Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone (PTH), vitamin D metabolites, and calcitonin on calcium transport in bone, kidneys, and the gastrointestinal tract. Parathyroid hormone deficiency results in hypocalcemia, hyperphosphatemia, and increased neuromuscular irritability with myalgias, muscle spasms, and in extreme cases tetany.
Postoperative complications of thyroidectomy and other types of head and neck surgery include transient or permanent:
The prevalence of hypoparathyroidism in the United States is estimated to be 24 to 37/100,000 person-years, most commonly a complication of a thyroidectomy or head and neck surgery. This complication may be transient or permanent, and the frequency is highly dependent upon the technical skills of the surgeon. Other causes tend to be rare, and the etiology is suspected based on the age of onset, family history, and associated clinical features.
The secretion of the parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The activity of the calcium-sensing receptor (CaSR), a G-protein coupled receptor, is affected by changes in the concentration of calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Parathyroid hormone activates the PTH receptor, another G-protein coupled receptor, increasing resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, the parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihyhroxyvitamin D. Deficient PTH results in hypocalcemia, hyperphosphatemia, while alkaline phosphatase, a marker of bone formation, is normal.
The clinician should determine if there has been any recent or remote thyroid or other types of head and neck surgery, the age of onset, and family history of hypocalcemia. If there is evidence of severe immune deficiency, the patient likely has DiGeorge Syndrome, while autoimmune problems such as adrenal insufficiency, or mucocutaneous candidiasis would suggest the etiology is a polyglandular autoimmune syndrome, type 1. Hypomagnesemia may be the cause if the patient is malnourished, recovering from diabetic ketoacidosis, abuses alcohol, has diarrhea, or been exposed to drugs that cause renal magnesium wasting. Significant hypocalcemia can cause numbness and paresthesias, muscle cramps and carpopedal spasms. When severe it can be life-threatening with laryngospasm, tetany, and seizures.
Hypocalcemia causes positive Chvostek’s and Trousseau signs.
Evaluation should include the following tests:
Traditional treatment of chronic hypoparathyroidism includes supplemental calcium along with active vitamin D metabolites. When replacing calcium it is essential to recognize that many formulations list the weight of the total calcium salt, but clinicians must be aware of the actual content of elemental calcium. For example, calcium carbonate is 40% calcium by weight while calcium gluconate is only 9%. A product stating it is 1250 mg of calcium carbonate has 500 mg of elemental calcium. A 10cc vial of 10% calcium gluconate has 1 gram of calcium gluconate but only 93 mg of elemental calcium.
Patients with hypoparathyroidism have classically been categorized as having "vitamin D resistance." Historically, this term was applied since normocalcemia can only be achieved by administering extremely large doses of vitamin D (ergocalciferol or cholecalciferol), doses that would likely cause hypercalcemia in normal individuals. In fact, patients with hypoparathyroidism are normally responsive to physiological doses of 1,25-dihydroxyvitamin D but have abnormal vitamin D metabolism. Conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D is stimulated by PTH and low phosphate levels. Since patients with hypoparathyroidism have low levels of PTH and hyperphosphatemia, production of the active vitamin D metabolite (1,25-dihydroxyvitamin D) is markedly reduced.
In past years patients were treated with supraphysiological doses of vitamin D (ergocalciferol or cholecalciferol) but the current recommendation is to treat with physiological doses of 1,25-dihydroxyvitamin D (calcitriol) along with supplemental calcium.
