Transcript Parathyroid

Assist prof. of Medical Physiology
Site:
• 4 glands on the posterior aspect of the thyroid gland.
Size and Weight
• Each measures 3-5 mm in diameter
• Combined weight of the 4 glands about 120 mg.
• Functions:
• Secrete ‘parathormone PTH’ (84 aa).
• PTH is essential for life
• Have essential role in the regulation of Ca2+
metabolism in the body
Histology:
• Parathyroid glands are formed of columns of;
a) Chief cells:
•
More numerous and secrete PTH.
b) Oxyphil cells:
•
Appear in the gland at 10th year of life.
•
Represent inactive chief cells.
The main function of PTH is to keep a normal plasma Ca2+
level (9-11 mg%).
– Parathormone increase the blood Ca2+ level.
– Maintains a constant ratio between plasma Ca 2+ & PO4,
• Ca x PO4 = K (constant). (solubility product)
• Ca2+ and PO4- are inversely related.
• PTH tend to raise lowered blood Ca by ;
PTGs
 Serum calcium
-
 Parathormone
 Ca++
absorption
 Ca++ reabsorption
 Ca++
 bone resorption
1. On the kidney
– On the ALH and distal CT
• Increase reabsorption of Ca2+
• Increase PO4 excretion.
– On the proximal CT
• Increase the reabsorption of Mg
• Activate vitamin D to (1,25 dihydroxycholecalciferol)
2. On the small intestine
1. Increase the absorption of:
Ca2+ Mediated by active vitamin D (1,25 dihydroxy
cholecalciferol)
2. Increase the absorption of:
PO4 and Mg.
3. On Bone
– Increase the number and activity of osteoclasts (bone
destroying cells).
– Results in resorption of bone, release of Ca2+
into the blood and hypercalcemia.
4. On breast
– Decrease Ca2+ secretion in milk.
Through cell membrane receptor:
• 1. Activation of adenyl cyclase enzyme &
– increase the intracellular cAMP.
• 2. Increase intracellular Ca2+ .
Ca2+
– Acts as a second messenger or
– Modulate adenyl cyclase response.
• a) Plasma Ca level:
• It the main regulator of PTH secretion.
• ↓ Plasma Ca level → ↑ PTH secretion
• b) Plasma Mg level: as Ca
• c) Plasma PO4 level: opposite to Ca
• d) Nervous factors:
• β-adrenergic receptors agonists as isoproterenol→↑
PTH secretion
• Epinephrine and isoproterenol stimulate PTH
secretion
– through β-adrenergic receptors identified on chief cells.
• Some Patients with pheochromocytoma Show
hypercalcemia
Excess PTH Secretion
Hyperparathyroidism
Decreased PTH Secretion
Hypoparathyroidism
• Causes
– Deficient parathyroid activity is uncommon
– Most cases result from:
• 1) Accidental removal of the parathyroid glands
or
• 2) Damage of their blood supply during
thyroidectomy.
• Characterized by:
– Hypocalcaemia
– Increase neuro-muscular excitability (tetany)
• Mechanism:
• Decrease plasma Ca2+ ions < 9 mg/dl
– Increase the excitability of Nervous system due to
• ↑ neuronal membrane permeability to Na+
– Hyperexcitable nerve fibres, spontaneously initiate
nerve impulses to peripheral sk ms
– thus eliciting tetanic contraction.
• Manifested by ↑ed neuromuscular excitability due to ↓
plasma ionized Ca2+
Causes:
• a) Hypoparathyroidism.
• b) Alkalaemia, decrease the solubility product of Ca2+&
PO4 and leads to
• reduced ionized Ca2+.
• precipitation of CaPO4;
• Causes:
• c) Decreased Ca2+ absorption from the intestine:
– 1. Low calcium intake.
– 2. Excess intake of antiacids (peptic ulcer) lead to Ca2+
precipitation and decreased absorption.
– 3. Steatorrhea (fatty diarrhea), where Ca2+ is lost in stools.
• These depend on the degree of ↓ed blood Ca2+ level:
• 1. Manifest tetany:
– Blood Ca2+ level is below 7 mg% (N 9-11 mg%).
– Muscular spasms in the hands and feet (Carpo-pedal spasm).
• 2. Latent tetany:
– Blood Ca2+ level is at 7-9 mg%,
– Muscle spasms only occur when the patient is exposed to
stress.
