AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hypoparathyroidism is a condition of parathyroid hormone (PTH) deficiency.

Primary hypoparathyroidism is a state of inadequate PTH activity. In the absence of adequate PTH activity, the ionized calcium concentration in the extracellular fluid falls below the reference range. Primary hypoparathyroidism, the subject of this article, is a syndrome resulting from iatrogenic causes or one of many rare diseases.

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).

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, 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 both 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 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. Recent 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Hypoparathyroidism results in hypocalcemia, which may be variably symptomatic. The history should focus on eliciting signs and symptoms of neuromuscular irritability, including the following:

• Paresthesias (involving fingertips, toes, perioral area)
• Hyperirritability
• Fatigue
• Anxiety
• Mood swings and/or personality disturbances
• Seizures (especially in patients with epilepsy)
• Hoarseness (due to laryngospasm)
• Wheezing and dyspnea (due to bronchospasm)
• Muscle cramps, diaphoresis, and biliary colic
• Hypomagnesemia, hypokalemia, and alkalosis (eg, hyperventilation), which worsen signs and symptoms of hypocalcemia

Physical

• Muscle cramps involving the lower back, legs, and feet are common in patients with hypoparathyroidism and hypocalcemia. Tetany develops if hypocalcemia is severe. In some patients, laryngospasm and bronchospasm may be life threatening.
• Increased neuromuscular irritability from hypoparathyroidism-induced hypocalcemia may be demonstrated at the bedside by eliciting the following signs:
• • Chvostek sign: Facial twitching, especially around the mouth, is induced by gently tapping the ipsilateral facial nerve as it courses just anterior to the ear.
  • Trousseau sign: Carpal spasm is induced by inflating a blood pressure cuff around the arm to a pressure 20 mm Hg above obliteration of the radial pulse for 3-5 minutes.
• Hypocalcemia of primary hypoparathyroidism may cause extrapyramidal choreoathetoid syndromes in patients with basal ganglia calcifications.
• Parkinsonism, dystonia, hemiballismus, and oculogyric crises may occur in approximately 5% of patients with idiopathic hypoparathyroidism.
• Spastic paraplegia, ataxia, dysphagia, and dysarthria have been documented in association with hypoparathyroidism-induced hypocalcemia. Severe hypocalcemia causes papilledema, which improves with treatment of the calcium derangement.
• Emotional instability, anxiety, depression, confusion, hallucinations, and psychosis have been described in patients with hypoparathyroidism when the calcium level is low. Normocalcemia corrects these conditions.
• Chronic hypocalcemia, as observed in primary hypoparathyroidism, is also associated with ocular cataracts; abnormal dentition; and dry, puffy, coarse skin. In severe hypocalcemia, a prolongation of the QT interval is observed on ECG, and congestive heart failure may develop. Correction of hypocalcemia reverses the cardiac effects of hypoparathyroidism.
• In patients with autoimmune polyglandular syndrome, idiopathic hypoparathyroidism is associated with adrenal insufficiency and moniliasis. Moniliasis may affect the skin, nails, oral cavity, and vaginal cavity. It is frequently intractable. The underlying etiology is likely a defect in cellular immunity. Some authors advocate the term HAM syndrome, ie, hypoparathyroidism, Addison disease, and moniliasis (HAM), to denote these cases.

Causes

Most people have 4 parathyroid glands; consequently, primary hypoparathyroidism is uncommon. Hypocalcemia from hypoparathyroidism requires all 4 parathyroid glands to be affected. Primary hypoparathyroidism may be permanent or reversible. Permanent primary hypoparathyroidism may be congenital or acquired.

