Monday, May 30, 2011

Parathyroid Glands and Parathyroid Hormone.

Parathyroid Glands and Parathyroid Hormone
          PKGhatak,MD



In 1880 Ivar Viktor Sandstrom, a Swedish medical student identified parathyroid glands in humans. That was the last major discovery in human anatomy. His discovery remained unknown till 1891 when Eugene Gley of France established the endocrine nature of these glands. In 1925 J.B.Collip purified the hormone from these glands and it was known as Collip hormone. The molecular structure of this hormone was established by Potts in 1971. The hormone was called parathormone and now it is known as Parathyroid hormone- in short PTH.

Anatomy and Embryology
------------------------------
In normal circumstances, a person has four Parathyroid glands. In rare circumstances, a person may have 8 or 16 parathyroid glands or none at all. Parathyroid glands are very small in size about 6 cm x 3 cm, weighing about 50 mg each. They are mustard yellow in color. They are located in the neck, two on the left side and two on the right side, hiding behind the thyroid gland.  The two parathyroid glands that lie behind the upper pole of the thyroid gland are called superior parathyroid glands and similarly, those two behind the lower pole of the thyroid gland are known as inferior parathyroid glands. Both glands are supplied by the inferior thyroid artery.
These glands develop from the endodermal cells of the pharyngeal pouch. The inferior parathyroid glands develop from the dorsal wing of the 3rd pharyngeal pouch; the thymus gland develops from the ventral wing of this pouch. By the 7th week of fetal development, these glands lose their connection with the pharynx and begin to descend in the neck; the parathyroid glands stop descending when they reach the lower end of the thyroid gland; the thymus descends further to the chest cavity and lies in front of the heart. The superior parathyroid glands develop from the dorsal wing of the 4th pharyngeal pouch and descend only a short distance to occupy their positions behind the upper part of the thyroid lobes.

In about 10 % of cases, supernumerary parathyroid is found due to fragmentation of glands during descent; in 3 % of cases, less than 4 glands are present. In about 20 % of cases, the ectopic location of the Parathyroid glands is seen. Thymus and inferior parathyroid glands descend together, any abnormalities of this process may lead to the positioning of inferior parathyroid glands in the lower part of the neck or further down in the chest- in front of the heart, behind the esophagus or paravertebral area, or within the thymus gland. Superior parathyroid glands descend with the thyroid gland and only for a short distance; as a result, abnormal positions of superior parathyroid glands are less scattered and located around the bifurcation of the common carotid artery or within the thyroid gland.

Chemistry and blood levels of the Parathyroid hormone.
---------------------------------------------------------------
Parathyroid hormone (PTH) is a straight long chain polypeptide. PTH is produced by the chief cells of parathyroid glands as a pro-pre-hormone containing 115 amino acids. It is immediately cleaved to a 90 amino acid pre-hormone. It is further cleaved to a linear protein containing 84 amino acids. In this form, it is stored in secretory granules. The Intact PTH or I-PTH (I-84) and PTH (I-34) - fragments are the biologically active parathyroid hormone. They have opposite effects on serum calcium and on the bone.  Biologically active PTH assay (BI PTH) is based on the sequential binding of amino acids I-4 of the PTH.
Normal serum levels of PTH are 10 - 65 pg/ml. It has a half-life of 4 minutes. Serum levels of BI-PTH are 6 - 40 pg/ml. BI-PTH levels are lowest at 2 AM.
Synthetic PTH N-terminal (I-11) has the same biological properties as native PTH (I-34).

Several factors can interfere with PTH blood level determination. Patients must fast in the morning before the blood sample is drawn. Milk and milk product consumption will give a false result. Patients taking lithium, rifampin, isoniazid, steroid, phenytoin and other anticonvulsant drugs, thiazide, furosemide, phosphate laxative have falsely elevated PTH levels. Falsely low levels are seen in patients taking cimetidine and propranolol.
Pregnancy and lactation can give false results. Hypercholesterolemia and high triglyceride also give false low PTH levels.  Patients who had radioactive scans should delay PTH determination by one week.
In situations where serum calcium levels are high, PTH (I-84) is broken down at a faster rate and the PTH secretion rate is slower but PTH fragments- PTH (7-84) levels do not decrease.
PTH (I-84) and PTH (I-34) are broken down rapidly by a chemical process (proteolysis) by the liver and kidney. The rate of removal is accelerated by high serum calcium and decreased by lower serum calcium.   Peripheral tissues also remove biologically active PTH rapidly and the process is independent of serum calcium levels. C-terminal PTH (7-84) circulates in the blood longer and is filtered out by the kidneys. PTH (7-84) suppresses the actions of PTH (1-84) and PTH (1-34).                                                                                                                                                

Parathyroid Hormone Related Peptide. PTHrP.
-------------------------------------------------------
Cells of many organs and tissues are capable of producing PTH like the hormone PTHrP. Structurally the PTHrP is distinct from PTH and may contain 134 to 173 amino acids. PTHrP also breaks down into smaller fragments like normal PTH. In an experimental animal, PTHrP behaves almost as if PTH is derived from parathyroid glands. It is, however, not shown to be present in a significant amount in the blood of normal adults. Whether PTHrP has significant actions on local tissues at the site of production and then degraded locally that is a conjecture at the moment, but when these cells turn malignant, they produce large quantities of PTHrP and are responsible for severely elevated serum calcium and may cause serious consequences.
Breast milk has a significant amount of PTHrP, it probably causes uterine contractions during lactation.  Placenta produces a significant amount of PTHrP and helps fetal bone development and growth.
In one area PTHrP differs from native PTH:   PTH binds to both PTH-R1 and PTH-R2 receptors, whereas PTHrP binds only to a PTH-R1 receptor.