Patients with hypoparathyroidism treated with calcium and calcitriol must have calcium, phosphorus, and renal function monitored periodically. When treatment is initiated calcium levels should be checked every few weeks. Once patients are on a stable dose of calcium and calcitriol the frequency of monitoring can be reduced to every 3-6 months. The absence of PTH reduces the renal tubular reabsorption of calcium. Therefore, patients treated for hypoparathyroidism are at risk of urolithiasis, or renal and other soft tissue calcifications. These risks can be minimized by titrating therapy to keep the serum calcium level in the low-normal range. In most cases, this will be sufficient to prevent muscle cramps and paresthesias yet limit the risk of extraskeletal calcifications or kidney stones. Urine calcium should periodically be measured to make sure that patients do not develop hypercalciuria. Urine calcium excretion of greater than 250 mg/day should alert the physician to reduce the dose of calcium or vitamin D. An alternative strategy is to add hydrochlorothiazide to decrease urinary calcium excretion.
While most with hypoparathyroidism are still treated with calcitriol and calcium, the FDA recently approved daily subcutaneous injections of recombinant human parathyroid hormone (1 to 84) to treat selected patients whose conditions are difficult to control on the more traditional therapy. Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements, and in some eliminate the need to use calcitriol. The advantages of replacing parathyroid hormone may be lower urine calcium excretion, more physiologic bone turnover, and improved quality of life. Replacement therapy is extremely expensive, and it remains unknown whether there may be long-term adverse effects. Administration of parathyroid hormone increases the risk of osteosarcomas in laboratory animals, although, at present, there is no reported increase in humans.
Acute, symptomatic hypocalcemia should be treated with intravenous calcium. Calcium gluconate is preferred over calcium chloride since the latter can cause tissue necrosis if it extravasates and should only be administered through a central venous line. Each 10cc ampoule of 10% calcium gluconate contains 1 gram of calcium gluconate but only 93 mg of elemental calcium. One-2 ampoules can be diluted in 5% dextrose and infused intravenously over 10 to 20 minutes. The serum calcium should be repeated in several hours and additional doses administered as needed. An alternative is to add 3 g to 5 g of 10% calcium gluconate (279 mg to 465 mg of elemental calcium) to a liter of 5% dextrose and infuse at a rate of 50 mg of calcium/hour. The dose can be adjusted based on subsequent measurements of serum calcium. In most cases, such as following thyroid surgery, it is also appropriate to initiate treatment with calcitriol.
Differential diagnoses to consider in patients presenting with symptoms of hypoparathyroidism include: Courtesy: Endotext. Hypocalcemia: Diagnosis and Treatment.
In the neonatal population, it is important to consider maternal hyperparathyroidism as well.
If magnesium depletion is the cause of hypocalcemia effective therapy requires the repletion of magnesium stores. Until magnesium levels are normal, treatment with calcium will result in only a temporary improvement in the serum calcium.
Autosomal Dominant Hypocalcemia
Patients with autosomal dominant hypocalcemia due to an activating mutation of the calcium-sensing receptor often have mild hypocalcemia and are asymptomatic. This genetic disorder leads to an increase in urine calcium excretion placing such individuals at high risk of nephrolithiasis and nephrocalcinosis when treated with vitamin D and calcium supplementation. Therefore, practitioners should only consider treatment for those patients who are symptomatic, and the calcium increased only to a point where symptoms are alleviated.
The medical management of hypoparathyroidism is done by an interprofessional team that consists of an emergency department physician, endocrinologist, internist, intensivist, general surgeon and a nurse practitioner. In all cases of acute hypocalcemia, intravenous calcium is required if the patient is symptomatic. In chronic cases, life long calcium supplements are necessary. All patients with hypoparathyroidism need monitoring of their calcium, phosphorus, and renal function periodically. When treatment is initiated calcium levels should be checked every few weeks. Once patients are on a stable dose of calcium and calcitriol the frequency of monitoring can be reduced to every 3-6 months.
While most with hypoparathyroidism are still treated with calcitriol and calcium, the FDA recently approved daily subcutaneous injections of recombinant human parathyroid hormone (1 to 84) to treat selected patients whose conditions are difficult to control on the more traditional therapy. Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements, and in some eliminate the need to use calcitriol. As long as the patient is compliant with therapy the outcomes are good.[Level 5]
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