Calcium & phosphate Flashcards
What are the 5 functions of calcium?
Neuromuscular excitability and muscle contraction Bone strength (calcium hydroxyapatite crystals)
Intracellular 2nd messenger system and co enzymes
Hormone/neurotransmitter stimulus secretion coupling
Blood coagulation (Factor IV)
Where is the majority of calcium stored?
99% stored within skeletons as calcium hydroxyapatite crystals
How is extracellular calcium regulated?
Parathyroid hormone and calcitriol (vitamin D)
What are the three main functions of phosphate?
Inorganic phosphate is essential for cellular metabolism and skeletal mineralisation.
Component of nucleic acids (RNA and DNA), as well as fundamental for phospholipids
Mediator of intracellular signalling (2nd messengers, and regulates protein activity)
Component of high energy ATP molecules
Describe the relationship between extracellular phosphate and extracellular calcium?
Inversely proportional relationship
Which cells synthesis vitamin D3?
Keratinocytes within epidermis
Which source of Vitamin d is synthesised by the body or obtained from dietary sources?
Cholecalciferol (D3)
What is vitamin d2?
Ergocalciferol
Which precursor molecule is converted into previtamin-d3 in the skin?
7-dehydrocholesterol
How is pre-vitamin D3 converted into Vitamin-D3?
UV radiation
Where does the initial hydroxylation of vitamin d3 occur?
Liver
Which enzyme catalyses the hydroxylation of Vitamin D3?
25-hydroxylase
What is the fate of vitamin-d3 in the liver?
Initiation hydroxylation of vitamin d3 into 25-hydroxy-cholecalciferol.
Where the second hydroxylation for vitamin d occur?
Proximal convoluted tubule (Kidney)
Which enzyme catalyses the second hydroxylation of vitamin d?
1-alpha-hydroxylase
Which molecule is formed from the second hydroxylation of vitamin d?
1,25-dihydroxycholecalciferol
Calcitriol
What is active vitamin D?
Calcitriol
What is the function of calcitriol?
Autoregulates synthesis by decreasing transcription of 1-alpha-hydroxylase, negative feedback.
Increased osteoblast activity
Increased calcium absorption
Increases phosphate and calcium reabsorption
Which receptors does vitamin D bind to?
vitamin D receptors (VDR), causes VDREs activation
How does vitamin d increases calcium absorption?
Increased production of calcium transport proteins (Calbindin-D proteins) in gut so increases uptake of calcium.
increases plasma calcium maintaining PTH secretion at low levels
What effect does calitriol have on PTH?
Exerts negative feedback ,inhibits release
How does vitamin D increases calcium and phosphate reabsorption?
Decreases urinary loss of calcium, and phosphate, to filtrate by stimulating reabsorption within the proximal convoluted tubule
Where are parathyroid hormones secreted from?
Parathyroid glands
Which cells secrete and synthesise parathyroid hormone?
Chief cells
What is the precursor of PTH?
pre-pro-PTH
Where does pre-pro-PTH cleavage occur?
Cleaved by proteases into smaller peptides, by endoplasmic reticulum and Golgi body
What are the two target sites for PTH?
Kidney and bone
What are the effects of PTH?
PTH increases the reabsorption of calcium from filtrate with the proximal convoluted tubule, and increases the expression of 1-alpha-hydroxylase, activating Vitamin-D
This increases the formation of calcitriol.
Increases phosphate and calcium absorption from gut
Increases phosphate excretion from kidney
Which types of receptors does parathyroid hormone bind onto on osteoblasts?
PTH receptors
Which factors are released from osteoblasts that stimulates osteoclastogenesis?
RANK ligand
Osteoclast activating factor (OAF)
Which nuclear factor is stimulated upon RANK L receptor activation?
Kappa b ligand
What are the functions of osteoclasts?
Cause déminéralisation of hydroxyapatite, thus releasing calcium and phosphate ions into the blood
Forms ruffled border, attaches the osteoclast to the bone
Which binding proteins attach osteoclasts to surface of bone?
Sialoprotein
Osteopontin
Which enzyme is the rate limiting step of vitamin D synthesis?
1-alpha-hydroxylase
Which enzyme is potentiated by parathyroid hormone?
