137; Calcium Homeostasis Flashcards
Why is VitD considered a hormone?
It is produced intrinsically and acts as different sites within the body
(Other vitamins acquired through diet)
What VitD derived from?
7-dehydrocholesterol
(A sterol)
What is the first step in VitD activation? Where does this occur?
7-dehydrocholesterol
–>
*UVlight @ skin*
–>
VitaminD3
What is the next step in VitD activation following formation of VitD3?
Where does this occur?
VitD3
–>
*25-hydroxylase, liver*
–>
25(OH)VitD3
What regulates the activity of 25-hydroxylase?
Nothing, it is active regardless of PTH/Ca levels
What is the next step in VitD activation following formation of 25(OH)VitD3?
Where does this occur?
25(OH)VitD3
–>
*renal 1-a-hydroxylase, kidneys*
–>
1,25(OH)VitD3
What regulates the activity of renal 1-a-hydroxylase?
PTH is stimulatory
Ca stimulates to a lesser extent
What is the best screening test for VitD adequacy?
25(OH)VitD3 blood test
Diagram fo VitD synthesis
Rocaltrol, Calcijex, Decostriol, Biowoz, Vectical… are market names for what?
VitaminD
On what type of receptor does VitD act?
Transmembrane GPCR
They exist internally and on cell surfaces (evolutionary similarities with steroid receptors)
What is the role of VitD in the gut?
Small intestine- stimulates trans-epithelial movement of Ca and PO4
This increases serum Ca levels
What is the role of VitD in bones?
Stimulate terminal differentiation of OsteoClasts (directly, and via OsteoBlasts), which resorb bone
…Increases serum Ca
What is the role of VitD on the Parathyroid glands?
Decreases transcription of the PTH gene;
PTH increases VitD production through its stimulatory action on renal 1-a-hydroxylase
Negative feedback
Where is PTH produced?
Parathyroid glands
It is an 84aa peptide hormone
On what organs within the body does VitD act?
GIT
Bones
Parathyroids
List 5 majorfunctions of PTH
- Maintain normal Ca and PO4 levels
- Activates VitD (VitD -ve feedback on PTH)
- Stimulates bone resorption
- Stimulates renal tubular reabsorption of Ca
- Stimulates activity of renal 1-a-hydroxylase (indirectly causing Ca absorption in gut)
What stimulates PTH secretion?
Falling Ca levels
What supresses PTH secretion?
VitD
Rising Ca levels
On what type of receptor does PTH act?
GPCR
The PTH receptor binds to PTH with the same affinity as which other protein?
PTHrP
ParaThyroid Hormone related Protein
What effect does PTH have on tubular reabsorption of minerals?
PTH promotes Ca reabsorption
PTH internalises and degrades Phosphate receptors leading to reduced reabsorption
How are Ca levels detected in various organs?
Via Ca-sensing receptors
…on the kidneys and parathyroids
Where is Calcitonin produced and secreted?
Parafollicular cells of the thyroid glands
(C-cells)
How is Calcitonin regulated?
Directly by Calcium
S T I M U L A T O R Y
What is the role of Calcitonin?
Inhibits OsteoClast function; thus reducing resorption
At high Ca levels, calcitonin decreases bone resorption It has no role in daily maintenance of Ca homeostasis
What is Hypercalcaemia?
Blood Ca level above 2.1 - 2.5 mmol/l
What are the signs and symptoms of Hypercalcaemia?
Stones; renal- diuresis, dehydration and kidney (&biliary) stones
Bones; bone resorption, bone pain, inc. fractures
Groans; nausea, vomiting, anorexia, abdominal pain
Thrones; constipation, polyuria
Phsychiatric Overtones; depression, anxiety, decreased alertness, coma, confusion
CV risks; cause/exacerbate hypertension, shorten QT interval
What are the hormonal causes for Hypercalcaemia?
- Primary hyperParathyroidism (eg Parathyroid tumour)
- Hypervitaminosis D
- Praneoplastic; PTHrP, cytokines…
What are the non-hormonal causes of Hypercalcaemia?
