Hypoparathyroidism describes a condition in which there are low circulating levels of parathyroid hormone (PTH) or insensitivity to its action.[1] Primary hypoparathyroidism results from iatrogenic causes or one of many rare diseases. In primary hypoparathyroidism, the absence of adequate PTH activity leads to a fall in the ionized calcium concentration in the extracellular fluid. Secondary hypoparathyroidism is a physiologic state in which PTH levels are low in response to a primary process that causes hypercalcemia.
In hypoparathyroidism, hypocalcemia can occur acutely and become a true medical emergency. The presentation of hypoparathyroidism varies depending on the chronicity of the resultant hypocalcemia. Muscle spasms/tetany, paresthesias, and seizures may occur in an acute onset, whereas chronic hypoparathyroidism may only be evidenced by visual impairment due to cataract formation. See Hypocalcemia for more information.
Urgent treatment of patients with hypoparathyroidism involves correcting the hypocalcemia by administering calcium and vitamin D. Recombinant human (rh) parathyroid hormone (PTH) was approved by the FDA as an adjunct to calcium and vitamin D to control hypocalcemia in patients with chronic hypoparathyroidism. However, there are limited data on the use of PTH in acute hypocalcemia. Cases have been reported in patients following parathyroidectomy, thyroidectomy, and renal transplant, and one hypoparathyroid individual with hypocalcemic cardiomyopathy, but there is have been no large-scale studies published on the use of rhPTH (1–84) in acute hypocalcemia of chronic hypoparathyroidism.[2]
Many underlying pathologic etiologies of hypoparathyroidism exist.
The most common causes are neck surgery and autoimmune processes. Hypoparathyroidism resulting from thyroid or parathyroid surgery can become clinically apparent 1-2 days after the procedure or follow the operation by many years. The incidence of permanent hypoparathyroidism varies with the extent of the procedure, the surgeon’s experience, and the underlying disease process being treated. Rarely, hypoparathyroidism can be a complication of radioactive iodine treatment of external localized radiotherapy.[3]
Autoimmune insult to the parathyroid gland can be isolated or associated with a variety of polyglandular syndromes. Antibodies to the parathyroids have been detected in up to 30% of patients with isolated hypoparathyroidism and 40% of patients with polyglandular disease.[4] The calcium sensor-receptor is another target of autoantibodies in hypoparathyroidism. In patients with type 1 polyglandular autoimmune syndrome, more than 50% will have this antibody.
Maternal hyperparathyroidism can result in transient neonatal hypoparathyroidism.[5, 6, 7] Maternal parathyroid hormone (PTH) suppresses neonatal parathyroid activity; however, this resolves rapidly after birth and removal from excessive maternal PTH.
Both hypermagnesemia and hypomagnesemia can result in decreased PTH secretion. In the case of hypermagnesemia, elevated magnesium levels result in stimulation of a calcium-sensing receptor on the pituitary. This, in turn, attenuates PTH secretion. In the case of chronic alcoholics with hypomagnesemia, there is diminution of PTH secretion levels and a resistance to hormone activity.[8, 9]
This condition is characterized by thymus and parathyroid dysgenesis, cardiac malformation, and facial dysmorphogenesis.[10] Other complex syndromes associated with hypoparathyroidism have been described and include DiGeorge Syndrome; Sanjat-Sakati syndrome; hypoparathyroidism, sensorineural deafness, and renal disease (HDR syndrome [Barakat syndrome]); Kenny-Caffey syndrome; Kearns-Sayre Syndrome; and Pearson marrow-pancreas syndrome.[11]
Infiltration of the parathyroid gland can lead to clinically significant hypoparathyroidism. Causes include metastatic carcinoma, hemochromatosis, transfusion-related iron overload, Wilson disease,[12] and sarcoidosis.[13]
PTH functions to maintain plasma calcium levels by withdrawing calcium from bone tissue, glomerular filtrate reabsorption, and indirectly through increased intestinal absorption of calcium by activation of vitamin D-1,25. Insufficient production of PTH is known as true hypoparathyroidism, while decreased action on target tissues is called pseudohypoparathyroidism.[4]
The most common cause of hypoparathyroidism is surgery.[14] Anterior neck surgery is the most frequent cause, reported to occur in 7–36% of surgeries, of which 38% are due to total thyroidectomy, 21% parathyroidectomy, 9% partial thyroidectomy, and 5% other neck surgeries. Most have transient hypoparathyroidism and parathyroid function recovers fully within in 6 months; approximately 1–5% of patients develop permanent hypoparathyroidism.[15]
The next most common acquired cause in adults is thought to be autoimmune disease, affecting either the parathyroid glands alone or multiple other endocrine glands.[1] Other rare, nonhereditary causes of hypoparathyroidism include parathyroid gland destruction such as irradiation and infiltrative disease (hemochromatosis, Wilson disease, granulomas, or metastatic cancer).
