Structure
1. Four
or five parathyroid gland embedded in the posterior surface of the thyroid’s
lateral lobe.
2. Tiny,
rounded bodies within thyroid tissue formed by compact, irregular row of cells.
3. Microscopically,
it is consist of two distinct cell types:
a. Chief
cells – clear cells and are the most abundant cell type. These cells secrete
parathyroid hormone
b. Oxyphil
cells – larger and less abundant, have a pyknotic nucleus, have an affinity for
acidic dyes and are believed to be senescent chief cells.
Functions of PTH
1. PTH
is an antagonist to calcitonin and acts to maintain calcium homeostasis
2. PTH
acts on bone, kidney and intestinal cells.
3. It
causes more bone to be dissolved, yielding calcium and phosphate; which enters
the blood stream.
4. It
causes phosphate to be secreted by the kidney cells into the urine to be
excreted.
5. Causes
increased intestinal absorption of calcium by activating Vitamin D.
Mechanism of action
PTH can produce an effect on three
tissues: bone, kidney and intestine. The mechanisms of action are by binding to
a cell membrane receptor and activating adenyl cyclase or facilitating a
cellular influx of calcium.
The bone consists of metabolically
active cells – osteoblasts, osteocytes and osteoclasts. These cells control the
formation and resorptive process of the bone. Osteoclasts
normally resorb bone, delivering calcium into the extracellular fluid. Osteoblasts,
on the other hand, synthesize unmineralized bone. Although the exact mechanism
of PTH on bone has not been fully described, under the influence of PTH; bone
resorption occurs, immediately followed by an increase in bone formation.
Of the amount of calcium that is
filtered at the glomerulus, about 10% is delivered to the distal tubules where
reabsorption is regulated by PTH. PTH causes increase calcium reabsorption and
reduced calcium excretion. PTH also promotes the reabsorption and reduced
calcium excretion. PTH also promotes the reabsorption of hydrogen ions,
magnesium and ammonia. Phosphate, sodium, potassium and bicarbonate ion
excretion is enhanced with the effect of PTH.
PTH stimulation of cAMP content and
calcium influx has not been demonstrated in the intestine. PTH does, however,
stimulate the intestinal transport of calcium and circulatory phosphorous. This
probably an indirect mechanism involving the circulating levels of the Vitamin
D metabolite, 1,25–dihydroxyvitamin D (1,25– [OH]2D3).
Control of secretion
PTH is rapidly released from the
parathyroid gland in response to decrease in the plasma ionic calcium. It acts
on kidney and bone and indirectly on intestine to restore the concentration of
this cation to just above the normal set point, which in turn inhibits
secretion of the hormone. (Click here for full details on Electrolytes)
The concentration of extracellular
ionic calcium is the major source regulator of PTH secretion. Other factors
influence secretion only indirectly through increasing or decreasing
extracellular ionic calcium. The effects of extracellular magnesium concentrations
on secretions are qualitatively similar to but physiologically less important
than those induced by ionic calcium.
Paradoxically, severe, prolonged
hypomagnesemia markedly inhibits secretion of PTH and may be associated with
hypocalcemia. Known direct PTH secretagogoues of questionable physiologic
importance include beta–adrenergic agonist, prostaglandins, dopamine and
histamine.
These agents, as well as decreased
ionic calcium, stimulate the production of cyclic, 3’,5’–adenosine
monophosphate (cAMP) in parathyroid cells in vitro. cAMP may be a
mediator of parathyroid cell secretagogoues, but intracellular calcium itself
and the phosphoionisotol–diacyl–glycerol system appears to be the dominant
mediators of extracellular calcium – regulated PTH secretion.
Biosynthesis
PTH is synthesized as a preprohormone
consisting of 115 amino acids. It is immediately cleaved to produce a
prohormone of 90 amino acids. The pro–PTH is packaged into secretory vesicles,
where six more amino acids are cleaved off to produce the form of PTH that is
secreted into the circulation. The half life of circulatory PTH is 15 to 20
minutes.
The liver and kidneys produce at least
two major fragments from circulating PTH. Therefore, three species of PTH exist
in the circulation: (1) intact PTH molecule, (2) a carboxyl–terminal fragment
and (3) an amino–terminal fragment. Only the intact molecule and the
amino–terminal fragment have biologic activity.
