Parathyroid hormone in the blood serum
Reference serum PTH concentration in adults is 8-24 ng / l( RIA, N-terminal PTH);intact PTH molecule - 10-65 ng / l.
PTH - a polypeptide consisting of 84 amino acid residues, is formed and secreted by parathyroid glands in the form of a high molecular weight prohormone. Progormone after exiting the cells undergoes proteolysis with the formation of PTH.The production, secretion and hydrolytic cleavage of PTH regulates the concentration of calcium in the blood. Reducing it leads to stimulation of synthesis and release of the hormone, and lowering causes the opposite effect. PTH increases the concentration of calcium and phosphate in the blood. PTH acts on osteoblasts, causing an increase in the demineralization of bone tissue. Active not only the hormone itself, but also its amino-terminal peptide( 1-34 amino acids).It is formed by the hydrolysis of PTH in hepatocytes and kidneys in the more quantity, the lower the concentration of calcium in the blood. In osteoclasts, enzymes that destroy the intermediate bone material are activated, and in the cells of the proximal tubules of the kidneys, the reverse reabsorption of phosphates is inhibited. Intestinal absorption of calcium is increased.
In the pathogenesis of hyperparathyroidism, the leading role is played by violations of calcium-phosphorus metabolism due to excessive production of PTH.Target organs PTH - bones, kidneys and small intestine. With the action of PTH on bone tissue, bone resorption increases due to activation of osteoblasts. The formation of a new bone lags behind its resorption, which leads to generalized osteoporosis, the washing of calcium from the bone depot and gipercalcemia. Osteoblasts activate the synthesis of collagen. The destruction of excess collagen by neutral proteases leads to the appearance of high concentrations of peptides containing oxyproline in the blood and increases their excretion in the urine. The effect of PTH on the kidneys is manifested by phosphaturia, caused by a decrease in the reabsorption of phosphate in the proximal tubules. PTH stimulates the formation of calcitriol, which enhances the absorption of calcium in the small intestine. Important role in the occurrence of ulcerative lesions of the stomach, duodenum and small intestine is played by hypercalcemia, which together with PTH has a direct stimulating effect on the mucosa of the gastrointestinal tract, and also causes the calcification of blood vessels.
Primary hyperparathyroidism can be of 3 types: sporadic;family with multiple endocrine neoplasia( MEN) I or MEN-II;Family without MEN( or family isolated).Primary sporadic hyperparathyroidism is caused either by an adenoma( blastoma) of parasitically prominent glands( in 85% of cases) or by their primary hyperplasia. Tumors of parathyroid glands are almost always benign. Only in rare cases, primary hyperparathyroidism is caused by carcinoma of parathyroid glands. With age, the frequency of adenoma of parathyroid glands increases. Primary hyperparathyroidism is characterized by an increase in the concentrationEffects of PTH
Fig. Effects PTH
walkie-talkies in blood PTH( 2-20 times), hypercalcemia with normal or reduced content of phosphates in the blood. In renal damage, usually due to hypercalcemia, a tendency to normalize the concentration of phosphates and calcium in the blood is observed. At this stage of the disease, diagnosis can be very difficult. The content of calcitonin in the blood is increased.
Family primary hyperparathyroidism without MEN is rarely observed, almost always it develops up to 10 years of age.
The drug treatment of primary hyperparathyroidism is ineffective, except for cases when it occurs in women after menopause( in the latter case, the administration of estradiol preparations allows to reduce the concentration of calcium in the blood and helps to maintain bone mass).
Parathyreectomy is the only effective treatment for primary hyperparathyroidism. Indications for surgical treatment:
■ concentration of total calcium in serum, by 0.25-0.4 mmol / l exceeding the upper limit of normal;
■ Reduced GFR by more than 30% compared to the norm;
■ Daily calcium excretion more than 10 mmol;
■ Radiologically confirmed urolithiasis;
■ bone density reduction by more than 2 standard deviations from the age norm;
■ age younger than 50 years;
■ clinical manifestations of hypercalcemia.
At lower values of calcium concentration in the blood of the patient should be monitored for 6-12 months, periodically controlling calcium, PTH, and markers of bone metabolism. Depending on the dynamics of laboratory indicators determine the further tactics.
Secondary hyperparathyroidism is a compensatory hyperfunction and hyperplasia of parathyroid glands that develops with prolonged hyperphosphatemia and hypocalcemia due to CRF, vitamin D and calcium deficiency, malabsorption syndrome, etc. In secondary hyperparathyroidism, the formation of PTH occurs in response to a decrease in the concentration of ionized calcium in the blood. This secretion of PTH is adequate in the sense that it is necessary to normalize the content of ionized calcium. If this effect is achieved, the stimulation of PTH secretion ceases. In this regard, if the functions of the feedback mechanism of PTH regulation are not violated, then any factor contributing to the reduction of ionized calcium in the blood can cause secondary hyperparathyroidism. With secondary gipoparathyroidism, the calcium concentration in the blood is either low( if increased production of PTH is inadequate for the correction of hypocalcemia), or is within the normal range, but is never elevated. The concentration of calcitonin in the blood is reduced.
