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Parathyroid Gland and Calcium MetabolismCALCIUM HOMEOSTASISCalcium MetabolismThe normal steady state regulation of calcium metabolism involves dietary intake, physicochemical factors and hormonal control. Intestinal calcium absorption is dependent upon various digestive mechanisms as well as the amount of calcium available from the diet. Cal-cium excretion is controlled by variation of renal tubular resorption. In addition to skeletal main-tenance, a constant concentration of ionized cal-cium is essential for normal neuromuscular func-tion, cell secretion and transport. Ninety -nine percent of total body calcium is stored in bone. Calcium is present in the blood as an ionized, a protein bound, and a complexed form. Calcium is complexed (10%) to phosphate, bicarbonate, citrate, and other similar ions. Ap-proximately 40% of calcium is protein bound, primarily to albumin. Ionized calcium con-stitutes 50% of the total serum concentration.
ParathyroidAnatomy and PhysiologyThe upper parathyroid glands are derived from 4th pouch and the lower pair from the 3rd pouch. They are small glands measuring about 3 mm in greatest diameter . Though most individuals have four glands some people have two and others six. This aspect has clinical significance because if the glands are removed, the person may develop parathyroid insufficiency. Development:Early in life the parathyroids are composed of sheets of chief cells, but as the individual matures, fat cells replace the tissue. Chief cells predominate (these contain secretory granules, large Golgi complex, and moderate numbers of mitochondria), they are the primary synthesizers of PTH. Larger, more eosinophilic Oxyphilic cells derive from chief cells. Biochemistry:PTH is an 84 residue peptide derived from a longer precursor. As soon as PTH is secreted, it is split into an N-terminal fragment (active site) and a C-terminal fragment with a longer half life (measurable by RIA)>. PTH binds to membrane receptors stimulating adenylate cyclase, formation of cAMP and release of Calcium by cells. Activity:PTH acts directly on kidney (glomerular Ca++ resorption) and bone Ca++ resorption (rate of dissolution of bone mineral) and indirectly on intestine via control of vit D derivative l-alpha-25-(OH)2D (calcitriol) synthesis in the kidney. Levels of PTH are regulated by a classic feedback loop. Vitamin D derivatives play a major role in the control of phosphorus and Ca++. Calcium in addition to its structural role in bones, intervenes in a wide array of functions (i.e. clotting, membrane permeability, cellular differentiation and proliferation, etc.) Pathology:Disease will affect parathyroid function in two main ways: Hyperparathyroidism or Hypoparathyroidism.
Hyperparathyroidism:
Primary Hyperparathyroidism:Cause of 30% of hypercalcemias, another 30% is caused by non-parathyroid carcinomas. Incidence of primary hyperparathyroidism 1:800.
MEN can present with hyperplasia or adenomas of parathyroid glands. Findings:
Clinically:Neuromuscular weakness, anxiety, psychosis, coma. Nephrocalcinosis, osteitis fibrosa cystica (after several years). Hypertension is also present (50%) of cases and isn't reversible by parathyroidectomy. Peptic ulcers (due to >gastrin secretion) and pancreatitis (Secondary to calculi?) which are more common in these patients. Metastatic calcification of soft tissues is also observed. Non-parathyroid malignancy as a cause for hypercalcemia: due to two mechanisms:
TumorsAdenomas:These tumors may be difficult to locate because of they are often small. Many are monoclonal and therefore represent true neoplasms. Average 1/2 gram to 5 gm, most often arise in lower glands. They may be pure or mixed cell in type, mostly of chief cells. A thin rim of normal tissue helps differentiate this lesion from hyperplasia. Water-clear cell adenomas may be seen. Patterns can vary depending on vascularity. The remaining glands are usually atrophic with cells containing intracellular fat. Some cells exhibit concentric laminated smooth faced cisternae. Nuclei may be hyperchromatic and atypical. Fig. 2 Parathyroid Adenoma Gross Image Fig. 3 Adenoma Microscopic Image Carcinoma of parathyroidCarcinoma of parathyroid is rare, it is can also be the cause of primary hyperfunction. However almost invariably these tumors are accompanied by hyperparathyroidism, and the symptoms are more severe than in adenomas. Difficult to diagnose, because benign tumors can be pleomorphic. Fig. 4 Gross Image of Parathyroid Carcinoma Fig. 5 Microscopic Image of Parathyroid Carcinoma Fig. 6 Metastatic Calcification of the Kidney due to high circulating calcium. In this case the hyper-production of parathormone was due to Parathyroid Carcinoma. Carcinomas are diagnosed by:
Outcome:Patients usually survive for many years, few patients die from hyperparathyroidism. HyperparathyroidismPrimary Hyperplasia:Hyperplasia may occur from slow renal Ca++ loss, heightened resistance to PTH, and from neck irradiation. Causes 15% of cases of Hyperparathyroidism. Mostly from chief cell hyperplasia. Most glands are enlarged but enlargement may be asymmetric. Hyperplasia may be nodular making the diagnosis of adenoma difficult. Clear cell hyperplasia is composed of cells with many small vacuoles. in a case of hyperparathyroidism due to hyperplasia. Fig. 7 Gross Image of Hyperplastic glands compared to atrophic gland in a case of hyperparathyroidism. Fig. 8 Microscopic Image of hyperplastic gland. Note no rim of normal parathyroid as compared to parathyroid adenoma. Fig. 9 Osteitic Fibrosa Cystica as result of hyperparathyroidism due to parathyroid hyperplasia. Secondary Hyperparathyroidism.Compensatory hypersecretion of PTH secondary to end organ resistance to the hormone, characterized by hypocalcemia. Causes:
Hypoparathyroidism:Inadequate secretion of PTH or ineffective hormone. Hypocalcemia and hyperphosphatemia result.
Causes:
May accompany Di George's syndrome. Pseudohypoparathyroidism-Renal resistance to PTH due to lack of binding to guanine nucleotide binding protein limiting CAMP synthesis. Normal or >PTH . Hypocalcemia and hyperphosphatemia. X-linked dominant (round face, short neck, short 4th-5th metacarpal-Albright osteodystrophy). May respond to large doses of Vit D. Pseudo pseudo hypoparathyroidismSigns similar to above with normal Calcium and Phosphorus. Some authors question its existence. Updated June 13, 2005
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