The ionized calcium concentration in
the circulation is the major regulatory mechanism for the synthesis and
secretion of PTH. High calcium levels inhibit PTH, whereas low levels
stimulate PTH. Other mechanisms may have the same influence on PTH
levels.
A low serum magnesium level can
stimulate PTH secretion if the level occurs rapidly; however, a low level may
impair the release of and tissue response to PTH. High serum phosphorous levels
also stimulate PTH secretion. This is actually an indirect mechanism because
the high phosphorous depresses the serum calcium. Since a receptor for Vitamin
D metabolites has been identified, it is now also possible that these
metabolites have the direct ability to suppress PTH release.
Factors influencing PTH
regulation
1.
Calcitonin
(CT)
CT is
biosynthesized and secreted by the ultimobrachial (parafollicular, “C”) cells.
Human CT is cleaved from a high molecular weight precursor that also contains
two other peptides, katalcin and calcitonin gene–related peptide (CGRP).
These peptides circulate in normal subjects in roughly equimotor relationship
to CT and, like CT, are secreted in excess in medullary carcinoma of the
thyroid. The physiologic roles of these peptides are not known, but CGRP is a
potent vasodilator.
The
ultimobrachial cells develop from neural crest tissue during embryonic life,
they form a discrete organ in submammalian vertebrates called the ultimobrachial
gland. In mammals, the angle of the cells merges with the embryonic
thyroid gland, ultimately becoming dispersed in the central region of each lobe
(of the thyroid gland), adjacent to the follicular cells, CT functions as
follows:
a. Influences
the processing of calcium by bone cells by decreasing blood calcium levels and
promoting conservation of hard bone matrix.
b. Parathyroid
hormone acts on antagonist to calcitonin to maintain calcium homeostasis.
2.
Vitamin D
The Vitamin D
itself lacks biologic activity and requires metabolic transformation to attain
potency.
Processes in
Vitamin D metabolism:
a. 25–hydroxylation – done by
microsomal enzymes – a process that occurs chiefly in the liver. This process
is subject to both seasonal and regional variation, owing to differences in
both diet and sunlight exposure. 25 OHD3 is the most
abundant circulating form of the hormone, and it is transported in serum bound to
specific globulin, Vitamin D–binding protein, as are the other
Vitamin D metabolites.
b.
1–alpha–hydroxylation
(1) Occurs
primarily in the mitochondria of renal tubules.
(2) This
process is tightly regulated and constitutes the rate–limiting step in the
production of the active metabolite, 1,25(OH)2D3.
(3) Hypocalcemia
and hypophosphatemia is the stimuli for activating renal 1–alpha–hydroxylase.
The Vitamin D
metabolites
a. 25,26
(OH)2D3
b. 1,24,25
(OH)3D3
c. 1,25,26
(OH)3D3
d. 25
OH–26,23–lactone
Active forms
of Vitamin D
a. Vitamin
D3 (cholecalciferol) is primarily synthesized in the skin
by ultraviolet irradiation of 7–dehydrocholesterol
b. Vitamin
D2 (ergocalciferol) which is used to fortify dairy products
is produced by ultraviolet irradiation of the plant sterol ergosterol.
Functions of
Vitamin D
a. Increases
plasma levels of calcium and phosphates and thus maintains conditions favorable
for bone mineralization.
b. Facilitates
in the absorption of calcium and phosphate by the intestine and much of our
knowledge concerning the molecular mechanism of action of Vitamin D has been
derived from studies of intestinal cell.
c. Muscular
contraction
d. Mineral
metabolism
e. Regulatory
role in bone marrow stem cell and their progeny, including cells of T–lymphocytes
lineage.
Clinical significance of PTH
1.
Hypercalcemia
Causes of
hypercalcemia
a.
Primary
hyperparathyroidism
Primary
hyperparathyroidism is caused by a single benign adenoma of the parathyroid
gland in 80% of patients. The remaining 15% to 20% of cases are due to
hyperplasia of two or more parathyroid gland.
The condition
is readily diagnosed by the presence of both hypercalcemia and elevated levels
of PTH. Additional laboratory findings include decreased serum phosphorous and
increased urinary excretion of calcium, phosphorous and cAMP. The increased
urinary calcium excretion can be explained by considering that there is a
greater filtered load of calcium due to the increased activity of PTH, which
exceeds the normal reabsorptive capacity of the kidney; thus the excess is
excreted in the urine.
