Disclosure
Calcium homeostasis is a complex process involving 4 key components—serum calcium, serum phosphate, 1,25-dihydroxyvitamin D-3, and parathyroid hormone (PTH). More than 99% of the total body calcium is stored in bone in the form of phosphate and hydroxide salts, predominantly as hydroxyapatite. Normally, a very small portion of this calcium is available for exchange in the serum. PTH is a peptide containing 84 amino acids that is secreted by the parathyroid glands after cleavage from preproparathyroid hormone (115 amino acids) to proparathyroid hormone (90 amino acids) to the mature hormone. PTH has 3 major actions. The first action is to increase renal calcium resorption and phosphate excretion. In the kidney, PTH blocks reabsorption of phosphate in the proximal tubule while promoting calcium reabsorption in the ascending loop of Henle, distal tubule, and collecting tubule. Calcium also may exert a direct effect on renal resorption. PTH promotes absorption of calcium from the bone in 2 ways. The rapid phase brings about a rise in serum calcium within minutes and appears to occur at the level of the osteoblasts and osteocytes. Although it may seem counterintuitive that the cells that promote deposition of bone are involved in resorption, these cells form an interconnected network known as the osteocytic membrane overlying the bone matrix, but with a small layer of interposed fluid termed bone fluid. When PTH binds to receptors on these cells, the osteocytic membrane pumps calcium ions from the bone fluid into the extracellular fluid. The slow phase of bone resorption occurs over several days and has 2 components. First, osteoclasts are activated to digest formed bone, and second, proliferation of osteoclasts occurs. Interestingly, mature osteoclasts lack PTH membrane receptors; activation and proliferation appear to be stimulated by cytokines released by activated osteoblasts and osteocytes or by differentiation of immature osteoclast precursors that possess PTH and vitamin D receptors. The third major action of PTH is conversion of 25-hydroxyvitamin D to its most active metabolite, 1,25-dihydroxyvitamin D-3 [1,25-(OH)2 D3], by activation of enzyme 1-hydroxylase in the proximal tubules of the kidney. Negative inhibition of PTH release occurs primarily by direct effect of calcium at the level of the parathyroid gland. Although not well elucidated, 1,25-(OH)2 D3 appears to exert a mild inhibitory effect on the parathyroid gland as well. Vitamin D-3 (cholecalciferol) is formed in the skin when a cholesterol precursor, 7-dehydroxycholesterol, is exposed to ultraviolet light. Activation occurs when the substance undergoes 25-hydroxylation in the liver and 1-hydroxylation in the kidney. The primary action of 1,25-(OH)2 D3 is to promote gut absorption of calcium by stimulating formation of calcium-binding protein within the intestinal epithelial cells. Vitamin D also promotes intestinal absorption of phosphate ion, although the exact mechanism is unclear. Negatively charged phosphate ion may passively flow through the intestinal cell because of flux of the positively charged calcium ion. In bone, vitamin D may play a synergistic role with PTH in stimulating osteoclast proliferation and bone resorption.
Hyperparathyroidism Primary hyperparathyroidism (HPT) is defined as an abnormal hypersecretion of PTH, producing hypercalcemia and hyperphosphatemia. As with other endocrine abnormalities, one must compare the hormone level to the substances that normally provide feedback. For example, when a patient has an elevated serum ionized calcium level, the serum PTH level should be low; a "normal" PTH level is pathologic. Primary HPT is the most common cause of elevated PTH and calcium levels. Approximately 85% of cases are found to be caused by an isolated adenoma, 15% caused by diffuse hyperplasia, and less than 1% by parathyroid carcinoma. Rarely, primary HPT may be related to multiple endocrine neoplasia (MEN); family history or other endocrine tumor warrants screening for MEN. Incidence of primary HPT in the United States has been reported as 5-50 per 10,000 individuals. The disease is common in individuals older than 40 years and has a female-to-male ratio of 3:1. Secondary HPT is a compensatory hyperfunctioning of the parathyroid glands caused by hypocalcemia or peripheral resistance to PTH. As opposed to primary HPT, treating the underlying cause can reverse secondary HPT. The most common setting is in a patient with end-organ failure from chronic renal insufficiency, with hypocalcemia and hyperphosphatemia. Less commonly, it may be caused by calcium malabsorption, osteomalacia, vitamin D deficiency, or deranged vitamin D metabolism. Tertiary HPT occurs in a setting of previous secondary HPT in which the glandular hyperfunction and hypersecretion continue despite correction of the underlying abnormality, as in renal transplantation. Familial hypocalciuric hypercalcemia (FHH) is a disease with an autosomal dominant mode of inheritance linked to a defect on