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Endo 1.16 Endocrine control of calcium and
phosphate metabolism
• Calcium and phosphate in the body
• Endocrine control of calcium and phosphate
• Causes of hyper- and hypocalcaemia
• Hyperparathyroidism
• Vitamin D deficiency
• Endocrine control of bone turnover osteoporosis and osteomalacia
Functions of Calcium
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Bone growth and remodelling
Secretion
Muscle contraction
Blood clotting
Co-enzyme
Stabilization of membrane potentials
Second messenger/stimulus response
coupling
Distribution of calcium in the body
Skeleton - 99%
Intracellular - 1%
Extracellular - 0.1%
Ionized
45%
Ca2+
2.2-2.6 mmol/l
Bound to
Plasma proteins
45%
PTH, Vit D
Ions e.g. Phosphate,
lactate, HCO3- 10%
Functions of phosphate
[ H2PO4- and HPO42-]
• 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
Distribution of phosphate
Skeleton - 90%
Intracellular - 5%
Extracellular - <0.03%
50% free
0.8-1.2 mmol/l
50% bound
Controlled by kidneys + effects of PTH
Daily turnover of calcium and
phosphate based on an intake of
1000mg/day
Ca2+  1
Pi
PTH,
Vitamin D
Ca2+
Ca2+ .B
Bound and free in equilibrium
Reduced plasma proteins and alkalosis
Acidosis
Ca2+
Ca2+
Bone - an important store of
calcium, phosphate and
other ions
Osteolysis - calcium is taken up from the
extracellular fluid into the osteocytes and
transported to the bone surface
Bone remodelling
Control of calcium and
phosphate
PTH and vitamin D increase
Ca2+ and decrease Pi
Calcitonin decreases Ca2+
Parathyroid glands
• 4 glands on upper and lower poles of each
lobe of the thyroid gland
• Supernumerary glands not uncommon
(source of PTH excess?)
• 30-50 mg weight
• Chief cells and oxyphill cells
• Supplied by blood from thyroid arteries
(thyroid surgery)
Synthesis of
parathyroid hormone 84
a.a. protein
Sensing circulating
calcium concentrations
and control of PTH
secretion
Functions of PTH
BONE
• Stimulates osteolytic osteolysis
• Stimulates bone resorption
KIDNEY
• Increases Ca2+ reabsorption, decreases
phosphate, HCO3- and Na+ reabsorption
• Increases 1a-hydroxylase enzyme
(25, OH-D
1,25 OH-D)
?
Hyperparathyroidism
hypercalcaemia
CLINICAL MANIFESTATIONS OF
HYPERCALCAEMIA
• Neurological - lethargy, confusion, loss of
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appetite
Psychiatric - depression, hallucination
GI - vomiting, constipation, anorexia
Renal - nephrogenic diabetes insipidus
Cardiovascular - increased contractility,
shortened ventricular systole
Rheumatological - joint and bone pains
Bone erosion hyperparathyroidism
BIOCHEMICAL ANALYSIS OF
HYPERPARATHYROIDISM
• SERUM MEASUREMENTS
High PTH, calcium, alkaline phosphatase
Decreased phosphate, decreased
bicarbonate
hyperchloraemic acidosis
• URINE MEASUREMENTS
Increased calcium, phosphate and cAMP
Major causes of hypercalcaemia
• 1o Hyperparathyroidism
• Malignancy (PTHrp)
Some other causes:
• Vitamin D related e.g. excess;
•
sarcoidosis, tuberculosis and other
granulomatous diseases, excess intake
• High bone turnover e.g. hyperthyroidism,
immobilization
• Renal failure
Parathyroid hormone related peptide (PTHrp)
• 3 splice variants from a single gene
• synthesized in various tissues
• discovered in patients with cancers of squamous cell origin
Does not stimulated renal
conversion of 25hydroxycholecalciferol
Unlike PTH
Synthesis of active
vitamin D
One hydroxylation in liver - C25
Second hydroxylation in
kidney - C1
Vitamin D receptors
Actions of Vitamin D in Calcium
homeostasis
• Increases Ca2+ absorption in the gut
Calcium absorbed by:
active uptake/extrusion
endocytosis/exocytosis
trans-cellular route
All require CaBP’s - synthesis stimulated by
Vitamin D
• Synergises with PTH on bone
• Inhibits PTH synthesis
• Inhibits 1a-hydroxylase
Absorption of calcium from the gut
Other actions of vitamin D
• Stimulates differentiation of monocytes to
macrophages
• Inhibits proliferation of T and B lymphocytes
• Anti-proliferative action on skin cells
(psoriasis?)
• Anti-proliferative action on certain tumours
• Increases production of 17b hydroxysteroid
dehydrogenase (oestradiol --> oestrone)
• Stimulates hair growth (alopecia?)
Causes of Vitamin D deficiency
Pseudo
• Liver/kidney disease (synthesis)
• Resistance to hormone (receptor)
(Rickets)
• Mal-absorption
• Dietary insufficiency
• Poor exposure to sunlight
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
Pseudohypoparathyroidism
• 1942 - Fuller Albright - hypocalcaemic and
hyperphosphataemic: PTH resistance
• Defect in stimulatory G protein (Type 1a)
• Albright’s Hereditary Osteodystrophy (AHO) short stature, short neck and fingers, obesity
• Other types not associated with abnormal Gs
Receptor/signal transduction defects?
Some causes and treatment of hypocalcaemia
Causes
• Vitamin D deficiency (2o hyperprathyroidism)
• Hypoparathyroidism (thyroid surgery)
• Pseudohypoparathyroidism
• Neonatal
• Activating mutation of Ca2+ receptor
Treatment
• Vitamin D - oral (injectable): cheap
• Calcium - acutely
PTH (recombinant): expensive - osteoporosis?
Osteoporosis - loss of bone mass
Osteomalacia - loss of bone
mineralization
Bone remodelling and the
action of vitamin D and PTH
Vit D
PTH
Vit D
PTH
Osteoporosis - low bone mass
and microarchitectural
deterioration of bone tissue
• Endocrine: hypogonadism, glucocorticoid
excess, hyperthyroidism
• Haematopoietic disease: e.g. leukaemia, sickle
cell disease
• Connective tissue disease:
• Drug induced: e.g. heparin, anticonvulsants
• Renal disease
• Nutritional: eg malabsorption
Bone density and age