of stimulating gut absorption of calcium (and Pi) in the intestine
What 3 things trigger the release of PTH in the first place
Released in response to
1. Mostly the
Decreased serum ionised Ca2+ sensed by parathyroid ca2+ sensing GPCR
- Increased serum phosphate
- Decreased serum Bioactive vit D
What is the pathway of bioactive Vitamin D (calcitriol, 1-25 dihydroxy vitamin D) formation
- UVB spectrum of sunlight activates a series of enzymatic steps which starts with a skin precursor, generating calciferol
- Calciferol is stored in the liver and can exit as inactive biliary metabolites or circulate as calcidiol after being hydroxylated (storage form)
- In the kidney the bioactive form of Vit D (calcitriol) is made via final enzymatic step which increases Ca2+ and Pi absorption in the intestine.
This step is regulated by PTH and Pi.
How does the receptor that senses serum Ca2+ changes work and where else is it.
Depending on the level of binding of Ca from the ECF it will signal more PTH or less.
Also depends on Mg as a cofactor so low Mg ->impaired PTH release
- This receptor also sits in membrane of the proximal tubule cell on the bm side. When bound by ECF Ca2+ it will turn off Ca2+, Mg2+ reabsorption from the tubule lumen
What is not a physiological regulator of serum calcium
Calcitonin
What is the Parathyroid hormone related peptide (PTHrP) and how does it affect calcium regulation in a disease state
It usually acts as a paracrine regulator of breast, skin, and bone development (just in tissue) and is not a physiological regulator of serum calcium
However some secreting cancers (eg. epithelial tumours) can lead to humoral hypercalcaemia of malignancy- severe and life threatening - as it acts very similarly to PTH signalling via PTHR1.
What are the differential causes of a high blood calcium - 3 categories
- PTH dependent - high sCa2+ and PTH
a) 1’ hyperparathyroidism : disorder of parathyroid gland, benign adenoma
b) inactivation of the Calcium sensing receptors through mutation (FBH- autosomal dominant, PTH in the normal range)
- PTH independent - high sCa2+ but low PTH because it is switched off
a) Cancer - PTHrP, extensive lytic bone disease (myeloma) - Vitamin D dependent: high sCa2+, high Vit D
a) Sarcoidosis - granulomatous disease makes the final conversion enzyme to active vit d
b) Vit D intoxication
What are the differential causes of a low blood calcium - 3 categories
- PTH deficient: Hypoparathyroidism
- Post surgical, post neck irradiation injury
- Autoimmune,
- Genetic activation of calcium sensing receptor - also in renal. (ADHH)
- Low magnesium co-factor for the receptor
- Abnormal mineral storage: B-thalassaemia: iron, Wilson’s disease (copper) - deposition in parathyroid gland
- PTH is there but doesn’t work = Parathyroid hormone resistance
- Pseudohypoparathyroidism caused by changes in one protein that takes the signal from PTH to the target tissues. - Abnormalities of Vit D metabolism
- Vitamin D deficiency- no sun light on the skin. The levels of substrate and product reduces Ca2+ absorption from diet.
- Renal failure
- Vit D resistance
What are the 3 compounds that affect Pi movement in the body and what are the 3 organs involved with Phosphate metabolism
- Vit D active stimulates the absorption of Pi in the gut
- PTH helps to promote excretion of Pi in the urine (but also releasing some from bone)
- Phosphatonins specifically increase phosphate excretion in the urine - not involved in calcium control
Organs
- Phosphate comes from the diet in the intestine.
- It is stored in bone.
- The kidney via tubular handling of phosphate (+/-) regulates the serum phosphate amount.
How does change in pH affect Pi movement between ECF and ICF
In alkalosis (febrile patients - hyperventilating, HF) There is decreased ECF Pi - more movement into ICF. This is corrected after treating the original cause
What are differential causes of hyperphosphatemia vs hypophosphataemia
Hyper
- Increased input through IV phosphate or cell death- trauma, burns, tumourlysis
- Decreased excretion in renal failure (low GFR)
- PTH deficiency or resistance
Hypo
1. Inadequate GI absorption in Vit D deficiency
2. Intracellular shift associated with respiratory alkalosis - self limiting
3. Renal loss due to hyperPTH (only mild), alcoholism
AND
-increased phosphatonins (Serious- causes osteomalacia), caused by abnormal break down enzyme PHEX
What is the most important Phosphatonin and its actions
what syndromes are similar/associated
FGF23 derived from bone
- impairs phosphate transport proteins in the renal tubule to decrease reabsorption
- similar to fanconi syndrome - inhibits the final enzymatic step of vit d to decrease bioactive vit d for gut absorption
Leads to hypophosphatemia
-> Tumour induced Osteomalacia/rickets if its a mesenchymal tumour or just Osteomalacia if its by congenital FGF23 activation
In what form does calcium exist in the ECF
45-50% ionised and bioactive
5-10% complexed with anions
45-50% protein bound to albumin and globulins
What is Osteomalacia (or rickets in children) and the 3 main causes
The failure of bone to mineralise - so histologically got accumulation of unmineralised osteoid.
- Calciopenic:
- Low dietary Ca2+, malabsorption (coeliacs disease), low calcidiol, vitamin D deficiency - Phosphopenic:
Increased renal phosphate loss -> genetic cause of increased phosphatonins activity or mesenchymal tissues tumour oversecreting - Osteoblast dysfunction: signalled by increased ALP
Aluminium (inhibits bone mineralisation), Hypophosphatasia (genetic impairment of mineralisation). Etidronate?
What are the 3 ways that Vit D deficiency can occur along the pathway of creation
(calcitriol, 1-25 dihydroxy vitamin D) formation)
- inadequate exposure to sun
- breakdown enzyme induction by drugs
- impaired 1a hydroxylase - does the final enzymatic step to active form
- (in rlly low sun) Poor diet and GI disease