chromosome 3. The exact mechanism of the disease is not known, but it appears that affected individuals have an abnormal calcium sensor. PTH levels may be elevated because of abnormal calcium detection. Since renal calcium resorption in these patients is greater than 99%, diagnosis is made by a calcium-to-creatinine clearance ratio of less than 0.010, while in those with primary HPT the ratio is 0.015-0.040. Patients should have a family history positive for hypercalcemia. Surgery is not indicated in these individuals. Hypoparathyroidism Hypoparathyroidism is an uncommon congenital or acquired condition in which PTH secretion is deficient or absent. Hypocalcemia and hyperphosphatemia are usually present. By far, hypoparathyroidism most commonly results from an iatrogenic cause; it usually follows parathyroid surgery or total thyroidectomy. Abnormalities of the third and fourth branchial pouches, such as DiGeorge syndrome, may lead to agenesis or dysgenesis of the parathyroid glands as well as athymia. Isolated familial cases of metabolic hypoparathyroidism have been reported. Some cases of hypoparathyroidism categorized as idiopathic may have an autoimmune basis and other endocrine deficiencies; T-cell dysfunction also may be involved. Differential diagnoses of hypercalcemia
The exact cause of parathyroid adenoma is unknown. Histologically, adenomas are hypercellular and have very little fat when compared to normal glandular tissue. Fat content tends to increase with age, thus comparison to a normal gland is important to ensure the diagnosis is adenoma. Chief cells, which have regular central nuclei, predominate. Foci of larger acidophilic oxyphilic cells and clear cells are present. Adenomas may have clear cell variants. In primary hyperplasia, the principal finding is chief cell hyperplasia, although clear cell variants can occur. Again, stromal fat is decreased in proportion to the magnitude of hyperplasia. A differentiating feature seen in approximately one third of adenomas but not in hyperplasia is a well-defined capsule separating the adenoma from normal parathyroid tissue. |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hyperparathyroidism The mnemonic "painful bones, psychic moans, abdominal groans, and renal stones" has become largely historical because most patients present long before the disease progresses to multiple-system involvement. In the United States, the most common presentation of HPT is an elevated serum calcium level reported on routine screening by a primary care physician. Another common scenario (15-20%) occurs when a patient presents with a calcium oxalate kidney stone and is found to be hypercalcemic (10% incidence with this type of stone). However, on careful questioning of an asymptomatic patient, one often can elicit subtle symptoms, such as nonspecific fatigue, weakness, musculoskeletal complaints, constipation, depression, or possibly a history of peptic ulcer, hypertension, cholelithiasis, pancreatitis, and gout or pseudogout. Additionally, prolonged hypercalcemia can lead to metastatic calcifications in blood vessels, soft tissues, and joints (chondrocalcinosis). Osteitis fibrosa cystica, in which subperiosteal bone resorption is followed by the formation of cysts that may distort bony architecture, is a rare presentation. The most commonly involved bones are the phalanges and distal clavicles; involvement of the mandible is less likely, and the maxilla is rarely affected. If hemorrhage into a cyst occurs, it is followed by giant cell reparative granulomas known as brown tumors. Diagnosis is confirmed by an elevated serum level of intact PTH or high normal PTH in the setting of hypercalcemia. Hypoparathyroidism Patients with hypoparathyroidism present with hypocalcemia, mental changes, and neuromuscular excitability or tetany. Anatomic abnormalities, though not readily apparent, include intracranial calcifications and cataract formation. Young children may have disturbed dentition. Pseudohypoparathyroidism is a rare hereditary disorder caused by end-organ failure of PTH. Most patients with this disorder have a characteristic phenotype of short stature, round face, brachydactyly, and heterotopic calcification. Low serum calcium and high phosphate levels are accompanied by a high PTH level. For a detailed discussion of the anatomy of parathyroid glands, please refer to the eMedicine article Parathyroid Surgery.
Severe hypercalcemia should be managed promptly with administration of intravenous fluids and a loop diuretic to block calcium resorption. Calcitonin (2-8 U/kg IV/IM/SC q6-12h) can lower serum calcium levels by inhibiting bone resorption, but tachyphylaxis occurs quickly. Bisphosphonates also inhibit bone resorption, but electrolyte abnormalities such as hyperphosphatemia or hypophosphatemia, hypocalcemia, and hypomagnesemia are common. Plicamycin (Mithracin) has been used for acute management of hypercalcemia; major adverse effects are thrombocytopenia, hepatocellular necrosis, and decreased levels of clotting factors.