Rare genetic disorders causing hypoparathyroidism include the following[16] :
Autoimmune polyglandular syndrome type 1 (APS-1)
DiGeorge syndrome
Kearns–Sayre syndrome
Bartter syndrome
Dubowitz syndrome
In addition, neonatal hypocalcemia of prematurity or secondary to maternal hypercalcemia, hypo- or hypermagnesemia, and calcium sensor receptor antibodies.[16] There has also been a report of hypoparathyroidism associated with immune checkpoint inhibitor therapy.[17]
A database comprised of information from 16 Italian referral centers for endocrinologic diseases identified 537 patients with chronic hypoparathyroidism, of which the primary etiology was postsurgical (67.6%), followed by idiopathic (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective parathyroid action (5.2%), nonsyndromic forms of genetic hypoparathyroidism (0.9%), and other forms of acquired hypoparathyroidism (0.7%) (due to infiltrative diseases, copper or iron overload, ionizing radiation exposure).[18]
The incidence of hypoparathyroidism in the United States is 37 per 100,000 person-years, with an estimate of 60,000–80,000 affected individuals.[19] Overall, 75% of cases are female and 25% are male. About 75% of these patients are aged 45 years or older, and roughly 75% of cases are due to neck surgery and 25% are reported to be due to nonsurgical causes.[15]
Maternal hyperparathyroidism resulting in newborn hypoparathyroidism usually manifests by the third week of life[5, 7] Patients with DiGeorge syndrome present for clinical evaluation between birth and age 3 months with a variety of symptoms. Patients with polyglandular autoimmune syndrome type I present early in life. These patients typically have candidiasis by age 5 years and hypoparathyroidism by age 10 years.
Prognosis is determined by the underlying cause of hypoparathyroidism. Acute hypocalcemia can be treated with good outcome. The mortality rate of hypoparathyroidism depends on the underlying cause. Complications of hypoparathyroidism may include the following:
Neuromuscular symptoms
Cataracts[20]
Intracranial calcifications[21, 22]
Growth stunting (with hypoparathyroidism, sensorineural deafness and renal disease [HDR syndrome (Barakat syndrome)])[23]
Tooth malformation[24]
Mental retardation (with HDR syndrome [Barakat syndrome])[23]
Hypothyroidism
Cardiomyopathy[25]
Parkinsonian symptoms[26]
Ossification of paravertebral ligaments[27]
Adhesive capsulitis[28]
A full surgical and family history is essential in cases of suspected hypoparathyroidism.
