Download 7-Endo PTH

At the end of this lecture, students should be able to:
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Describe the role of calcium in the body
Enumerate the hormones affecting plasma calcium
Describe the actions of parathyroid hormone
Know the source and actions of calcitonin
Describe the role of calcitriol
Describe Pathophysiology of hypoparathyroidism &
hyperparathyroidism
• Calcium in plasma or serum exists in three forms:
1) Protein-bound calcium accounts for approximately onethird of the total serum calcium concentration. Proteinbound calcium cannot diffuse through membranes and
thus is not usable by tissues.
2) Ionized or free calcium is the physiologically active form
that accounts for 50%–60% of total calcium concentration.
3) Complexed or chelated calcium is bound to phosphate,
bicarbonate, sulfate, citrate, and lactate and accounts for
~10% of the total calcium concentration.
Total Body Ca++
Body fluids (1%)
ECF (0.1%)
Free form (50%)
Skeleton & teeth
(99%)
ICF in soft
tissues (0.9%)
Bound (50%)
 Functions of calcium:
1) The calcium ion is an essential structural component of the
skeleton
2) It plays a key role in muscle Contraction, blood Coagulation,
Enzyme activity, neural Excitability, secondary Messengers,
hormone release, and Membrane permeability.
 Plasma calcium level:
• Normally kept constant within a range of 9 to 11 mg/100 ml.
• 50 % exists as free calcium.
* The principal regulatory hormones:
A- Parathyroid hormone (PTH).
B- Calcitriol or (1, 25-(OH)2- cholecalciferol).
C- Calcitonin.
• Others:
Adrenal
corticosteroids,
estrogens,
thyroxine,
and
somatotropin may also contribute to the maintenance of
calcium homeostasis.
• Parathyroid
glands
are
essential for life. They
secrete
Parathyrin
or
Parathyroid hormone (PTH)
(84 a.a.) by chief cells.
• Four rice grain-sized glands
located on the back surface
of the thyroid gland, one in
each corner.
• Ca2+ sensors in cells of the parathyroid glands regulate
PTH synthesis and secretion in response to changes in
the plasma concentration of ionized Ca2+ .
• More PTH is secreted into the blood stream whenever
Ca2+ concentration falls below normal (hypocalcemia).
• Inversely, PTH secretion decreases when Ca2+ level rises.
• The primary function of PTH is to normalize the
decreased Ca2+ conc. in the blood. It is a Ca2+ increasing
hormone.
• It is essential for life. Complete
absence of PTH ensues death within
few days.
• PTH essentially acts to increase the
concentration of calcium in the blood
by
acting upon
the
parathyroid
hormone 1 receptor, which is present
at high levels in bone and kidney, and
the parathyroid hormone 2 receptor,
which is present at high levels in the
central nervous system, pancreas,
testis, and placenta.
Calcium regulation:
• Maintenance of plasma Ca++ level at 10 mg %, and also
phosphate level to keep solubility product = [Ca++] X
[PO4-3] = constant.
A) On bone:
• PTH raises plasma Ca2+ by withdrawing Ca2+ from the
bone bank.
• induces a fast Ca2+ efflux into the plasma from the small
labile pool of Ca2+ in the bone fluid.
• Second, by stimulating bone dissolution, it promotes a
slow transfer into the plasma of both Ca2+ & PO43- from
the stable pool of bone minerals in bone itself.
• Bone resorption is the normal destruction of bone by
osteoclasts, which are indirectly stimulated by PTH.
• Osteoclasts do not have receptors for PTH.
• PTH binds to osteoblasts to increase their expression
of RANKL and inhibits their expression of OPG.
• The binding of RANKL to RANK stimulates these
osteoclast precursors to fuse, forming new
osteoclasts, which ultimately enhances bone
resorption.
PTH
Calcitriol
Estrogen
Calcitonin
•  reabsorption of Calcium in DCT & CD of nephrons 
 plasma Ca++ level.
•  reabsorption of Phosphate in PCT of nephrons  
plasma Phosphate level.
• When the (calcium : phosphate ratio) increases, more
calcium is free in the circulation.
• PTH accelerates the final step of calcitriol synthesis in
the kidney, resulting in increased absorption of Ca++ from
the GIT.
• It enhances the absorption of calcium in the intestine by
increasing the production of activated vitamin D.
• PTH increases the activity of 1-α-hydroxylase enzyme,
which converts 25-hydroxycholecalciferol, the major
circulating form of inactive vitamin D, into 1,25dihydroxycholecalciferol (Calcitriol), the active form of
vitamin D, in the kidney.
• This activated form of vitamin D (Calcitriol) increases the
absorption of Ca2+ ions by the intestine via calbindin.
