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Hypoparathyroidism

Hypoparathyroidism
Author:
David Goltzman, MD
Section Editors:
Clifford J Rosen, MD
Joseph I Wolfsdorf, MD, BCh
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 10, 2021.

INTRODUCTION — Parathyroid hormone (PTH) is one of the major hormones that regulates serum calcium (along with vitamin D) via direct effects on bone and kidney and indirect effects on the gastrointestinal tract. Hypoparathyroidism occurs when there is destruction of the parathyroid glands (autoimmune, surgical), abnormal parathyroid gland development, altered regulation of PTH production, or impaired PTH action (table 1). When PTH secretion is insufficient, hypocalcemia develops. Hypocalcemia due to hypoparathyroidism may be associated with a spectrum of clinical manifestations, ranging from few if any symptoms, if the hypocalcemia is mild, to life-threatening seizures, refractory heart failure, or laryngospasm if it is severe. In addition to severity of hypocalcemia, the rate of development and chronicity determine the clinical manifestations.

The clinical features, diagnosis, and management of hypoparathyroidism will be reviewed here. The etiology, clinical manifestations, diagnostic approach to, and treatment of hypocalcemia in general are reviewed separately.

(See "Etiology of hypocalcemia in adults".)

(See "Etiology of hypocalcemia in infants and children".)

(See "Neonatal hypocalcemia".)

(See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

(See "Clinical manifestations of hypocalcemia".)

(See "Diagnostic approach to hypocalcemia".)

(See "Treatment of hypocalcemia".)

ETIOLOGY — Acquired hypoparathyroidism is most often the result of postsurgical or autoimmune damage to the parathyroid glands (table 1). In adults, the most common cause is surgical. In a retrospective analysis of adults evaluated in a metabolic bone unit of an endocrinology service in Brazil, over 80 percent of cases of acquired hypoparathyroidism were postsurgical, whereas less than 20 percent were autoimmune [1].

Postsurgical – Postsurgical hypoparathyroidism can occur after thyroid, parathyroid, or radical neck surgery for head and neck cancer, and it may be transient, with recovery in days, weeks, or months; permanent; or even intermittent. In observational studies, transient hypoparathyroidism occurred in up to 20 percent of patients after surgery for thyroid cancer, and permanent hypoparathyroidism in 0.8 to 3.0 percent of patients after total thyroidectomy [2,3]. Permanent hypoparathyroidism occurs particularly when the goiter is extensive and anatomic landmarks are displaced and obscured during surgery. Transient hypoparathyroidism may be due to manipulation of the blood supply to or removal of one or more parathyroid glands during surgery, whereas intermittent hypoparathyroidism is due to decreased parathyroid reserve (parathyroid insufficiency). (See "Differentiated thyroid cancer: Surgical treatment", section on 'Hypoparathyroidism' and "Surgical management of hyperthyroidism", section on 'Hypocalcemia' and 'Parathyroid insufficiency' below.)

Autoimmune – Immune-mediated destruction of the parathyroid glands typically results in permanent hypoparathyroidism. Permanent hypoparathyroidism is part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, also known as polyglandular autoimmune syndrome type 1 (PAS 1). It is a result of mutations in the autoimmune regulator (AIRE) gene. Hypoparathyroidism typically appears during childhood or adolescence. (See "Etiology of hypocalcemia in infants and children", section on 'Autoimmune mechanisms'.)

Activating antibodies to the calcium-sensing receptor (CaSR) have been reported in patients with isolated acquired hypoparathyroidism and in patients with hypoparathyroidism associated with polyglandular autoimmune syndrome. These antibodies decrease parathyroid hormone (PTH) secretion but do not appear to be destructive. Hypoparathyroidism resulting from activating antibodies to the CaSR may remit spontaneously. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Hypoparathyroidism'.)

Genetic disorders – Genetic defects may be identified in infants and children due to defects associated with abnormal parathyroid development, including isolated hypoparathyroidism, hypoparathyroidism with congenital multisystem abnormalities, hypoparathyroidism with congenital metabolic abnormalities, and parathyroid resistance syndromes. These disorders are reviewed separately. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms' and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

Other – Other causes of hypoparathyroidism due to parathyroid gland destruction, all very rare, include irradiation and storage or infiltrative diseases of the parathyroid glands (hemochromatosis, Wilson's disease, granulomas, or metastatic cancer) (table 1). (See "Etiology of hypocalcemia in adults", section on 'Hypocalcemia with low PTH (hypoparathyroidism)'.)

CLINICAL FEATURES — Hypoparathyroidism may be associated with a spectrum of clinical manifestations, ranging from few if any symptoms if hypocalcemia is mild, to life-threatening seizures, refractory heart failure, or laryngospasm if it is severe. In addition to severity, the rate of development of hypocalcemia and chronicity determine the clinical manifestations (table 2).

Acute manifestations — The acute manifestations of hypoparathyroidism (eg, postsurgical hypoparathyroidism) are due to acute hypocalcemia. The hallmark of acute hypocalcemia is tetany, which is a disorder characterized by neuromuscular irritability. The symptoms of tetany may be mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) or severe (carpopedal spasm, laryngospasm, and focal or generalized seizures, which must be distinguished from the generalized tonic muscle contractions that occur in severe tetany). The classic physical findings in patients with neuromuscular irritability due to latent tetany are Trousseau's and Chvostek's signs. (See "Clinical manifestations of hypocalcemia", section on 'Acute manifestations'.)

