Parathyroid Gland, Calcium And Phosphate Regualtion Flashcards
Calcium
Plasma calcium levels
Calcium is used for ?
Adult human contains ~1000 g of calcium
99% is sequested in bone in the form of hydroxyapatite crystals (Ca10(PO4)6(OH)2)
Skeleton provides
structural support
major reserve of calcium
Helps to buffer serum levels
Releasing calcium phosphate into interstitium
Up taking calcium phosphate
~300-600 mg of calcium is exchanged between bone and ECF each day
PLASMA CALCIUM LEVELS - Serum calcium 2.2-2.6mM
ECF [Ca2+] a very small fraction of total-body calcium (>1% )
Distributed among three interconvertible fractions
Biologically active free ionized [Ca2+] closely regulated to 1.0-1.3mM
Most of the calcium in the body is stored in skeleton
Calcium is used for: Building and maintaining teeth and bones Regulating heart rhythm Easing insomnia Regulation of passage of nutrients in and out of cells Assist in normal blood clotting Maintaining nerve and muscle function Lowers bp Normal kidney function Enzyme activity and hormone receptor binding Reducing cholesterol and colon cancer levels IC signalling pathways
Regulation of Ca and phosphate
Three hormones involved
Parathyroid Hormone (PTH)
Calcitriol, - also called 1,25-dihydroxycholecalciferol, or 1alpha,25-dihydroxyvitamin D3 - hormonally active metabolite of vitamin D which has three hydroxyl groups.
It can be abbreviated 1
Parathyroid gland (PTG)
PTG - Contains adipose tissue
Chiefs cells
Oxyphil cells
Parathyroid hormone (PTH) synthesis - PTH has no serum binding protein
Straight chain polypeptide hormone- Pro-pre-hormone (115AA long), cleaved to 84AA
Synthesis is regulated both at transcriptional and post transcriptional levels
Low serum calcium up-regulates gene transcription
High serum calcium down-regulate
low serum calcium prolongs survival of mRNA (mechanism not known)
T ½ is 4 min and released PTH cleaved in liver
PTH continually synthesised but little stored
Chief cells degrade hormone as well as synthesis it
Cleavage of PTH in chief cells accelerated by high serum calcium levels
Calcium receptor (CaR)
Is part of a GPCR - that activates PLC which leads to IP3 and DAG production, therefore increased Ca2+ release from IC stores
This increase in Ca2+ in the cell causes phosphorylation of PLA which produces AA which go and inhibit PTH secretion in the PTG
This therefore inhibits PTH secretion and reduces PTH synthesis
Therefore if there is too much calcium in the blood then this will feedback negatively to the PTG
PTH target organs and its physiological effects
Bone - Increase resorption
Intestine - Activates Vitamin D and hence increases transcellular uptake from GI tract
Kidney - Decreases loss to urine
Ca2+ and phosphate in the kidney
In biological systems, phosphorus is found as a free phosphate ion in solution and is called inorganic phosphate, to distinguish it from phosphates bound in various phosphate esters.
Inorganic phosphate is generally denoted Pi and at physiological (homeostatic) pH primarily consists of a mixture of HPO2
PTH action in the gut
Dietary intake of calcium is typically 1000 mg/d
Only 30% of which is absorbed by a paracellular uptake effective when [Ca2+] is not limited
Absorption is significantly increase by Vitamin D via a transcellular uptake
PTH stimulates conversion of vitamin D to its active form which
Calcium balance and actions of PTH on bone
Skeleton has two primary functions
structural support and maintaining serum Ca2+ conc.
