03 September 2016

Lecture #6: THE PARATHYROID GLAND




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.






  




No comments: