Hypoparathyroidism

Updated: Oct 10, 2022
  • Author: Joseph Michael Gonzalez-Campoy, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

Hypoparathyroidism is a condition of parathyroid hormone (PTH) deficiency. Primary hypoparathyroidism, the subject of this article, is a state of inadequate PTH activity; this syndrome results from iatrogenic causes or one of many rare diseases. In the absence of adequate PTH activity, the ionized calcium concentration in the extracellular fluid falls below the reference range. [1, 2, 3]

Secondary hypoparathyroidism is a physiologic state in which PTH levels are low in response to a primary process that causes hypercalcemia. The primary processes that lead to hypercalcemia are discussed in other articles (see Hypercalcemia).

Treatment of patients with hypoparathyroidism involves correcting the hypocalcemia by administering calcium and vitamin D. [4] Recombinant human PTH (rhPTH[1-84], Natpara) is commercially available in the United States and is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.

Signs and symptoms of hypoparathyroidism

Signs and symptoms of hypoparathyroidism can include the following:

  • Muscle cramps involving the lower back, legs, and feet are common in patients with hypoparathyroidism and hypocalcemia
  • Increased neuromuscular irritability from hypoparathyroidism-induced hypocalcemia can be found at beside by eliciting the Chvostek and Trousseau signs
  • Hypocalcemia of primary hypoparathyroidism may cause extrapyramidal choreoathetoid syndromes in patients with basal ganglia calcifications [5]
  • Parkinsonism, dystonia, hemiballismus, and oculogyric crises may occur in approximately 5% of patients with idiopathic hypoparathyroidism [6]
  • Spastic paraplegia, ataxia, dysphagia, and dysarthria have been documented in association with hypoparathyroidism-induced hypocalcemia
  • Emotional instability, anxiety, depression, confusion, hallucinations, and psychosis have been described in patients with hypoparathyroidism when the calcium level is low
  • Chronic hypocalcemia, as observed in primary hypoparathyroidism, is associated with ocular cataracts, abnormal dentition, and dry, puffy, coarse skin
  • In severe hypocalcemia, a prolongation of the QT interval is observed on electrocardiography (ECG), and congestive heart failure may develop
  • In patients with autoimmune polyglandular syndrome, idiopathic hypoparathyroidism is associated with adrenal insufficiency and moniliasis

Workup in hypoparathyroidism

Laboratory tests in the workup of hypoparathyroidism include parathyroid and hormone studies, with primary hypoparathyroidism being defined by a low concentration of PTH with a concomitant low calcium level.

Moreover, measurement of 25-hydroxy vitamin D is important to exclude vitamin D deficiency as a cause of hypocalcemia.

Serum magnesium is measured because hypomagnesemia may cause PTH deficiency and subsequent hypocalcemia.

Also, serum phosphorus levels are tested because PTH is a phosphaturic hormone; in its absence, phosphorus levels in the blood rise.

Management of hypoparathyroidism

Treatment of patients with hypoparathyroidism involves correcting the hypocalcemia by administering calcium and vitamin D. [4]

A diet rich in calcium content (ie, emphasizing dairy products) is recommended for patients with primary hypoparathyroidism.

Patients undergoing parathyroidectomy for parathyroid hyperplasia are at high risk of developing permanent primary hypoparathyroidism. Patients may be treated with an autotransplant of a segment of parathyroid gland to prevent hypoparathyroidism. [7] This autotransplant is usually placed subcutaneously in the forearm or in the neck. If the autotransplantation fails, patients receive the same treatment that is administered to other patients with hypoparathyroidism.

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Pathophysiology

The ionized calcium concentration in the extracellular fluid (ECF) remains nearly constant, at a level of approximately 1 mM. Ionized calcium in the ECF is in equilibrium with ionized calcium in storage pools such as bone and proteins in the circulation, and within the intracellular fluid. The intracellular fluid concentration of calcium is more than 10,000-fold lower than in the ECF. The maintenance of ionized calcium concentrations in the intracellular and extracellular fluids is highly regulated and modulates the functions of bone, renal tubular cells, clotting factors, adhesion molecules, excitable tissues, and a myriad of intracellular processes.