maintenance of serum Ca2+ conc is the priority
Diseases in bone that affect structural integrity have consequences for serum calcium conc. and
vice versa
Calcium phosphate crystals found within collagen fibrils - Ca2+ + Pi = hydroxyapatite crystals
Bone deposition:- osteoblasts produce collagen matrix which is mineralized by hydroxyapatite
Bone reabsorption - osteoclasts produce acid micro-environment hydroxyapatite dissolves
Bone is dynamic
Actions of PTH on bone - 1-2 hrs PTH stimulates osteolysis
PTH induces osteoblastic cells to synthesis and secrete cytokines on cell surface
Cytokines stimulate differentiation and activity in Osteoclasts and protect them from apoptosis
PTH decreases Osteoblasts activity exposing bony surface to Osteoclasts
Reabsorption of mineralized bone and release of Pi (inorganic phosphate) and Ca2+ into extracellular fluid
Calciferol - source and activation of vitamin D
The body itself makes vitamin D when it is exposed to the sun
Cheese, butter, margarine, milk, fish and some cereals are exogenous sources of vitamin D
1) “ Vitamin” D3 (Cholecalciferol) is the hormone- precursor molecule required to synthesis 25(OH)D - This is the crucial element provided mostly by UVB light on skin, can be taken in supplement form & diet (fish & meat)
2) 25(OH)D is the pre-hormone substrate. Its produced in the liver from D3(Cholecalciferol)
3) 1,25(OH)2D (Calcitriol) is the active hormone. It is produced in the kidney and elsewhere from 25(OH)D
How does D3 compare to hormones:
Vitamin D3 is NOT secreted by a classical endocrine gland, but its metabolite acts as a hormone by a mechanism similar to that of thyroid and steroid hormones
Vitamin D3 formed in the skin or from diet and absorbed in the gut bound to protein in blood (CBP)
Calcitonin
Helps regulate calcium and phosphate in the blood
Reduces calcium levels in the blood by inhibiting osteoclasts and decreasing reputable of Ca2+ from the kidneys
When calcium balance goes wrong
Chronic hypercalcaemia - Occurs in the renal calculi
Get kidney damage, constipation, dehydration, tiredness and depression
Chronic Hypocalcaemia - hyper-excitability of the NMJs
Lower serum calcium causes increase Na+ entry into neurones, leading to depolarisation and increase likelihood of AP
Therfore get - pins and needles, tetany (muscle spasms), paralysis and convulsions
Aetiology of Hypercalcaemia
Malignant osteolytic bone metastasis
Multiple myeloma
Common cancers that metastasise to bone causing lytic lesions and hypercalcemia
Breast Lung Renal Thyroid
Due to the osteolytic nature of these cancers - calcium in the blood will be very high
Prostate cancer is also a common cause of bone metastasis, However, it causes osteoblastic metastasis that do not cause hypercalcemia
Common sites for bone metastasis - vertebrae, pelvis, ribs, proximal parts of humerus and femur , and skull
Hyperparathyroidism - This would occur when the serum calcium > 3.0 mmol/L
At high calcium levels the polyuria can lead to dehydration which then exacerbates the hypercalcemis.
This can lead to - Lethargy, Weakness, Confusion, Coma, Renal failure
Rehydration is the mainstay of treatment
In patients with malignant hypercalcemia and coma this is not necessarily a terminal event. After rehydration many can return home
Hyperparathyroidism
Primary –
One of the 4 parathyroid glands develops an adenoma and secretes excessive parathyroid hormone.
This causes serum calcium to rise and serum phosphate to fall
Secondary –
All 4 parathyroid glands become hyperplastic (increase in the number of cells in the organ (these are not cancerous but they may become cancer)
This is seen in patients with Vitamin D deficiency - Vitamin D Deficiency means that their calcium absorption is low resulting in low serum calcium levels, that then causes PTH levels to rise - increase use of PTH glands means hyperplasia occurs
Vitamin D deficiency can be dietary/environmental, or seen in chronic renal failure due to failure of the 25 hydroxylation of Vitamin D
SYMPTOMS: PRIMARY HYPERPARATHYROIDISM (adenoma in one of the PTGs)
Stones – kidney stones. Also polyuria due to impaired sodium and water reabsorption
Moans – tired, exhausted, depressed
Groans – constipation, peptic ulcers, pancreatitis
Bones – bone and muscle aches
Calcium and neuronal activity
Symptomatic hypocalcemia
To understand the symptoms of hypocalcemia/hypercalcemia you need to understand that calcium raises the threshold for nerve membrane depolarisation and therefore the development of an action potential:
So:
Hypercalcemia leads to supression of neuronal activity – lethargy, confusion, coma
Hypocalcemia leads to ‘excitable’ nerves – tingling, muscle tetany and even epilepsy
SYMPTOMATIC HYPOCALCEMIA
Seen mostly in post total-thyroidectomy patients (because of inadvertent removal/ischaemia of parathyroid glands)
Symptoms can develop when serum calcium falls below 2.10 mmol/L and can start within 6 hrs of thyroidectomy
Get tingling around mouth and fingers, and can sometimes get tetany (involuntary contractions) of muscles (due to the lower threshold for an AP) - e.g. carpopedal spasms - v painful cramps in muscles
Osteomalacia vs osteoporosis
OP is when the bone is fully mineralised but the structure has been degraded by overworking OC, or underworking OB
OM is where the bones structural integrity is the same as normal bone, but the bone is undermineralised (not enough vitamin D) therefore making it weak and soft
Osteomalacia is due to vitamin D deficiency:
OM in children is called rickets - can be dietary (i.e. environmental), or it can be herditary - due to chronic renal disease such as renal osteodystrophy
OM in adults causes bone pain, muscle weakness and may lead to deformity