Neuromuscular irritability, arising from hypocalcemia, is the hallmark of the condition. These features can range from mild-to-moderate paresthesias of the extremities or lips to painful muscle cramps. In severe cases, tetany can result in carpopedal spasm, laryngospasm,[29] or generalized seizures.[30] Recurrent laryngospasm should prompt an investigation of underlying hypoparathyroidism.[31]
Additionally, severe hypocalcemia can result in neuropsychiatric and cardiovascular abnormalities. Neuropsychiatric manifestations include irritability, anxiety, psychosis, dementia, hallucinations, depression, and confusion. The cardiovascular effects of hypocalcemia are usually bradydysrhythmias or prolongation of the QT interval. Severe hypocalcemia can rarely mimic myocardial infarction.[32]
Gastrointestinal complaints may result from hypocalcemia as well. Smooth muscle spasms can result in intestinal and biliary cramping. Several cases of dysphagia have been described in the setting of hypocalcemia.[33]
Symptoms are rare unless the ionized calcium level drops below 2.8 mg/dL.[4]
The clinical manifestation of hypoparathyroidism is due to hypocalcemia.
Head, ears, eyes, nose, and throat signs include surgical/traumatic scars and mucocutaneous candidiasis (in the setting of polyglandular failure type 1[34] ).
Neurologic signs include hyperreflexia, tetany, seizures, and altered mental status.
Chvostek sign has low sensitivity and specificity. Twenty-five percent of healthy persons will have a positive result; 29% of hypocalcemic patients will have a negative result.[4]
Trousseau sign (carpal spasm caused by occluding the brachial artery) is more reliable. Only 1-4% of healthy persons will have a positive sign; 94% of hypocalcemic persons will have a positive sign.[4]
Cardiovascular signs include heart failure,[35, 36, 37] bradycardia,[38] and hypotension not responsive to fluids or pressors.[39]
A slit lamp exam should be conducted for signs of cataracts and calcifications.
Signs in infants include the following:
Vomiting
Abdominal distention
Apneic spells
Intermittent cyanosis
Twitching, tremors, and seizures
Hypoparathyroidism should be distinguished from pseudohypoparathyroidism, a genetic disorder of parathyroid (PTH) resistance in which the circulating PTH concentration is elevated.[40]
The diagnosis of hypoparathyroidism is supported by hypocalcemia, hyperphosphatemia, and low parathyroid hormone levels in the absence of renal failure or intestinal malabsorption.
Both total and ionized calcium are decreased. Normal total serum calcium levels range from 9 to 10.5 mg/dL (2.2-2.6 mmol/L). Normal ionized calcium levels are 4.5-5.6 mg/dL (1.1-1.4 mmol/L).
Serum magnesium level can be low, high, or normal.
Transient symptomatic hypocalcemia can occur immediately after thyroid surgery; normal parathyroid levels 3 hours after surgery and a normal serum calcium level on the postoperative day one rules out persistent hypoparathyroidism.[41]
For D-xylose absorption test, the results are usually normal.[42]
ECG may show prolonged QT interval,[43] bradycardia or, rarely, ST-segment elevations.[32]
Bone density is increased[44] ; tooth enamel and root abnormalities have been described.[24] Ossification of the paravertebral ligaments is frequently observed.[27]
Calcification of subcortical nuclei, dentate nucleus,[21] and basal ganglia[22] can occur.
Acute, symptomatic hypocalcemia is a medical emergency. The main goal of treatment is to restore serum calcium levels to alleviate symptoms of acute hypocalcemia.[45] In the setting of severe symptoms, calcium therapy should be given even if serum levels are only mildly reduced.
Prehospital care should address and stabilize the airways, breathing, and circulation ("the ABCs"), obtain intravenous access, and control seizures with benzodiazepines. Care to prevent long-term complications from hypocalcemia or hypercalcemia[25] should be coordinated with an endocrinologist.