• blood Ca2+ level is below 7 mg% (N. 9-11 mg%).
• ‘Carpo-pedal spasm’.
• The hands (Carpal spasm),
– 1) Flexion of:
• Wrists and
• Metacarpo-phalangeal joints,
– 2) Extension of the inter-phalangeal joints and
– 3) Adduction of the thumb.
Carpal spasm
• The feet (pedal spasm),
– Dorsiflexion of the ankle
– Planterflexion of the toes
• Occasionally,
– Few patients, children, may have generalized
convulsions.
– Infants with tetany show spasm in the laryngeal ms
leading to: a difficulty in breathing (laryngismus stridulus).
• Blood Ca2+ level is at 7-9 mg%,
– Ms spasms only occur when the patient is exposed
to stress.
– The patient have widespread:
• tingling feelings and
• sensations of heat & flushing (parasthesia).
• Provokative tests:
• tests used to demonstrate the neuro-muscular hyperexcitability in latent tetany:
• a) Chvostek’s test:
– Tapping over the facial nerve in front of the ear
– Produce twitching of the ipsilateral (same side)
facial ms, especially those of the upper lip.
Chvostek’s test
• Provokative tests:
• b) Trousseau’s test:
• Inflating the sphygmomanometer cuff round the upper arm
to a pressure above the systolic BP for 2 minutes.
– Leads to Carpal spasm:
• Explanation
– Ischaemia increase the excitability of the nerve trunks
and increase the effect of hypocalcaemia.
• Provokative tests:
• c) Erb’s sign:
• Stimulation of motor nerve by a subthreshold
galvanic current
– Induce muscle contraction.
• 1. IV injection of Ca2+ gluconate during ms spasm.
– stops immediately the tetanic spasms.
• 2. Calcium level is then maintained by:
– giving vitamin D and administration of oral calcium.
• 3. Acidifying salts as ammonium chloride
– help Ca2+ absorption as they increase the ionization of Ca2+.
• 4. In hypoparathyroidism:
• Repeated administration of parathormone leads to
– formation of antihormone which antagonizes its action.
• A synthetic steroid ‘dihydrotachysterol (or AT 10)’
– Has similar effects as parathormone and vitamin D,
– Not produce antihormone.
Def.,
• Excess production of
parathormone
Cause:
– usually due to parathyroid tumor
Effect
– Leads to hypercalcaemia (blood
Ca2+ level may exceed 20 mg%).
Manifestations
• 1. Bone resorption due to:
– Increased osteoclastic activity with
mobilization of Ca2+ from bones
(decalcification).
– In severe cases the affected
bones show formation of fibrous
masses and cysts (osteitis fibrosa
cystic).
– Increased bone fragility leads to
spontaneous fractures.
• Manifestations
• 2. The high Ca2+ levels in the kidney filtrate lead to:
– Precipitation of Ca2+ compounds and the formation of calculi.
– Renal failure eventually develops.
• 3. Polyuria, due to:
– a) Osmotic diuresis by excess excretion of Ca2+ and PO4 in
urine.
• High filtration of Ca2+ exceeds the effect of parathormone
on Ca2+ reabsorption.
– b) Renal damage due to the frequent formation of calculi.
• Manifestations
• 4. Hypotonia of muscles, and muscle weakness.
• 5. Vomiting, constipation and intestinal pain.
• 6. Severe cases show:
– Cardiac irregularities
– Mental confusion, even coma.
• Treatment of hyperparathyroidism:
– Surgical removal of the parathyroid tumor
– is the only line of treatment.
• 1. Neoplasms with secondary deposits in bones.
• 2. Neoplasms secreting parathormone-like
substance.
• 3. Excessive intake of vitamin D.
1. Participates in numerous
enzymatic reactions.
2. Vital component in the
mechanism of hormone secretion
and a mediator of hormonal
effects.
3. Involved in neurotransmission, in
muscle contraction, and in blood
clotting.
4. Major cation in the crystalline
structure of bone and teeth.
Total Body Calcium
(1000 g (1 Kg))
Less than 1%
In ECF (900 mg)
More than 99%
In bone and teeth (910 g)
After the 3rd decade of life, bone resorption
exceeds bone accretion (i.e. formation), and
there a slow but progressive loss of bone occurs
which is greater in women than in men.