Other patients have less specific symptoms, such as fatigue, hyperirritability, anxiety, and depression, and some patients, even with severe hypocalcemia, have no neuromuscular symptoms. Cardiac findings may include a prolonged QT interval, hypotension, heart failure, and arrhythmia. (See "Clinical manifestations of hypocalcemia", section on 'Cardiovascular'.)

Chronic manifestations — Although the signs and symptoms of acute hypocalcemia are similar regardless of the etiology, there are several features that are unique to chronic hypoparathyroidism. These include the presence of basal ganglia calcifications, cataracts, dental abnormalities, and ectodermal manifestations.

Extrapyramidal disorders — Basal ganglia calcifications are a manifestation of longstanding hypoparathyroidism [4,5]. They can be detected by computed tomography (CT) when routine skull radiographs are normal [6]. Some patients with basal ganglia calcifications develop parkinsonism, other movement disorders (dystonia, hemiballismus, choreoathetosis, and oculogyric crises), or dementia, while others remain asymptomatic [5,7]. In some cases, extrapyramidal symptoms improve after treatment with vitamin D and calcium [4,8].

Ocular disease — Chronic hypocalcemia, particularly when due to hypoparathyroidism, may cause cataracts, and treatment of hypocalcemia arrests their progression [9-11]. Keratoconjunctivitis has also been described [12].

Skeletal — While patients with several hypocalcemic disorders have skeletal abnormalities, such findings do not appear to be direct consequences of hypocalcemia but rather are related to the underlying disease. Patients with hypoparathyroidism have variable skeletal abnormalities.

Patients with idiopathic or postsurgical hypoparathyroidism may have increased bone mineral density (BMD) as compared with normal subjects [13,14].

Patients with congenital hypoparathyroid syndromes may have osteosclerosis, cortical thickening, and craniofacial abnormalities. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms'.)

Dental abnormalities — Dental abnormalities occur when hypocalcemia is present during early development. They include dental hypoplasia, failure of tooth eruption, defective enamel and root formation, and abraded carious teeth [11,15]. Early treatment of hypocalcemia can reverse these changes.

Ectodermal manifestations — In patients with chronic hypocalcemia, the skin is dry, puffy, and coarse. Other dermatologic manifestations include coarse, brittle, and sparse hair with patchy alopecia, and brittle nails with characteristic transverse grooves [11]. These abnormalities correlate with the severity and chronicity of hypocalcemia, are not specific to hypoparathyroidism, and are reversible with restoration of normocalcemia.

Moniliasis occurs only in patients with idiopathic hypoparathyroidism, usually as a component of polyglandular autoimmune syndrome type 1 (PAS 1), which is characterized by mutations in the autoimmune regulator (AIRE) gene and may be sporadic or inherited as an autosomal recessive disorder. Moniliasis precedes the other immune disorders and first appears during childhood or adolescence. This disorder is associated with defective cellular immunity that persists despite correction of hypocalcemia. The nails, skin, and gastrointestinal tract are typically involved. The moniliasis is often refractory to antifungal therapy. Other associated clinical manifestations of PAS 1 include those of adrenal insufficiency and, less frequently, those of other autoimmune disorders. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'.)

Laboratory findings — The main biochemical finding in patients with hypoparathyroidism is hypocalcemia with a low or inappropriately normal (for the degree of hypocalcemia) serum intact parathyroid hormone (PTH) level. In addition to these findings, most patients with hypoparathyroidism have an elevated serum phosphorus level. Patients with hypoparathyroidism typically have normal serum 25-hydroxyvitamin D (25[OH]D), normal or low 1,25-dihydroxyvitamin D (1,25D) concentrations (because of the reduced capacity of PTH to stimulate renal production of 1,25D), and normal magnesium and creatinine levels.

Although hypocalciuria is a feature of all hypocalcemic states due to a decreased filtered load, urinary calcium excretion is relatively high in patients with hypoparathyroidism because of loss of the stimulatory effect of PTH on renal tubular calcium reabsorption. Therefore, frank hypercalciuria can occur as the serum calcium concentration is raised toward normal, and concern about hypercalciuria and possible nephrolithiasis may prevent full correction of hypocalcemia. (See 'Preventing hypercalciuria' below.)

In contrast to relatively high urinary calcium excretion noted in patients with hypoparathyroidism, loss of the inhibitory effect of PTH on renal tubular phosphorus reabsorption can result in reduced renal phosphorus excretion.

DIAGNOSIS — Persistent hypocalcemia with a low or inappropriately normal parathyroid hormone (PTH) level and hyperphosphatemia is, in the absence of hypomagnesemia, virtually diagnostic of hypoparathyroidism (PTH deficiency).

Although the diagnosis of postsurgical hypoparathyroidism is usually obvious in a patient who has acute onset of symptoms of hypocalcemia (eg, neuromuscular irritability) immediately following neck surgery, hypoparathyroidism should also be suspected in any patient with mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) or severe (carpopedal spasm, laryngospasm, and focal or generalized seizures) symptoms of neuromuscular irritability. The diagnosis is confirmed by simultaneously measuring serum total calcium, albumin, magnesium, and intact PTH levels. In patients with hypoalbuminemia or hyperalbuminemia, the measured serum calcium concentration should be corrected for the abnormality in albumin [(calculator 1) or for the international system of units, (calculator 2)]. If a laboratory known to measure ionized calcium reliably is available, measurement of serum ionized calcium is an alternative to determining corrected serum calcium. (See "Treatment of hypocalcemia", section on 'Interpretation of serum calcium'.)

In addition, hypoparathyroidism should be suspected in patients who are incidentally noted to have a low serum total calcium or low ionized calcium, particularly when there is a personal or family history of autoimmune diseases, past history of head and neck surgery, or the presence of a neck scar. Such patients may have mild symptoms of hypocalcemia (eg, muscle cramps) or no symptoms. The presence of a low serum calcium concentration should be confirmed by repeat sampling and corrected for albumin, if needed. Serum intact PTH, creatinine, phosphorus, and magnesium should be measured to determine the cause of the hypocalcemia. Serum PTH can be interpreted correctly only when serum calcium is measured simultaneously. (See "Diagnostic approach to hypocalcemia".)

DIFFERENTIAL DIAGNOSIS — The combination of low or inappropriately normal intact parathyroid hormone (PTH) with a low corrected serum calcium may also be found in patients with hypomagnesemia and in patients with an activating mutation of the calcium-sensing receptor (CaSR) or its downstream pathway. Although kidney disease, vitamin D deficiency (as diagnosed by low 25-hydroxyvitamin D [25(OH)D]), and pancreatitis may all cause hypocalcemia, PTH levels are generally increased rather than decreased in association with the low serum calcium in these other clinical conditions. (See "Etiology of hypocalcemia in adults".)

Hypomagnesemia – Hypomagnesemia (serum magnesium concentration below 0.8 mEq/L [1 mg/dL or 0.4 mmol/L]) causes hypocalcemia by inducing PTH resistance or deficiency. It is therefore a reversible cause of hypocalcemia associated with low or inappropriately normal PTH. Hypocalcemia should resolve within minutes or hours after restoration of normal serum magnesium concentrations if hypomagnesemia was the cause of the hypocalcemia. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypoparathyroidism and parathyroid hormone resistance' and "Hypomagnesemia: Causes of hypomagnesemia" and "Hypomagnesemia: Evaluation and treatment".)

Activating mutation of CaSR – The CaSR couples to heterotrimeric G proteins (G alpha 11) and gain-of-function (activating) germline mutations of CaSR or of G alpha 11, that decrease the set point of CaSR, so that PTH is not released at serum calcium concentrations that normally trigger PTH release, give rise to familial or autosomal dominant hypocalcemia types 1 and 2 (ADH1 and ADH2), respectively [16] or to sporadic disease. Patients with ADH may have symptomatic hypocalcemia; however, the majority of patients with ADH are asymptomatic and therefore are not diagnosed until adulthood, when hypocalcemia is incidentally noted. Most biochemical tests do not reliably discriminate this disorder from other forms of PTH-deficient hypoparathyroidism; however, patients with ADH have relative or absolute hypercalciuria. The major clinical clues to this syndrome are the absence of symptoms, its familial nature, and the tendency of patients to develop ectopic calcifications affecting the kidneys, especially during treatment with calcium and vitamin D supplementation. The diagnosis can be confirmed by analysis for mutations in the CaSR gene or its downstream pathway. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Autosomal dominant hypocalcemia' and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Hypoparathyroidism'.)

ADDITIONAL EVALUATION AFTER DIAGNOSIS — Once hypoparathyroidism is diagnosed, we measure 24-hour urine calcium to establish a baseline urine calcium excretion prior to initiating therapy. In addition, we typically measure serum 25-hydroxyvitamin D (25[OH]D) in order to correct underlying vitamin D deficiency, which is prevalent in the population. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

For patients with suspected autoimmune hypoparathyroidism (a personal or family history of autoimmune diseases, no history of head and neck surgery), some experts measure autoantibodies against the parathyroid glands [17]. Although polyglandular autoimmune syndrome type 1 (PAS 1) usually presents in childhood, components of the syndrome, including hypoparathyroidism, may occur in early adult life [18]. Consequently, on the rare occasion that an adult patient presents with hypoparathyroidism and a history of one component of PAS 1 such as candidiasis, it would be important to assess adrenal function to exclude adrenal insufficiency and to consider assessment for an autoimmune regulator (AIRE) gene mutation. (See "Diagnosis of adrenal insufficiency in adults" and "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'.)

MANAGEMENT — The management of hypoparathyroidism depends upon whether the presentation is severe and acute (with potential life-threatening issues such as seizures, refractory heart failure, laryngospasm) or mild and chronic. (See 'Acute hypoparathyroidism' below and 'Chronic hypoparathyroidism' below.)

The goals of therapy in patients with hypoparathyroidism are to relieve symptoms, to raise and maintain the serum calcium concentration in the low-normal range, eg, 8.0 to 8.5 mg/dL (2.0 to 2.1 mmol/L), and to prevent iatrogenic development of kidney stones. Attainment of higher serum calcium values is not necessary and is usually limited by the development of hypercalciuria due to the loss of renal calcium-retaining effects of parathyroid hormone (PTH). (See 'Monitoring and adverse effects' below and 'Preventing hypercalciuria' below.)

The treatment approach outlined below assumes normal magnesium levels. To effectively treat hypocalcemia in patients with magnesium deficiency, hypomagnesemia should be corrected first. (See "Hypomagnesemia: Evaluation and treatment" and "Treatment of hypocalcemia", section on 'Concurrent hypomagnesemia'.)

Postsurgical hypoparathyroidism — Acute hypoparathyroidism can occur after total or near-total thyroidectomy. Monitoring for hypocalcemia after near-total or total thyroidectomy is necessary. Serum calcium and albumin should be measured on the evening of surgery and the next morning. Oral and/or intravenous calcium and oral calcitriol supplementation should be administered based upon the results of the serum calcium corrected for albumin (table 3). Supplementation protocols are often hospital-specific; there are few data evaluating outcomes [19].

Transient acute hypocalcemia may also occur after partial or total parathyroidectomy. In addition, vitamin D-deficient patients undergoing parathyroidectomy are at increased risk for developing hungry bone syndrome [20]. Hungry bone syndrome most often occurs in hyperparathyroid patients who developed bone disease preoperatively due to a chronic increase in bone resorption induced by high levels of PTH (osteitis fibrosa). In these patients, calcium is avidly taken up by the demineralized bone after surgery, and calcium supplementation is required to maintain a normal serum calcium concentration. Vitamin D-deficient post-parathyroidectomy patients may require prolonged, massive calcium and vitamin D therapy due to hungry bone syndrome. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Classical' and "Hungry bone syndrome following parathyroidectomy in end-stage kidney disease patients", section on 'Treatment'.)

Acute hypoparathyroidism — Patients with acute, symptomatic postsurgical hypoparathyroidism are initially treated with intravenous calcium plus oral calcitriol supplementation. We also suggest intravenous calcium therapy in patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (1.9 mmol/L), even if they are asymptomatic. Oral calcium should be initiated as soon the patient is able to take supplements orally, in order to facilitate weaning of intravenous calcium.

Severe symptoms or acute decrease to ≤7.5 mg/dL – Patients with acute hypoparathyroidism may have a rapid decline in serum calcium and PTH, precipitating severe symptoms. Emergency therapy is indicated in patients with tetany, seizures, or markedly prolonged QT intervals on electrocardiogram and also in patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (1.9 mmol/L), even if they are asymptomatic.

Treatment in adults is initiated with the intravenous administration of one 10 mL ampule of 10 percent calcium gluconate (90 mg of elemental calcium per 10 mL) in 50 mL of 5 percent dextrose infused over 10 to 20 minutes, followed by an intravenous infusion of calcium gluconate. (See "Treatment of hypocalcemia", section on 'Intravenous calcium dosing'.)

Oral calcitriol (0.5 mcg two times daily) and calcium (1 to 4 g of elemental calcium carbonate daily in divided doses) should be initiated as soon as possible (ie, when the patient is able to take oral supplements). When the serum calcium is in a safe range (>7.5 mg/dL [1.9 mmol/L]) and the patient is asymptomatic, intravenous calcium is gradually weaned.

Acute management in children is with intravenous administration of calcium gluconate (90 mg elemental calcium/10 mL vial) at a slow rate (not greater than 2 mL [1.86 mg of elemental calcium]/kg over 10 minutes) while closely monitoring pulse rate (and the QT interval).

Mild to moderate symptoms – For adults with milder degrees of symptoms (eg, paresthesias) and hypocalcemia (corrected serum calcium >7.5 mg/dL [1.9 mmol/L]), initial treatment with oral calcium and vitamin D supplementation is sufficient (table 3). The initial dose in adults is 1 to 4 g of elemental calcium carbonate in divided doses along with calcitriol 0.5 mcg twice daily. If symptoms do not improve with oral calcium, intravenous calcium infusion is required.

For children with milder degrees of symptoms of hypocalcemia in the postoperative period, initial treatment is with intravenous calcium gluconate (10 mL = 90 mg elemental calcium in 100 mL) infused at a rate sufficient to maintain calcium levels in the asymptomatic, low-normal range. Oral calcium citrate or calcium glubionate (25 to 50 mg/kg elemental calcium daily in divided doses) and calcitriol (infants 0.04 to 0.08 mcg/kg daily, children >1 year 0.25 mcg daily) are also initiated. When the serum calcium is normal and the child is asymptomatic, the intravenous calcium is gradually weaned.

Postsurgical hypoparathyroidism may be transient, resolving within three to six weeks but occasionally only after a year [21]. Because it may be transient, calcium and vitamin D supplements should be tapered slowly three to six weeks after surgery. Most patients are able to discontinue supplements entirely. Patients with a recurrence of hypocalcemia during the taper are more likely to have permanent hypoparathyroidism and should remain on oral supplementation. (See 'Chronic hypoparathyroidism' below.)

Prevention — As an alternative and especially in patients whose risk of postoperative hypocalcemia is high, some centers routinely administer calcium and calcitriol in the immediate postoperative period (regardless of serum calcium levels) to decrease the development of hypocalcemia symptoms and allow for an earlier discharge. Rapid assessment of postoperative serum PTH level is used in some centers to predict risk of hypocalcemia. The prevention of post-thyroidectomy hypocalcemia is reviewed in more detail elsewhere. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Hypoparathyroidism' and "Surgical management of hyperthyroidism", section on 'Hypocalcemia'.)

Chronic hypoparathyroidism — Hypoparathyroidism due to autoimmune parathyroid gland destruction, irradiation, or infiltrative diseases is more insidious in onset, and these patients typically do not require intravenous calcium supplementation. However, intravenous calcium is indicated to prevent acute hypocalcemia in patients with chronic hypoparathyroidism who become unable to take or absorb oral supplements, as may occur after complex surgical procedures requiring prolonged recuperation. (See "Treatment of hypocalcemia", section on 'Intravenous calcium dosing'.)

Initial treatment — For the initial management of patients with chronic hypoparathyroidism, we suggest oral calcium and vitamin D supplementation (table 4), rather than recombinant human PTH.

Calcitriol is the vitamin D metabolite of choice because it does not require renal activation, it has a rapid onset of action (hours), and a shorter half-life. Other acceptable vitamin D analogs include alfacalcidol or dihydrotachysterol. Patients with chronic hypoparathyroidism require lifelong calcium and vitamin D supplementation.

Calcium and vitamin D

Adults – For adults with stable chronic hypoparathyroidism, the dose of oral calcium is typically 1 to 2 g of elemental calcium daily, in divided doses (table 4) [22]. Although calcium carbonate is often used (it is the least expensive), it may be less well absorbed in older patients and those who have achlorhydria. These patients might be treated with another preparation, such as calcium citrate. (See "Treatment of hypocalcemia", section on 'Mildly symptomatic or chronic hypocalcemia'.)

A typical starting dose of calcitriol is 0.25 mcg twice daily, with weekly dose increments to achieve a low-normal serum calcium. Many adults require up to 2 mcg daily. Vitamin D requirements vary considerably from patient to patient and the correct dose in any given patient is primarily determined by trial and error.

Children – For children, oral calcium glubionate, calcium carbonate, or calcium citrate is administered (25 to 50 mg/kg elemental calcium daily) in divided doses, along with calcitriol (infants 0.04 to 0.08 mcg/kg daily, children >1 year initial dose 0.25 mcg daily). The dose of calcitriol may be increased by 0.25 mcg at two- to four-week intervals to maintain the serum calcium concentrations within the low-normal range and to avoid hypercalciuria (table 4).

Several preparations of vitamin D are available for the treatment of hypocalcemia due to hypoparathyroidism (table 4). The various preparations differ in onset of action, duration of action, and cost. Because PTH is required for the renal conversion of calcidiol (25-hydroxyvitamin D [25(OH)D]) to the active metabolite calcitriol (1,25-dihydroxyvitamin D [1,25D]), calcitriol is often regarded as the treatment of choice [11,22]. Calcitriol is the most active metabolite of vitamin D. Other advantages of calcitriol include rapid onset of action (hours) and a biologic half-life of approximately four to six hours. While hypercalcemia is more common during treatment with calcitriol than with vitamin D, cessation of treatment is followed by resolution of hypercalcemia in a few days rather than a few weeks [23,24].

Alfacalcidol (1-alpha-hydroxyvitamin D3) is a synthetic analog of vitamin D that is converted in the liver to the active metabolite 1,25D. Similar to calcitriol, it has a rapid onset of action and relatively short half-life. Although it is not available in the United States, it is used in other countries for the treatment of hypocalcemia associated with hypoparathyroidism [25] and as a treatment adjunct in chronic kidney disease.

Dihydrotachysterol is the functional equivalent of 1-hydroxyvitamin D, in that only 25-hydroxylation in the liver is required to form the active drug. As a result, dihydrotachysterol is effective in patients in whom renal 1-hydroxylation is impaired, such as those with chronic kidney disease. It has a rapid onset of action and a relatively short duration of action, so that toxicity resolves in a few days.

Monitoring and adverse effects — Monitoring of urinary and serum calcium and serum phosphate is required weekly initially, until a stable serum calcium concentration (at the low end of the normal range) is reached. Thereafter, monitoring at three- to six-month intervals is sufficient [26].

The major side effects of calcium and vitamin D replacement in patients with hypoparathyroidism are hypercalcemia and hypercalciuria, which, if chronic, can cause nephrolithiasis, nephrocalcinosis, and renal failure [23,24,27]. Hypercalciuria is the earliest sign of toxicity and can develop in the absence of hypercalcemia.

Preventing hypercalciuria — An increase in urinary calcium excretion is a predictable consequence of raising the serum calcium in patients with hypoparathyroidism [28]. These patients lack the normal stimulatory effect of PTH on renal tubular calcium reabsorption [29] and, therefore, excrete more calcium than normal subjects at the same serum calcium concentration.

Thus, completely correcting hypocalcemia may lead to hypercalciuria, which can produce nephrolithiasis, nephrocalcinosis, and possible chronic kidney disease [30]. To prevent these complications, urinary calcium excretion should be measured periodically and the dose of calcium and vitamin D reduced if it is elevated (≥300 mg [7.5 mmol] in 24 hours).