Most commonly,
primary hyperparathyroidism is an asymptomatic disorder with mild but
persistent hypercalcemia. The major sites of involvement in symptomatic cases
are the skeleton or the kidneys. The most common complications are the renal
manifestations such as nephrolithiasis and nephrocalcinosis. The classic
symptom of skeletal involvement is osteitis fibrosa cystica, an
erosive bone disease.
b.
Malignancy
Hypercalcemia
of malignancy is frequently due to direct invasion of bone by the tumor. The invasive
tumors of multiple myeloma and breast carcinoma, for example, activate the
osteoclasts, causing bone resorption with resultant hypercalcemia.
Activity of
the parathyroid gland is inhibited in malignancy; thus an elevated PTH, which
is typical of primary hyperparathyroidism would not be expected in malignancy
c.
Toxicity
Hypercalcemia
may be associated with Vitamin D toxicity. Such toxicity can occur in
conjunction with therapy for hyperparathyroid states or can result from
excessive ingestion of Vitamin D. However, an excess of 50,000 IU of Vitamin D
consumed over several months is required to produce hypercalcemia.
Excessive
calcium ingestion (3 to 6 grams / day) in association with the use of
absorbable antacids for the treatment of peptic ulcer can lead to a form of
hypercalcemia known as milk–alkali syndrome. Though not currently
a common finding, this syndrome may be more frequently encountered as a result
of the use of calcium carbonate as a supplemental nutrient.
d.
Miscellaneous
(1) In
sarcoidosis, the mechanism responsible for the elevated calcium levels is
presumably the production of 1,25–(OH)2D3 by the
granulomatous tissue. This extra renal production of 1,25–(OH)2D3
is probably not subject to the tight regulatory control found in the kidney.
(2) Immobilization
may cause hypercalcemia in children and adolescents but is rarely associated
with hypercalcemia in adults. The hypercalcemia appears to be a result of
disproportionate rate of bone formation and resorption due to the sudden loss
of weight bearing. The calcium levels usually return to normal on resumption of
activity.
Signs and
symptoms of hypercalcemia
a. General
symptoms include weakness, anorexia, nausea and constipation due, in part, to
skeletal and intestinal smooth muscle hypofunction
b. Central
nervous system involvement is manifested by impaired concentration and degrees
of mental confusion, ranging from lethargy to stupor and coma.
c. Renal
involvement is accompanied by polyuria due to calcification of the tubules with
loss of concentrating ability. Prolonged deposition of calcium salts can lead
to nephrolithiasis, the formation of renal stones.
d. Cardiovascular
involvement causing hypertension and changes in the electrocardiogram.
e. Skeletal
system involvement results in bone pain, cysts and fractures.
f.
Continued hypercalcemia may
lead to calcium deposits in soft tissues such as kidneys, vessels and joints.
g. Calcium
salts may be deposited in the cornea of the eye, a manifestation known as brand
kerotherapy
Treatment of
hypercalcemia
a. Rehydration
promotes calcium excretion and may be the only treatment necessary for mild
hypercalcemia with few accompanying symptoms.
b. More
severe symptoms require prompt therapy that may include the use of drugs such
as furosemide or ethacrynic acid to promote renal calcium excretion.
2.
Hypocalcemia
Causes of
hypocalcemia
a.
Hypoparathyroidism
Classification
of hyporathyroidism
(1)
Surgical
hypoparathyroidism – may occur after any surgical procedure in which
the anterior neck is explored, including thyroidectomy.
(2)
Idiopathic
hypoparathyroidism – is a broad category of disorders undoubtedly
with more than cause. It can be classified as
(a) Early
onset – MEDAC or Multiple Endocrine Deficiency – Autoimmune Candidiasis
Syndrome
(b) Late
onset – occurs sporadically without circulating glandular autoantibodies.
(3)
Functional hypoparathyroidism – occurs in
patients who have undergone long periods of hypomagnesemia.
Grading of
hypoparathyroidism
Grade 1 and 2
– in hypocalcemia and in constant spontaneous hypocalcemia, respectively.
Grade 3,4,5 –
represents patients whose serum calcium is below 8.5, 7.5, 6.5 mg/dl,
respectively.
b.
