Calcium Metabolism Flashcards
What is Calcium vital for?
Bone formation
Nerve and muscle function
How is calcium important for nerve and muscle function?
Ca2+ stimulates synaptic vesicles to release neurotransmitter into synaptic cleft
Calcium released from sarcoplasmic reticulum binds to Troponin at the TnC part of this 3 complex protein. This causes a conformational change pulling the protective Troponin-tropomyosin complex away exposing the actins active sites to the myosin heads
What can happen as a result of a sudden change in calcium levels?
Seizures and palpitations due to changes in Ca2+ levels in nerves
Which gland is responsible for regulating Calcium levels?
Parathyroid glands
What is the hormone that the parathyroid glands synthesise and secrete?
Parathyroid hormone (PTH)
Which 3 parts of the body does PTH act on regulating Ca2+ levels?
Bone
Kidney
Gut
Where are the parathyroid glands located?
Posterior to the thyroid gland
They are completely separate in structure and function
How many parathyroid gland tissues are there in the parathyroid and how are they distributed?
There are 4
2 in each lobe
Each lobe has an upper parathyroid and lower parathyroid
What is the embryological origin of the lower left and right parathyroids?
The III Brachial arch
What is the embryological Origin of the left and right upper parathyroids?
The IV Brachial Arch
What are the cells called that secrete PTH in the Parathyroid gland?
Chief cells
What type of hormone is PTH?
Peptide hormone
What form is PTH first produced in?
PreproPTH
How is preproPTH processed to its active form?
Signal sequence cleaved out of PreproPTH forming proPTH in ENdoplasmic reticulum
ProPTH enters Golgi and is cleaved to active PTH form
Generally what does PTH do to the:
-Gut/intestines
-Bone
-Kidney
In terms of calcium levels
Increases Ca2+ absorption in gut
Increases Ca2+ resorption from bone
Increases Ca2+ retention in kidney
What do receptors on chief cells detect?
Ca2+ levels
What affect does PTH have on Phosphate?
Causes phosphate loss
What does a patient with low phosphate levels indicate in terms of PTH?
Indicates phosphate loss so high PTH levels
What does a patient with high phosphate levels indicate in terms of PTH levels?
Indicates low phosphate loss so low PTH
What protein actually causes the phosphate loss as a result of high PTH?
FGF23
What type of molecule is Vitamin D?
A steroid hormone
How does vitamin D work inside a cell?
Works in nucleus affecting gene expression
What is required to synthesise inactive Vitamin D3 in the skin?
UV light
What is the name of the inactive Vitamin D3 synthesised in the skin?
Cholecalciferol
How is the Inactive Vitamin D3 (cholecalciferol) converted into Active Vitamin D3?
Hydroxylation in the LIVER
Then Hydroxylation in the KIDNEY
Molecule is now ACTIVE VITAMIN D (Calcitriol)
How is vitamin D2 and Vitamin D3 obtained?
Vitamin D2 = diet
Vitamin D3 (cholecalciferol) = diet fish and made in skin
What must happen to vitamin D2 before it can become activated Vitamin D
Must be converted to inactive vitamin D3 (cholecalciferol)
What is the role of Active Vitamin D3?
Increases Ca2+ levels in the body
How does activated Vitamin D3 increase calcium levels?
Stimulates kidney to produce enzymes (C-1 Hydroxylase) to convert cholecalciferol into active vitamin D3
Vitamin D3 stimulates kidney to re absorb more Ca2+
Stimulates gut to absorb more Ca2+
How does PTH increase resorption of Ca2+ from bone into the blood?
Increases osteoclast activity so more bone is broken down and Ca2+ and phosphate released into blood
What is the definition of Hypercalcaemia?
Serum calcium> 2.51mmol/L
So higher than normal range of serum calcium
What are the 4 main symptoms of Hypercalcaemia?
-Polydipsia and polyuria (Nephrogenic diabetes Insipidus)
-Constipation
-Kidney stones
-Confusion
Why does high calcium levels cause Nephrogenic Diabetes Insipidus?
Calcium reduces nephrons sensitivity to ADH by degrading aquaporins so less water is reabsorbed
To remember symptoms of Hypercalcaemia what pneumonic should I remember?
Bones, stones, groans and psychic moans
What are being referred to in remembering the symptoms of Hypercalcaemia in Bones, groans, stones and psychic moans?
Bones = painful bones due to HIGH PTH causing abnormally high bone resorption/remodelling
Groans = abdominal pain from constipation
Stones= kidney stones (normally made of calcium)
Psychic moans = confusion
What are the 2 causes of Hypercalcaemia?
PTH Independant
PTH dependant
What does it mean I terms of PTH levels if the cause of Hypercalcaemia is PTH independent?