The initial treatment of hypercalciuria in patients with hypoparathyroidism is reducing the dose of calcium and vitamin D. Some patients will require the addition of thiazide diuretics (eg, hydrochlorothiazide, 12.5 to 50 mg daily or twice daily), with or without dietary sodium restriction, to decrease urinary calcium excretion [31,32]. A thiazide is typically added when the 24-hour urinary calcium approaches 250 mg (6.25 mmol) [22]. Thiazide diuretics are not recommended in congenital hypoparathyroidism due to PAS1, or in patients who concurrently have Addison's disease. In patients who develop thiazide-induced hypokalemia, potassium supplementation is necessary, or a potassium- and magnesium-sparing diuretic (eg, amiloride 2.5 to 5 mg once or twice a day) may be used with the thiazide to prevent hypokalemia and hypomagnesemia. The mechanism by which both PTH and thiazides enhance distal calcium reabsorption is reviewed elsewhere. (See "Diuretics and calcium balance".)

Second-line therapy — In view of the fact that hypoparathyroidism is a hormonal deficiency, replacement of the missing hormone, ie, PTH 1-84, is a potentially attractive intervention [33]. The addition of recombinant human PTH 1-84 (rhPTH 1-84) is an option for patients with chronic hypoparathyroidism who cannot maintain stable serum and urinary calcium levels with calcium and vitamin D supplementation [34]. In small trials, rhPTH 1-84 has been shown to maintain serum calcium levels while reducing the need for large doses of calcium and vitamin D (see 'Recombinant human PTH' below). However, rhPTH 1-84 is not yet initial therapy, because of high cost, the necessity for subcutaneous administration, and uncertainty about long-term safety of dosing for primary hypoparathyroidism (related to its skeletal effects, particularly in growing children who may be at greater risk of osteosarcoma).

Recombinant human PTH — Subcutaneous administration of PTH 1-34 (teriparatide) and rhPTH 1-84 is effective in reducing the doses of oral calcium and vitamin D supplementation in patients with hypoparathyroidism, as illustrated by the following trials [30,35-44]:

In two randomized trials from the same group, subcutaneous administration of synthetic PTH 1-34 controlled hypocalcemia with a lower risk of hypercalciuria when compared with calcitriol (all subjects received oral calcium supplementation) [30,35]. Twice-daily administration of PTH 1-34 provided better metabolic control and allowed a reduction in total daily PTH dose (46 versus 97 mcg daily) [36]. Similar findings were noted in a trial comparing once- versus twice-daily PTH 1-34 administration in 14 children with chronic hypoparathyroidism (total daily dose 25 versus 58 mcg) [37].

In a double-blind, randomized trial of rhPTH 1-84 (initial dose 50 mcg daily, titrated up to 75 and then 100 mcg daily) or placebo in 134 hypoparathyroid patients, rhPTH 1-84 significantly reduced supplemental calcium and calcitriol requirements without altering serum and urinary calcium concentrations [41].

Recombinant human PTH may also improve abnormal skeletal properties in hypoparathyroidism, in which bone turnover may be quite reduced [45]. In a study of rhPTH 1-84 in 30 patients with hypoparathyroidism, bone mineral density (BMD) significantly increased in the lumbar spine (2.9 percent) and decreased in the distal one-third radius (2.4 percent) [38]. In a histomorphometric analysis of paired iliac crest biopsy samples from 30 patients with primary hypoparathyroidism, rhPTH 1-84 treatment was associated with an increase in the remodeling rate in both trabecular and cortical compartments with tunneling resorption in the trabecular compartments [39]. These findings suggest that PTH restores bone metabolism to levels more typical of euparathyroid individuals; however, the clinical significance of this finding is not clear.

Dosing and monitoring — For patients in the United States, rhPTH 1-84 is available through a Risk Evaluation and Mitigation Strategy (REMS) program to minimize the potential risk of osteosarcoma [46]. Prior to administering rhPTH 1-84, serum 25(OH)D should be measured in order to correct underlying vitamin D deficiency. Patients should be receiving adequate supplemental calcium and active vitamin D (eg, calcitriol), as evidenced by serum calcium concentrations >7.5 mg/dL (1.9 mmol/L) [47].

rhPTH 1-84 is injected subcutaneously in the thigh each morning using a multidose injection pen device. The initial dose is 50 mcg. The dose of calcitriol should be reduced by 50 percent upon initiation of rhPTH 1-84, whereas the dose of supplemental calcium should be maintained [47]. Serum calcium should be measured within three to seven days after initiating rhPTH 1-84, and the dose of supplemental calcitriol and calcium reduced, as needed, to maintain the serum calcium within the lower half of the normal range. Weekly monitoring of urinary and serum calcium should continue until calcitriol is discontinued, and a stable serum calcium concentration (at the low end of the normal range) is reached. If the serum calcium cannot be maintained above 8 mg/dL without calcitriol, the dose of rhPTH 1-84 can be increased by 25 mcg every four weeks up to a maximum daily dose of 100 mcg.

The goal is to find the lowest dose of rhPTH 1-84 to maintain the serum calcium concentration in the lower half of the normal range, without the need for active vitamin D (eg, calcitriol) and with calcium supplementation sufficient to meet daily requirements. Once a maintenance dose is achieved, monitoring at three- to six-month intervals is likely sufficient. Monitoring of serum calcium should be performed more frequently in patients taking digoxin because hypercalcemia increases the risk of digoxin toxicity. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Plasma digoxin levels associated with toxicity'.)

Discontinuation instructions — Approximately 12 hours after the last dose of rhPTH1-84, increase the dose of calcium supplementation to doses used before initiation of rhPTH 1-84 and resume active vitamin D (eg, calcitriol). Because some patients transiently may require significantly higher doses of calcium/calcitriol therapy than before starting rhPTH 1-84, careful monitoring of serum calcium post-discontinuation is necessary. In a report of nine patients with hypoparathyroidism treated with PTH 1-34 and then transitioned back to calcium/calcitriol, two patients required higher pretreatment doses of calcium/calcitriol to maintain calcium levels, presumably secondary to sequestration of calcium in bone, as occurs in hungry bone syndrome [48]. Experts differ on the magnitude of the dosing change for calcium and calcitriol, but this should be guided by close follow-up (eg, approximately every three days) of serum calcium during the transition [49].

Adverse effects — The most commonly reported adverse events are tingling, pricking, burning of skin, hypocalcemia, hypercalcemia, headache, nausea, vomiting, arthralgia, and hypercalciuria.

rhPTH 1-84 can cause hypercalcemia, particularly during initial therapy when the doses of supplemental calcium and vitamin D are being reduced. Hypercalcemia may be mitigated by careful patient monitoring, with titration of calcium, calcitriol, and rhPTH 1– 84 (see 'Dosing and monitoring' above). Hypercalcemia may cause nausea, vomiting, constipation, low energy, or muscle weakness. If a dose of PTH is missed, hypocalcemia may develop. Symptoms of hypocalcemia include paresthesias, cramping of the hands and feet, or twitching of the facial muscles.

There are few data evaluating long-term safety. Chronic use of rhPTH 1-84 appears to be well tolerated. In a report of 24 patients treated with rhPTH 1-84 for eight years, urinary calcium excretion was lower and estimated glomerular filtration rate (eGFR) unchanged compared with baseline values [50]. Hypercalcemia and hypocalcemia were uncommon. There was one episode of nephrolithiasis.

In a report of 31 patients treated with PTH 1-34 for up to five years, 16 patients developed new-onset or progressive nephrocalcinosis or nephrolithiasis, possibly due to hypocitraturia and an elevated urinary calcium to urinary citrate ratio [51]. In a separate case report, diffuse joint pain with bone scan evidence of intense bone uptake in the peripheral joints and in the axial skeleton developed after three years of PTH 1-34 (administered once or twice daily) [52]. Although symptoms resolved within 48 hours of discontinuing therapy, the patient developed transient hypocalcemia requiring high doses of intravenous calcium with alfacalcidol, presumably due to hungry bone syndrome.

In a rat model, PTH 1-84 caused an increase in the incidence of osteosarcoma [53]. The risk was dependent on dose and duration of treatment. However, extensive clinical experience in adults treated for osteoporosis with rhPTH 1-84 or PTH 1-34 has not shown an increased risk for the development of osteosarcoma, and no limit has been imposed on the duration of rhPTH 1-84 therapy for hypoparathyroidism. Nevertheless, although data are not available in humans, rhPTH 1-84 is contraindicated in patients who are at increased risk for developing osteosarcoma, such as patients with a prior history of external beam radiation therapy involving the skeleton, Paget disease of bone, unexplained elevations in alkaline phosphatase, or in children with open epiphyses [47].

Parathyroid insufficiency — Parathyroid insufficiency is a term used to describe decreased parathyroid reserve. It is described most often in patients undergoing routine postoperative monitoring of serum calcium and PTH after thyroid or other neck surgery and is believed to be due to intraoperative injury to the parathyroid glands or their vascular supply [54]. Patients with parathyroid insufficiency have intermittent mild hypocalcemia (7.0 to 8 mg/dL [1.75 to 2.0 mmol/L]) with inappropriately low normal serum PTH levels (11.6 to 24.5 pg/mL [normal range 6 to 40 pg/mL]). They are typically asymptomatic and do not require calcium and vitamin D supplements to maintain stable serum calcium concentrations.

However, patients with parathyroid insufficiency are at risk for developing more severe hypocalcemia with the initiation of certain medications, such as bisphosphonates and denosumab, or in the setting of severe vitamin D deficiency. Hypocalcemia is more likely to occur when high doses of especially potent bisphosphonates, such as zoledronic acid, are used [55]. Patients should be alerted to this risk and should receive adequate calcium and vitamin D supplementation during bisphosphonate or denosumab therapy. (See "Denosumab for osteoporosis", section on 'Hypocalcemia' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Hypocalcemia'.)

Pregnancy — Special care should be taken in the management of women with hypoparathyroidism during pregnancy and following delivery. There are conflicting data as to whether calcitriol requirements fall [56-58] or do not fall during pregnancy [59-63]. On the other hand, there is uniform agreement that calcitriol requirements decrease during lactation [56-58,62,64,65].

Serum concentrations of 1,25D (calcitriol) double during a normal pregnancy. However, intact PTH concentrations remain low to normal, suggesting that PTH does not mediate the late partum rise in 1,25D production. The increase in serum 1,25D may be regulated by other pregnancy hormones, which are normal in hypoparathyroid women, such as PTH-related protein (PTHrP), prolactin, estrogen, and placental growth hormone [56,64,66].

