ENDO Flashcards
Endocrine control of calcium and phosphate metabolism by Prof Seal
Functions of Calcium
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Bone growth and remodelling
Secretion
Muscle contraction
Blood clotting
Co-enzyme
Stabilization of membrane potentials
Second messenger/stimulus response coupling
ikEndocrine control of calcium and phosphate metabolism by Prof Seal
Functions of phosphate [ H2PO4- and HPO42-]
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Element in:
High energy compounds e.g. ATP
Second messengers e.g. cAMP
Constituent of:
DNA/RNA,
phospholipid membranes
bone
Intracellular anion
Phosphorylation (activation) of enzymes
Endocrine control of calcium and phosphate metabolism by Prof Seal
The most common intracellular signalling is
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Phosphorylation of enymes
(such as phsophodiesterase in cGMP in the Eye)
Endocrine control of calcium and phosphate metabolism by Prof Seal
Calcium is an ____ ion
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Extracellular
(Skeleton 99%
Intracellular 0.001, extracellular 0.99%)
45% ionised
45% plasma proteins
10% ions bound to phosphate etc.
Endocrine control of calcium and phosphate metabolism by Prof Seal
Phosphate is an ____ ion
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Intracellular
(Skeleton 90%
Intracellular 9.97, extracellular 0.03%)
50% Free, 50% bound
Endocrine control of calcium and phosphate metabolism by Prof Seal
Daily turnover of calcium and phosphate
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Bone- long term storage
Kidney- rapid response for modifying levels
Endocrine control of calcium and phosphate metabolism by Prof Seal
Which hormones are important in calcium balance?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Oestrogen, Androgens, GH
PTH, VitD
Thyroxine and steroid activates bone breakdown
Endocrine control of calcium and phosphate metabolism by Prof Seal
Why do bones have more strength at stress areas?
*LOB: Describe the process of calcium and phosphate homeostasis in relat
Osteoblasts respond to peizioelectricity
So stress encourages calcium to store
Greater bone strength in stressed areas.
Gravity is required for good bone formation
Endocrine control of calcium and phosphate metabolism by Prof Seal
The Bones are endocrine organs. They act on….
*LOB: Describe the process of calcium and phosphate homeostasis in relat
Osteocytes produce fibroblast growth factor 23 (FGF23)
Osteoblasts produce uncarboxylated osteocalcin (uOCN)
FGF23 acts on the kidney to decrease synthesis of active vitamin D and to increase excretion of inorganic phosphate (Pi)
uOCN acts on pancreatic β-cells to increase insulin production and secretion, on adipocytes to increase adiponectin and on muscle to increase insulin sensitivity and glucose uptake.
Endocrine control of calcium and phosphate metabolism by Prof Seal
What is the parathyroid
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
2 Pairs (4 Glands )
3-5 mm
30-50mg
Closely related to thyroid
May be ectopic
Chief cells (main cell) and oxyphill cells
Supplied by blood from the inferior thyroid arteries (thyroid surgery)
Endocrine control of calcium and phosphate metabolism by Prof Seal
Anatomy of the Parathyroid
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Endocrine control of calcium and phosphate metabolism by Prof Seal
Parathyroid hormone
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
- Only 1-34 amino acids required for full biological activity
- Long N-terminally truncated PTH also in circulation
- Ratio of fragments to full length PTH increases when plasma Ca2+ is high
- T1/2 2-4 minutes, longer for fragments.
- Only 20% of circulating PTH is the full length PTH
- The fragments have a half life of 3-4 hours and are filtered by the kidney
- Assay for this requires 2 Ab as the fragments need to be measured- and the biologically active is what we need
Endocrine control of calcium and phosphate metabolism by Prof Seal
What is corrected calcium?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Looking for whats biologically active
Such as low album- make calcium look very low.