Control of PTH secretion and Calcium sensor receptor.
-------------------------------------------------------------------.
PTH is primarily responsible for keeping the ionized calcium levels of blood within a very narrow range of 1.1 to 1.3m.mol/L. Blood ionized calcium, on the other hand, controls PTH secretion by interacting with the Calcium sensor CaSR. CaSRs are located on cells of parathyroid glands.
 Calcitonin is produced by the C-cells of the thyroid gland, kidney, brain, pancreas, osteoblasts of bone, hemopoietic cells of bone marrow, squamous cells of the esophagus, gastrointestinal mucosa, and other tissues.   

PTH and PTHrP Receptors
--------------------------------.
Biologically active Parathyroid hormone and Parathyroid related proteins both bind to the Parathyroid hormone receptor PTHR.  The C-terminal mid region PTH binds to a different receptor called the c-PHR receptor.
There are two distinct classes of PTH receptors known as PTH-R1 and PTH-R2. 
The biologically active PTH binds with both PTH-R1 and PTH-R2 receptors. The PTHrP binds with only the PTH-R1 receptor.
Immediate release of calcium in repose to hypocalcemia is the chief function. PTH receptors are present on osteoblasts but not on osteoclasts of bone. When short intermittent PTH stimulations occur an increase in the number of both osteoblast and osteoclast is seen and more trabecular bone is formed.
 The remodeling of bone takes place by PTH induces activation of the following processes-
1. Increased collagen synthesis.
2. Increased alkaline phosphatase activities.
3. Increased activities of various decarboxylases and glucose 6 phosphate dehydrogenase.
4. Increased synthesis of DNA. proteins, and phospholipids.
5. Increased calcium and phosphate transport.
In prolonged sustained PTH, stimulation osteoclasts are stimulated by Cytokines released by osteoblasts and bone resorption takes place.

In Kidney, the PTH acts on many sites and has many actions.
1. In proximal tubules, it suppresses phosphate and bicarbonate transport.
2.Activates Na +/ Ca2+ transport. ( + = ion)
3. In distal tubules, it stimulates Ca2 + transport. 
4. Activates 1- alpha-hydroxylase enzyme and converts vitamin 25(OH)D to active vitamin 1,25(OH)2D.

In the Gastrointestinal tract, PTH influences calcium absorption via activated vitamin D.

The final effect of these activities is the maintenance of a steady calcium environment and healthy bone.

Disorder of Parathyroid Hormone function.
____________________________________________.

Various hereditary and acquired conditions can affect parathyroid function.   Renal failure is the most common clinical condition where hyperfunction of the parathyroid gland is seen. In this situation, the renal distal tubular conversion of vitamin D to active vitamin D is impaired and calcium absorption in the gut is poor. In addition, phosphate blood levels are high due to the failure of the kidney to eliminate phosphate in the urine. Serum calcium levels fall further due to the microscopic precipitation of calcium-phosphate in various tissues.   PTH (7-84) levels may reach 60% of blood PTH levels. PTH (7-84) interferes with the normal functions of biologically active PTH. Serum calcium is restored by the parathyroid gland by producing excessive amounts of PTH at the expense of bone calcium. The stimulation of PTH secretion remains high as long as the renal failure continues. Ultimately, parathyroid glands undergo hypertrophy and occasionally turn into an adenoma.

In about 20% of cases, hyperthyroidism is associated with hyperparathyroidism.

Radiation therapy to the neck, radioactive Iodine treatment for Graves’ disease of the thyroid, and carelessly done thyroid surgery can lead to damage and destruction of parathyroid glands. Under such conditions low PTH secretion and low serum calcium are present. This is called secondary hypoparathyroidism. Sarcoidosis, lymphoma, multiple myeloma, vitamin D toxicity, histiocytosis X    hemochromatosis, Wilson’s disease and low serum magnesium may also produce secondary hypoparathyroidism.

Familial hypocalciuric hypercalcemia –FHH is a hereditary disease of the calcium sensor receptors CaSR of the parathyroid glands and renal tubules. CaSR mistakenly senses low calcium when serum calcium is normal. Parathyroid glands respond by producing excess PTH.  This results in high serum calcium and excess urinary calcium loss.
A reverse condition is also present where CaSR senses high serum calcium in face of normal serum calcium. It results in decreased secretion of PTH and hypocalcemia. This condition is inherited as an autosomal dominant trait. And is known as ADHH-autosomal dominant hypocalcemic hypocalciuria.
Bartter’s syndrome V is a variant of this disorder. In addition to CaSR malfunction, other abnormalities of the ion-transport system result in excessive sodium, calcium and chloride loss in the urine. Low serum sodium leads to secondary hyperaldosteronism and hypokalemia and metabolic alkalosis. Renal calcification and renal stone formation are common.  

