Hypoparathyroidism

Etiology

Though multiple causes of hypoparathyroidism exist, unintended excision or iatrogenic injury during head and neck surgery (eg, thyroidectomy) is the most common etiology.[4][5] Other causes include the following:

• Genetic syndromes or mutations (eg, DiGeorge syndrome and autosomal dominant hypocalcemia)[10]
• Autoimmune destruction of parathyroid tissue (eg, type 1 polyglandular autoimmune syndrome)[3]
• Immune checkpoint inhibitors
• Magnesium deficiency or excess 
• Infiltration of parathyroid tissue (eg, granulomatous disease, hemochromatosis, and metastatic disease)
• Parathyroid gland radiation injury
• Acute illness or severe burn 
• Maternal familial hypocalciuric hypercalcemia
• Idiopathic [5][4][11][12]

Epidemiology

The prevalence of hypoparathyroidism in the United States is estimated to be 6.4 to 37 per 100,000 person-years, with 75% of cases caused by a thyroidectomy or head and neck surgery complication.[5] This complication may be transient or permanent, and the frequency highly depends on 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.[13][14]

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 calcium concentration changes. 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.[1] 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, PTH plays an essential role in vitamin D metabolism by activating vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D. The intestinal absorption of calcium and phosphorus is subsequently increased by 1,25-dihydroxyvitamin D and, along with PTH, facilitates bone resorption. 

Consequently, PTH deficiency results in hypocalcemia and hyperphosphatemia, while alkaline phosphatase, a marker of bone formation, is normal.[1][15] Additionally, magnesium depletion can cause hypocalcemia by inducing a state of parathyroid hormone resistance. When patients are severely depleted, PTH secretion is also decreased.[12]

History and Physical

Clinical History

The initial assessment of hypoparathyroidism not only includes a comprehensive history and evaluation of clinical signs and symptoms but also the identification of secondary complications that may have developed. In most patients, hypoparathyroidism is clinically apparent in patients who become symptomatic immediately following neck surgery. Clinicians should also evaluate patients for hypoparathyroidism if neuromuscular irritability symptoms (eg, perioral numbness, paresthesias of the hands and feet, muscle cramps, carpopedal spasm, laryngospasm, and focal or generalized seizures) are present. Asymptomatic patients with incidental hypocalcemia on laboratory studies and personal or family history of autoimmune diseases or history of head and neck surgery should also be assessed for PTH deficiency.[4][5] 

A history of severe immune deficiency may indicate DiGeorge syndrome, while autoimmune problems such as adrenal insufficiency or mucocutaneous candidiasis may indicate polyglandular autoimmune syndrome type 1. Patients with a history of malnourishment, diabetic ketoacidosis, alcohol abuse, severe diarrhea, or exposure to renal magnesium wasting medications may also have hypoparathyroidism symptoms secondary to magnesium deficiency.[15]

Physical Exam Findings

Hypoparathyroidism should be suspected if acute signs of hypocalcemia follow a head and neck procedure. These findings on physical examination are called Chvostek's and Trousseau's signs. Clinical findings of various conditions that can arise secondary to hypoparathyroidism may be present as well. Physical exam findings associated with hypoparathyroidism include:

• Chvostek sign: This finding 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 sign: After inflating a blood pressure cuff from 10 mm Hg to 20 mm Hg over the patient's systolic blood pressure, the Trousseau sign is considered positive if carpal spasm develops, with flexion of the thumb and adduction of the finger within 3 minutes. However, this can be painful, so the time should be noted, and the cuff should be deflated once the test is positive.

• Ophthalmologic and neurological findings: Cataracts and neuropsychiatric conditions, including anxiety, depression, bipolar affective disorder, seizures, and paresthesias, are commonly identified in patients with longstanding hypoparathyroidism.[5][16][5]

Evaluation

Once hypomagnesemia has been excluded, hypoparathyroidism is typically diagnosed with laboratory studies confirming a low corrected calcium level as well as a decreased or undetectable parathyroid hormone level. Other laboratory studies are also utilized to help exclude differential diagnoses and support a hypoparathyroidism diagnosis.

Diagnostic Laboratory Study Indications

Laboratory studies are indicated in the following patients:

• Those who become symptomatic immediately following head and neck surgery
• Who have neuromuscular irritability symptoms
• Asymptomatic patients found to have incidental hypocalcemia in laboratory studies and a history of autoimmune diseases or head and neck surgery should be assessed for PTH deficiency.[5]

Initial Diagnostic Laboratory Studies

A decreased corrected calcium in conjunction with a reduced or undetectable PTH level on 2 different serum tests at least 2 weeks apart confirms the diagnosis; therefore, these and some other supportive laboratory tests are recommended when assessing patients for PTH deficiency.[5] The following diagnostic studies and associated findings are characteristic during the initial evaluation of hypoparathyroidism:

• Albumin: utilized for calcium correction calculation
• Corrected serum calcium: decreased
  • Approximately 50% of total serum calcium is protein-bound, principally to albumin; only the free or ionized fraction is biologically active.
  • Corrected calcium = serum total calcium + .8 x (4 - albumin)
  • Ionized calcium is occasionally utilized in selected cases when the accuracy of the corrected total calcium is uncertain.
• Parathyroid hormone: decreased or inappropriately normal in the setting of hypocalcemia
• Phosphorus: elevated
• Fractional urinary calcium excretion: elevated
• Blood urea nitrogen (BUN), creatinine, and creatinine clearance: vary depending on whether kidney function is impaired [5][8][4]

Additional Diagnostic Studies

Following confirmation of PTH deficiency, the following studies are recommended to provide a baseline for comparison after treatment is initiated and to identify additional abnormalities or complications needing therapy. Repeated laboratory testing every 6 to 12 months is recommended in stabilized patients; however, testing should be done more frequently in patients unresponsive to treatment.[5] 

• Alkaline phosphatase: to monitor bone formation markers
• 25-hydroxyvitamin D: assesses vitamin D deficiency
• 24-hour urine calcium and creatinine: to monitor kidney function
• Electrocardiogram: findings consistent with hypoparathyroidism include a prolonged QT interval and T-wave alternans [2][3]
• Renal ultrasound or computerized tomography (CT): to evaluate for nephrocalcinosis or nephrolithiasis [5] 

Treatment / Management

Postsurgical Hypocalcemia and Hypoparathyroidism

In stable patients diagnosed with hypoparathyroidism after neck surgeries (eg, thyroidectomy), the recommended standard treatment is oral elemental calcium 2 to 3 g and calcitriol .5 to 1.5 μg daily. Within a month, approximately 70% to 80% of these patients will improve to the point that medical therapy can be gradually tapered down under close surveillance.[5] In unstable patients with a corrected calcium of less than 7 mg/dL or developing cardiac, respiratory, or severe neurologic complications secondary to hypocalcemia, emergent treatment with an intravenous calcium bolus of 90 to 180 mg is recommended. This bolus should be infused over 10 to 20 minutes in conjunction with cardiac monitoring. Standard oral calcium and calcitriol therapy should be initiated after the initial calcium bolus. Commonly, a maintenance intravenous calcium infusion of 900 mg elemental calcium in 1 L of 5% dextrose water or normal saline at a rate of 50 mL per hour is administered in addition to oral therapy. The maintenance solution should be adjusted to keep the patient's serum calcium slightly below the normal range.[5]

Chronic Hypoparathyroidism

Long-term PTH deficiency treatment also involves supplementation with calcium and vitamin D to keep serum calcium levels at 8 to 9 mg/dL.[4][2][5][17][18] When replacing calcium, clinicians should recognize that many formulations list the weight of the total calcium salt, but the actual content of elemental calcium is what should be calculated. For example, calcium carbonate is 40% calcium by weight, and calcium gluconate is only 9%.[3] Therefore, a product listed as 1250 mg of calcium carbonate only contains 500 mg of elemental calcium, while a 10 cc vial of 10% calcium gluconate has 1 g of calcium gluconate but only 93 mg of elemental calcium.[19][20](B3)

