Calcium, phosphate and parathyroid hormone metabolism

1. BASIC SCIENCE:
CALCIUM AND PHOSPHATE
METABOLISM
1
11th September 2023
Presenter:
Dr Siti Nur Izzati (ED)
Dr Tan Si Yuan (ED)
Dr Nurshafinaz Salmah (Paeds)
Supervisor: Assoc Prof Dr Suhaimi Hussain

2. 1) Normal Calcium and Phosphate Metabolism
 Parathyroid Hormone
 Calcium
 Vitamin D
 Calcitonin
 FGF 23
2) Disorder of Calcium and Phosphate Metabolism
2
OUTLINE OF PRESENTATION

3.  Parathyroid Hormone
 PTH actions
 Regulation of PTH
 Calcium
 Normal Value
 Distribution of Calcium in the body
 Calcium turnover
 Calcium homeostasis
 Vitamin D
 Vitamin D activation
 Vitamin D actions
 Calcitonin
 Calcitonin actions
 FGF 23
 Function of FGF 23
 Clinical significance of FGF 23
2
Normal Calcium and Phosphate Metabolism

4. Parathyroid glands
3
 The smallest endocrine gland
 4 parathyroid glands posterior
to thyroid gland (6x3x2mm)
 The blood supply to the
parathyroid glands is from the
thyroid arteries.
 Total weight : 200 mg
 Accidentally can be removed
during thyroid surgery
 2 types of cells: chief &
oxyphil (modified chief cells
that no longer secrete
hormone)

5. PTH
• Source of secretion: chief cells of the parathyroid glands
• Chemistry: A linear polypeptide hormone, MW 9500,
consists
84 aa
• Half life: 10 minutes
• Degraded and excreted by liver and kidney
4

6. PTH action
The overall action of PTH is to
 plasma Ca2+
 plasma phosphate
– Bones: stimulates Ca2+
resorption
– Kidney: stimulates Ca2+
reabsorption in the distal
tubule of the kidney and to
inhibit reabsorption of
phosphate (thereby
stimulating its excretion).
– Intestine: indirectly stimulates
Ca2+ absorption by
stimulating 1,25-
dihydroxycholecalciferol
synthesis
5

7. 6

8. 19/06/2023 7
Regulation of PTH secretion

9. Calcium
 Normal value of Calcium
•Total body content: Child: 8.8-10.8 mg/dL; 2.2-
2.7 mmol/L (Medscape)
 Calcium is distributed
 In bones ~99%
 As exchangeable calcium pool in
plasma:~1%
 3 forms of calcium in plasma
i. Free ionized~50%;essential for vital
function (neuronal activity, muscle
contraction, cardiac activity, etc)
ii. Calcium complexes with anions
(eg:citrate, phosphate) ~ 10%
iii. Calcium bound to plasma
protein.eg:albumin,globulin~
40%
9

10. Physiological importance of Calcium
 Calcium salts in
bone provide
structure integrity
of the skeleton
 Ca2+ in extracellular
and cellular fluids is
essential to normal
function of a host of
biochemical
processes
10
Ca2+
Neuronal
activity
Skeletal
Muscle
activity
Cardiac
activity
Smooth
muscle
activity
Secretory
glands
activity
Blood
Coagulation
Bone and
teeth
formation
Cell division
and growth
Calcium

11. Calcium Balance
 Input to plasma calcium : intestinal absorption and
bone resorption
 Output to plasma calcium: renal excretion and bone
formation
 Calcium balance between input and output is
regulated by PTH, calcitonin and Vit D actions on
intestine, bone and kidneys
11

12. Daily Calciumturnover
12
Vit D
+
+
PTH
Vit D
calcitonin
-

13. Urinary excretion of Phosphate
 Renal phosphate excretion is controlled by an overflow
mechanism
 when phosphate concentration in the plasma is below the critical
value of about 1 mmol/L, all the phosphate in the glomerular
filtrate is reabsorbed and no phosphateis lost in the urine.
 above this critical concentration, the rate of phosphate loss is
directly proportional to the additionalincrease.
However, PTH can greatly increase phosphate excretion by the
kidneys, thereby playing an important role in the control of
plasma phosphate concentration and calcium concentration.
15

14. Effect of PTH on Calcium and Phosphate
Concentrations in the ECF
 Rise in calcium concentration
is caused by :
1. Effect of PTH to increase
calcium and phosphate
absorption from the bone
2. A rapid effect of PTH to
decrease the excretion of
calcium by the kidneys.
 Decline in phosphate
concentration is caused by a
strong effect of PTH to increase
renal phosphate excretion, an
effect that is usually great enough
to override increased phosphate
absorption from the bone

15.  Parathyroid Hormone
 PTH actions
 Regulation of PTH
 Calcium
 Normal Value
 Distribution of Calcium in the body
 Calcium turnover
 Calcium homeostasis
 Vitamin D
 Vitamin D activation
 Vitamin D actions
 Calcitonin
 Calcitonin actions
 FGF 23
 Function of FGF 23
 Clinical significance of FGF 23
2
Normal Calcium and Phosphate Metabolism

16. 19

17. Vitamin D3: Actions
22

18.  Parathyroid Hormone
 PTH actions
 Regulation of PTH
 Calcium
 Normal Value
 Distribution of Calcium in the body
 Calcium turnover
 Calcium homeostasis
 Vitamin D
 Vitamin D activation
 Vitamin D actions
 Calcitonin
 Calcitonin actions
 FGF 23
 Function of FGF 23
 Clinical significance of FGF 23
2
Normal Calcium and Phosphate Metabolism

19. Calcitonin
• Calcitonin is a peptide hormone
secreted by the parafollicular cells or
clear cells (C cells) situated amongst
the follicles in the thyroid gland
• Calcitonin is a polypeptide chain with
32 amino acid, synthesized from a
larger prohormone
• Plasma level : 1-2ng/dL; half life ; 5-10
mins
24
parafollicular or C cells
• Degraded and excreted by liver and
kidney
Calcitonin

20. Calcitonin:Actions
Calcitonin has the ability
to decrease blood
calcium levels
– Bone: stimulates
osteoblastic
activity, stimulates
deposition of
calcium on bones,
inhibits bone
resorption by
inhibiting the
activity of
osteoclasts
– Kidney: inhibits
tubular reabsorption
of Ca 2+ and PO -,
4
– Intestine: inhibits
absorption of Ca2+
from intestine to
blood
Calcitonin has minor effects on
calcium absorption in the kidney
tubules and GIT

21. 27

22. Actions of Ca2+ regulatoryhormones
Bone Kidney GIT
PTH  bone
resorption
(Ca2+ &PO4
-)
 Ca2+ and 
PO4
-
reabsorption
No direct
effect
Vitamin D  bone
resorption
(in the
presence of
PTH)
 Ca2+ and 
PO4
-
reabsorption
 Ca2+ and 
PO4
-
absorption
Calcitonin  bone
resorption
(Ca2+ &PO4
-)
 Ca2+ and 
PO4
-
reabsorption
No direct
effect
28

23. Calcium Homeostasis
17

24. Increased Plasma Ca2+ Concentration Stimulates
Calcitonin Secretion
 increase in plasma Ca2+
concentration of about 10 %
 causes an immediate
twofold or more increase in
the rate of secretion of
calcitonin
 provides a second
hormonal feedback
mechanism for controlling
the plasma Ca2+
concentration
 The primary stimulus for
calcitonin secretion is
increased plasma Ca2+
concentration
30

25.  Parathyroid Hormone
 PTH actions
 Regulation of PTH
 Calcium
 Normal Value
 Distribution of Calcium in the body
 Calcium turnover
 Calcium homeostasis
 Vitamin D
 Vitamin D activation
 Vitamin D actions
 Calcitonin
 Calcitonin actions
 FGF 23
 Function of FGF 23
 Clinical significance of FGF 23
2
Normal Calcium and Phosphate Metabolism

26. FGF 23
(Fibroblast Growth Factor 23)
• FGF23 is secreted by osteocytes in response to increased calcitriol
and phosphate
• Regulate phosphate concentration in plasma by decreasing
reabsorption of phosphate in kidney which means phosphate is
excreted in urine (phosphaturia)
• Act on kidney by decreasing the expression of NPT2 (sodium
phosphate co-transporter 2) in proximal tubule of kidney
• Suppress 1-alpha hydroxylase, reducing its ability to activate vitamin
d and subsequently impaired calcium absorption

27. Function of FGF23
• Is a protein and member of fibroblast growth factor family
• Mainly participate in regulation of phosphate in plasma and vitamin d
metabolism
• Encoded by FGF23 gene in human, located in chromosome 12 and
composed of three exons
• FGF23 decrease reabsorption of phosphate in kidney
• Mutation in FGF23 can lead to increased its activity which leading to
Autosomal Dominant Hypophosphatemic Ricket (ADHR)

28. Clinical significance of FGF23
• Mutation in FGF23 which render the protein resistant to proteolytic
cleavage, lead to its increased activity and to renal phosphate loss,
in human disease ADHR
• Also overproduced by some types of tumor such as benign
mesenchymal neoplasm phosphaturic mesenchymal tumor causing
tumor-induced osteomalacia, a paraneoplastic syndrome
• Loss of FGF23 activity is thought to lead to increase phosphate level
and clinical syndrome of familial tumor calcinosis (formation of
calcium deposit in any soft tissue). Mice lacking either FGF23 or the
klotho enzyme age prematurely due to hyperphosphatemia

29. Clinical significance of FGF23
• Over-expression of FGF23 has been associated by CVS disease in
CKD patient including cardiomyocyte hypertrophy, vascular
calcification, stroke and endothelial dysfunction
• FGF23 expression and cleavage is promoted by iron deficiency and
inflammation
• FGF23 is associated with at least 7 non-nutritional disease of
hypophosphatemia:
• Autosomal dominant hypophosphatemic ricket (ADHR)
• X-linked hypophosphatemia
• Autosomal recessive hypophosphatemic ricket type 1, 2 and 3
• Tumor-induced osteomalacia
• Hypophosphatemic ricket with hypercalciuria