1-alpha-hydroxylase
What happens to a PTH secretion during hypocalacaemic conditions?
Increases
What effect does PTH have on osteoclast activity?
Stimulates osteoclast activity
Which hormone is responsible during elevated calcium serum levels?
Calcitonin
Which cells secrete calcitonin?
Parafollicular cells
What suggests that calcitonin does not play a significant role in calcium homeostasis?
Removal of thyroid gland does not affect serum calcium
Where does phosphate reabsorption occur in the body?
Proximal convoluted tubule and gastrointestinal tract
Which transporters reabsorb phosphate?
Sodium phosphate co transporters
What effect does parathyroid hormone have on renal phosphate reabsorption?
Inhibits these transporters- therefore there is increased phosphate loss in the urine, reducing serum phosphate levels
What condition causes increased phosphate loss in urine?
Hyperparathyroidism (serum phosphate is low due to increased phosphate excretion)
Which cells produce FGF23?
Osteocytes
What is FGF23?
Fibroblast growth factor-23
Why is FGF23 secreted?
Due to elevated calcitriol levels
What effects do FGF23 exert?
Less phosphate reabsorption from gut due to decreased expression of co-transport NPT2 in proximal tubule cells
Inhibitory effects towards the synthesis of calcitriol
What is hypercalcaemia?
High serum calcium
What are the main effects of hypercalcaemia?
Action potential generation in neuroskeletal muscle requires sodium influx for depolarisation of the cell membrane at the nods of ranvier in order to stimulate the threshold voltage, and conduct an electrical impulse
High extracellular calcium reduces the membrane excitability
What is hypocalcaemia?
Low serum calcium
What are the effects of hypocalcaemia?
Reduction in calcium ions increases the ability of sodium ion influx, thus the membrane is more excitable
What are the clinical effects of hypocalcaemia?
Sensitises excitable tissues, resulting in increased stimulation of muscles , causing muscle fatigue, tetany & tingling
Convulsions, arrythmnias, paraesthesisa
What is Chvostek’s sign?
Tap the zygomatic branch of the facial nerve, examine positive response = twitching of the facial muscles - this indicates neuromuscular irritability due to hypocalcaemia
What is Trousseau’s sign?
Inflation of BP cuff for several minutes induces carpopedal spasm = neuromuscular irritability due to hypocalcaemia
What are the five main causes of hypocalcaemia?
Surgical neck injury: Autoimmune disease
Magnesium deficiency
Congenital
Vitamin-D deficiency
Which congenital disorder contributes to cause of hypocalcaemia?
Hypoparathyroidism is a sporadic or inherited condition whereby the parathyroid glands are absent or atrophied
Why does a magnesium deficiency cause hypocalcaemia?
Magnesium is required for PTH synthesis
What are the 4 causes of vitamin-d deficiency?
Renal disorder for the second hydroxylation of 25-hydroxycholecalciferol into calcitriol (Insufficient synthesis of 1-alpha-hydroxylase)
Insufficient consumption or UV exposure
Liver disease: Reduction in the synthesis of 25-hydroxylase reducing the conversion of vitamin D into 25-hydroxy-D3
What are the consequences of a vitamin-d deficiency?
Lack of bone mineralisation (reduction of hydroxyapatite) = causing soft bones
Rickets in children *Bowing of bones cannot support growing weight)
In adults; Osteomalacia (fractures proemial myopathy)
What effect does parathyroid hormone related peptide exert?
Behaves as an agonist to PTH, thus is attributed to hypercalcaemia
What are the clinical signs of hypercalcaemia?
STONES MOANS GROANS
Kidney stones: Increased calcium serum concentrations within the filtrate result in accumulation and kidney stone formation
Nephrocalcinosis (deposition of calcium salts)
Abdominal moans: Dyspepsia, anorexia,constipation
Psychic groans: CNS effects, depression, impaired concentration,fatigue
What is primary hyperparathyroidism?
Results in increased secretion of parathyroid hormone.
Unresponsive from negative feedback system due to elevated calcium serum concentrations
How does malignancy cause hypercalcaemia?
Bony metastases produce local factors to activate osteoclasts (increased bone retortion)
What are squamous cell carcinomas?
Secrete PTH related peptides that act on PTH receptors
