Diseases of parathyroid gland

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By: drneorotomaca (37 month(s) ago)

very very good presentation .will you send me ?

By: nadeem.83 (37 month(s) ago)

drneorotomaca send your email id to dr.nadeem.pasha83@gmail .com to get the PPT

 

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Seminar on Diseases of parathyroid gland:

Seminar on Diseases of parathyroid gland Chairperson- Prof.Dr.M.A.Balakrishna Presenter – Dr.Nadeem pasha

Historical Background:

Historical Background In 1849, the curator of the London Zoological Gardens, Sir Richard Owen, provided the first accurate description of the normal parathyroid gland after autopsy examination of an Indian rhinoceros. Human parathyroids were grossly and microscopically described in 1879 by Ivar Sandström , a medical student in Sweden . He suggested that these glands be named the glandulae parathyroideae . The association of HPT and the bone disease osteitis fibrosa cystica (described by von Recklinghausen) was recognized in 1903. Calcium measurement became possible in 1909, and the association between serum calcium levels and the parathyroid glands was established. The first successful parathyroidectomy was performed in 1925 by Felix Mandl on a 38-year-old man who had severe bone pain secondary to advanced osteitis fibrosa cystica . The patient's condition dramatically improved after the operation, and he lived for another 7 years before dying of recurrent HPT. In 1926, Edward Churchill, assisted by an intern named Oliver Cope, operated on the famous sea captain Charles Martell for severe PHPT. It was not until his seventh operation, which included total thyroidectomy , that an ectopic adenoma was found substernally . The first successful parathyroidectomy for HPT in the United States was performed on a 56-year-old woman in 1928 by Isaac Y. Olch .

Embryology:

Embryology In humans, the superior parathyroid glands are derived from the fourth branchial pouch , which also gives rise to the thyroid gland. The third branchial pouches give rise to the inferior parathyroid glands and the thymus . The parathyroids remain closely associated with their respective branchial pouch derivatives. The position of normal superior parathyroid glands is more consistent, with 80% of these glands being found near the posterior aspect of the upper and middle 1/3 thyroid lobes, at the level of the cricoid cartilage. Approximately 1% of normal upper glands may be found in the paraesophageal or retroesophageal space. Enlarged superior glands may descend in the tracheoesophageal groove and come to lie caudal to the inferior glands.

Embryology:

Embryology Truly ectopic superior parathyroid glands are rare, but may be found in the middle or posterior mediastinum , or in the aortopulmonary window. As the embryo matures, the thymus and inferior parathyroids migrate together caudally in the neck. The most common location for inferior glands is within a distance of 1 cm from a point centered where the inferior thyroid artery and RLN cross. Approximately 15% of inferior glands are found in the thymus. The position of the inferior glands, however, tends to be more variable due to their longer migratory path. Undescended inferior glands may be found near the skull base, angle of the mandible, or superior to the upper parathyroid glands along with an undescended thymus. The frequency of intrathyroidal glands is about 2%.

Anatomy :

Anatomy Most patients have four parathyroid glands. Normal parathyroid glands are gray and semitransparent in newborns but appear golden yellow to light brown in adults. Parathyroid color depends on cellularity , fat content, and vascularity . Normal parathyroid glands are located in loose tissue or fat and are ovoid. They measure up to 7 mm in size and weigh approximately 40 to 50 mg each. Parathyroid glands usually derive their blood supply from branches of the inferior thyroid artery, although branches from the superior thyroid artery supply at least 20% of upper glands. Branches from the thyroidea ima , and vessels to the trachea, esophagus , and larynx , may also contribute. The parathyroid glands drain ipsilaterally by the superior, middle, and inferior thyroid veins . The superior glands usually are dorsal to the RLN at the level of the cricoid cartilage, whereas the inferior parathyroid glands are located ventral to the nerve.

Histology of Parathyroid gland :

Histology of Parathyroid gland Histologically , parathyroid glands are composed of chief cells and oxyphil cells arranged in trabeculae , within a stroma composed primarily of adipose cells . The parathyroid glands of infants and children are composed mainly of chief cells, which produce parathyroid hormone (PTH). Acidophilic, mitochondria-rich oxyphil cells are derived from chief cells, can be seen around puberty, and increase in numbers in adulthood. A third group of cells, known as water-clear cells , also are derived from chief cells, are present in small numbers, and are rich in glycogen. Although most oxyphil and water-clear cells retain the ability to secrete PTH, their functional significance is not known.

Calcium Homeostasis:

Calcium Homeostasis Calcium is the most abundant cation in human beings, and has several crucial functions. Extracellular calcium levels are 10,000-fold higher than intracellular levels, and both are tightly controlled. Extracellular calcium is important for excitation-contraction coupling in muscle tissues, synaptic transmission in the nervous system, coagulation, and secretion of other hormones. Intracellular calcium is an important second messenger regulating cell division, motility, membrane trafficking, and secretion. Extracellular calcium (900 mg) accounts for only 1% of the body's calcium stores, the majority of which is sequestered in the skeletal system.

Calcium Homeostasis:

Calcium Homeostasis Approximately 50% of the serum calcium is in the ionized form, which is the active component. The remainder is bound to albumin (40%) and organic anions such as phosphate and citrate (10%). The total serum calcium levels range from 8.5 to 10.5 mg/ dL (2.1 to 2.6 mmol /L) and ionized calcium levels range from 4.4 to 5.2 mg/ dL (1.1 to 1.3 mmol /L). Both concentrations are tightly regulated. The total serum calcium level must always be considered in its relationship to plasma protein levels, especially serum albumin. For each gram per deciliter of alteration of serum albumin above or below 4.0 mg/ dL , there is a 0.8 mg/ dL increase or decrease in protein-bound calcium, and thus, in total serum calcium levels.

Calcium balance and fluxes in a normal human:

Calcium balance and fluxes in a normal human

Parathyroid Hormone Physiology :

Parathyroid Hormone Physiology The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. The hormone acts directly on bone and kidney and indirectly on intestine through its effects on synthesis of 1,25(OH) 2 D to increase serum calcium concentrations; in turn, PTH production is closely regulated by the concentration of serum ionized calcium. This feedback system is the critical homeostatic mechanism for maintenance of ECF calcium. Any tendency toward hypocalcemia , as might be induced by calcium-deficient diets, is counteracted by an increased secretion of PTH.This in turn, (1) increases the rate of dissolution of bone mineral, thereby increasing the flow of calcium from bone into blood ; (2) reduces the renal clearance of calcium, returning more of the calcium filtered at the glomerulus into ECF ; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH) 2 D .

Parathyroid Hormone Physiology:

Parathyroid Hormone Physiology Immediate control of blood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. The renal actions of the hormone are exerted at multiple sites and include inhibition of phosphate transport (proximal tubule), increased reabsorption of calcium (distal tubule), and stimulation of the renal 25(OH)D-1-hydroxylase. PTH has multiple actions on bone, some direct and some indirect. PTH-mediated changes in bone calcium release can be seen within minutes. The chronic effects of PTH are to increase the number of bone cells, both osteoblasts and osteoclasts , and to increase the remodeling of bone.

Parathyroid Hormone Physiology:

Parathyroid Hormone Physiology Continuous exposure to elevated PTH (as in hyperparathyroidism) leads to increased osteoclast -mediated bone resorption . However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Osteoblasts (or stromal cell precursors), which have PTH receptors, are crucial to this bone-forming effect of PTH; osteoclasts , which mediate bone breakdown, lack PTH receptors. PTH-mediated stimulation of osteoclasts is believed to be indirect, acting in part through cytokines released from osteoblasts to activate osteoclasts .

Parathyroid Hormone:

Parathyroid Hormone Structure and Synthesis PTH is an 84-amino-acid single-chain peptide. The amino acid portion, PTH(1–34), is highly conserved and is critical for the biologic actions of the molecule. The PTH gene is located on chromosome 11. PTH is initially synthesized as a larger molecule ( preproparathyroid hormone, consisting of 115 amino acids), which is then reduced in size by a second cleavage ( proparathyroid hormone, 90 amino acids) before secretion as the 84-amino-acid peptide. Transcriptional suppression of the PTH gene by calcium is nearly maximal at physiologic calcium concentrations. Hypocalcemia increases transcriptional activity within hours. 1,25(OH) 2 D 3 strongly suppresses PTH gene transcription.

Parathyroid Hormone:

Parathyroid Hormone Regulation of PTH Secretion PTH secretion increases steeply to a maximum value of five times the basal rate of secretion as calcium concentration falls from normal to the range of 7.5–8.0 mg/ dL . The ionized fraction of blood calcium is the important determinant of hormone secretion. ECF calcium controls PTH secretion by interaction with a calcium sensor, a G protein–coupled receptor (GPCR) for which Ca 2+ ions act as the ligand . Stimulation of the receptor by high calcium levels suppresses PTH secretion. The receptor is present in parathyroid glands. Point mutations associated with loss of function cause a syndrome FHH resembling hyperparathyroidism but with hypocalciuria . On the other hand, gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism . Metabolism Secreted PTH has a half-life of 2 to 4 minutes. In the liver, PTH is metabolized into the active N-terminal component and the relatively inactive C-terminal fraction. The C-terminal component is excreted by the kidneys .Much of the proteolysis of hormone occurs in the liver and kidney.

Calcitonin and Vitamin D :

Calcitonin and Vitamin D Calcitonin is produced by thyroid C cells and functions as an antihypercalcemic hormone by inhibiting osteoclast -mediated bone resorption . Calcitonin production is stimulated by calcium and catecholamines , cholecystokinin , and glucagon. At the kidney, calcitonin increases phosphate excretion by inhibiting its reabsorption . Calcitonin plays a minimal, if any, role in the regulation of calcium levels in humans. However, it is very useful as a marker of MTC and in treating acute hypercalcemic crisis. Vitamin D refers to vitamin D2 and vitamin D3 , both of which are produced by photolysis of naturally occurring sterol precursors. Vitamin D 2 is available commercially, whereas vitamin D 3 is the most important physiologic compound . Vitamin D is metabolized in the liver to its primary circulating form, 25-hydroxyvitamin D. Further hydroxylation in the kidney results in 1,25-dihydroxy vitamin D, which is the most metabolically active form of vitamin D. Vitamin D stimulates the absorption of calcium and phosphate from the gut and the resorption of calcium from the bone.

Hyperparathyroidism :

Hyperparathyroidism Hyperfunction of the parathyroid glands may be classified as primary, secondary, or tertiary. PHPT arises from increased PTH production from abnormal parathyroid glands and results from a disturbance of normal feedback control exerted by serum calcium. Elevated PTH levels may also occur as a compensatory response to hypocalcemic states resulting from chronic renal failure or GI malabsorption of calcium. This secondary HPT can be reversed by correction of the underlying problem (e.g., kidney transplantation for chronic renal failure). However, chronically stimulated glands may occasionally become autonomous, resulting in persistence or recurrence of hypercalcemia after successful renal transplantation, resulting in tertiary HPT .

Primary Hyperparathyroidism :

Primary Hyperparathyroidism PHPT is a common disorder, affecting 100,000 individuals annually in the United States. PHPT occurs in 0.1 to 0.3% of the general population and is more common in women (1:500) than in men (1:2000). Increased PTH production leads to hypercalcemia via increased GI absorption of calcium, increased production of vitamin D3 , and reduced renal calcium clearance. PHPT is characterized by increased parathyroid cell proliferation and PTH secretion that is independent of calcium levels.

Etiology:

Etiology The exact cause of PHPT is unknown, Exposure to low-dose therapeutic ionizing radiation and Familial predisposition account for some cases. Declining renal function with age as well as alteration in the sensitivity of parathyroid glands to suppression by calcium. Lithium therapy has been known to shift the set point for PTH secretion in parathyroid cells, thereby resulting in elevated PTH levels and mild hypercalcemia . Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo. PHPT results from the enlargement of a single gland or parathyroid adenoma in approximately 80% of cases, multiple adenomas or hyperplasia in 15 to 20% of patients, and parathyroid carcinoma in 1% of patients. When more than one abnormal parathyroid gland is identified preoperatively or intraoperatively , the patient has hyperplasia (all glands abnormal) until proven otherwise. Genetics-Most cases of PHPT are sporadic. However, PHPT also occurs within the spectrum of a number of inherited disorders such as MEN1, MEN2A, isolated familial HPT, and familial HPT with jaw- tumor syndrome. All of these syndromes are inherited in an autosomal dominant fashion.

MEN-1:

MEN-1 PHPT is the earliest and most common manifestation of MEN1 and develops in 80 to 100% of patients by age 40 years old. These patients also are prone to pancreatic neuroendocrine tumors and pituitary adenomas and, less commonly, to adrenocortical tumors , lipomas , skin angiomas , and carcinoid tumors of the bronchus, thymus, or stomach. Prolactinomas occur in 10 to 50% of MEN1 patients and constitute the most common pituitary lesion. MEN1 has been shown to result from germline mutations in the MEN1 gene, a tumor -suppressor gene located on chromosome 11q12-13 which encodes menin , a protein that is postulated to interact with the transcription factors .

MEN2A and other syndromes:

MEN2A and other syndromes HPT develops in about 20% of patients with MEN2A and generally is less severe. MEN2A ( Sipple syndrome) , is characterized by pheochromocytoma , medullary carcinoma, and parathyroid hyperplasia. MEN2A is caused by germline mutations of the RET proto-oncogene located on chromosome 10. Patients with the familial HPT with jaw- tumor syndrome have an increased predisposition to parathyroid carcinoma. This syndrome maps to a tumor -suppressor locus HRPT2 , on chromosome 1. Patients belonging to isolated HPT kindreds also appear to demonstrate linkage to HRPT2 .l]

Genetics :

Genetics Approximately 25 to 40% of sporadic parathyroid adenomas and some hyperplastic parathyroid glands have mutation at 11q 13, the site of the MEN1 gene. The parathyroid adenoma 1 oncogene ( PRAD1 ), which encodes cyclin D1, a cell cycle control protein, is overexpressed in about 18% of parathyroid adenomas. Other chromosomal regions deleted in parathyroid adenomas include 1p, 6q, 15q, 16p and 19p. Sporadic parathyroid cancers are characterized by uniform loss of the tumor -suppressor gene RB , which is involved in cell cycle regulation, and 60% have HRPT2 mutations. These alterations are rare in benign parathyroid tumors and may have implications for diagnosis. The p53 tumor -suppressor gene is also inactivated in a subset (30%) of parathyroid carcinomas.

Clinical Manifestations :

Clinical Manifestations Patients with PHPT formerly presented with the "classic" pentad of symptoms (i.e., kidney stones, painful bones, abdominal groans, psychic moans, and fatigue overtones). Currently, most patients present with weakness, fatigue, polydipsia , polyuria , nocturia , bone and joint pain, constipation, decreased appetite, nausea, heartburn, pruritus , depression, and memory loss. Furthermore, these symptoms and signs improve in most, but certainly not all, patients after parathyroidectomy . Truly "asymptomatic" PHPT appears to be rare, occurring in <5% of patients.

Renal Disease:

Renal Disease Approximately 80% of patients with PHPT have some degree of renal dysfunction or symptoms. Kidney stones were previously reported in up to 80% of patients but now occur in about 20 to 25%. The calculi are typically composed of calcium phosphate or oxalate. Nephrocalcinosis , which refers to renal parenchymal calcification, is found in <5% of patients and is more likely to lead to renal dysfunction. Chronic hypercalcemia also can impair concentrating ability, thereby resulting in polyuria , polydipsia , and nocturia . Hypertension is reported to occur in up to 50% of patients with PHPT. Hypertension appears to be more common in older patients and correlates with the magnitude of renal dysfunction and, in contrast to other symptoms, is least likely to improve after parathyroidectomy .

Bone Disease:

Bone Disease Bone disease, including osteopenia , osteoporosis, and osteitis fibrosa cystica , is found in about 15% of patients with PHPT. Increased bone turnover, as found in patients with osteitis fibrosa cystica , can be determined by an elevated blood alkaline phosphatase level. Advanced PHPT with osteitis fibrosa cystica now occurs in <5% of patients. It has pathognomonic radiologic findings, which are best seen on x-rays of the hands and are characterized by subperiosteal resorption (most apparent on the radial aspect of the middle phalanx of the second and third fingers), bone cysts, and tufting of the distal phalanges . The skull also may be affected and appears mottled with a loss of definition of the inner and outer cortices. Brown or osteoclastic tumors and bone cysts also may be present. Severe bone disease, resulting in bone pain and tenderness and/or pathologic fractures, is rarely observed nowadays.

Bone Disease:

Bone Disease Reductions of bone mineral density (BMD) with osteopenia and osteoporosis are more common. Patients with normal serum alkaline phosphatase levels almost never have clinically apparent osteitis fibrosa cystica . HPT typically results in a loss of bone mass at sites of cortical bone such as the radius and relative preservation of cancellous bone such as that located at the vertebral bodies. Patients with PHPT, however, also may have osteoporosis of the lumbar spine that improves dramatically following parathyroidectomy . Fractures also occur more frequently in patients with PHPT, and the incidence of fractures also decreases after parathyroidectomy . Bone disease correlates with serum PTH and vitamin D levels.

Gastrointestinal Complications:

Gastrointestinal Complications PHPT has been associated with peptic ulcer disease. An increased incidence of pancreatitis also has been reported in patients with PHPT, although this appears to occur only in patients with profound hypercalcemia (Ca 2+ ≥12.5 mg/ dL ). Patients with PHPT also have an increased incidence of cholelithiasis , presumably due to an increase in biliary calcium, which leads to the formation of calcium bilirubinate stones.

Neuropsychiatric Complications :

Neuropsychiatric Complications Severe hypercalcemia may lead to various neuropsychiatric manifestations such as florid psychosis, obtundation , or coma. In mild hypercalcemia symptoms such as depression, anxiety, and fatigue are more commonly observed. The etiology of these symptoms is not known. Studies demonstrate that levels of certain neurotransmitters (monoamine metabolites 5-hydroxyindoleacetic acid and homovanillic acid) are reduced in the cerebrospinal fluid of patients with PHPT when compared to controls. Electroencephalogram abnormalities also occur in patients with primary and secondary HPT and normalize following parathyroidectomy .

Other Features:

Other Features PHPT also can lead to fatigue and muscle weakness, which is prominent in the proximal muscle groups. Although the exact etiology of this finding is not known, muscle biopsy studies show that weakness results from a neuropathy, rather than a primary myopathic abnormality. Patients with HPT also have an increased incidence of chondrocalcinosis , gout, and pseudogout , with deposition of uric acid, calcium, pyrophosphate crystals in the joints. Calcification at ectopic sites such as blood vessels, cardiac valves, and skin also has been reported, as has hypertrophy of the left ventricle independent of the presence of hypertension.

Physical Findings:

Physical Findings Parathyroid tumors are seldom palpable, except in patients with profound hypercalcemia . A palpable neck mass in a patient with PHPT is more likely to be thyroid in origin or a parathyroid cancer. Patients also may demonstrate evidence of band keratopathy , a deposition of calcium in Bowman's membrane just inside the iris of the eye. This nonspecific condition generally is caused by chronic eye diseases such as uveitis , and glaucoma, but also may occur in the presence of conditions associated with high calcium or phosphate levels. Fibro-osseous jaw tumors , and or the presence of familial disease in patients with PHPT and jaw tumors , if present, should alert the physician to the possibility of parathyroid carcinoma.

Differential Diagnosis :

Differential Diagnosis Hypercalcemia may be caused by a multitude of conditions. PHPT and malignancy account for >90% of all cases of hypercalcemia . PHPT is more common in the outpatient setting, whereas malignancy is the leading cause of hypercalcemia in hospitalized patients. PHPT can virtually always be distinguished from other diseases causing hypercalcemia by a combination of history, physical examination, and appropriate laboratory investigations. Hypercalcemia associated with malignancy includes three distinct syndromes. Bone metastases may cause hypercalcemia due to osteolytic activity, Patients with solid tumors of the lung, breast, kidney, head and neck, and ovary often have humoral hypercalcemia of malignancy, without any associated bony metastases. Humoral hypercalcemia of malignancy is known to be mediated primarily by PTH-related peptide ( PTHrP ), which also plays a role in the hypercalcemia associated with bone metastases and multiple myeloma. In addition, hypercalcemia also may be associated with hematologic malignancies such as multiple myeloma.

Differential Diagnosis of Hypercalcemia:

Differential Diagnosis of Hypercalcemia Hyperparathyroidism—primary, secondary, tertiary Malignancy—hematologic (multiple myeloma), solid tumors (due to PTHrP ) Endocrine diseases—hyperthyroidism, addisonian crisis, VIPoma Granulomatous diseases— sarcoidosis , tuberculosis, berylliosis , histoplasmosis Milk-alkali syndrome Drugs— thiazide diuretics, lithium, vitamin A or D intoxication Familial hypocalciuric hypercalcemia Paget's disease Immobilization

Differential Diagnosis of Hypercalcemia:

Differential Diagnosis of Hypercalcemia Thiazide diuretics cause hypercalcemia by decreasing renal clearance of calcium. This corrects in normal patients within days to weeks after discontinuing the diuretic, but patients with PHPT continue to be hypercalcemic . Familial hypocalciuric hypercalcemia (FHH) is a rare autosomal dominant condition with nearly 100% penetrance and results from inherited heterozygous mutations in the CASR gene located on chromosome 3. Homozygous germline mutations at this locus result in neonatal hypercalcemia , a condition that can rapidly prove fatal. Patients with FHH have lifelong hypercalcemia , which is not corrected by parathyroidectomy . Hypercalcemia also is found in approximately 10% of patients with sarcoidosis secondary to increased 25-hydroxy vitamin D 1-hydroxylase activity in lymphoid tissue and pulmonary macrophages, which is not subject to inhibitory feedback control by serum calcium.

Differential Diagnosis of Hypercalcemia:

Differential Diagnosis of Hypercalcemia Thyroid hormone also has bone- resorption properties, thus causing hypercalcemia in thyrotoxic states, especially in immobilized patients. Hemoconcentration appears to be an important factor in the hypercalcemia associated with adrenal insufficiency and pheochromocytoma , although the latter patients may have associated parathyroid tumors (MEN2A), and some pheochromocytomas are known to secrete PTHrP . Other endocrine lesions such as vasoactive intestinal peptide-secreting tumors may be associated with hypercalcemia due to increased secretion of PTHrP . Milk-alkali syndrome requires the ingestion of large quantities of calcium with an absorbable alkali such as that used in the treatment of peptic ulcer disease with antacids. Ingestion of large quantities of vitamin D and A are infrequent causes of hypercalcemia , as is immobilization.

Diagnostic Investigations:

Diagnostic Investigations Biochemical Studies The presence of an elevated serum calcium and intact PTH or two-site PTH levels, without hypocalciuria establishes the diagnosis of PHPT with virtual certainty. These sensitive PTH assays use immunoradiometric or immunochemiluminescent techniques and can reliably distinguish PHPT from other causes of hypercalcemia . Furthermore, they do not cross-react with PTHrP . In patients with metastatic cancer and hypercalcemia , intact PTH levels help to determine whether the patient also has concurrent PHPT. Although extremely rare, a patient with hypercalcemia may have a tumor that secretes PTH. FNAB of such a tumor for PTH levels or selective venous catheterization of the veins draining such tumors help clarify the diagnosis. Patients with PHPT also typically have decreased serum phosphate (~50%) and elevated 24-hour urinary calcium concentrations (~60%). A mild hyperchloremic metabolic acidosis also is present (80%), thereby leading to an elevated chloride to phosphate ratio (>33). Urinary calcium levels need not be measured routinely, except in patients who have not had previously documented normocalcemia or have a family history of hypercalcemia to rule out FHH. In patients with FHH, 24-hour urinary calcium excretion is characteristically low (<100 mg/d). Furthermore, the serum calcium to creatinine clearance ratio usually is <0.01 in patients with FHH, whereas it is typically >0.02 in patients with PHPT. Other biochemical features of PHPT are listed in Table.

Table-2. Biochemical Features of Primary Hyperparathyroidism:

Table-2. Biochemical Features of Primary Hyperparathyroidism Serum Tests Alteration Calcium Increased, except in normocalcemic primary hyperparathyroidism Intact PTH Increased or inappropriately high Chloride Increased or high normal Phosphate Decreased or low normal Chloride:phosphate ratio Increased (usually >33) Magnesium Unchanged or decreased (in patients with osteitis fibrosa cystica) Uric acid Normal or increased Alkaline phosphatase Normal or increased (in the presence of high turnover bone disease) Acid-base status Mild hyperchloremic metabolic acidosis Calcium:creatinine ratio >0.02 (vs. <0.01 in BFHH) 1,25-dihydroxy vitamin D Normal or increased Urine tests 24-h urinary calcium Normal or increased

Diagnostic Investigations:

Diagnostic Investigations Elevated levels of alkaline phosphatase may be found in approximately 10% of patients with PHPT and are indicative of high turnover bone disease. These patients are prone to developing postoperative hypocalcemia due to bone hunger. Serum and urine protein electrophoresis may be necessary to exclude multiple myeloma. Occasionally, patients present with normocalcemic PHPT due to vitamin D deficiency, a low serum albumin, excessive hydration, a high phosphate diet, or a low normal blood calcium set point. These patients have increased total PTH levels with or without increased blood ionized calcium levels and must be distinguished from patients with renal leak hypercalciuria who also have increased PTH levels due to excessive calcium loss in the urine. This can be accomplished by administering thiazide diuretics. In patients with idiopathic hypercalciuria , the urinary calcium level falls, and the secondary increase in the blood PTH level also decreases to normal whereas patients with normocalcemic HPT continue to have elevated urine calcium and blood PTH levels, and may, in fact, become hypercalcemic .

Radiologic Tests :

Radiologic Tests In patients with profound hypercalcemia or PHPT associated with vitamin D deficiency, hand and skull x-rays may demonstrate osteitis fibrosa cystica . X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline ( subperiosteal resorption ). BMD studies using dual energy absorptiometry are being increasingly used to assess the effects of PHPT on bone. Dual-energy x-ray absorptiometry (DEXA) of the spine provides reproducible quantitative estimates (within a few percent) of spinal bone density. Substantially decreased bone mineral density at the lumbar spine, hip, or distal radius (>2.5 SD below peak bone mass. CT is a very sensitive technique, but reproducibility of standard CT is no better than 5%. Cortical bone density is reduced while cancellous bone density, especially in the spine, is relatively preserved. Abdominal ultrasound examination is used selectively to document renal stones. Parathyroid localization studies are not used to confirm the diagnosis of PHPT, but rather to aid in identifying the location of the offending gland(s).

Medical management:

Medical management A number of medical therapies such as selective estrogen receptor modifiers and bisphosphonates have been used to successfully lower serum calcium and increase BMD in patients with PHPT. More recently, calcimimetics (modifiers of the sensitivity of the CASR) have been used in randomized, multicenter controlled trials and have been shown to decrease both serum calcium and PTH levels in both symptomatic and asymptomatic PHPT patients. Although these therapies show promise, long-term outcome data are lacking, and their routine use is not advocated at this time.

Medical management:

Medical management Bisphosphonates 5–7 days in doses used First available bisphosphonate ; intermediate onset of action Less effective than other bisphosphonates 1st generation: etidronate 2d generation: pamidronate 10–14 days to weeks High potency; intermediate onset of action Fever in 20 % pt, hypophosphatemia , hypocalcemia , hypomagnesemia 3d generation: zolendronate >3 weeks High potency; rapid infusion; prolonged duration of action Minor; fever, rarely hypocalcemia or hypophosphatemia Calcitonin 1–2 days Rapid onset of action; useful as adjunct in severe hypercalcemia Rapid tachyphylaxis

Treatment :

Treatment Indications for Parathyroidectomy in Patients with Asymptomatic Primary HPT (2002 NIH Consensus Conference Guidelines) Serum calcium >1 mg/ dL above the upper limits of normal Life-threatening hypercalcemic episode Creatine clearance reduced by 30% Kidney stones on abdominal x-rays Markedly elevated 24-h urinary calcium excretion (≥400 mg/d) Substantially decreased bone mineral density at the lumbar spine, hip, or distal radius (>2.5 SD below peak bone mass, T score <–2.5 Age <50 y Long-term medical surveillance not desired or possible

Effects of Surgical Treatment:

Effects of Surgical Treatment Successful parathyroidectomy results in resolution of osteitis fibrosa cystica , improved BMD (6 to 8% in the first year and up to 12 to 15% at 15 years), decreased formation of new renal stones, increased muscle strength, and decreased left ventricular hypertrophy. In addition, it also improves peptic ulcer disease and a number of the nonspecific manifestations of PHPT such as fatigue, polydipsia , polyuria and nocturia , bone and joint pain, constipation, nausea, and depression in most, but not all, patients. The results were similar in a randomized controlled trial of patients with mild PHPT. The increased death rate in patients with PHPT appears to be reversible by successful parathyroidectomy . Lastly, parathyroidectomy can be accomplished with >95% success rates with minimal morbidity, even in elderly patients and is the only curative treatment option for PHPT.

Preoperative Localization Tests:

Preoperative Localization Tests Most endocrine surgeons agree that localization studies are mandatory and invaluable before any neck redo-parathyroid surgery, but their use before initial neck exploration continues to be controversial. Localization studies have permitted surgeons to perform more limited operations, some of them under local anesthesia . These "minimally invasive" procedures include unilateral and focused neck exploration, radio-guided parathyroidectomy , and several endoscopic or video-assisted approaches. The use of localization studies has been shown in some studies to be associated with lower morbidity rates ( hypoparathyroidism and RLN injury) and decreased operative times, reduced duration of hospital stay and improved cosmetic outcomes; while maintaining success rates similar to those obtained with traditional bilateral neck explorations.

Slide 43:

Sl.no Study Advantages Disadvantages 1 . 2 . Preoperative, noninvasive Sestamibi- 99m technetium scan Ultrasound Allows planar and SPECT imaging Identification of juxta - and intrathyroidal tumors Relatively inexpensive False-positive tests due to thyroid neoplasms , lymphadenopathy . False-negative study more common with multiple abnormal parathyroids . False-positive results due to thyroid nodules, cysts, lymph nodes, esophageal lesions . False-negatives result from substernal , ectopic, and undescended tumors .

Slide 44:

Sl.no Study Advantages Disadvantages 3 . 4. Preoperative, noninvasive CT scan MRI scan Localization of ectopic ( mediastinal ) glands Localization of ectopic tumors . No radiation exposure No IV contrast No metal clip artifact Not useful for juxta - or intrathyroidal glands False positives from lymph nodes Relatively high cost Radiation exposure Requires IV contrast Expensive False positives from lymph nodes and thyroid nodules. Cannot be used in claustrophobic patients

Slide 45:

Sl.no Study Advantages Disadvantages 1 . 2 . 3 . 1. Preoperative, invasive FNAB Angiogram Venous sampling Intraoperative PTH assay Can distinguish parathyroid tumor from lymphadenopathy using PTH assay Provides a road map for selective venous sampling Treatment of mediastinal tumors by embolization Useful to lateralize tumor in equivocal cases or negative localization studies Immediate confirmation of tumor removal Experienced cytologist needed Expensive Experienced radiologist needed Expensive , experienced radiologist needed Expensive, Increased operative time, decreased accuracy in multiple gland disease

Sestamibi scan:

Sestamibi scan 99m Tc-labeled sestamibi is the most widely used and accurate modality with a sensitivity >80% for detection of parathyroid adenomas. Sestamibi initially was introduced for cardiac imaging and is concentrated in mitochondria-rich tissue. It was subsequently noted to be useful for parathyroid localization due to the delayed washout of the radionuclide from hypercellular parathyroid tissue compared to thyroid tissue. Sestamibi is a small protein which is labeled with the radio-pharmaceutical technetium-99. This very mild and safe. Sestamibi scans are NOT diagnostic scans and should never be used to determine if a parathyroid tumor is present Sestamibi scans generally are complemented by neck ultrasound, which can identify adenomas with >75% sensitivity in experienced centers , and is most useful in identifying intrathyroidal parathyroids .

Localization studies:

Localization studies Single-photon emission computed tomography(SPECT), particularly when used with CT, has been shown to be superior to other nuclear medicine–based imaging. Specifically, single-photon emission computed tomography can indicate whether an adenoma is located in the anterior or posterior mediastinum ( aortopulmonary window), thus enabling the surgeon to modify the operative approach accordingly. CT and MRI scans are less sensitive than sestamibi scans, but are helpful in localizing large paraesophageal and mediastinal glands. IOPTH was initially introduced in 1993 and is used to determine the adequacy of parathyroid resection. According to one commonly used criterion, when the PTH falls by 50% or greater 10 minutes after removal of a parathyroid tumor , as compared to the highest preremoval value, the test is considered positive, and the operation is terminated. IOPTH measurements, like other localization studies, are less reliable in multiglandular disease.

Parathyroidectomy (Standard Bilateral Exploration):

Parathyroidectomy (Standard Bilateral Exploration) A standard bilateral neck exploration is planned if , Parathyroid localization studies or IOPTH are not available; If the localizing studies fail to identify any abnormal parathyroid gland or Identify multiple abnormal glands, in patients with a family history of PHPT, MEN1, or MEN2A; or A concomitant thyroid disorder requires bilateral exploration. In addition, finding a minimally abnormal parathyroid gland on the side indicated by localization studies during focal exploration should prompt a bilateral exploration or at least the identification of a normal parathyroid gland on the same side.

Identification of Parathyroids:

Identification of Parathyroids A bloodless field is important to allow identification of parathyroid glands. The middle thyroid veins are ligated and divided, thus enabling medial and anterior retraction of the thyroid lobe. The space between the carotid sheath and thyroid is then opened by gentle blunt dissection, from the cricoid cartilage superiorly to the thymus inferiorly and the RLN is identified. Approximately 85% of the parathyroid glands are found within 1 cm of the junction of the inferior thyroid artery and RLNs. The upper parathyroid glands usually are superior to this junction and dorsal to the nerve, whereas the lower glands are located inferior to the junction and ventral to the recurrent nerve. Because parathyroid glands are partly surrounded by fat, any fat lobule at typical parathyroid locations should be explored because the normal or abnormal parathyroid gland may be concealed in the fatty tissue. Intraoperatively , a suspicious nodule may be aspirated using a fine needle attached to a syringe containing 1 cc of saline. Very high PTH levels in the aspirate have been shown to be diagnostic in the intraoperative identification of parathyroid glands.

Parathyroidectomy:

Parathyroidectomy Conduct of parathyroidectomy . A. Exposure of the lower parathyroid gland near the inferior pole of the thyroid gland and anterior to the recurrent laryngeal nerve. B. Exposure of the upper parathyroid gland near the insertion of the recurrent laryngeal nerve at the level of the cricothyroid muscle.

Location of Parathyroid Glands:

Location of Parathyroid Glands Upper parathyroid glands are more consistent in position and usually are found near the junction of the upper and middle thirds of the gland, at the level of the cricoid cartilage. The majority of lower parathyroid glands are found in proximity to the lower thyroid pole , if not found at this location, the thyrothymic ligament and thymus should be mobilized. The carotid sheath also should be opened from the bifurcation to the base of the neck if the parathyroid tumor cannot be found. If these maneuvers are unsuccessful, an intrathyroidal gland should be sought by using intraoperative ultrasound, incising the thyroid capsule on its posterolateral surface or by performing an ipsilateral thyroid lobectomy and "bread-loafing" the thyroid lobe. Preoperative or intraoperative ultrasonography can be useful for identifying intrathyroidal parathyroid glands. Rarely, ectopic upper glands may be found in carotid sheath, tracheoesophageal groove, retroesophageal , or in the posterior mediastinum . Every attempt must be made to identify all four glands. Treatment depends upon the number of abnormal glands.

Parathyroidectomy:

Parathyroidectomy A single adenoma is presumed to be the cause of a patient's PHPT if only one parathyroid tumor is identified and the other parathyroid glands are normal, a situation present in about 80% of patients with PHPT. Adenomas typically have an atrophic rim of normal parathyroid tissue. Care should be taken to not rupture the parathyroid gland to decrease the risk of parathyromatosis . If two abnormal and two normal glands are identified, the patient has double adenomas. Triple adenomas are present if three glands are abnormal and one is normal. Multiple adenomas are more common in older patients with an incidence of up to 10% in patients >60 years old. The abnormal glands should be excised, provided the remaining glands are confirmed as such, thus excluding asymmetric hyperplasia after biopsy and frozen section.

Parathyroidectomy:

Parathyroidectomy If all parathyroid glands are enlarged or hypercellular , patients have parathyroid hyperplasia that has been shown to occur in about 15% of patients in various series. These glands are often lobulated , usually lack the rim of normal parathyroid gland seen in adenomas, and may be variable in size. Patients with hyperplasia may be treated by subtotal parathyroidectomy or by total parathyroidectomy and autotransplantation . Initial studies demonstrated equivalent cure rates and postoperative hypocalcemia for the two techniques, with the latter having the added advantage of avoiding recurrence in the neck. However, autotransplanted tissue may fail to function in about 5% of cases.

Unilateral parathyroid exploration:

Unilateral parathyroid exploration Initially, the choice of side to be explored is marked by preoperative localization studies. In the focused approach only the enlarged parathyroid gland identified, and no attempts are made to locate other normal parathyroid glands. Unilateral neck explorations have several advantages over bilateral neck exploration, including reduced operative times and complications, such as injury to the RLN and hypoparathyroidism . Another argument against a unilateral exploration is the risk of missing another adenoma on the opposite side of the neck. The incidence of double adenomas has been reported to range from 0 to 10%, with a higher incidence of multiple adenomas, in patients with familial HPT, MEN syndromes, and the elderly.

Radio-guided parathyroidectomy:

Radio-guided parathyroidectomy Radio-guided parathyroidectomy takes advantage of the ability of parathyroid tumors to retain 99m Tc-sestamibi. One to two mCi of the isotope is injected before surgery and a hand-held gamma probe is used to guide the identification of the enlarged gland. Reported advantages include easier localization, particularly in reoperative cases, and the ability to perform the procedure under local anesthetic or sedation using smaller incisions. Many studies demonstrated the feasibility of this technique; however, it is rarely used now, largely because it offers little advantage over preoperative sestamibi scans and is associated with increased operative times.

Endoscopic approaches:

Endoscopic approaches Endoscopic approaches include both video-assisted and total endoscopic techniques. Total endoscopic parathyroidectomy was first described by Gagner in 1996. Although port placements are variable, as is the case with endoscopic thyroidectomy , with the reported advantages being superior cosmesis and excellent visualization. Although feasible, these techniques also have been associated with increased operating times, more personnel, and greater expense, and have, in general, not been useful for patients with multiglandular disease, a large thyroid mass, or previous neck surgery and irradiation. Their greatest use has been in patients with tumors at ectopic sites such as the mediastinum where thoracoscopic parathyroidectomy is an excellent alternative to sternotomy .