In rare autoimmune diseases, antibodies are directed against CaSR. Stimulation of CaSR by antibodies leads to suppression of PTH secretion and low serum calcium. In the Polyglandular autoimmune type, 1 deficiency adrenal glands and ovaries are affected in addition to parathyroid glands. Vitiligo, alopecia, pernicious anemia and mucocutaneous candida infection are present. The defect lies on chromosome 21.

Jensen’s disease is a rare autosomal dominant inherited disease of the PTH-R1 receptor. PTH-R1 is upregulated and excessive PTH-R1 actions are seen in bones and kidneys. Calcium is mobilized from bone and blood calcium level rises. In children, this condition leads to short-limb- dwarfism and in adults bone changes resemble hyperparathyroidism.
In DiGeorge syndrome, there is a defective development of 3rd pharyngeal pouch. In this condition both the thymus and parathyroid glands are rudimentary. Abnormal development of bones and arteries derived from the 3rd pharyngeal pouch takes place. This condition is transmitted by autosomal dominant inheritance and due to a mutation on chromosome 10. Sporadic cases of DiGeorge syndrome are due to other chromosomal abnormalities like Kenny- Caffey syndrome, Sanjad -Sakate syndrome.

In hereditary mitochondrial disorders like Kearns- Sayre syndrome and Melas syndrome hypofunction of parathyroidism is associated with other metabolic defects.

Hypoparathyroidism, in the previous generation, was classified as Primary Hypoparathyroidism, Pseudohypoparathyroidism and Pseudo-pseudohypoparathyroidism.  Current progress in molecular biology has simplified many such disease entities, and they are now known by more clear terms. But some Hypoparathyroidism remains to be defined in those terms and this class of disorder is called Primary hypoparathyroidism. Primary hypothyroidism may be due to a failure of the gland to synthesize PTH or fail to secrete bio-active PTH. 
Symptoms of hypoparathyroidism vary depending on whether the condition is of acute onset or chronic.
In an acute situation, hypocalcemia produces muscle cramps, tetany, carpopedal spasm, and abnormal sensation around the mouth, hand, and feet. Serious cardiac arrhythmias may develop.
In a chronic situation, Parkinson's disease like rigidity and extrapyramidal movements like athetosis and chorea are present and associated with calcification of the Basal ganglia of the brain.  Increased intracranial pressure and papilledema, alopecia, cataract and candida infection may be present.

In pseudohypoparathyroidism (PHP) the defect is in the end-organ -PTH response. Hyperplasia of the parathyroid glands with the increase in PTH secretion takes place in association with clinical features of hypoparathyroidism. This is an inherited disorder due to an abnormality of chromosome 20. In PHP the PTH fails to activate the guanyl-nucleotide binding protein complex, as a result, the intracellular cyclic AMP fails to increase. the kidney 

Tumors and Malignancy of Parathyroid glands.
---------------------------------------------------------
Multiple endocrine neoplasias (MEN) are associated with tumors of the parathyroid gland. In general, all inherited malignant diseases are due to overexpression of proto-oncogenes and / loss of function of tumor suppressor genes.
In MEN1 hyperparathyroidism is associated with tumors of the pituitary and pancreas. Patients present with symptoms of excessive gastric secretion and recurrent gastric ulcers. Mutations of tumor-suppressor genes on chromosome 11q13 are seen.
In MEN2A hyperparathyroidism is associated with medullary carcinoma of the thyroid gland and pheochromocytoma of the adrenal glands.
In MEN2B in addition to features of MEN2A, multiple neuromas are present and hyperparathyroidism is absent in some cases.
There are other hereditary cancers that involve parathyroid glands only, not in association with other endocrine organs.
Certain malignant tumors of various organs produce PTHrP and the presenting symptoms are due to hypercalcemia and hyperparathyroidism.

Primary Hyperparathyroidism is due to inappropriate excessive PTH secretion, and most often due to a benign adenoma and occasionally hyperplasia of one of the parathyroid glands.
Symptoms are variable: in many cases patients are healthy and serum calcium is minimally elevated; in others, recurrent renal stones, peptic ulcers, recurrent pancreatitis, mental changes, cardiac rhythm abnormalities and demineralization of bone are seen.   Parathyroid adenoma in primary hyperparathyroidism is almost always benign and very rarely progresses to carcinoma.
**************************
Who links to my website?
       

2 comments:

Carolina-Jane said...

I bought desiccated thyroid supplement with the hopes of speeding up a possibly sluggish thyroid gland in order to lose weight. I took it for four weeks and noticed great development. It sped my metabolism back again to normal.

Shelley Michele said...
This comment has been removed by a blog administrator.

Heart Failure

  Heart failure: The human heart is divided into 4 chambers, two upper chambers receives blood and two lower chambers - right and left ve...