Professional Documents
Culture Documents
PARATHYROID HORMON
Integrative Teaching Bloc 9
Prof. dr. Hardi Darmawan, MPH&TM, FRSTM
Dr. Swanny, MSc
1
Learning Objectives
After studying this section, you will be able
to :
1.Learn how the body controls the calcium
level.
2.Understand the inter - action of
Parathyroid hormone, vitamin D3 and
calcitonin in homeostatic regulation of
extra and intracellular calcium level.
2
Learning Objectives
3.Recognize the clinical manifestations of
calcium homeostatic disturbances.
4.Recognize and understand the
pathophysiology of the diseases related to
disturbances of endocrine control of
calcium homeostasis.
CALCIUM BALANCE
99% of calcium in the body is found in
BONES.
Calcium pool in bone is relatively stable.
1% of non bone calcium that is most critical
to physiological functioning.
FUNCTION of Calcium
1. Extracellular calcium : 99% of total
calcium in the body.
located in the bone.
Function : calcified matrix of bone
CA AS BONE MATRIX
6
FUNCTION of Calcium
2. Extracellular fluid: 0,1 %
Function :
- Cement for tight junctions
- Myocardial and smooth muscle contraction
- Release of neurotransmitters at synapses
- Excitability of neurons due to effect on Na
permeability
- Cofactor for coagulation cascade
7
FUNCTION of Calcium
3. Intracellular : 0,9 %
Function :
- Signal in second messenger pathways.
- Muscle contraction.
2. CEMENT
Calcium is part of the intercellular cement
that holds cells together at tight junctions
10
4. Excitability of neurons
Clinically related
Hypocalcemia : neuronal permeability to Na
increases, neurons depolarizes, and the nervous
system become hyperexcitable.
It will cause sustained contraction (Tetany) of
hand: carpopedal spasm , of respiratory
muscles, resulting in asphyxiation.
Hypercalcemia : causes depressing neuromuscular
activity.
13
Homeostasis of Calcium
Calcium is critical to many physiological
functions.
Calcium level must very closely regulated.
Principle of calcium homeostasis :
TOTAL BODY CALCIUM = INTAKE - OUTPUT
14
15
INTAKE of calcium
Required daily amounts of Ca : 1,2 gram
Intake is dietary ingestion and uptake in
small intestine ( duodenum ). Calcium
absorption is active transport and
hormonally regulated.
Absorption is exactly controlled in relation to
the need of the body for calcium.
16
OUTPUT of calcium
Calcium loss : primarily through Kidney.
small amounts in feces
Ionized Ca is freely filtered at glomerulus.
Reabsorbed along the length of nephron.
Hormonally regulated reabsorption occurs
in distal nephron.
17
18
EXTRACELLULAR CALCIUM
1. PLASMA CALCIUM.
Ca concentration : 9 10 mg/dl. Equivalent to 2,4 mmol Ca
/ liter.
40% (1 mmol/ l ) is combined with plasma protein. This
form is nondiffusible to capillary membrane.
10% (0,2 mmol/ l ) is combined with other substances of
plasma and interstitial fluid (citrate , phosphate).
Diffusible to capillary membrane.
50% is ionized and diffusible.
19
INTRACELLULAR CALCIUM
The concentration of free calcium in cytosol
is about 0,001 mM. Calcium is
concentrated inside mitochondria and
sarcoplasmic reticulum.
These electrochemical gradients favor
movement of Ca++ into cytosol when
Ca++ channels open.
20
22
PHOSPHATE HOMEOSTASIS
Closely links to Calcium homeostasis.
Most found in bone, especially in hydroxyapatite of
bone , Ca10(PO4)6(OH)2 .
Phosphate homeostasis parallels that of Ca++.
Absorbed in intestines, filtered, reabsorbed in
kidneys.
Divided between bones, ECF, and intracellular.
23
FUNCTION of PHOSPHATE
Energy transfer
Storage in high energy-phosphate bonds
Activation and deactivation of enzymes,
transporters, and ion channels.
Part of the DNA and RNA backbone.