Minimally invasive parathyroidectomy:

Minimally invasive parathyroidectomy Patients with sporadic PHPT are candidates for a focused neck exploration, an approach that is most commonly referred to as minimally invasive parathyroidectomy

Autotransplantation:

Autotransplantation For patients with hyperplasia, a titanium clip is placed across the most normal gland, leaving a 50-mg remnant and taking care to avoid disturbing the vascular pedicle and that the gland is resected with a sharp scalpel. The resected parathyroid tissue is confirmed by frozen section or PTH assay. Whenever multiple parathyroids are resected , it is preferable to cryopreserve tissue, so that it may be autotransplanted should the patient become hypoparathyroid . Parathyroid tissue usually is transplanted into the nondominant forearm. A horizontal skin incision is made overlying the brachioradialis muscle a few centimeters below the antecubital fossa . Pockets are made in the belly of the muscle and one to two pieces of parathyroid tissue measuring 1 mm each are placed into each pocket. A total of 12 to 14 pieces are transplanted.

Sternotomy:

Sternotomy A sternotomy is usually not recommended at the initial operation, unless the calcium level is >13 mg/ dL . Preoperative Localization studies shows mediastinal glands. Mediastinal glands also may be found in the aortopulmonary window or pericardium, or attached to the ascending aorta, aortic arch, or its branches. Lower parathyroid glands tend to migrate into the anterior mediastinum in the thymus or perithymic fat and usually can be approached via a cervical incision. A sternotomy is needed to deliver these tumors in approximately 5% of cases. Upper glands tend to migrate to the posterior mediastinum in the tracheoesophageal groove. Generally, the gland can be approached by a partial sternotomy to the third intercostal space.

Complications of Parathyroid Surgery:

Complications of Parathyroid Surgery Transient and permanent vocal cord palsy and hypoparathyroidism . The latter is more likely to occur in patients who undergo four-gland exploration with biopsies, subtotal resection with an inadequate remnant, or total parathyroidectomy with a failure of autotransplanted tissue. Vocal cord paralysis and hypoparathyroidism are considered permanent if they persist for >6 months. Incidence is approximately 1%. Patients with symptomatic hypocalcemia or those with calcium levels <8 mg/ dL are treated with oral calcium supplementation (up to 1 to 2 g every 4 hours). 1,25-dihydroxy vitamin D [ calcitriol ( Rocaltrol ) 0.25 to 0.5 g bid] may also be required, particularly in patients with severe hypercalcemia and elevated serum alkaline phosphatase levels preoperatively and with osteitis fibrosa cystica . Intravenous calcium supplementation rarely is needed, except in cases of severe, symptomatic hypocalcemia .

Parathyroid Carcinoma:

Parathyroid Carcinoma Accounts for approximately 1% of PHPT cases. Suspected preoperatively by the presence of severe symptoms, serum calcium levels >14 mg/ dL , significantly elevated PTH levels (5 x normal), and a palpable parathyroid gland. Local invasion is most common; approximately 15% of patients have lymph node metastases and 33% have distant metastases at presentation. Intraoperatively , parathyroid cancer is suggested by the presence of invasion into surrounding tissues like muscle, thyroid, RLN, trachea, or esophagus . Accurate diagnosis necessitates histologic examination that reveals local tissue invasion, vascular or capsular invasion, trabecular or fibrous stroma , and frequent mitoses. Treatment of parathyroid cancer consists of Bilateral neck exploration, with en bloc excision of the tumor and the ipsilateral thyroid lobe. Modified radical neck dissection is recommended in the presence of lymph node metastases.

Parathyroid Carcinoma:

Parathyroid Carcinoma Prophylactic neck dissection is not advised because it is associated with an increased risk of complications and does not appear to have a significant impact on survival. Reoperation is indicated for locally recurrent or metastatic disease to control hypercalcemia . Radiation and chemotherapy may be considered in patients with unresectable disease. Bisphosphonates have shown some effectiveness in treating hypercalcemia associated with parathyroid carcinoma. Cinacalcet hydrochloride, a calcimimetic , can reduce PTH levels by directly binding to the CASR cells on the parathyroid gland and has been shown to be useful in controlling hypercalcemia in patients with refractory parathyroid carcinoma.

Familial Hyperparathyroidism:

Familial Hyperparathyroidism Generally have a higher incidence of multiglandular disease, supernumerary glands, and recurrent or persistent disease. Warrant a more aggressive approach and are not candidates for various focused surgical approaches. Preoperative sestamibi scan and ultrasound can be obtained in patients with inherited HPT to identify potential ectopic glands. A standard bilateral neck exploration is performed, along with a bilateral cervical thymectomy , regardless of the results of localization studies. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation are appropriate and parathyroid tissue also should be cryopreserved . The normal-appearing glands on the contralateral side are biopsied and marked, so that only one side of the neck will need to be explored in the event of recurrence. Patients with MEN2A require total thyroidectomy and central neck dissection for prevention/treatment of MTC.

Parathyromatosis:

Parathyromatosis Parathyromatosis is a rare condition characterized by the finding of multiple nodules of hyper-functioning parathyroid tissue throughout the neck and mediastinum , usually following a previous parathyroidectomy . The true etiology of parathyromatosis is not known. It is postulated to arise either from overgrowth of congenital parathyroid rests or seeding at surgery from rupture of parathyroid tumors or subtotal resection of hyperplastic glands. Parathyromatosis represents a rare cause of persistent or recurrent HPT and can be identified intraoperatively . Aggressive local resection of these deposits can result in normocalcemia but is rarely curative.

Secondary Hyperparathyroidism:

Secondary Hyperparathyroidism Secondary HPT commonly occurs in patients with chronic renal failure but also may occur in those with hypocalcemia secondary to inadequate calcium or vitamin D intake, or malabsorption . The pathophysiology of HPT in chronic renal failure is complex and appears to be related to hyperphosphatemia (and resultant hypocalcemia ), deficiency of 1,25-dihydroxy vitamin D due to loss of renal tissue, low calcium intake, decreased calcium absorption. Patients generally are hypocalcemic or normocalcemic . Aluminum hydroxide, which often was used as a phosphate binder, has been shown to contribute to the osteomalacia observed in this disease. These patients generally are treated medically with a low-phosphate diet, phosphate binders, adequate intake of calcium and 1,25-dihydroxy vitamin D and a high calcium, low- aluminum dialysis bath. Calcimimetics have been shown to control parathyroid hyperplasia and osteitis fibrosa cystica associated with secondary HPT and to decrease plasma PTH and total and ionized calcium levels in humans.

Secondary Hyperparathyroidism:

Secondary Hyperparathyroidism Surgical treatment was traditionally recommended for, patients with bone pain, pruritus , and a calcium-phosphate product ≥70, calcium >11 mg/ dL with markedly elevated PTH, calciphylaxis , progressive renal osteodystrophy , and soft tissue calcification and tumoral calcinosis , despite maximal medical therapy. The role of parathyroidectomy in the era of calcimetics will require long-term studies; however, parathyroidectomy should be considered if PTH levels remain high despite optimal therapy.