An extracellular calcium-sensing receptor has been isolated from parathyroid, kidney, and brain cells. The extracellular calcium-sensing receptor is G-protein coupled. Mutations in the extracellular calcium-sensing receptor have been demonstrated to result in hypercalcemic or hypocalcemic states. Normally, the extracellular calcium-sensing receptor is extremely sensitive and responds to changes in the ECF calcium ion concentration of as small as 2%.

In parathyroid cells, the extracellular calcium-sensing receptor regulates the secretion of PTH. Inactivating mutations of the extracellular calcium-sensing receptor lead to hypercalcemia, as observed in familial hypocalciuric hypercalcemia (heterozygous mutation) and neonatal severe hyperparathyroidism (homozygous mutation). Conversely, activating mutations of the extracellular calcium-sensing receptor lead to hypocalcemia, as observed in some families with autosomal-dominant hypocalcemia.

The intracellular mechanism(s) whereby activation of the extracellular calcium-sensing receptor leads to inhibition of PTH exocytosis is unknown. Because pertussis toxin blocks the inhibition of cyclic adenosine monophosphate (cAMP), but not PTH, in response to a high ECF ionized calcium concentration, cAMP is probably not an important second messenger for the extracellular calcium-sensing receptor. Candidate second messengers include protein kinase C, phospholipase A2, and intracellular calcium.

Conversely, a fall in ECF ionized calcium concentration leads to exocytosis of PTH. PTH has the overall effect of returning the ECF ionized calcium concentration to the reference range by its effects on the kidneys and the skeleton.

PTH activates osteoclasts. Osteoclast activation results in bone resorption and a release of ionized calcium into the ECF. Evidence suggests that small pulse doses of PTH activate osteoblasts, with ensuing bone deposition. The effect of PTH on osteoclasts seems more important than the effect on osteoblasts.

PTH inhibits the proximal tubular transport of phosphate from the lumen to the interstitium. In conditions of primary PTH excess, hypophosphatemia tends to occur. Conversely, in hypoparathyroidism, the phosphate concentration in the plasma is within the reference range or slightly elevated.

PTH has a calcium-retaining effect on the distal tubule. The PTH-mediated calcium reabsorption is independent of any effects on sodium or water reabsorption. This effect of PTH is important in hypoparathyroidism because, in the absence of this distal tubular calcium reabsorption, the kidneys waste calcium. This depletes the ECF ionized calcium and increases the urinary calcium concentration.

PTH stimulates renal 1-alpha-hydroxylase, the enzyme that synthesizes formation of 1,25-dihydroxy vitamin D; 1,25-dihydroxy vitamin D allows for better dietary calcium absorption. Thus, 1,25-dihydroxy vitamin D has a synergistic effect with PTH; both contribute to a rise in the ECF ionized calcium concentration.

In the absence of PTH, bone resorption, phosphaturic effect, renal distal tubular calcium reabsorption, and 1,25-dihydroxy vitamin D–mediated dietary calcium absorption cannot occur. Therefore, the consequence of PTH deficiency is hypocalcemia.

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Epidemiology

Hypoparathyroidism has an estimated prevalence in the United States of 37 per 100,000 person-years. In Denmark, it is estimated to be 22 per 100,000 person-years. [8]

Age-related demographics

A study by Powers et al found 74% of US hypoparathyroid patients to be aged 45 years or older. [9]

Sex-related demographics

In the United States, 75% of hypoparathyroidism cases are in females and 25% in males. [1]  Similarly, in an Italian study, Cipriani et al found the rate of hospitalizations for hypoparathyroidism in women and men to be 72.2% and 27.8%, respectively. [10]

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