• It is not under control
of hypothalamus nor
anterior pituitary.
• It
is
controlled
by
Plasma Ca++ Level (and
to
a
lesser
extent
magnesium) by – ve
feedback mechanism.
i.e.  plasma Ca++ 
 PTH secretion.
• It is a 32-amino acid linear polypeptide hormone produced
in humans primarily by parafollicular C-cells of the thyroid.
• Calcitonin counteracts parathyroid hormone. Calcitonin
reduces calcium levels in the blood by two main
mechanisms:
1. Inhibits osteoclast activity in bones. Therefore, the
inhibition of osteoclasts by calcitonin directly reduces
the amount of calcium released into the blood.
2. Inhibits renal tubular cells reabsorption of Ca2+ allowing
it to be excreted in the urine.
• The actions of PTH and calcitonin are antagonistic on bone
resorption but synergistic on decreasing the renal tubular
reabsorption of phosphorus.
• Calcitonin protects against calcium loss from skeleton during
periods of calcium mobilization, such as pregnancy and
lactation. Calcitonin prevents postprandial hypercalcemia
resulting from absorption of Ca2+ .
• Salmon calcitonin is used for treatment of: Postmenopausal
osteoporosis, Hypercalcaemia & Paget's disease.
• A steroid like compound essential for Ca++
absorption in the intestine. Activated by
the addition of two (-OH) groups.
• The first reaction occurs in the liver & the
second in kidneys.
• It is the active metabolite of vitamin D3
• PTH accelerates the final step of calcitriol
synthesis in the kidney. Its release from
kidney is increased by decreased plasma
Ca++.
 Calcitriol increases blood calcium levels by:
1) increasing absorption of dietary calcium from the
gastrointestinal tract
2) increasing renal tubular reabsorption of calcium, thus
reducing the loss of calcium in the urine.
 Calcitriol also stimulates release of calcium from bone
by its action on the specific type of bone cells referred to
as osteoblasts, causing them to release RANKL, which in
turn activates osteoclasts.
 The observation that calcitriol stimulates the release of
calcium from bone seems contradictory, given that sufficient
levels of serum calcitriol generally prevent overall loss of calcium
from bone.
 It is believed that the increased levels of serum calcium
resulting from calcitriol-stimulated intestinal uptake causes bone
to take up more calcium than it loses by hormonal stimulation of
osteoclasts.
 Only when there are conditions, such as dietary calcium
deficiency or defects in intestinal transport, which result in a
reduction of serum calcium does an overall loss of calcium from
bone occur.
• Causes:
1. Adenoma of parathyroid gland (in 80% of cases).
2. Multiple adenomas or hyperplasia (in 15% of cases).
3. Carcinoma (in less than 5% of cases).
• Characterized by hypercalcemia & hypophosphatemia.
• Clinical features:
Bones
Stones
Abdominal groans
Psychic moans
p. 730
• Causes:
1. Accidental removal of parathyroids surgically with
thyroid in cases of thyroid carcinoma.
2. Autoimmune disease.
•
Characterized
by
hyperphosphatemia.
•
Clinical picture:
hypocalcemia
&
Hypocalcaemia  neuromuscular hyperexcitability
 Tetany.
• Def. ↓ ionized Ca++ in ECF → ↑ Na+ influx → ↑
Neuromuscular excitability.
• Causes:
1. Hypoparathyroidiam  hypocalcaemia.
2. Alkalemia as in Hyperventilation & Vomiting.
3. ↓ Absorption of Ca++ from GIT due to:
Low calcium intake
Lack of vitamin D.
1) Manifest tetany:
 Plasma Ca++ level is below 7 mg%
 Hypocalcaemia manifest itself by cramps of the
limbs in form of:
• Carpal Spasm: (Obstetrician's hand) flexion at
elbow, wrist, metacarpophalangeal joints &
extension at interphalangeal joints and adduction
of thumb.
• Pedal Spasm: Dorsiflexion of foot and planter
flexion of toes.
• Laryngeal spasm: Asphyxia (fatal).
• Plasma Ca++ level is above 7 mg% and below 9 mg%.
• Appears after exposure to stress, pregnancy,
lactation & hyperventilation ...
• Diagnosis of latent tetany:
1) Plasma Ca++ level.
2) Trousseau's sign:  blood flow in arm with a
sphygmomanometer cuff  carpal spasm in less
than 3 minutes (pressure must be more than
systolic pressure).
3) Chvostek's sign: Sharp tap on facial nerve at angle
of mandible  twitch of facial muscles.
• During attack: Calcium gluconate by very slow
intravenous injection.
• For latent tetany: Vitamin D & Oral calcium.
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