Accounts for bound Calcium in plasma
Specifically Albumin
Endocrine control of calcium and phosphate metabolism by Prof Seal
Calcium correction and Acidosis
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Calcium can be displaced in acidosis
If in phlebotomy the tornique is on too long, the blood goes into a state of acidosis.
SO MUST DO CALCIUM FROM FREE FLOWING BLOOD
Endocrine control of calcium and phosphate metabolism by Prof Seal
Relationship between serum Ca2+ and PTH secretion
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Very tightly controlled
When interpreting a high Calcium, you should have NO PTH in the blood stream.
Endocrine control of calcium and phosphate metabolism by Prof Seal
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Very tightly controlled
When Vit D is high, PTH is turned off.
Endocrine control of calcium and phosphate metabolism by Prof Seal
Actions of parathyroid hormone
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
- Stimulate osteoblasts to produce M-CSF and RANK ligand for increased bone resorption
- Increase Ca2+ reabsorption in the distal convoluted tubule
- Increase phosphate excretion
- Increases 1-α hydroxylase in the proximal tubule
*
Endocrine control of calcium and phosphate metabolism by Prof Seal
Actions of PTH in the kidney
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and 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
Endocrine control of calcium and phosphate metabolism by Prof Seal
Actions of parathyroid hormone on bone
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
- Stimulates osteoblasts
- Production of M-CSF and RANKL
- Osteoclast differentiation
- Bone resorption, increased calcium and phosphate
- Release of growth factors to stimulate maturation of osteoblasts and new bone formation
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Endocrine control of calcium and phosphate metabolism by Prof Seal
What is the function of Vitamin D?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Negative feedback of PTH
Endocrine control of calcium and phosphate metabolism by Prof Seal
What is PTH RP
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
- PTH-related peptide
- Transepithelial calcium transport in the kidney placenta and mammary gland.
- Sent aside by Osteoblasts and activates the osteoclast in bone
- Smooth muscle relaxation in the uterus, bladder, gastrointestinal tract and arterial wall.
- Cellular differentiation and apoptosis of multiple tissues.
- PTHrP is important in development.
- Skeletal and dental
- Haematopoietic
- Mammodevelopment
- Embryonic gene deletion is lethal in mammals.
- Role in lactation to release because from the bone from a production
- Morning placenta to transport calcium from the mother to the foetus
- Seen in some forms of cancer- seen in malignancy
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Endocrine control of calcium and phosphate metabolism by Prof Seal
Where is Vit D syntheised?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
In the skin, in the presence of UV light
Ubiquitous and constant
REGULATORY: 1α hydroxylase at CYP27B1 to form ________
Endocrine control of calcium and phosphate metabolism by Prof Seal
What is the function of Vit D?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Increases Ca2+ absorption in the gut
Requires CaBP’s - synthesis stimulated by Vitamin D
Synergises with PTH on bone
Inhibits PTH synthesis
Inhibits 1a-hydroxylase
Endocrine control of calcium and phosphate metabolism by Prof Seal
What are Vit D receptors?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors.
Endocrine control of calcium and phosphate metabolism by Prof Seal
How is calcium transported across the epithelial cells of the intestine?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Acitvated by VitD
Endocrine control of calcium and phosphate metabolism by Prof Seal
How does VitD Act in the bone
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Normal: Maturation of osteoblasts
High: Downreg of Osteoclast action
Endocrine control of calcium and phosphate metabolism by Prof Seal
Where else is Vit D present?
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Vitamin D receptors found in more than 30 different cell types e.g keratinocytes in the skin, lymphocytes, macrophages, adipocytes, pancreatic β cells, cells of breast, testis, ovary, prostate, colon etc.
Several tissues can also locally synthesis 1,25 (OH)2D from circulating 25(OH)D because they have 1α-hydroxylase (CYP27B1). Tissues/cells include macrophages and monocytes, keratinocytes, breat tissue, parathyroid, colon, placenta etc.
Endocrine control of calcium and phosphate metabolism by Prof Seal
Overall actions of FGF23 in calcium and phosphate homeostasis.
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Regulation
Increased FGF 23
high Phosphate
High 1,25(OH)2 Vitamin D
Action
increases phosphate excretion
inhibits 1a-hydroxylase (CYP27B1)
Inhibits PTH Secretion
Endocrine control of calcium and phosphate metabolism by Prof Seal
Control of serum phosphate concentration by FGF23, PTH, and vitamin D (1,25-dihydroxyvitamin D).
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
PTH
Increases PO4 via bone resporbtion activating Osteoclast
And stimulates Vit D
Vit D
Increases phosphate
via GUT to increase absorption via protein transporters
FGF23
Decreases Phosphate.
Supresses 1a hydroxylase, inhibits gut Pi absorption, inhibits Kidney reabsorption
Endocrine control of calcium and phosphate metabolism by Prof Seal
Actions of Vitamin D elsewhere
*LOB: Describe the process of calcium and phosphate homeostasis in relation to its endocrinological control and the roles of bone, parathyroid glands and kidney
Endocrine control of calcium and phosphate metabolism by Prof Seal
Causes of Hypocalcaemia
Low PTH/Action
Hypoparathyroidism
Pseudo-hypoparathyroidism
Pseudo- pseudo- hypoparathyroidism
Activating mutation of Ca2+ receptor
High PTH
Vitamin D deficiency
Renal Disease
Liver disease
Poor Dietary Ca
Malabsorption
Chelation
Massive Blood transfusion
Endocrine control of calcium and phosphate metabolism by Prof Seal
Causes of Hypercalcaemia
High PTH
1’ Hyperparathyroidism
Cancer
Low PTH
Cancer
Hypervitaminosis D
Exogenous
Granulomatous Disease
(10% cases extra renal conversion of 25-OH D 1,25-OH D)
Increased Bone Turnover
Acromegaly
Thyrotoxicosis
What are primary, secondary and tertiary hyperparathyroidism?
1’ Hyperparathyroidism
Commonest cause of elevated PTH and calcium levels
- 0.5-5 per 1000
- older than 40 years
- female-to-male ratio of 3:1
- 85% of cases are single adenoma
- 15% caused by diffuse hyperplasia
- < 1% by parathyroid carcinoma
- May be related to multiple endocrine neoplasia (MEN) (Adenomas of multiple glands)
2’ Hyperparathyroidism
compensatory hyperfunctioning of the parathyroid glands caused by hypocalcaemia or peripheral resistance to PTH.
chronic renal insufficiency,
calcium malabsorption,
vitamin D deficiency,
deranged vitamin D metabolism.
3’ Hyperparathyroidism
occurs following previous secondary HPT in which the glandular hyperfunction continue despite correction of the underlying abnormality,
renal transplantation.
But the parathyroid is so over conditioned it no longer responds to negative feedback and control
Hormonal Causes of the Hypercalcaemia of Malignancy
PTH
Small Cell Lung Cancer
PTH-RP
Lung
Lymphoma
multiple myeloma
Osteoclast-activating factor
Lymphoma
Multiple myeloma
Metastatic Solid tumours
lung
breast
Kidney
prostate
Why do Granulatomous Diseases effect Vit D?
Macrophages express 1 alpha hydroxylase
This activates vitamin D
Overactivates Vit D
Diseases include:
Sarcoidosis
Tuberculosis
Berylliosis
Mycoses
Miscellaneous causes of Hypercalcaemia
HYPERCALCAEMIA
Immobilization
Recovery from renal transplant
Familial hypocalciuric hypercalcemia
Milk-alkali syndrome
Thiazide diuretics
ASTRONAUTS??