Tertiary hyperparathyroidism occurs within the secondary, when against an background of prolonged secondary hyperplasia of parathyroid glands an adenoma with autonomous functioning and violation of the feedback mechanism between the concentration of calcium in the blood and the production of PTH is formed. This pathological condition is identical to the primary hyperparathyroidism, with the exception of the previous hypocalcemia in the anamnesis. Spontaneous change of low or normal calcium concentration in the blood to hyper-percalcemia is considered the boundary of the transition of secondary hyperparathyroidism to tertiary. In tertiary hyperparathyroidism, severe osteomalacia and high concentrations in the blood of PTH( 10-20 times higher than normal), alkaline phosphatase and osteocalcin are observed.
Hyperparathyroidism in the ectopic secretion of PTH( pseudo-hyperparathyroidism) occurs when malignant tumors of non-endocrine tissues produce foreign peptides, one of which may be
PTH.Many malignant neoplasms are accompanied by ectopic secretion of PTH.When ectopic secretion is detected not by PTH itself, but by a protein similar to PTH.This protein consists of several peptides containing 139-173 amino acid residues. The eight first amino acids in these peptides are identical to those of PTH.Elevated values of PTH are found in hepatoma, renal cell carcinoma, bronchogenic cancer, as well as in epidermoid lung cancer. The most common ectopic secretion of PTH occurs with kidney cancer and bronchogenic cancer. Most patients with bone metastases show hypercalcemia, elevated concentrations of PTH, and alkaline phosphatase activity in the blood.
MEN are rarely observed, they are characterized by the formation of adenomas of two or more endocrine glands that secrete inadequate amounts of hormones. There are several MEN groups. With MEN-I, the following endocrine organs may be involved in the pathological process: parathyroid glands( hyperplasia or adenoma), pancreatic islet cells( gastrinomas, insulinomas), anterior pituitary gland, adrenal cortex, thyroid gland. MEEN II includes medullary thyroid carcinoma, pheochromocytoma, adenoma or parathyroid gland carcinoma. Primary hyperparathyroidism is the most frequent manifestation of MEN( 20-30% of cases with MENE IIa and somewhat less often with MEN-IIb).At MEN-I it is observed in more than 95% of patients. At MEN-I, as a rule, they detect predominantly diffuse hyperplasia of parathyroid glands, and with MEN-IIa, adenomas.
The content of PTH in the blood can increase with hypovitaminosis D, in patients with enterogenic tetany and tetany of pregnant women. Most patients with bone metastases develop hypercalcemia and elevated levels of PTH in the blood.
Hypoparathyroidism is an inadequate function of parathyroid glands, characterized by a decreased production of PTH, which leads to a disruption in the exchange of calcium and phosphorus. The lack of PTH leads to an increase in the concentration of phosphates in the blood( due to a decrease in the renal PTH effect), as well as to hypocalcemia caused by a decrease in calcium absorption in the intestine, its mobilization from the bones, and inadequate reabsorption in the renal tubules. The concentration of calcitonin in the blood is reduced. Most often, hypothyroidism is caused by surgical damage to either the parathyroid glands themselves, or their blood supply with partial thyroidectomy( during total thyroidectomy and laryngectomy, parathyroid glands are usually removed).
The decrease in PTH in the blood revealed during the study may be accompanied by an increase in the calcium concentration. The causes of hypercalcemia with a reduced concentration of PTH in the blood may be an excess of vitamin D, idiopathic hypercalcemia in children, sarcoidosis, very severe thyrotoxicosis, some cases of myeloma.
Pseudohypoparathyroidism is a term that unites a group of syndromes characterized by tissue resistance to PTH.With all these syndromes, hypo-calciumemia and hyperphosphatemia are observed in the blood on the background of increased concentration of PTH in the blood.
■ Type I pseudohypoparathyroidism( Albright's syndrome, hereditary osteodystrophy) is a rare hereditary disease caused by
mutations of the gene encoding the stimulating a-subunit of the regulatory protein Gsa. This protein mediates between the PTH receptors on the surface of target cells and adenylate cyclase, which catalyzes the synthesis of cAMP, mediating the effects of PTH in the cell. In patients with pseudohypoparathyroidism Ia type, Gsa activity is 2 times lower than in healthy people, therefore the reaction of target cells to PTH is weakened. In addition to resistance to PTH in these patients, there may be other disorders: resistance to TSH( hypothyroidism), GnRH( amenorrhea), ADH( nephrogenic diabetes insipidus).Laboratory signs of pseudohypoparathyroidism Ia type: decreased activity of Gsa in erythrocytes;hypocalcemia and hyperphosphatemia against a background of increased concentrations of PTH;after the administration of PTH, the concentration of cAMP in urine does not increase or increases slightly, the concentration of phosphate in the urine does not change or decreases.
■ Type II pseudohypoparathyroidism is a hereditary autosomal dominant disease, which is based on a defect of PTH receptors on target cells. The change in laboratory parameters is similar to pseudohypoparathyreosis Ie type, but Gsa activity in erythrocytes is normal.
■ Type II pseudohypoparathyroidism is a rare form of resistance to PTH, based on hereditary metabolic disorders of vitamin D. When carrying out a test with PTH, increased excretion of cAMP in the urine is noted, but the concentration of phosphate in the urine does not increase.
In some patients with pseudohypoparathyroidism, resistance to PTH is limited to the kidneys, whereas bone tissue responds to raising the hormone level normally. This variant of the disease is sometimes called psevdogipogiperparatireozom. At the heart of the disease is a defect in the synthesis of calcitriol [1,25( OH) 2D3] in the kidneys, which leads to increased excretion of calcium in the urine. The change in laboratory parameters for the main causes of hypocalcemia is presented in the table.
Table Changes in laboratory indicators for the main causes of hypo-calcemia