Pseudohypoparathyroidism
Pseudohypoparathyroidism
is a rare hereditary disorder. It is characterized by symptoms of
hypoparathyroidism with hypocalcemia, but serum levels of PTH are elevated
instead of decreased. The common causative factor is target organ resistance
(bone and kidneys) to the action of PTH because of a receptor defect.
In addition to
symptoms of hypocalcemia, characteristic skeletal abnormalities are seen. These
include a round face, short stature and shortening of the fourth and fifth
metacarpals and metatarsals. Some degree of mental retardation may also occur.
In
pseudohypoprathyroidism, administration of PTH does not result in increased
urinary cAMP excretion because of the target organ resistance to PTH. Thus, the
PTH infusion test is useful in the differential diagnosis.
In another
rare condition, pseudohypothyroidism, similar to skeletal abnormalities are
present but the serum calcium concentration is normal; thus, hypocalcemic
symptoms are not observed.
c.
Vitamin D
deficiency
Vitamin D
deficiency may be due to inadequate dietary intake, malabsorption or inadequate
exposure to ultraviolet sunlight. Whatever the cause, the end result is a
decreased amount of 25–OHD3, the substrate necessary for the
synthesis of the active form of the vitamin 1,25–(OH)2D3.
Since 1,25–(OH)2D3 facilitates intestinal absorption of
calcium and phosphorous, its deficiency leads to their decreased absorption
and, hence decreased serum levels.
Secondary
hyperparathyroidism results from increased PTH secretion stimulated by the
hypocalcemia. In late stages of the vitamin deficiency, PTH is unable to
restore calcium levels to normal, but its hypophosphatemic effects are
noticeable.
Without
adequate calcium and phosphorous levels, the tendency towards bone
mineralization does not occur. The bone involvement characteristic of Vitamin D
deficiency is age related. In children, the condition is known as rickets
and in adults, it is called osteomalacia. In both conditions,
there is a defective mineralization of bone, so that the bones becomes soft,
bend easily and are prone to deformities. In rickets, the growing skeleton is
involved, and defective mineralization occurs in the epiphyseal cartilage as
well as in the bone. The bones are incapable of withstanding normal mechanical
stresses and tend to undergo bowing deformities during growth. Frequent
fractures occur because of the inadequate skeletal structure.
In
osteomalacia, the skeletal deformities are not prominent. The major symptoms
are varying degrees of skeletal pain and tenderness. However, minor trauma may
cause bone fractures.
d. Chronic
renal failure (renal osteodystrophy)
Serum PTH
levels are elevated in many patients with chronic renal failure. Renal disease
is associated with decreased synthesis of 1,25–(OH)2D3,
which leads to hypocalcemia. The body responds to the low calcium levels by increasing
the secretion of PTH. Hypocalcemia associated with increased PTH levels is also
known as secondary hyperparathyroidism and may occur in
conditions other than chronic renal failure.
The increase
in PTH, however, may not be able to restore normal calcium homeostasis as the
renal failure progresses. Because of the absence of sufficient 1,25–(OH)2D3,
the bone is resistant to the calcium–mobilizing effect of PTH. Elevated serum
phosphorous levels are also present in renal disease. The hyperphosphatemia is
due, in part to renal phosphate retention from the reduced filtered load of
phosphate. The hyperphosphatemia also plays an important role in producing
hypocalcemia.
Skeletal
lesions also occur in chronic renal failure owing to defective bone
mineralization from the altered calcium phosphorous concentration. The
condition is referred to as renal osteodystrophy when bone involvement is
present.
Signs and
symptoms of hypocalcemia
a. Paresthesias
– numbness and tingling may occur, around the mouth, in the tips of the finger
and sometimes in the feet.
b. Tetany
– an attack of tetany usually begins with prodromal paresthesias and is
followed by spasms of the muscles of the extremities and face. The hands,
forearms and less commonly, the feet become contorted in a characteristic way.
First, the
thumb is strongly adducted, followed by flexion of the metacarpophalangeal
joints, extension of the interphalangeal joints (finger together), and flexion
of the wrist and elbow joints. This is somewhat grotesque spastic condition,
although quiet painful when full blown, is more alarming than dangerous.
c. Hyperventilation
– can cause increased secretion of epinephrine and may cause hypocapnia and
alkalosis, which in turn worsen hypocalcemia by causing increased binding of
ionic calcium to plasma proteins.
d. Adrenergic
symptoms – increased epinephrine secretion produces further anxiety,
tachycardia, sweating and peripheral and circumoral pallor.
e. Convulsion,
categorized as:
(1) Generalized
form of tetany followed by prolonged tonic spasms.
