Control of Calcium and Phosphate Metabolism (S3) Flashcards
What are functions of calcium?
- bone growth and remodelling
- secretion
- muscle contraction
- blood clotting
- co-enzyme
- stabilzation of membrane potentials
- second messenger/stimulus response coupling
What are the functions of phosphate?
- Element in high energy compounds (ATP) + second msgrs (cAMP)
- DNA/RNA, phopholipid membranes, bone
- intracellular anion
- phosphorylation (activation) of enzymes
What cells are involved in calcium homeostasis (in bone)?
Osteoblasts + osteoclasts
What are the 4 stages of bone remodelling?
- resorption - by osteoclasts differentiated from stem cells
- reversal - mopping up by macrophages
- formation - new osteoid by osteoblasts
- resting/activation
Describe the role of the RANK ligand in osteoclast differentiation
Osteoblast stimulates the differentiation of osteoclasts by the prod of RANK ligand.
This activates the RANK receptor on osteoclast precursor and via activation of nuclear kappa beta stimulates gene transcription + diff of osteoclasts.
Osteoprotogerin binding to RANK inhibits differentiation.
What is the action of FGF23?
Produced by osteocytes, FGF23 acts on the kidney to decrease synthesis of active vitamin D and to increase excretion of inorganic phosphate (Pi), so:
- > decrease vit D
- > decrease serum phosphate
What is the action of uOCN (uncarboxylated osteocalcin)?
Produced by osteoBLASTS
Acts on:
- pancreatic b-cells -> increase insulin prod/secretion
- adipocytes -> inc adiponectin + insulin sensitivity
- muscle -> inc insulin sensitivity + glucose uptake
Describe the anatomy of the parathyroid glands
- 4 glands on upper + lower poles of each lobe
- supermumerary glands not uncommon
- 30-50mg weight
- chief cells + oxyphill cells
- supplied by inferior thyroid arteries
Describe the pathway for the synthesis of PTH
pre-pro PTH -> pro PTH -> active PTH (84AA)
Why does increased plasma proteins and alkalosis result in decreased free ionised calcium?
Alkalosis means a decrease in acids, so less acids are binding to plasma proteins - less acids competing with calcium, so more plasma proteins as well meaning more calcium can bind to them therefore overall resulting in a decrease of ionised calcium
Describe the mechanism and response of the calcium sensing receptor when calcium is too high
Circulating calcium levels sensed by Ca2+ receptor
- Gi activated so ↓ AC -> ↓cAMP -> ↓PKA
- Gq activated so ↑PLC -> DAG + IP3 -> ↑PKC + ↑Ca2+
These products lead to a DECREASE in PTH
Describe the mechanism and response of the calcium sensing receptor when calcium is too low
Gq inhibited so IP3 decreases
PKA increases -> PTH increases
What does parathyroid hormone do?
- stimulate osteoblasts to produce M-CSF and RANK ligand -> inc bone resorption
- osteoclast differentiation
- increase ca2+ reabsorption in distal conv tubule
- inc phosphate excretion
- inc 1-a hydroxylase in the proximal tubule
How does parathyroid hormone act in the kidney?
Activity of the cAMP/PKA pathway stimulates insertion of epithelial Ca2+ channels in the luminal membrane of the distal convoluted tubule. Entry driven by the steep electrochemical gradient between the filtrate and the cytoplasm.
Calcium is bound and transported to the basolateral surface by calbindin. PTH also stimulates the sodium calcium exchanger and the calcium ATPase.
TLDR; increases calcium reabsorption
What are the major causes of hypercalcaemia?
- 1o hyperparathyroidism
- malignancy (PTHrP)
- vitamin D related
- excess intake
- sarcoidosis, tuberculosis and other granulomatous diseases
- high bone turnover eg. hyperthroidism, immobilization
- renal failure
What is bone erosion a sign of?
Hyperparathyroidism because PTH stimulates osteoblasts to produce RANKL which results in osteoclast differentiation -> increased bone resorption!
Name some symptoms of hypercalcemia
Neuro - dec concentration, confusion, fatigue, coma
Renal - polyuria, polydipsia, nephrolithiasis, nephrocalcinosis
MSK - muscle weakness, bone pain, osteoporosis
Cardio - shortening of QT, bradycardia, hypertension
Gastro - anorexia, nausea/vom, constipation, pancreatitis, peptic ulcer disease
What is the pathway of synthesis of the active form of vitamin D3?
Mainly obtained through diet/UV light, hydroxylated in liver and hydroxylated in kidney
What are the actions of vitamin D in calcium homeostasis?
- increases Ca2+ absorption in gut
- requires CaBP’s - synthesis sitmulated by Vit D
- Synergises with PTH on bone
- inhibits PTH synthesis
- inhibits 1a-hydroxylase
Explain the 2 main ways calcium is transported across the epithelial cells of the intestine?
Via paracellular transport - diffusion through tight junctions dependent on concentration gradient; does not require energy.
Via transcellular transport - at apical region calcium enters cell through a selective calcium transporter (TRPV), binds to calbindin, transported across cell and extruded at basolateral membrane by a Na-Ca exchanger and a Ca2+ / ATPase transporter
What other actions does vitamin D have beyond the gut, bone and kidney?
- Keratinocytes, lymphocytes, macrophages, adipocytes, pancreatic B cells, cells of the breast, testis, ovary, prostate, colon
- Regulation of cell growth (cancer prev)
- Heart - prevention of CVD by modulated RAAS
- Decrease insulin resistance
- Inc muscle strength
What are the main causes of vitamin D deficiency?
- Liver/kidney disease
- Resistance to hormone
- malabsorption
- dietary insufficiency
- poor exposure to sunlight (block, obesity, latitude, skin pigmentation)
What are the symptoms of vitamin D deficiency?
- aches and pains in bones
- proximal myopathy
- mild hypocalcaemia - 2o hyperparathyroidism
- hypophosphataemia and hypercholaremic acidosis
- bone deformaties - osteomalacia
Describe the endocrine responses to vitamin D deficiency
What are some of the causes of hypocalcaemia?
- vitamin D deficiency (2o hyperparathyroidism)
- hypoparathyroidism (thyroid surgery)
- Chelation - removing minerals/metals from body
- pseudohypoparathyroidism
- neonatal
- activating mutation of Ca2+ receptor
How does vitamin D deficiency cause secondary hyperparathyroidism?
Vit D is needed to increase calcium, so without it there is low calcium and PTH is used to increase calcium as well so therefore the parathyroid releases more PTH to compensate for the low Ca!
What are the endocrine responses to hypocalcemia?
Symptoms of hypocalcemia
- muscle cramps
- pins and needles
- shortness of breath (bronchospasm)
- biliary and intestinal colic
- tetany
- confusion, hallucinations, seziures
- Chvostek’s and Trousseau’s signs