30. DISORDER OF CALCIUM AND
PHOSPHATE METABOLISM
• RICKETS
• HYPERPARATHYROIDISM

31. RICKETS
Defective mineralization of the bone plates caused by deficient /
impaired metabolism of calcium, phosphate or vitamin D

32. Causes of Rickets
CALCIUM DEFICIENCY
Low intake
Diet
Premature infants (rickets of prematurity)
Malabsorption
Primary disease
Dietary inhibitors of calcium absorption
(high fibre food with phytic acid, food with
oxalic acid)
PHOSPHATE DEFICIENCY
Inadequate intake
Premature infants (rickets of prematurity)
Aluminum-containing antacids
VITAMIN D DEFICIENCY
Vitamin D deficiency – Nutritional / Congenital / Secondary
Malabsorption
Increased degradation
Decreased liver 25-hydroxylase
Vitamin D–dependent rickets type 1
Vitamin D–dependent rickets type 2
Chronic kidney disease
RENAL LOSSES
X-linked hypophosphatemic rickets*
Autosomal dominant hypophosphatemic rickets*
Autosomal recessive hypophosphatemic rickets types 1 and 2*
Hereditary hypophosphatemic rickets with hypercalciuria
Overproduction of fibroblast growth factor-23
Tumor-induced rickets*
McCune-Albright syndrome*
Epidermal nevus syndrome*
Neurofibromatosis*
Fanconi syndrome
Dent disease
Distal renal tubular acidosis
* Disorders secondary to excess fibroblast growth factor-23.

33. Clinical Features of Rickets
GENERAL
Failure to thrive
Protruding abdomen
Muscle weakness (especially proximal)
Hypocalcemic dilated cardiomyopathy
Fractures (pathologic / minimal trauma)
HEAD
Craniotabes
Frontal bossing
Delayed fontanelle closure
Delayed dentition
Caries
Craniosynostosis
CHEST
Rachitic rosary
Harrison groove
Respiratory infections and atelectasis
BACK
Scoliosis
Kyphosis
Lordosis
EXTREMITIES
Enlargement of wrists and ankles
Valgus or varus deformities
Windswept deformity
Anterior bowing of tibia and femur
Coxa vara
Leg pain
EXTREMITIES
Tetany
Seizures
Stridor caused by laryngeal spasm

34. Radiological Features of Rickets
Widening of Growth Plate
Metaphyseal fraying
Normal
Metaphyseal fraying and
cupping

35. Biochemical Investigation and Diagnosis
Calcium Phosphate ALP iPTH 25-OHD 1,25(OH)2D Urine
Ca
Urine
PO4
FGF 23
NEONATE Nutritional rickets
Calcium deficiency ↓ N ↑ ↑ N ↑ ↓ ↑ ↓
Phosphate deficiency N ↓ ↑ N /↓ N ↑ ↑ ↓ ↑
Vitamin D deficiency N / ↓ ↓ ↑ ↑ ↓ ↓ / N / ↑ ↓ ↑ ↓
CHILDREN Vitamin D Dependent Rickets
(VDDR)
VDDR
Type 1
Autosomal
Recessive
N /↓ ↓ ↑ ↑ N / ↓ ↓ ↓ ↑ ↓
VDDR
Type 2
Autosomal
Recessive
N / ↓ ↓ ↑ ↑ N ↑↑ ↓ ↑ ↓

36. Biochemical Investigation and Diagnosis
Calcium Phosphate ALP iPTH 25-OHD 1,25(OH)2D Urine
Ca
Urine
PO4
FGF 23
CHILDREN Hereditary Hypophosphatemic
Rickets
X-linked hypophosphatemia
(XLH)
X-linked dominant
N ↓ ↑ N / ↑ N N / ↓ ↓ ↑ ↑
Autosomal dominant
hypophosphatemic rickets
(ADHR)
N ↓ ↑ N N N / ↓ ↓ ↑ ↑
Autosomal recessive
hypophosphatemic rickets
(ARHR)
N ↓ ↑ N N N / ↓ ↓ ↑ ↑
ADOLESCEN
T
Hypophosphatemic
nephrolithiasis/ osteoporosis
syndromes
(NPHLOP)
↑ ↓ ↑ ↓ N ↑ ↑ ↑ ↑

37. Parathyroid gland disorder - Hyperparathyroidism
Causes Calcium Phosphate iPTH
Primary - Primarily by adenomas of parathyroid
glands
- parathyroid gland hyperplasia
↑ ↓ ↑
Secondary - Chronic kidney disease
(CKD)
- Vitamin D deficiency
- Malnutrition
The increase in PTH
production is a physiological response
to hypocalcemia
↓ ↑ in CKD
↓ in other cause
↑↑
Tertiary Progressive stage of secondary
hyperparathyroidism with
unresponsive flow of PTH
↑ ↑ ↑↑↑

38. Summary
• The main calcium trophic hormones are PTH and Vitamin D, and
small role from calcitonin
• FGF23 is also known to regulate Calcium and phosphate
• It is important to have a complete biochemical profile in order to
pinpoint specific calcium and phosphate disorder