Patients with hypoparathyroidism have classically been categorized as having vitamin D resistance, a term historically applied because normal serum calcium could only be achieved by administering extremely large doses of vitamin D (ie, ergocalciferol or cholecalciferol), which would likely cause hypercalcemia. Patients with hypoparathyroidism generally respond to physiological doses of the active metabolite of vitamin D and 1,25-dihydroxyvitamin D but have abnormal vitamin D metabolism. PTH and low phosphate levels stimulate the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Since patients with hypoparathyroidism have low levels of PTH and hyperphosphatemia, the production of 1,25-dihydroxyvitamin D is markedly reduced. In past years, patients were treated with supraphysiological doses of ergocalciferol or cholecalciferol, but the current recommendation is treatment with physiological doses of calcitriol and supplemental calcium. For patients with chronic hypoparathyroidism, the following regimens are recommended:[5]

• Supplemental calcium carbonate or calcium citrate 500 mg to 3 g orally 3 times a day with meals
• Calcitriol .25 to 3 mcg daily in divided doses

Calcium carbonate is 40% elemental calcium and is better absorbed with food. Gastrointestinal absorption is reduced if patients have achlorhydria or are taking H2 blockers or proton pump inhibitors. Calcium citrate, 21% elemental calcium, can be taken with or without food, and gastric pH does not affect absorption.[5]

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.[9][21] These risks can be minimized by titrating therapy to keep the serum calcium level in the low-normal range. In most cases, keeping serum calcium in that range is sufficient to prevent muscle cramps and paresthesias while reducing the risk of extraskeletal calcifications or kidney stones.[2][3] Urine calcium should periodically be measured to ensure that patients do not develop hypercalciuria. A urine calcium excretion of over 200 to 250 mg daily should alert clinicians that the calcium and vitamin D dose needs to be reduced. An alternative strategy is to add hydrochlorothiazide to reduce urinary calcium excretion.[20](A1)

While most patients with hypoparathyroidism are still treated with calcitriol and calcium, selected patients who are more difficult to control with standard therapy can be treated with parathyroid hormone replacement. In 2015, the FDA approved parathyroid hormone 1-84, but several years later was recalled for a manufacturing defect and is no longer available. Alopegteriparatide is a modification of the parathyroid hormone molecule that allows for a sustained release of the active hormone currently under review by the FDA.[22] In the great majority of patients with hypoparathyroidism, a single daily subcutaneous injection of alopegteriparatide results in normal calcium and phosphorus levels and reduced urine calcium excretion without the need for supplemental treatment with calcitriol or a large dose of oral calcium. Other beneficial effects include more physiological bone turnover and improved quality of life.[23][22] The recently published guidelines of the Second International Workshop recommend that clinicians consider parathyroid hormone replacement for those not adequately controlled by conventional therapy (ie, with symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor quality of life). Clinicians may also consider this therapy for those with poor compliance, malabsorption, or difficulty tolerating large doses of calcium or calcitriol.[5] Whether there may be long-term adverse effects remains unknown, however. Administration of large doses of parathyroid hormone increases the risk of osteosarcomas in laboratory animals, although, at present, there is no reported increase in humans.[23](A1)

Differential Diagnosis

Differential diagnoses to consider in patients presenting with symptoms of hypoparathyroidism include hypomagnesemia and falsely low PTH secondary to assay interference.[24]

Parathyroid hormone resistance (ie, pseudohypoparathyroidism) is a condition that also causes hypocalcemia; however, PTH is elevated. Some patients with pseudohypoparathyroidism type 1 have an unusual phenotype known as Albright hereditary osteodystrophy, characterized by short stature, round face, and shortened fourth metacarpal bones. The etiology of pseudohypoparathyroidism is an inactivating mutation of the G-alpha subunit of the parathyroid hormone receptor.[25][26]

Prognosis

In chronic PTH deficiency cases, lifelong calcium supplements and calcitriol are necessary. Most can live healthy, functional lives, but some have persistent complaints that may be improved by replacing parathyroid hormone. Traditional therapy with calcium and calcitriol also increases the risk of patients developing renal insufficiency.

Complications

The most common complications of hypoparathyroidism are chronic kidney disease and kidney stones. Other complications include cataracts, cognitive dysfunction, cardiac arrhythmias, anxiety, and depression.[4][5][6][7][8][9] 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 a parathyroid hormone analog, alopegteriparatide, has been shown to normalize serum calcium and phosphorus, lower urine calcium excretion, and improve quality of life. Currently, alopegteriparatide is under review by the FDA.[23][22]