Secondary Hyperparathyroidism:

Secondary Hyperparathyroidism Patients should undergo routine dialysis the day before surgery. Localization studies are not necessary. A bilateral neck exploration is indicated. The parathyroid glands in secondary HPT are characterized by asymmetric enlargement and nodular hyperplasia. These patients may be treated by subtotal resection, leaving about 50 mg of the most normal parathyroid gland or total parathyroidectomy and autotransplantation of parathyroid tissue. Upper thymectomy is performed because 15 to 20% of patients have one or more parathyroid glands situated in perithymic fat. Bone and joint pain improve in approximately 75% of patients who undergo parathyroidectomy . Pruritus and malaise, BMD, sexual function, muscle strength, and survival in patients with secondary HPT.

Tertiary Hyperparathyroidism:

Tertiary Hyperparathyroidism Generally, renal transplantation is an excellent method of treating secondary HPT, but some patients develop autonomous parathyroid gland function i,e . Tertiary HPT. Tertiary HPT can cause problems similar to PHPT, such as pathologic fractures, bone pain, renal stones, peptic ulcer disease, pancreatitis, and mental status changes. The transplanted kidney is also at risk. Operative intervention is indicated for symptomatic disease or if autonomous PTH secretion persists for >1 year after a successful transplant. Subtotal or total parathyroidectomy with autotransplantation and an upper thymectomy . All parathyroid glands be identified and subtotal parathyroidectomy be performed as long-term follow-up studies show that limited excisions in these patients are associated with an up to fivefold increased risk of recurrent or persistent disease.

Hypoparathyroidism:

Hypoparathyroidism Hypoparathyroidism is an endocrine disorder in which hypocalcemia and hyperphosphatemia are the result of a deficiency in PTH secretion or action. The parathyroid glands may be congenitally absent in DiGeorge syndrome, an autosomal dominant form involving microdeletions of chromosome 22q11.2 has been described which also is characterized by lack of thymic development and, cardiovascular, facial, and other developmental defects, and most patients die in early childhood with severe infections, hypocalcemia and seizures, or cardiovascular complications

Hypoparathyroidism:

Hypoparathyroidism It can occur as part of a multiglandular endocrine deficiency syndrome (type 1) characterized most commonly by hypoparathyroidism , adrenal insufficiency, and mucocutaneous candidiasis . By far, the most common cause of hypoparathyroidism is thyroid surgery , particularly total thyroidectomy with a concomitant central neck dissection. Patients often develop transient hypocalcemia due to ischemia of the parathyroid glands; permanent hypoparathyroidism is rare. Hypoparathyroidism also may occur after parathyroid surgery, which is more likely if patients undergo a subtotal resection or total parathyroidectomy with parathyroid autotransplantation .

Conditions Causing Hypocalcemia:

Conditions Causing Hypocalcemia Hypoparathyroidism Surgical Neonatal Familial Heavy metal deposition Magnesium depletion Resistance to the action of parathyroid hormone Pseudohypoparathyroidism Renal failure Medications— calcitonin , bisphosphonates , mithramycin Failure of normal 1,25-dihydroxy vitamin D production Resistance to the action of 1,25-dihydroxy vitamin D Acute complex formation or deposition of calcium Acute hyperphosphatemia Acute pancreatitis Massive blood transfusion (citrate overload)

Clinical features:

Clinical features Patients initially develop circumoral and fingertip numbness and tingling. Mental symptoms include anxiety, confusion, and depression. Physical examination reveals positive Chvostek's sign (contraction of facial muscles elicited by tapping on the facial nerve anterior to tragus of the ear) and Trousseau's sign ( carpopedal spasm which is elicited by occluding blood flow to the forearm with a blood pressure cuff for 2 to 3 minutes). Erb`s sign – increased electric excitability of the muscles. Tetany , which is characterized by tonic- clonic seizures, carpopedal spasm, and laryngeal stridor , may prove fatal and should be prevented.

Treatment :

Treatment Most patients with postoperative hypocalcemia can be treated with oral calcium and vitamin D supplements; IV calcium infusion is rarely required except in patients with preoperative osteitis fibrosa cystica . IV calcium gluconate infusion for the treatment of moderate to severe hypocalcemia

Pseudohypoparathyroidism:

Pseudohypoparathyroidism PHP is a hereditary disorder characterized by symptoms and signs of hypoparathyroidism , typically in association with distinctive skeletal and developmental defects. The hypoparathyroidism is due to a deficient end-organ response to PTH. Hyperplasia of the parathyroids , a response to hormone resistance, causes elevation of PTH levels.

Pseudohypoparathyroidism:

Pseudohypoparathyroidism Patients have low calcium and high phosphate levels, as with true hypoparathyroidism . PTH levels, however, are elevated, reflecting resistance to hormone action. AHO, consisting of short stature, round face, skeletal anomalies ( brachydactyly ), and heterotopic calcification is seen in PHP-Ia. Response of Urinary cAMP to PTH is low in Type-l and normal in Type 2.

Slide 76:

Classification of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism (PPHP) Type Hypocalcemia , Hyperphosphatemia Response of Urinary cAMP to PTH Serum PTH G s α Subunit Deficiency AHO PHP- Ia Yes ↓ ↑ Yes Yes PHP-Ib Yes ↓ ↑ No No PHP-II Yes Normal ↑ No No PPHP No Normal Normal Yes Yes

Genetics :

Genetics Multiple defects have now been identified in the GNAS-1 gene in PHP- Ia and PPHP patients. This gene, which is located on chromosome 20q13, encodes the stimulatory G-protein subunit G s α . PHP- Ia and PPHP, have an inheritance pattern consistent with gene imprinting —only females, can transmit the full disease with hypocalcemia . In the renal cortex, it is postulated that only the maternal allele is normally active (independent of any mutation). Maternal gene imprinting- PHP-la. Paternal gene imprinting- PPHP.

Pseudohypoparathyroidism:

Pseudohypoparathyroidism Ellsworth-Howard test- Measurement of serum and urinary phosphorus after intravenous administration of parathyroid extract (200U); used in the diagnosis of pseudohypoparathyroidism . Normally -5 fold increase in urinary phosphorus excretion. Hypoparathyroidism -10 fold increase in urinary phosphorus excretion. Pseudohypoparathyroidism - <2 fold increase in urinary phosphorus excretion. Treatment Similar to that of hypoparathyroidism , except that the doses of vitamin D and calcium are usually lower than those required in true hypoparathyroidism .

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