Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and often causes chronic tetany.
Etiology of Hypoparathyroidism
Hypoparathyroidism results from a parathyroid hormone (PTH) deficiency, which can occur in
Removal of or damage to several parathyroid glands during thyroidectomy or parathyroidectomy
Inherited or autoimmune disorders
Postoperative hypoparathyroidism
Transient hypoparathyroidism is common after thyroidectomy, but permanent hypoparathyroidism occurs after < 3% of such thyroidectomies done by experienced surgeons. Manifestations of hypocalcemia usually begin about 24 to 48 hours postoperatively but may occur after months or years. PTH deficiency is more common after radical thyroidectomy for cancer or as the result of surgery on the parathyroid glands (subtotal or total parathyroidectomy). Risk factors for severe hypocalcemia after subtotal parathyroidectomy include
Severe preoperative hypercalcemia
Removal of a large thyroid adenoma
Elevated alkaline phosphatase
Idiopathic hypoparathyroidism
Idiopathic hypoparathyroidism is uncommon. It can be due to sporadic or inherited conditions in which the parathyroid glands are absent or atrophied. It manifests in childhood. The parathyroid glands are occasionally absent, and thymic aplasia and abnormalities of the tissue arising from the branchial arches (DiGeorge syndrome) are present.
Other causes include polyglandular autoimmune failure syndrome, autoimmune hypoparathyroidism associated with mucocutaneous candidiasis, and X-linked recessive idiopathic hypoparathyroidism.
Pseudohypoparathyroidism
Pseudohypoparathyroidism is an uncommon group of disorders characterized by target organ resistance to PTH, not by hormone deficiency. Genetic transmission of these disorders occurs through different modes of inheritance (ie, autosomal recessive, dominant, and x-linked forms) and different genes (and genes that control these genes) that all play a role in a complex pathway.
Type Ia pseudohypoparathyroidism (Albright hereditary osteodystrophy) is caused by a mutation in the stimulatory Gs-alpha1 protein of the adenylyl cyclase complex (GNAS1). The result is failure of normal renal phosphaturic response or increase in urinary cAMP (cyclic adenosine monophosphate) to PTH.
Patients are usually hypocalcemic and hyperphosphatemic. Secondary hyperparathyroidism and hyperparathyroid bone disease can occur. Associated abnormalities include short stature, round facies, intellectual disability with calcification of the basal ganglia, shortened metacarpal and metatarsal bones, mild hypothyroidism, and other subtle endocrine abnormalities.
Because only the maternal allele for GNAS1 is expressed in the kidneys, patients whose abnormal gene is paternal do not have hypocalcemia, hyperphosphatemia, or secondary hyperparathyroidism; this condition is sometimes described as pseudopseudohypoparathyroidism, although patients have many of the somatic features of the disease.
Type Ib pseudohypoparathyroidism is less well known. Affected patients have hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism but do not have the other associated abnormalities.
Type II pseudohypoparathyroidism is even less common than type I. In affected patients, exogenous PTH raises the urinary cAMP normally but does not raise serum calcium or urinary phosphate. An intracellular resistance to cAMP has been proposed.
Symptoms and Signs of Hypoparathyroidism
The presence of hypoparathyroidism may be suggested by symptoms due to hypocalcemia, including tingling in the hands or around the mouth and muscle cramps. In severe cases, tetany occurs.
The clinical manifestations of any underlying disorder may be present:
Patients with type Ia pseudohypoparathyroidism frequently have skeletal abnormalities, including short stature and shortened 1st, 4th, and 5th metacarpals, a round face, intellectual disability, basal ganglia calcification, and sometimes vitiligo.
Patients with type Ib disease have renal manifestations of hypocalcemia and hyperphosphatemia without the skeletal abnormalities that occur in type Ia.
Patients with type II pseudohypoparathyroidism also have the renal abnormalities.
Patients with mutations involving the catalytic subunit of cAMP also have multiple hormonal resistance, intellectual disability, and short digits.
Diagnosis of Hypoparathyroidism
PTH and calcium measurement
PTH concentration should be measured as an assay of the intact molecule. Because hypocalcemia is the major stimulus for PTH secretion, PTH normally should be elevated in response to hypocalcemia. Thus,
Low or even low-normal PTH concentration in patients with hypocalcemia is inappropriate and suggests hypoparathyroidism.
An undetectable PTH concentration suggests idiopathic hypoparathyroidism.
A high PTH concentration suggests pseudohypoparathyroidism or an abnormality of vitamin D metabolism
Hypoparathyroidism is further characterized by high serum phosphate and normal alkaline phosphatase.
In type I pseudohypoparathyroidism, despite the presence of a high concentration of circulating PTH, urinary cAMP and urinary phosphate are absent. Provocative testing by injection of parathyroid extract or recombinant human PTH fails to raise serum or urinary cAMP.
Treatment of Hypoparathyroidism
Key Points
Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or removal of the glands during thyroidectomy.
Hypoparathyroidism causes hypocalcemia and related symptoms of tingling in the hands or around the mouth and muscle cramps. In severe cases, tetany occurs.
Diagnosis is made by finding low or even low-normal PTH concentrations in a patient with hypocalcemia.
