Continuing Education Activity

Parathyroid hormone deficiency, also called hypoparathyroidism, results in hypocalcemia, hyperphosphatemia, and increased neuromuscular irritability. Patients may present with myalgias, muscle spasms, and in extreme cases, tetany. Though there are multiple causes of hypoparathyroidism, most cases occur as complications of thyroidectomy and other types of head and neck surgery. This activity reviews when this condition should be considered on differential diagnosis, how to properly evaluate for it, and the role of the interprofessional team in caring for affected patients.

Objectives:

• Outline the causes of hypoparathyroidism.
• Describe the features commonly seen in patients with hypoparathyroidism.
• Summarize the management strategies for hypoparathyroidism.
• Review the importance of enhancing care coordination among the interprofessional team to ensure proper evaluation and management of hypoparathyroidism.

Introduction

Under physiologic circumstances, calcium concentration in the extracellular fluid is maintained within a very narrow range.[1] Normal calcium homeostasis depends on 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.[2][3] Parathyroid hormone deficiency results in hypocalcemia, hyperphosphatemia, and increased neuromuscular irritability with myalgias, muscle spasms, and in extreme cases, tetany.[4]

Etiology

There are numerous possible etiologies of hypoparathyroidism.

• Postoperative complications of thyroidectomy and other types of head and neck surgery - may be transient or permanent[2][5]
• Abnormal development of parathyroid tissue, for example, DiGeorge syndrome[2][6]
• Autoimmune destruction of parathyroid tissue, for example, polyglandular autoimmune syndrome, Type 1[3]
• Activating mutations of the calcium-sensing receptor - autosomal dominant hypocalcemia[3][7]
• Activating antibodies of the calcium-sensing receptor[4]
• Hypomagnesemia[4][8]
• Infiltration of parathyroid tissue, for example, granulomatous disease, hemochromatosis, metastatic disease
• Radiation injury[9]
• Parathyroid hormone resistance, pseudohypoparathyroidism; some patients with pseudohypoparathyroidism (Type 1a) have an unusual phenotype known as Albright’s hereditary osteodystrophy, characterized by short stature, round face, and shortened fourth metacarpal bones. The etiology is an inactivating mutation of the G-alpha subunit of the parathyroid hormone receptor. Due to the resistance to parathyroid hormone, patients have hypocalcemia and hyperphosphatemia but increased serum levels of parathyroid hormone.[9][10]

Epidemiology

The prevalence of hypoparathyroidism in the United States is estimated to be 24 to 37 per 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 surgeon's technical skill. Other causes tend to be rare, and the etiology is suspected based on the age of onset, family history, and associated clinical features.[11]

Pathophysiology

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 the secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases, and parathyroid hormone secretion increases as calcium levels decline.[12]

Parathyroid hormone activates the PTH receptor, another G-protein coupled receptor, increasing the resorption of calcium and phosphorus from bone, enhancing the distal tubular reabsorption of calcium, and decreasing the renal tubular reabsorption of phosphorus. Furthermore, 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-dihydroxy vitamin D. Deficient PTH results in hypocalcemia, hyperphosphatemia, while alkaline phosphatase, a marker of bone formation, is normal.[12][13]

History and Physical

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 polyglandular autoimmune syndrome, type 1. Hypomagnesemia may be the cause if the patient is malnourished, recovering from diabetic ketoacidosis, abuses alcohol, has diarrhea, or has been exposed to drugs that cause renal magnesium wasting. Significant hypocalcemia can cause numbness, paresthesias, muscle cramps, and carpopedal spasms. When severe, it can be life-threatening with laryngospasm, tetany, and seizures.[13]

Hypocalcemia causes positive Chvostek’s and Trousseau's signs.[14]

• Chvostek’s sign is elicited by tapping over the facial nerve as it exits from the parotid gland. The increased neuromuscular irritability leads to the ipsilateral twitching of the upper lip and side of the mouth.
• Trousseau’s sign is sought by inflating a blood pressure cuff from 10 mmHg to 20 mmHg over systolic blood pressure. A positive sign is the development of carpal spasm with flexion of the thumb and adduction of the finger within three minutes. This can be quite painful, so the time should be noted and the cuff deflated once the test is positive.
• Ophthalmologic and neurological examinations are essential since longstanding hypoparathyroidism places patients at a high risk of developing cataracts and calcifications in the brain, primarily in the basal ganglia.
• Some patients with pseudohypoparathyroidism (Type 1a) have an unusual phenotype known as Albright’s hereditary osteodystrophy, characterized by short stature, round face, and shortened fourth metacarpal bones. The etiology is an inactivating mutation of the G-alpha subunit of the parathyroid hormone receptor. Due to the resistance to parathyroid hormone, patients have hypocalcemia and hyperphosphatemia but increased serum levels of parathyroid hormone.[10]

Evaluation

Evaluation should include the following tests:

• Total calcium
• Albumin
• Calculation of the “corrected” serum calcium.
• Approximately 50% of total serum calcium is protein-bound, principally to albumin, and only the free or ionized fraction is biologically active.
• Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin)
• (calcium measured in mg/dL; albumin measured in g/L)
• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium
• Parathyroid hormone level
• Phosphorus
• Blood urea nitrogen (BUN) and creatinine
• Alkaline phosphatase
• 25-hydroxyvitamin D
• Urine calcium and creatinine
• Electrocardiogram[2][3]

Treatment / Management

Chronic Hypoparathyroidism

Traditional treatment of chronic hypoparathyroidism includes supplemental calcium and active vitamin D metabolites.[1][2] 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%.[3] 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.[15][16]

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 the active metabolite of vitamin D, 1,25-dihydroxy vitamin D but have abnormal vitamin D metabolism. Conversion of 25-hydroxyvitamin D to 1,25-dihydroxy vitamin D is stimulated by PTH and low phosphate levels. Since patients with hypoparathyroidism have low levels of PTH and hyperphosphatemia, the production of the active vitamin D metabolite (1,25-dihydroxy vitamin 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-dihydroxy vitamin D (calcitriol) along with supplemental calcium.

• Supplemental calcium 1-2 grams of elemental calcium in divided doses, as calcium carbonate or calcium citrate
• Calcitriol 0.25-2.0 mcg daily

Patients with hypoparathyroidism treated with calcium and calcitriol must be monitored periodically for calcium, phosphorus, and renal function. 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 to 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.[17] 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.[2][3] Urine calcium should periodically be measured to ensure that patients do not develop hypercalciuria. Urine calcium excretion of greater than 200 to 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.[16]

While most hypoparathyroidism is still treated with calcitriol and calcium, selected patients who are more difficult to control on traditional therapy can be treated with daily subcutaneous injections of recombinant human parathyroid hormone (1-84). Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements and, in some cases, eliminate the need to use calcitriol.[16][18] The advantages of replacing parathyroid hormone may be lower urine calcium excretion, more physiological 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. Recombinant human parathyroid hormone is currently only available in the United States through a special use program.[19]

Differential Diagnosis

Differential diagnoses to consider in patients presenting with symptoms of hypoparathyroidism include: 

• Hypomagnesemia
• Postoperative complications of thyroidectomy and other types of head and neck surgery - may be transient or permanent:
• Abnormal development of parathyroid tissue, for example, DiGeorge Syndrome
• Activating mutations of the calcium-sensing receptor - autosomal dominant hypocalcemia
• Activating antibodies of the calcium-sensing receptor
• Autoimmune destruction of parathyroid tissue, for example, polyglandular autoimmune syndrome, Type 1
• Infiltration of parathyroid tissue, for example, granulomatous disease, hemochromatosis, metastatic disease
• Radiation injury
• Parathyroid hormone resistance, pseudohypoparathyroidism

Prognosis

In chronic cases, lifelong calcium supplements along with calcitriol are necessary. Most can live healthy, functional lives, but some have persistent complaints that may be improved by replacing parathyroid hormone. 

Complications

Acute Hypocalcemia

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.[2][3] 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.[16]

Chronic Hypocalcemia

Patients treated with calcium and calcitriol can experience episodes of hypocalcemia or hypercalcemia and are at an increased risk of developing nephrolithiasis and renal insufficiency. In addition, they score poorly on scales that measure the quality of life. Due to the increased risk of renal complications, patients should have periodic imaging of the abdomen looking for nephrolithiasis or nephrocalcinosis. CT scans may be more sensitive than ultrasounds but expose patients to higher radiation levels.[2][3] Clinicians should also consider dual-energy X-ray absorptiometry and imaging of the brain if there are neurologic abnormalities. Treatment with daily subcutaneous injections of parathyroid hormone has been shown lower urine calcium excretion and improve quality of life but is currently only available in the United States through a special use program.[16]

Deterrence and Patient Education

Patients with hypoparathyroidism must be educated about the importance of compliance in taking calcium and calcitriol supplements and the need for periodic monitoring of calcium, phosphorus, and renal function biochemical studies. The goal is to maintain serum calcium levels in the low-normal range, control symptoms, and avoid hypercalciuria.[20]

Pearls and Other Issues

Hypomagnesemia

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 only temporarily improve the serum calcium.[8]

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 increases 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 symptomatic patients, and the calcium increased only to a point where symptoms are alleviated.[3][7]

Enhancing Healthcare Team Outcomes

The medical management of hypoparathyroidism is done by an interprofessional team that consists of an emergency department physician, endocrinologist, surgeon, and primary care provider. In all cases of acute hypocalcemia, intravenous calcium is required if the patient is symptomatic. In chronic cases, lifelong calcium supplements and calcitriol are necessary. All patients with hypoparathyroidism need periodic monitoring of their calcium, phosphorus, renal function, and urine calcium excretion. 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 to 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 and avoid hypercalciuria. While most hypoparathyroidism is still treated with calcitriol and calcium, selected patients who are more challenging to control on traditional therapy can be treated with daily subcutaneous injections of recombinant human parathyroid hormone (1-84). Parathyroid hormone replacement can reduce the oral calcium and calcitriol requirements and, in some, eliminate the need to use calcitriol. In addition, it can improve bone turnover and quality of life.