(2) Typical
epileptiform seizure (grand mal, jacksonian, focal or petal mal)
f.
Signs of latent tetany
(1)
Chvostek’s
sign
– elicited by tapping the facial nerve just anterior to the ear lobe, just
below the zygomatic arch or between the zygomatic arch and the corner of the mouth.
The response ranges from twitching of the tip at the corner of the mouth to
twitching of all the facial muscles on the stimulated side.
(2)
Trousseau’s
sign
– elicited by inflating a blood pressure cuff to above the systolic pressure. A
typical attack of carpal spasm will occur within 2 – 3 minutes. This is the
most reliable sign of latent tetany and serial tests for it should be performed
and the results recorded in the immediate post – operative period after
anterior neck surgery.
g. Extrapyramidal
sign – includes classic parkinsonian due to calcification of the basal ganglia.
h. Posterior
lenticular cataract – characterize by confluent and total opacity of the lens
which makes it different from senile cataracts.
i.
Cardiac manifestations –
manifested by prolonged QT interval in ECG. Resistance to digitalis,
hypotension and refractory congestive heart failure with cardiomegaly may
occur, these are reversed by normalization of the serum calcium.
j.
Dental manifestations –
abnormalities in enamel formation, delayed or absent dental eruption and
defective dental root formation with short or blunted roots indicate that
hypocalcemia was present during childhood.
k. Malabsorption
syndrome with steatorrhea
3.
Metabolic bone
disease
a.
Paget’s
disease
Paget’s
disease or osteitis deformans is a bone disorder characterized by
excessive bone resorption due to increased osteoclastic activity. This event is
followed by an increase in bone formation as the osteoblasts attempt to
compensate. The deposition of new bone is often haphazard and irregular. The
incidence of Paget’s disease is estimated to be about 3% in individuals over
the age of 40. The cause is unknown.
The increased
bone resorption causes calcium and phosphate ions to be released from bone. However,
since these ions are reused for new bone formation, their plasma levels are
commonly within the normal reference range. Hypercalcemia and hypercalciuria
may rarely occur if the rate of bone resorption is markedly greater than that
of bone formation. High levels of alkaline phosphatase are observed because of
the increased osteoclastic activity.
Many patients
with Paget’s disease are asymptomatic, with disorder being discovered during
the course of examination for unrelated complaints. Other individuals may
detect swelling or deformity of long bones with associated pain. Therapy ranges
from treatment with mild analgesics or non–steroidal anti–inflammatory drugs
for pain relief to orthopedic procedures in more severe cases.
b.
Osteoporosis
Osteoporosis
is a term used to describe disease from numerous causes in which the bone mass
is reduced to a level below that required to maintain adequate mechanical
support. There is no known abnormality in the mineral structure of organic
matrix of the bone. The reduction in bone mass indicates that the rate of bone
resorption is greater than the rate of bone formation.
The major clinical
manifestations are due to vertebral fractures in addition to fractures of other
bones such as the wrists, hip, humerus and tibia. The major accompanying
symptoms are pain, fractures, and spinal deformity.
Loss of bone
mass with advancing age is a universal finding. However, it begins early and
advances more rapidly in women than in men. The perimenopausal years are associated
with a tendency toward accelerated bone loss. Numerous factors have been
implicated in the acceleration of bone loss, including decreased estrogen
availability, decreased calcium intake and intestinal calcium absorption,
cigarette smoking and the inability to synthesize adequate amounts of 1,25–(OH)2D3.
The plasma
levels of calcium and phosphorous are usually normal in patients with
osteoporosis. Post–menopausal women may have slightly hyperphosphatemia and
about 20% may have significant hypercalciuria. Alkaline phosphatase levels are
usually normal but may be increased after fractures.
The course of
treatment depends on the underlying disorder to the development of
osteoporosis. The use of estrogens tends to decrease the rate of bone
resorption but does not restore skeletal mass. The major role of estrogen
therapy is prevention rather than treatment. Oral calcium preparations also
tend to decrease bone resorption in some patients but do not cure the
osteoporosis. Oral administration of Vitamin D may also be helpful in some
cases.
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