Background
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]
Pathophysiology
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]
Etiology
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] :
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Autoimmune polyglandular syndrome type 1 (APS-1)
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DiGeorge syndrome
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Kearns–Sayre syndrome
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Bartter syndrome
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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]
Epidemiology
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
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:
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Neuromuscular symptoms
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Cataracts [20]
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Growth stunting (with hypoparathyroidism, sensorineural deafness and renal disease [HDR syndrome (Barakat syndrome)]) [23]
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Tooth malformation [24]
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Intellectual disability (with HDR syndrome [Barakat syndrome]) [23]
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Hypothyroidism
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Cardiomyopathy [25]
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Parkinsonian symptoms [26]
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Ossification of paravertebral ligaments [27]
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Adhesive capsulitis [28]