Recombinant human (rh) parathyroid hormone (PTH) (rhPTH[1-84] Natpara) was approved by the FDA as an adjunct to calcium and vitamin D to control hypocalcemia in patients with chronic hypoparathyroidism. Therapy with rhPTH (1-84) is associated with at least a 50% reduction in calcium and active vitamin D requirements as well as maintenance of serum calcium levels.[46] However, there are limited data on the use of PTH in acute hypocalcemia. Cases have been reported in patients following parathyroidectomy, thyroidectomy, and renal transplantation, as well as one hypoparathyroid individual with hypocalcemic cardiomyopathy, but there have been no large-scale studies published on the use of rhPTH (1–84) in acute hypocalcemia of chronic hypoparathyroidism.[2]
Preliminary findings from a phase 2 trial (N = 59) of an investigational long-acting prodrug of PTH(1-34) (TransCon PTH) appear to show a majority of hypoparathyroid patients (91%) treated with this agent achieved independence from oral active vitamin D and decreased calcium supplements (≤500 mg/day), as well as achieved normal serum levels of calcium, phosphate, urinary calcium, and calcium-phosphate product, at week 26.[47] The drug (15, 18, or 21 microgram per day) was well tolerated; no serious or severe adverse events were associated with treatment regimens. This randomized, double-blind, placebo controlled 4-week trial was followed by a 22-week open-label extension in which PTH(1-34) was titrated (6-60 microgram per day).[47] More data from larger and longer studies are needed to evaluate the safety and efficacy PTH(1-34).
Also see guidelines from the First International Conference on the Management of Hypoparathyroidism for managing hypoparathyroidism[48] ; the European Society of Endocrinology for treatment of chronic hypoparathyroidism in adults[49] ; and the Society for Endocrinology for emegency management of acute hypocalcemia in adults.[50]
Administer 10 mL of 10% calcium gluconate in 50 mL of 5% dextrose intravenously (IV) over 10 minutes, with electrocardiographic (ECG) monitoring. This can be repeated until the patient is asymptomatic. This process should be followed up with a calcium gluconate infusion.
Treat the underlying cause of the hypoparathyroidism. In postoperative hypocalcemia and other cases of hypoparathyroidism, this consists of alfacalcidol or calcitriol therapy. Starting doses should be approximately 0.25–0.5 micrograms per day
Treat vitamin D deficiency or hypomagnesemia.
Infuse children with 1.86 mg/kg elemental calcium, IV over 10 minutes, while closely monitoring the pulse rate and QT interval.
Oral therapy consists of calcium carbonate, 1-2 g or more per day, in 3-4 divided doses. This regimen may be appropriate for patients with mildly lowered calcium levels and mild or no symptoms.
Patients with cardiac arrhythmias or who are on digoxin therapy require continuous ECG monitoring during IV calcium replacement. Large-volume calcium infusions should not be used in patients with end-stage renal failure or those who are on dialysis.[50]
Following the First International Conference on the Management of Hypoparathyroidism in Florence, Italy in 2015, guidelines on the diagnosis and treatment hypoparathyroidism were released. Diagnosis is based on the following findings[48] :
Hypocalcemia confirmed twice, at least 2 weeks apart.
Parathyroid hormone (PTH) concentration, by second- or third-generation immunoassay, that is undetectable or inappropriately low (ie, < 20 pg/mL) in the presence of hypocalcemia on at least two occasions.
Phosphate levels in the upper normal or frankly elevated range supports diagnosis but is not mandatory. After neck surgery, chronic hypoparathyroidism can only be diagnosed after 6 months.
Urgent management of acute hypoparathyroidism requires intravenous calcium over 10 to 20 minutes followed by a slower infusion of calcium gluconate over an 8- to 10-hour period.
Management of chronic hypocalcemia in patients with hypoparathyroidism include the following[48] :
Dietary calcium and oral calcium supplements
Active vitamin D or analogs
Magnesium
Thiazide diuretics when necessary to help manage hypercalciuria and low salt diet
Phosphate binders and low phosphate diet, if necessary to control hyperphosphatemia
Indications for consideration of rhPTH (1-84) therapy include the following[48] :
Inadequate control of the serum calcium concentration
Excessive amounts of oral calcium and active vitamin D required to control symptoms
Hypercalciuria, renal stones, nephrocalcinosis, stone risk, or reduced creatinine clearance or eGFR (< 60 mL/min)
Hyperphosphatemia and/or calcium-phosphate product that exceeds 55 mgb/dLb (4.4 mmolb/Lb)
A gastrointestinal tract disorder that is associated with malabsorption
Reduced quality of life
Guidelines on chronic hypoparathyroidism by the European Society of Endocrinology include the following[49] :
Consider a diagnosis of chronic hypoparathyroidism (HypoPT) in a patient with hypocalcemia and inappropriately low parathyroid hormone (PTH) levels.