Plasma Ca+ concentration = 9 -11 mg/dl
Nondiffusable
(40%)
Bound to albumin
Diffusible
(60%)
Complexed Ca+
such as CaHCO3
(10%)
Ionized Ca+
(50%)
(Active form)
Daily recommendations:
• Minimum daily requirement for Ca2+ is 400 mg for
adults
• Greater amounts are needed in childhood, pregnancy
and lactation.
• However, the intestine has a remarkable facility for
adapting to a low Ca diet by increasing the proportion
of the absorbed dietary Ca2+.
Absorption:
Site:
• from all parts of the small
intestine.
• The greatest absorbing capacity is
in the duodenum
Mechanism:
1. In duodenum by active transport
mechanism controlled by vitamin
D (such action of vit. D is
facilitated by parathromone)
2. In jejunum and ileum Ca2+
absorption takes place by passive
or facilitated diffusion
Factors affecting Ca+ absorption
Factors that ↓ Ca+
absorption
1. Vitamin D deficiency
2. Renal failure
3. Intestinal malabsorption
4. Phytic acid, phosphates
or steroids
5. Excess unabsorbed fatty
acids in the intestine
6. Advancing age
Factors that ↑ Ca+
absorption
1. Parathormone
2. Growth hormone
not in the absence of
vitamin D.
Kidney :
Filtered amount :
• About 9 gm Ca2+daily into the
GFR.
Site of reabsorption:
• Most of filtered Ca is reabsorbed
by the tubules
Urinary excretion :
• About 80-400 (150 mg/day)
Factors affecting:
1. ↑ed in hyperparathyroidism
2. ↓ed hypoparathyroidism, sodium
diuretics, calcitonin and excess
corticosteroids
1. Integral component of all
glycolytic compounds as G-1-P
2. Part of structure of high energy
transfer compounds such as
ATP and creatine phosphate
3. Part of cofactors such as NAD
and NADH
4. Part of lipids such as
phosphatidyl choline
5. Modifier of numerous
enzymes and an important
component of bones.
Plasma PO4- concentration = 2.5 -4.5 mg/dl
Nondiffusable
(12 %)
Bound to proteins
Diffusible
(88%)
Dietary PO4-:
•
•
•
•
Since phosphorus is present in all animal and plant
cells, dietary deficiency never occurs in man.
Phosphate depletion may occur as a result of:
1. Renal tubular disorders.
2. Excessive intake of aluminium hydroxide, an
antacid which binds phosphorus in the gut.
Intestinal Absorption:
Percentage :
• % of phosphate absorbed from the diet is relatively constant
• Linearly related to the intake over a wide range
• Adaptive bowel regulation is of minor importance
Renal Absorption:
• Major mechanism for
preserving phosphate
balance.
• 90% of the filtered
phosphorus is reabsorbed in
the tubule.
• This ratio varies from 70100%, to compensate for
large swings in dietary intake
Other hormones that affect bone
and calcium metabolism
• Osteoblasts
– Primary cells concerned with synthesis of new bone.
– Produce bone osteoid which will subsequently undergo
calcification.
• Osteocytes
– Mature bone cells which are less active than osteoblasts.
• Osteoclasts
– Multinucleated cells derived from macrophages which
function to resorb bone.
• Def:
• Is a continuous process throughout life, even after
epiphyseal fusion and cessation of linear bone growth.
• Remodeling consists of bone formation and bone
resorption.
• PTH and Calcitonin are the major Ca2+ regulating hormones,
• A number of hormones have an important influence on bone
and mineral metabolism, These include:
1) Vitamin D
2) Estrogens and androgens
3) Glucocorticoids
4) Thyroid hormones
5) Growth hormone
• Protein hormone (32 a.a)
• Secreted by the parafollicular
cells or C-cells of the thyroid
gland.
• Its plasma concentration (10100 pg/ml)
• Synthesis:
• As protein hormones:
– it is as pre-prohormone which is transformed into
prohormone and stored in secretory granules.
• There is species variation in calcitonin
• Fish & animal calcitonin are active in human.
• Stimuli for Release
• 1. Rise in serum Ca2+ (The major stimulus), e.g.
– Acute rise of serum Ca2+ as little as 1 mg% (increases 2-10
times).