• Iatrogenic causes
• • The most common cause of primary hypoparathyroidism is excision of all parathyroid glands via surgery in the treatment of thyroid, laryngeal, or other neck malignancy. Patients with parathyroid hyperplasia, as observed in the multiple endocrine neoplasia (MEN) syndromes, are treated by surgical removal of the parathyroid glands. Attempts at restoring normal PTH levels and normocalcemia by autotransplantation of a fraction of one of the parathyroid glands sometimes are effective, but many patients become hypoparathyroid. Repeated neck explorations for primary hyperparathyroidism caused by parathyroid adenoma may also cause hypoparathyroidism.
  • Extensive irradiation to the face, neck, or mediastinum may cause destruction of all 4 parathyroid glands, with ensuing primary hypoparathyroidism and hypocalcemia.
  • The "hungry bone syndrome" develops after a parathyroidectomy for hyperparathyroidism. The body has been accustomed to high levels of PTH, causing hypercalcemia. Much of this hypercalcemic effect is because of resorption of bone. When the parathyroid gland or glands responsible for the hypersecretion of PTH are removed, the PTH level in the blood drops suddenly, and the patient experiences transient hypoparathyroidism. The bone, which has been starved of calcium, avidly retains it under the influence of osteoblasts. Without PTH and with bone now using calcium to remineralize, the ECF ionized calcium level falls. Postoperatively, patients require aggressive treatment with calcium for several hours to several days. Eventually, the hypoparathyroid state resolves, and calcium homeostasis is re-achieved.
• Autoimmune causes
• • Type 1 autoimmune polyglandular syndrome (also referred to as HAM syndrome) includes primary hypoparathyroidism that is due to destruction of the parathyroid glands. On average, these patients develop primary hypoparathyroidism by age 10 years.
  • Autoimmune hypoparathyroidism may exist alone or in sporadic or familial forms. For patients with autoimmune primary hypoparathyroidism, the average age for development of hypocalcemia is 7 years, with a range of 6 months to 20 years.
• Congenital causes
• • Numerous conditions are described in the literature that result in congenital agenesis or hypoplasia and, therefore, can produce primary hypoparathyroidism with symptomatic hypocalcemia at birth or in the newborn period. These conditions, which are summarized from Goltzman and Cole (1996), are as follows:¹
  • • Isolated primary hypoparathyroidism
    • X-linked primary hypoparathyroidism (band Xq26-Xq27)
    • X autosomal-recessive primary hypoparathyroidism
    • Branchial dysgenesis (DiGeorge syndrome)
    • Chromosomal defects dup(1q),del(5p),dup(8q),del(10q),del (22q)
    • Monogenic hypoparathyroidism
    • Isolated autosomal-dominant conditions
    • Isolated autosomal-recessive conditions
    • Velocardiofacial (Shprintzen) syndrome (CATCH 22 [for cardiac, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q deletion] is a mnemonic for the features of this syndrome.)
    • Zellweger syndrome
    • Teratogenic effects
    • Diabetic embryopathy
    • Fetal alcohol syndrome
    • Retinoid embryopathy
    • Associational arhinencephalia and/or DiGeorge syndrome and the coloboma, heart disease, choanal atresia, retarded growth and development, genital anomalies, ear anomalies (CHARGE) syndrome and/or DiGeorge syndrome
    • Cardiofacial–DiGeorge–Kenny-Caffey syndrome (ie, absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones)
    • Kearns-Sayre syndrome (ie, mitochondrial myopathy, ophthalmoplegia, retinal degeneration, cardiac conduction defects, primary hypoparathyroidism)
    • Barakat syndrome (ie, primary hypoparathyroidism, nerve deafness, steroid-resistant nephrosis)
    • Hypoparathyroidism with short stature, mental retardation, and seizures
  • In addition to the above list, several other genetic defects cause primary hypoparathyroidism. As opposed to the conditions listed above, no agenesis or hypoplasia of the parathyroid glands occurs in these other genetic defects. These mutations are functional, not anatomic, and are listed as follows:
  • • Mutation of chromosome arm 3q has been demonstrated to cause primary hypoparathyroidism in several kindreds because of activation of the parathyroid extracellular calcium-sensing receptor. These patients have mild-to-moderate hypocalcemia, urinary calcium excretion that is high relative to serum calcium (presumably the extracellular calcium-sensing receptor in the kidney contributes to this), and serum PTH concentration that is within the reference range (but is inappropriately low).
    • Familial isolated hypoparathyroidism is a heterogenous mix of disorders as follows: autosomal dominant abnormal prepro-PTH allele (C-to-T substitution in codon 18 of the prepeptide encoding region does not allow for cleavage to pro-PTH) and autosomal recessive abnormal prepro-PTH allele (C-to-G substitution in the first nucleotide position of prepro-PTH intron 2).
• Causes related to metal overload (ion deficiency)
• • Hemochromatosis and thalassemia, both of which are associated with iron overload, may result in primary hypoparathyroidism.
  • Wilson disease, with copper overload, may also cause primary hypoparathyroidism.
  • Hypermagnesemia has been demonstrated to decrease PTH release. Correction of hypermagnesemia leads to correction of the primary hypoparathyroidism.
  • Aluminum deposition within the parathyroid glands may cause primary hypoparathyroidism in patients with end-stage renal disease who are on hemodialysis.
  • Hypomagnesemia causes reversible functional primary hypoparathyroidism.
• Causes related to infiltration of the parathyroid glands
• • In addition to hemochromatosis and Wilson disease, parathyroid gland destruction has been reported as a result of metastatic disease, granulomatous disease, amyloidosis, syphilis, and progressive systemic sclerosis.
  • Of note, clinically significant hypocalcemia is not always apparent in these patients.
• Neonatal causes
• • The unborn baby of a mother with hypercalcemia has chronic suppression of parathyroid gland function. In the worst circumstances, the parathyroid glands may become atrophic.
  • At birth, the maternal calcium excess is eliminated, and newborns are at risk of hypocalcemia caused by primary hypoparathyroidism.
  • Clinically significant hypocalcemia may develop within the first 3 weeks of life but may occur as late as 1 year after birth. The primary hypoparathyroidism in these patients is self-limited.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Parathyroid hormone
• • Primary hypoparathyroidism is defined by a low concentration of PTH with a concomitant low calcium level.
  • In pseudohypoparathyroidism, the serum PTH concentration is elevated as a result of resistance to PTH caused by mutations in the PTH receptor system.
  • In secondary hypoparathyroidism, the serum PTH concentration is low and the serum calcium concentration is elevated.
• Calcium
• • The calcium ion is highly bound to protein. A total calcium level cannot be interpreted without a total protein or albumin level.
  • Hypoalbuminemia causes a drop in total calcium concentration, but the ionized fraction may be within the reference range. Elevated protein states, such as multiple myeloma and paraproteinemias, may cause an elevation of the total calcium concentration, but the ionized fraction may be within the reference range.
  • Conversely, in the presence of albumin or protein excess, low ionized calcium levels with reference range levels of total calcium are possible. Likewise, if the patient is hypoalbuminemic, high ionized calcium levels with a reference range level of total calcium are possible.
  • Measurement of ionized calcium concentration in the plasma is ideal; however, it is not readily available in many places.
  • The relationship between total serum calcium and albumin is defined by the following simple rule: the serum total calcium concentration falls by 0.8 mg/dL for every 1-g/dL fall in serum albumin concentration. This rule assumes that normal albumin equals 4.0 g/dL and normal calcium is 10.0 mg/dL.
  • Alkalosis causes ionized calcium to bind to albumin more strongly. This causes a decrease in the ionized calcium and may trigger symptoms of hypocalcemia.
• Measurement of 25-hydroxy vitamin D: This measurement is important to exclude vitamin D deficiency as a cause of hypocalcemia.
• Serum magnesium: Hypomagnesemia may cause PTH deficiency and subsequent hypocalcemia. Exclude it in any patient with primary hypoparathyroidism.
• Serum phosphorus: PTH is a phosphaturic hormone. In its absence, phosphorus levels in the blood rise.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• PTH is commercially available for use in the treatment of osteoporosis. Its use for patients with hypoparathyroidism is not approved by the Food and Drug Administration.
• Currently, treatment of patients with hypoparathyroidism involves correcting the hypocalcemia by administering calcium and vitamin D.