Thus, serum calcium concentrations should be measured frequently during late pregnancy and lactation in women with hypoparathyroidism, who may have a rise in serum calcium requiring a decrease in calcitriol dose [56-58,64]. If the calcitriol dose is not reduced, the combination of elevated serum 1,25D and PTHrP can lead to increases in intestinal absorption and bone resorption and hypercalcemia [62]. The requirement for calcitriol will return to antepartum levels with cessation of lactation.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Hypoparathyroidism (The Basics)")

SUMMARY AND RECOMMENDATIONS

Hypoparathyroidism occurs when there is destruction of the parathyroid glands (surgical, autoimmune), abnormal parathyroid gland development, altered regulation of parathyroid hormone (PTH) production, or impaired PTH action (table 1). Acquired hypoparathyroidism is most often the result of postsurgical or autoimmune damage to the parathyroid glands. (See 'Etiology' above.)

Hypoparathyroidism may be associated with a spectrum of clinical manifestations, ranging from few if any symptoms if hypocalcemia is mild, to life-threatening seizures, refractory heart failure, or laryngospasm if it is severe. In addition to severity, the rate of development of hypocalcemia and chronicity determine the clinical manifestations (table 2). (See 'Clinical features' above.)

Hypoparathyroidism should be suspected in patients with mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) or severe (carpopedal spasm, laryngospasm, and focal or generalized seizures) symptoms of neuromuscular irritability or in asymptomatic patients who are incidentally noted to have a low serum total calcium, particularly when there is a personal or family history of autoimmune diseases, past history of head and neck surgery, or the presence of a neck scar.

The diagnosis is confirmed by simultaneously measuring serum total calcium, albumin, magnesium, phosphorus, and intact PTH levels. In patients with hypoalbuminemia or hyperalbuminemia, the measured serum calcium concentration should be corrected for the abnormality in albumin [(calculator 1), or for the international system of units, (calculator 2)], or ionized calcium should be determined. Persistent hypocalcemia with a low or inappropriately normal PTH level and hyperphosphatemia is, in the absence of hypomagnesemia, virtually diagnostic of hypoparathyroidism (PTH deficiency). (See 'Diagnosis' above.)

The combination of low or inappropriately normal intact PTH with a low corrected serum calcium may also be found in patients with hypomagnesemia and in patients with an activating mutation of the calcium-sensing receptor (CaSR) or its downstream pathway. (See 'Differential diagnosis' above and "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypoparathyroidism and parathyroid hormone resistance' and "Hypomagnesemia: Evaluation and treatment" and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Autosomal dominant hypocalcemia'.)

Acute hypoparathyroidism can occur after total or near-total thyroidectomy. Monitoring for hypocalcemia after near-total or total thyroidectomy is necessary. Serum calcium and albumin should be measured on the evening of surgery and the next morning. Oral and/or intravenous calcium and oral calcitriol supplementation should be administered based upon the results of the serum calcium corrected for albumin (table 3). (See 'Postsurgical hypoparathyroidism' above.)

Patients with acute hypoparathyroidism have a rapid decline in serum calcium and PTH, precipitating acute symptoms. Emergency therapy is indicated in patients with tetany, seizures, or markedly prolonged QT intervals on electrocardiogram.

In adults, treatment is initiated with the intravenous administration of one 10 mL ampule of 10 percent calcium gluconate (90 mg of elemental calcium per 10 mL) in 50 mL of 5 percent dextrose infused over 10 to 20 minutes, followed by an intravenous infusion of calcium gluconate.

In children, acute management is with intravenous administration of calcium gluconate (90 mg elemental calcium/10 mL vial) at a slow rate (not greater than 2 mL [1.86 mg of elemental calcium]/kg over 10 minutes) while closely monitoring pulse rate (and the QT interval).

For asymptomatic patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL (1.9 mmol/L), we also suggest intravenous calcium therapy (Grade 2C). (See 'Acute hypoparathyroidism' above.)

For adults with milder degrees of symptoms (eg, paresthesias) and hypocalcemia (corrected serum calcium >7.5 mg/dL [1.9 mmol/L]), initial treatment with oral calcium and vitamin D supplementation is sufficient (table 3).

For the initial management of patients with chronic hypoparathyroidism, we suggest calcium and vitamin D supplementation rather than recombinant human PTH (Grade 2B). Calcitriol is the vitamin D metabolite of choice because it does not require renal activation, has a rapid onset of action (hours), and has a shorter half-life. Other acceptable vitamin D analogs include alfacalcidol or dihydrotachysterol (table 4). (See 'Initial treatment' above and 'Second-line therapy' above.)

The addition of recombinant rhPTH 1-84 is an option for patients with chronic hypoparathyroidism who cannot maintain stable serum and urinary calcium levels with calcium and vitamin D supplementation. (See 'Recombinant human PTH' above.)

Monitoring of urinary and serum calcium and serum phosphate is required weekly initially, until a stable serum calcium concentration (at the low end of the normal range) is reached. Thereafter, monitoring at three- to six-month intervals is likely sufficient. (See 'Monitoring and adverse effects' above.)

The goals of therapy in patients with hypoparathyroidism are to relieve symptoms, to raise and maintain the serum calcium concentration in the low normal range (eg, 8.0 to 8.5 mg/dL [2.0 to 2.1 mmol/L]), and to prevent iatrogenic development of kidney stones. Attainment of higher values is not necessary and is usually limited by the development of hypercalciuria due to the loss of renal calcium-retaining effects of PTH. (See 'Management' above.)

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