24
Parathyroid hormone
Essential for life.
Cell of origin : parathyroid glands
Chemical nature : 84-amino acids peptide
Biosynthesis : continuous production, little
stored
Transport : dissolved in plasma
Half life : less than 20 minutes
28
Parathyroid hormone
Factor affecting release : decrease plasma
Ca++
Target cell : Kidney, bone, intestine
Target receptor : membrane receptor acts
via cAMP
Whole body or tissue action : increase
plasma Ca++
29
Actions of
parathyroid
hormone (PTH) on
the kidney and
bone
30
Parathyroid hormone
Action at cellular level :
Increase vit.D3 synthesis
Increase renal reabsorption of Ca++
Increase bone resorption
Action at molecular level :
Rapidly alters Ca++ transport but also initiates
protein synthesis in osteoclasts.
31
Activation of vitamin D (25 (OH) vitamin D3, 25 hydroxyvitamin D3; 1,25(OH)2 vitamin D3, 1,25dihydroxyvitamin D3)
32
Parathyroid hormone
Onset of action :
2 3 hours for bone, with increased
osteoclast activity requiring 1 2 hours; 1
2 days for intestinal absorption; within
minutes for kidney transport.
Feed back regulation : Negative feed back
by increasing plasma Ca++
33
Other information
Osteoclast have no PTH receptors, so are
affected by PTH induced paracrines.
PTH is ESSENTIAL FOR LIFE.
Absence of PTH causes hypocalcemic
tetany, which may lead to death.
34
35
36
Actions of
parathyroid
hormone (PTH) on
the kidney and
bone
37
38
Calcitriol
Stimulus for synthesis : decrease of Ca++;
indirectly via PTH, prolactin also stimulates
synthesis.
Target cells/tissues : Intestine, bone, kidney
Target receptor
: nuclear
Whole body or tissue action : increase of
plasma calcium
41
Calcitriol
Action at molecular level : stimulates
production of calbindin, a Ca++ -binding
protein; associated with intestinal
transport by unknown mechanism.
Feed back regulation : plasma Ca++ shuts
off PTH secretion
42
Calcitonin
Cell of origin : C cells of thyroid gland
(parafollicular cells)
Chemical nature : 32-amino acid peptide
Biosynthesis : typical peptide
Transport
: dissolved in plasma
Half life
: less than 10 minutes
Factor affecting release : increase plasma
Ca++.
43
Calcitonin
Target cell/tissues : bone and kidney
Target receptor
: G-protein-coupled
membrane receptor
Whole body action : prevents bone
resorption; enhances kidney excretion.
Action at molecular level : signal
transduction pathways appear to vary
during cell cycle.
44
Calcitonin
Other information :
Experimentally decreases plasma Ca++, but
has little apparent physiological effect in
adult humans; possible effect on skeletal
development; possible protection of bone
Ca++ stores during pregnancy and
lactation.
45
Calcitonin
Plays a minor role in daily calcium balance in
adult human.
Medically, used to treat patients with
PAGET disease, a genetic disorder in
which osteoclasts are overactive and bone
is weakened by resorption.
Speculation : most important during
childhood growth, pregnancy and lactation
46
Cortisol
Minor role.
At low levels : necessary for normal bone
growth.
At high levels : inhibits bone formation, that
may leads to osteoporosis.
48
Growth Hormone
Minor role
Increase the formation of bone at normal
level.
Action of GH on bone is mediated via
Somatomedin.
49
Sex Steroids
Minor role.
Estrogen and testosteron causes closure of
epiphyse of bone.
After menopause, estrogen level decreases,
bone resorption increases which is may
cause osteoporosis.
50
51
52
HYPOCALCEMIA
Causes :
1. Hypoparathyroidsm :
caused by : a. autoimmune atrophy.
b. inadvertent removal of
parathyroid glands at
thyroidectomy
PTH level low
Ca++ level low
Phosphate level high
53
2. Pseudohypoparathyroidism.
a rare hereditary disorder.
failure of target cells to response to PTH.
PTH levels high.
