ENDO Flashcards by Rebecca Owens

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

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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

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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)

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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.

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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

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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

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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

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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

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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.

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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)

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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

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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

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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

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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

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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.

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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.

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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
*

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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

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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

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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 ________

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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

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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.

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# Endocrine control of calcium and phosphate metabolism by Prof Seal How is calcium transported across the epithelial cells of the intestine? ## Footnote *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 ## Footnote *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? ## Footnote *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. ## Footnote *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). ## Footnote *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 ## Footnote *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 < 0.02 mmol/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)

ENDO Flashcards

(62 cards)