A: Acromegaly
S: Sarcoidosis
T: Thyrotoxicosis
R: Renal failure
O: Osteolytic bone metastases
N: Vitamin D excess
A: Addison disease
U: Use of thiazide diuretics
T: Thyroid hormone excess
S: Vitamin A excess
Familial Hypercalcaemia Hypocalciuria
- Most cases are associated with loss of function mutations in the CaSR gene, which encodes a calcium-sensing receptor
- Autosomal dominant (test family)
- Asymptomatic
- Hypercalcaemia
- Hypocalciuria
- (Ca excretion rate < 0.02mmol/L/24hr)
- Normal to high PTH
- Hypermagnesaemia
- Normal bone Mineral density
No disease outcome.
Symptoms of Hypercalcaemia
“stones, bones, abdominal groans and psychiatric moans”
Short QRS
What is Band Keritopathy?
Cloudy band of calcium deposits across the cornea.
Hyperparathyroidism
Diagnostic Algorithm for Hypercalcaemia
Treatment Hypercalcamia
Saline Rehydration 3-6L
Frusemide
Pamidronate Infusion 15-90mg
Calcitonin 400iU im qds
Prednisolone 40mg
Dialysis
Treatment Hyperparathyroidism
- Surgery
- Parathyroidectomy
- Medical
- Observation
- Bisphosponates (inhibits osteoclasts)
- Calcimimetics (Cinacalcet) ( allosteric activators of the CaR, enhancing signaling and decreasing PTH)
Causes of Impaired Parathyroid Hormone Secretion or Action
Primary hypoparathyroidism
Congenital
Autoimmune
Secondary hypoparathyroidism
After neck surgery or trauma
Radioiodine
Neonatal
Hypomagnesemia
Hypermagnesemia
Causes of Vit D deficiency
Liver/kidney disease (synthesis)
Resistance to hormone (receptor)
Mal-absorption
Dietary insufficiency
Poor exposure to sunlight
Sun block
Obesity
Latitude
Skin pigmentation (melanocytes)
Endocrine responses to vitamin D deficiency.
How do we stop blood samples clotting?
To reduce Ca2+
Reversible anticoagulant
Citrate
WARNING for lots of blood transfused- recorrected by clotting factors and calcium
Antifreeze poisoning
Ethylene glycol acts on same CYP as alcohol but stronger
Causes acidosis
Acidosis reduces Ca
Symptoms of Hypocalcaemia
prolonged QT
What is Troussau’s sign
Muscular cramp when acidosis via BP cuff
What is Chvosteks sign
Tap the facial nerve for mouth twitching
What is Chvosteks sign
Tap the facial nerve for mouth twitching
Comparing ricketts, osteomalacia, osteoporosis
Typical signs and symptoms of Vitamin D deficiency
Aches and pains in bones
Proximal myopathy
Mild hypocalcaemia - 2o hyperparathyroidism
Hypophosphataemia and hyperchloraemic acidosis
Bone deformities - osteomalacia
Treatment of Hypocalcaemia
Treat underlying cause
Discontinue offending drugs
Correct other electrolyte disorders
Oral (enteral): Up to 2g per day
Vitamin D supplementation
Treatment of Severe Hypocalcaemia
Iv 10ml 10% Calcium gluconate diluted in 200ml N saline over 10 minutes
(gluconate chelates calcium for transport)
Side Effects.
Carpopedal spasm
Fitting
Arrhythmia
Calcium < 1.7mmol/l
Treatment of Vitamin D Deficiency
Calcium and vitamin D tablets 800-1000IU daily
Vitamin D injection 300 000U im every 6 months
Alpha calcidol (1alpha hydroxy vitamin D) 0.25-1mg daily
Pseudohypoparathyroidism
NO QUESTIONS JUST APPRECIATE
Post receptor defect of PTH Receptor
Low Ca2+
High PO4
Low Vit D Hydroxylation
High PTH
Body habitus
Short stature
Obesity
Round face
Reduced IQ
Brachydactyly
Ectopic Calcification
Valgus vs Varus
Valgus- away from
Varus- into
So hip valgus, knee varus
ALWAYS paired
Calcium Metabolism (SIMPLE)