Ca++ low
Phosphate levels high
54
3. Vitamin D deficiency.
Causes : a. inadequate enzymatic
conversion.
b. increase rate of metabolism
c. insufficient sun or intake
PTH levels high.
Ca++ levels low
Phosphate levels low
55
4. Renal disease.
Failure to excrete phosphate and reabsorp
Ca++.
Ca++ levels low
Phosphate levels high
PTH level high
56
57
HYPERCALCEMIA
1. Hyperparathyroidism
Caused by : tumor of parathyroid gland
PTH levels high
Ca++ levels high
Phosphate levels low
58
2. Vitamin D toxicity.
Ca++ levels high
Phosphate levels high
PTH levels low
59
Symptoms and
signs of
hypercalcaemia
60
62
63
Hyperparathyroidism
Caused by tumor of parathyroid glands.
Occurs more frequently in women, because
pregnancy and lactation stimulates the
glands.
Osteoclastic activity increases elevates
Ca++ concentration in ECF, depressed
phosphate concentration due to increased
renal excretion.
64
Effects of hypercalcemia in
hyperparathyroidism
Plasma calcium level : 12 -15 mg/ dl.
Cause depression of CNS and peripheral
nervous system --- muscle weakness,
constipation, abdominal pain, peptic ulcer,
lack of appetite, depressed relaxation of
heart during diastole.
66
Kidney stones
Crystals of calcium phosphate tend to
precipitate in kidney forming kidney
stones.
Tendency for forming renal calculi is greater
in alkaline urine, because the solubility of
renal stones is slight in alkaline media.
68
RICKETS
Occur mainly in children.
Caused by : deficiency of vit. D.
Plasma level of calcium and phosphate
decreases.
Ordinarily, plasma calcium is slightly
depressed, but phosphate concentration is
greatly depressed.
69
Tetany in RICKETS
Tetany occurs when the blood concentration
of calcium falls below 7 mg%.
The child may die of tetanic respiratory
spasm.
Treatment of tetany : intravenous calcium.
71
72
Osteomalacia
Adult Rickets.
Deficiency of vit. D or calcium is caused by
steatorrhea ( failure to absorb fat).
Prolonged kidney damage renal rickets.
Caused by renal failure to form 1,25-(OH)2 vit.D3.
Often a serious problem for patients whose
kidneys have been removed or destroyed and
are being treated by hemodialysis.
73
74
OSTEOPOROSIS
Most common bone diseases in adults,
especially in old age.
Disease of bone loss, due to bone resorption
exceeding bone deposition. The result is
fragile, weakened bones that are easily
fractured.
Particularly affect spongy trabecular bone, in
vertebrae, hip and wrist.
75
76
Causes of Osteoporosis
1.
2.
3.
4.
5.
78
Calcium Regulation
The regulation of Ca++ involves 3 tissues :
1.
Bone
Intestine
Kidney
2.
Parathormone
Calcitonin
Activated vitamin D3 (activated calciferols)
79
3.
Osteoblasts
Osteocytes
Osteoclasts
80
Hormonal Control
81
Parathormone
83
Calcitonin
Vitamin D3 (Cholecalciferol)
a.
b.
Calcitriol (1.25-dihydroxyvitamin D3 or
1.25 dihydroxycholecalciferol)
7-dehydrocholesterol
vitamin D3
(skin)
b)
uv light
Vitamin D3
25 hydroxyvitamin D3
25-hydroxylase
c)
25 hydroxyvitamin D3
1.25 dihydroxy
1 = hydroxylase
vitamin D3
(kidney)
87
Osteoblasts
2.
Osteocytes
Osteocytic osteolysis :
Osteolaclasts
Osseous Tissue
Parathormone action on bone :
increased Ca++ phosphate mobilization
(bone dissolution) from non readily
exchangeable Ca++ pool.
2.
3.
References.
1. Guyton and Hall, Text book of Medical
Physiology.
2. Ganong, W.F. , Review of Medical
Physiology.
3. Silverthorn, D.U., Human Physiology, An
integrated approach.
93
THANK YOU
94