- Milk-alkali syndrome
- Renal failure
- Medications; Thiazide diuretics, Lithium
What is Hypocalcaemia?
How is it measured?
Blood Ca level below 2.1mmol/l
Measured through ionised Ca;
cannot be accurately measured without knowing serum albumin levels
What are the signs and symptoms of Hypocalcaemia?
Lowers depolarisation threshold; associated with increased activity
- Perioral tingling and parasthesia
- Tetany
- Facial spasms
- Hyper-reflexia
- Laryngospasm
- Cardiac arrhythmias
What are the hormonal causes of Hypocalcaemia?
Hypoparathyroidism ee. Surgical removal
Autoimmune
Pseudo hypoparathyroidism (PTH receptor dysfunction)
Idiopathic
What are the non-hormonal causes of Hypocalcaemia?
HypovitaminosisD; diet, rickets, osteomalacia
Organ dysfunction; GI mamabsorption, renal loss
Genetic; Ca-sensing receptor dysfunction
Or an endocrine response to a non-hypoparathyroid hypocalcaemia, causing secondary hyperparathyroidism?
What is Rickets?
VitD deficiency in children
What are the signs and symptoms of rickets?
Bowed legs
Abnormal amounts of unmineralised osteoid
Soft bones; easily fractured, loss of rigidity
What is Osteomalacia?
VitD deficiency in adults
What are the signs and symptoms of Osteomalacia?
Increased amounts of unmineralised osteoid
Reduced bone strength, easily fractured
Adults with VitD deficiency do not have bowed legs because epiphyses are fused, bone growth complete
What does Ca-sensing receptor dysfunction cause?
Hypocalcuric-Hypercalcaemia (familial)
An inactivating mutation desensitises the receptor for Ca; higher Ca levels required to supress PTH
Mild in Hetero-, lethal in Homo- children due to extreme Hypercalcaemia
Also causes reduced Ca loss from urine
What does PTH receptor dysfunction cause?
Pseudo-Hypoparathyroidism Hypocalcaemia
PTH levels are high but receptors are resistant. Caused by mutation i one of G subunits
What 2 major factors are required for Ca absorption?
VitD
Sunlight
Give examples of GI dysfunctions that reduce Ca absorption
Short bowel
Malabsorptive disorders
IBS
Why might a high phosphate diet compromise Ca absorption?
Phosphate binds with high affinity for Ca;
With high PO4 less Ca is available for absorption
Give examples of Renal dysfunctions that cause Hypocalcaemia
Abnormal response to PTH;
- 1-a-hydroxyl activation
- Ca reabsorption in tubules
Insufficiency of 1,25(OH)D3
Genetic tubular Ca leak;
- hypercalciuria
- secondary hyperparathyroidism
What is the main cause of Hypercalcaemia?
Primary hyperparathyroidism;
Adenoma or hyperplasia of parathyroids
What are the clinical features of primary hyperparathyroidism?
Hypercalcaemia
High PTH
Hypercalciuria
Increased fractures
Increased risk of kidney stones
Renal failure-associated hypercalcaemia…
Renal failure can cause hyper- and hypo- calcaemia.
Hypercalcaemia due to;
Reduced tubular Ca clearance
Increased resorption from bones (high PTH)
Renal failure causes:
PTH elevation
Low endogenous 1,25(OH)D3
Abolished Ca and PO4 clearance (dialysis filters these poorly also)
What are the causes of hypervitaminosis D?
Excess dietary intake; through supplements
Excess intrinsic production; Extra-renal 1-a-hydroxylase activity
Granulomas (MO) or lymphomas
1-a-OH not regulated by PTH or Ca
What are the clinical features of Hypervitaminosis D?
HypoPTH
Hypercalcaemia
Study this diagram of Ca homeostasis
Study this diagram of VitD synthesis
Name a population at risk of VitD deficiency
Finnish
Anyone with lack of sunlight
What are the problems with using VitD and PTH as medications?
They are peptides; Will be digested if taken orally
Ca, PTH & VitD feedback loops:
Detailed Ca homeostasis diagram