Surgical Care

• 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. This autotransplant is usually placed subcutaneously in the forearm or in the neck.
• If the autotransplantation fails, patients are treated as any other patient with hypoparathyroidism.

Consultations

An endocrinologist should be involved in the care of all patients who have primary hypoparathyroidism or who are at risk of developing it.

Diet

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

Activity

Patients with symptomatic hypocalcemia develop tetany. Otherwise, no restriction in activity for these patients is necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Calcium and vitamin D are the mainstays of treatment.

Drug Category: Calcium salts

Without PTH, the ionized calcium levels in the plasma drop. Bone becomes an inefficient source of calcium for plasma, and kidneys waste calcium. Calcium helps maintain the ionized calcium level close to the reference range.

Drug Category: Vitamin D preparations

Vitamin D is synthesized by the kidneys, and the synthesis of 1,25-dihydroxy vitamin D is PTH dependent. In most patients with chronic hypoparathyroidism, treatment with the active vitamin D form is necessary.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients with primary hypoparathyroidism have a lifelong risk of symptomatic tetany.
• Without access to calcium, a patient may die.
• All patients should wear a chain or bracelet that identifies them as having primary hypoparathyroidism.

Complications

• Nephrocalcinosis
• Nephrolithiasis

Patient Education

• Diuretic use: The use of any diuretic medication may alter calcium homeostasis. Patients must know this and should remind their practitioner whenever new medications are prescribed.
• Pregnancy: Medications that alter the synthesis of proteins and albumin in the liver and/or hyperestrogenic states, such as pregnancy, may lead to alterations in calcium homeostasis. Instruct patients to consult their doctor prior to any changes in any medications.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• In discussing the risks of untreated primary hypoparathyroidism with patients, document the signs and symptoms of severe hypocalcemia.
• Direct patients to the emergency department for treatment if mental status changes or respiratory distress develops.
• Recommend that patients wear a chain or bracelet identifying them as having primary hypoparathyroidism; document this recommendation in the chart.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Goltzman D, Cole DEC. Hypoparathyroidism. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Pa: Lippincott-Raven; 1996:220-3.
2. Brown EM, Harris HW, Vassilev PM. The biology of the extracellular Ca2+-sensing receptor. In: Bilezikian JP, ed. Principles of Bone Biology. San Diego, Calif: Academic Press; 1996:243-62.
3. Cole DEC, Hendy GN. Hypoparathyroidism and pseudohypoparathyroidism. Endotext.com. 2005, Available at. [Full Text].
4. Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med. Dec 21 2000;343(25):1863-75. [Medline].
5. Thakker RV. Molecular basis of PTH underexpression. In: Bilezikian JP, et al, eds. Principles of Bone Biology. San Diego, Calif: Academic Press; 1996:837-51.

Article Last Updated: Sep 21, 2007