– Ca2+ increase intracellular cAMP→ stimulate calcitonin release .
• 2. Ingestion of food stimulates calcitonin secretion.
– Mediated by several GIT hormones
– The most potent of which is gastrin.
• Although its physiological role in human is uncertain,
calcitonin is important regulator of plasma Ca2+ in
lower animals that live in aquatic environment high in
Ca2+.
• The major effect of calcitonin administration to
produce a rapid fall in plasma Ca2+
• Young growing animals are more affected than
adults, (have more stable skeleton &, only a minimal
response is seen).
• Through acting on bones, kidney and intestine
1) Bones:
• Inhibit osteolysis by osteocytes
• Reduce bone resorption by osteoclasts.
• Decrease Ca2+ mobilization from bone to blood
(inhibits Ca2+ permeability of bone cells).
• 2. A physiological antagonist to
parathormone with respect to Ca2+,
• but has the same effect of
parathormone on PO4.
– decreases plasma PO4 level, and
• has no effect on plasma magnesium
level.
• 4. Increase urinary excretion of Ca2+ and PO4.
• 5. Decrease Ca2+ absorption from the intestine.
• Active Vitamin D is a steroid hormone having both dietary and
endogenous precursors.
• Vitamin D2 (ergocalciferol)
– is formed in plants from ergosterol
• Vitamin D3 (cholecalciferol)
– is formed by ultraviolet rays from precursor 7dehydrocholesterol in skin.
• Biological effects of vitamin D:
1. Intestine (is the principal target)
2. Bone
3. Kidney
4. Immune system.
• 1) On the intestine
–
Stimulates both Ca2+ and phosphorus absorption .
• 2) On Bone (the second major target of vitamin D).
–
Provides Ca2+ and phosphate to initiate the
crystallization of bone osteoid.
• 3) On the kidney
– Vitamin D increase renal tubular reabsorption of both Ca2+
and phosphate.
• 4) On the immune system has important regulatory
effects.
– Promotes differentiation of monocyte precursors to
monocytes and macrophages.
– Bone resorbing osteoclasts arise from this differentiation
pathway.
– Affects both T and B lymphocytes, inhibiting IL-2 production
and other effector functions.
• Gonadal steroids are involved in:
– Pubertal growth spurt
– Closure of the epiphyses.
• During childhood and puberty,
– Gonadal steroids favor bone formation over resorption.
• In the adult female
– Estrogens protect the skeleton from osteoporosis or decreased bone
mass by:
• a) Inhibiting PTH mediated bone resorption.
– Estrogen receptors have been detected in osteoblasts, and
– Osteoblasts release factors that inhibit osteoclastic resorption.
• b) Reduce bone-resorbing cytokines such as IL-1 & IL-6 in
bone.
• c) Increase serum parathormone,
– due to the hypocalaemic effect of the inhibition of bone
resorption.
– It also facilitates parathormone action at the kidney
• with greater phosphate excretion,
• calcium absorption and
• vitamin D3 activation.
• Androgens protect men from osteoporosis, as
evidenced by:
– Excessive bone loss in hypogonadal conditions such
as:
• Klinefelter’s syndrome (47, XXY), and
• following castration (removal of testicles).
At physiological levels
– glucocorticoids are necessary for skeletal growth.
Prolonged excess glucocorticoids ,
have deleterious effects on Ca2+ homeostasis:
– a) decrease renal tubular Ca2+ absorption.
– b) interfere with intestinal Ca2+ absorption.
Excess glucocorticoids
• c) Increase parathormone secretion through:
– Direct effect on parathyroid ,
– Secondary hyperparathyroidism due to low Ca2+ level.
• d) They inhibit osteoblastic bone formation.
• e) They suppress gonadal estrogen and testosterone
production
• The thyroid hormones are important for the development and
growth of the skeleton in infancy and childhood.
• Hypothyroidism:
– Show retarded bone age, as indicated by:
• delayed ossification of the cartilaginous bone growth
centres.
• Hyperthyroidism
– Causes increased bone resorption.
• It has striking effects on bone growth
– Through somatomedin or IGF-1 (mitogenic for chondrocytes
and osteoblasts).
• Growth hormone also
– increase intestinal Ca2+ absorption by
• a vitamin D-dependent mechanism,
– increase renal tubular phosphate reabsorption.
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