PTH LOW
What does it mean in terms of PTH levels if the cause of Hypercalcaemia is PTH dependent?
PTH HIGH
Describe what happens in PTH Independent Hypercalcaemia:
PTH levels are actually low
But PTH related peptides are being made (PTHrp)
These PTHrp act on PTH receptors stimulating the actions that PTH would cause like:
-increased bone resorption
-increased re absorption of Ca2+ in kidneys
-increased Ca2+ absorption in gut
What is the most likely explanation if somebody has a PTH independent Hypercalcaemia?
So PTH levels are low but Serum Ca2+ > 2.6
Cancers producing PTH related peptides
What cancers cause high calcium?
Myeloma = cancer of blood cells (plasma cells)
Bone metastases = cancer has spread to bone activating more osteoclasts increasing bone resorption
PTH independant Hypercalcaemia can also be caused be things that affect/ increase Vitamin D
TB
Granulomas
What is primary hyperparathyroidism?
When there is a problem with the parathyroid gland itself causing over production of PTH
Leads to Hypercalcaemia
Why is a PTH Dependant Hypercalcaemia (Primary Hyperparathyroidism) better than a PTH independant Hypercalcaemia?
If Ca2+ levels are high and PTH levels are high it indicates that the high calcium is being cause by the parathyroid glands and not a Cancer /malignancy
So what normally causes Primary hyperparathyroidism?
A benign parathyroid adenoma
Produces more PTH
What are the effects of Primary Hyperparathyroidism on a patient?
-Hypercalcaemia symptoms (Think Bones, stones, groans, psychic moans)
-High calcium and low phosphate
-Signs of increased bone turnover (bone pain)
What is Alkaline Phosphatase a marker of?
Bone resorption rate
Increased ALP = increase bone resorption
How to treat Acute severe Hypercalcaemia?
So over 3 or 4mmol/L
Normal 2.2 - 2.6
Give IV fluids quick due to dehydration
Then treat underlying cause
What is Hypocalcaemia?
Low serum calcium
Below normal 2.2 -2.6 range
What are the Symptoms of Hypocalcaemia?
Numbness
Muscle cramps
Palpitations
Seizures
Due to neuromuscular junctions being affected
What can cause Hypocalcaemia?
Vitamin D deficiency
Hypoparathyroidism
Why does Vitamin D deficiency cause Hypocalcaemia?
Vit D needed to:
-absorb Ca2+ from gut
-reabsorb Ca2+ from urine in kidneys
What happens biochemically when vitamin D is low?
Low calcium (Hypocalcaemia)
Body stimulates PTH production causing high PTH to try and increase vitamin D synthesis and bone resorption to increase serum Ca2+
High PTH causes low Phosphate due to PTH causing production of FGF23
What causes Vitamin D deficiency?
Lack of sunlight
Pigmented or covered skin
Dietary deficiency
GI disease
Kidney disease
What condition does severe Vitamin D deficiency cause in Kids?
Rickets
What condition does serve Vitamin D deficiency cause in Adults?
Osteomalacia
Why does Rickets happen with Vitamin D deficiency?
Low Ca2+ in the body
Ca2+ and phosphate needed to mineralised bone to form strong hydroxyapatite crystals
Symptoms of Rickets
Bowed legs
Neonatal seizures
Why does Vitamin D deficiency lead to Osteomalacia?
Bone is soft due to low Ca2+ in body
Ca2+ not available to mineralised bone with phosphate
What symptoms does osteomalacia present?
Gluteal muscle weakness causing waddling gait
Multiple fractures possible
In rickets and osteomalacia is the bone structure normal?
Yes it’s just under-mineralised making it soft
What happens in the chief cells during Hypoparathyroidism?
Cell not producing PTH so:
Ca2+ not reabsorbed in kidney
Ca2+ not resorted from bone
Ca2+ not absorbed in gut
Why would phosphate levels be high in Hypoparathyroidism?
Low PTH means less phosphate loss due to less FGF23 made
What can cause Hypoparathyroidism?
Parathyroid damaged or removed in SURGERY
Pathology of parathyroid
Failed embryological development of 3rd or 4th brachial arch
How do you treat Acute Severe Hypocalcaemia
Give intravenous calcium and monitor them and their heart (ECG)
What occurs in Osteoporosis?
Cortical bone is broken down reducing bone density making bones brittle and easily broken
What is the cause of Primary Type 1 osteoporosis?
Occurs mainly in post menopausal women
Lack of oestrogen overly stimulates osteoclast activity causing more bone to be resorped/broken down than is reformed
What is the cause of Primary Type 2 osteoporosis?
Occurs in elderly men and women
Caused by reduced osteoblast function as patient ages
What are the risk factors for osteoporosis?
Post menopausal females
Family history of osteoporosis
Smoking and sedentary lifestyle
Endocrine disease