Parathyroidectomy is indicated for most patients with primary HPT and for those with confirmed tertiary HPT, particularly healthy patients younger than 50 years. Unequivocal indications for surgery include the following:
Removal of the abnormal gland is indicated for adenoma, and resection of 3.5 glands is the standard treatment for 4-gland hyperplasia. For a detailed discussion of surgical anatomy and technique, please refer to Parathyroid Surgery.
Preoperative details
A good deal of controversy exists concerning the utility of preoperative localization studies for parathyroid adenoma and whether these studies alter intraoperative management. Please refer to Parathyroid Surgery.
Preoperative screening should include a serum calcium level and a confirmed elevated or inappropriately high normal intact PTH level. Intact PTH assay differentiates primary HPT from hypercalcemia of malignancy because the parathyroid-related peptide secreted from some tumors is a much larger protein, which shares a 50% homology with the 36 N-terminal amino acids of PTH. Many endocrinologists also recommend a 24-hour calcium collection for calculation of the calcium-to-creatinine clearance ratio to exclude FHH.
The most common conduction abnormality observed with hypercalcemia is a shortened QT interval, which should be documented with an electrocardiogram.
Postoperative details
Short-term hypocalcemia can be expected following most parathyroidectomies and generally is left untreated unless serum calcium is markedly decreased or the patient becomes symptomatic. The author's postoperative routine is to empirically treat patients with oral vitamin D-3 (0.5 mcg/d for 3 d) along with calcium carbonate or calcium citrate (2 g/d for 1 wk, followed by 1 g/d for approximately 1 mo).
Hungry bone syndrome is a condition that may follow parathyroidectomy; it is marked by hypocalcemia and hypophosphatemia. It usually is seen in patients with long-standing HPT and extensive bone resorption. Proposed mechanism is a rebound uptake of calcium and phosphorus by bones, which have long been starved of these metabolites. If symptomatic, treatment is IV calcium (2 g q8h).
Follow-up care
Postoperative serum calcium and PTH levels should be checked in 12-24 hours to confirm correction of hypercalcemia and elevated PTH. Serum calcium should be monitored several weeks after surgery until calcium levels have stabilized. Calcium and PTH are checked 6 months postoperatively to exclude persistent HPT. Disruption of vascular supply may lead to hypoparathyroidism, particularly when all 4 glands are dissected or a gland is autotransplanted. Patients with hypoparathyroidism are treated with oral calcium and vitamin D; intravenous calcium is reserved for symptomatic hypocalcemia. When at least one parathyroid gland is identified and preserved, PTH levels usually return to normal, but inadvertent 4-gland removal, as sometimes occurs with total thyroidectomy, can lead to permanent hypoparathyroidism.
Complications
Temporary hypocalcemia is a very common and somewhat expected consequence of parathyroidectomy. Other short-term complications of parathyroidectomy include recurrent laryngeal nerve paralysis/paresis, bleeding and hematoma, and, rarely, wound infection.
Persistent hypoparathyroidism is an uncommon consequence that requires long-term calcium and vitamin D-3 supplementation. Recurrent laryngeal nerve paralysis may be well compensated over time, but voice complaints or aspiration may warrant vocal fold medialization by thyroplasty, arytenoid adduction, injection, or a combination.
Outcome and prognosis
Cure rate following initial parathyroidectomy is 95-97%. Reexploration for recurrent or persistent hypercalcemia has a slightly lower success rate of 85-90%.
Radio-guided parathyroidectomy currently is being performed at an increasing number of centers in the United States. To qualify for this procedure, the patient must have an adenoma that enhances on sestamibi scanning. If uptake has been previously confirmed, the tracer is again injected 1.5-3 hours before surgery to allow for thyroid washout. Through a small incision or a standard Kocher incision, the surgeon uses a gamma probe to locate the abnormal gland, keeping dissection and blood loss to a minimum. In reoperated patients, the gamma probe can be an invaluable tool, eliminating hours of surgery. This promising technique offers other advantages to the patient, including local anesthesia with sedation instead of a general anesthetic. In the author's experience, operative time has been much shorter, often less than 30 minutes for primary operations; the procedure can be performed on an outpatient basis.
Therapeutic angiographic embolization also has been reported with immediate decrease in venous PTH. One series of 24 patients with persistent HPT following surgery reported a long-term success rate of 71%.
Recent identification and cloning of the calcium sensor in the parathyroid gland has opened speculation into pharmacologic inhibition of PTH release. Until such a drug is approved, primary HPT remains a surgical disease.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
){kind=small}