Consider genetic testing and/or family screening in a patient with HypoPT of unknown etiology.
Treatment targeted to maintain serum calcium level (albumin adjusted total calcium or ionized calcium) in the lower part or slightly below the lower limit of the reference range (target range) is suggested, with patients being free of symptoms or signs of hypocalcemia.
Treat patients with chronic HypoPT with symptoms of hypocalcemia and/or an albumin adjusted serum calcium level < 2.0 mmol/L (< 8.0 mg/dL/ionized serum calcium levels [S-Ca2] < 1.00 mmol/L).
Offer treatment to asymptomatic patients with chronic HypoPT and an albumin adjusted calcium level between 2.0 mmol/L (8.0 mg/dL/S-Ca2+ 1.00 mmol/L) and the lower limit of the reference range in order to assess whether this may improve their well-being.
Use activated vitamin D analogues plus calcium supplements in divided doses as the primary therapy.
If activated vitamin D analogues are not available, treat with calciferol (preferentially cholecalciferol).
Titrate activated vitamin D analogues or cholecalciferol in such a manner that patients are without symptoms of hypocalcaemia and serum calcium levels are maintained within the target range.
Provide vitamin D supplementation in a daily dose of 400–800 IU to patients treated with activated vitamin D analogues.
In a patient with hypercalciuria, consider a reduction in calcium intake, a sodium-restricted diet, and/or treatment with a thiazide diuretic.
In a patient with renal stones, evaluate renal stone risk factors and management according to relevant international guidelines.
In a patient with hyperphosphatemia and/or an elevated calcium-phosphate product, consider dietary interventions and/or adjustment of treatment with calcium and vitamin D analogues.
In a patient with hypomagnesemia, consider measures that may increase serum magnesium levels.
The routine use of replacement therapy with PTH or PTH analogues is not recommended.
The Society for Endocrinology guidelines for the emergency management of hypocalcemia in adults includes the following recommendations for postoperative hypocalcemia and hypoparathyroidism[50] :
Administer intravenous (IV) calcium gluconate over 10 minutes with electrocardiographic (ECG) monitoring; repeat until patient is asymptomatic. Titrate the rate of infusion to achieve normocalcemia and continue until treatment of the underlying cause has taken effect.
Treat hypoparathyroidism with alfacalcidol or calcitriol therapy. If there are concerns about absorbtion or difficulties with oral administration, alfacalcidol can be given intravenously.
The guidelines note that adverse effects of calcium administration include local thrombophlebitis, cardiotoxicity, hypotension, calcium taste, flushing, nausea, vomiting and sweating. Patients with cardiac arrhythmias or on digoxin therapy need continuous ECG monitoring during IV calcium replacement. Large volume calcium infusions should not be used in patients with end stage renal failure or who are on dialysis.
Hypoparathyroidism is treated primarily with vitamin D.[51] Dietary supplementation with calcium may be necessary.
Hypoparathyroidism manifests as hypocalcemia. As a result, calcium supplementation may be indicated.
Can be given IV initially, then maintained as high-calcium diet. Some patients require calcium supplementation. The 10% IV solution provides 100 mg/mL of calcium gluconate that equals 9 mg/mL (0.46 mEq/mL) of elemental calcium. One 10-mL ampule contains 93 mg of elemental calcium.
Vitamin D enhances absorption of calcium and maintains calcium homeostasis.
Stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood.