Hypoparathyroidism can be either genetic or acquired. Genetic hypoparathyroidism includes developmental and autoimmune hypoparathyroidism and mutations in Ca²⁺-sensing receptor

Developmental hypoparathyroidism occurs in the neonates because of branchial dysembryogenesis, resulting in absent parathyroid glands and thymus

A common example is DiGeorges’s syndrome, which is characterized by hypocalcemia, cardiac abnormalities, and a defect in T cell mediated immunity

Autoimmune hypoparathyroidism, called polyglandular autoimmune syndrome type I, is due to mutations in autoimmune regulatory gene (AIRE) on chromosome 21q22.3

Characterized by a triad of hypothyroidism, hypoadrenalism, and mucocutaneous candidiasis

Activating mutations of Ca²⁺-sensing receptor (CaSR) is characterized by autoantibodies to CaSR, hypocalcemia, hypomagnesemia, hypercalciuria, and low to normal parathyroid hormone (PTH) level

Treatment of the above three conditions of genetic hypoparathyroidism includes calcium supplements and sufficient vitamin D to suppress symptoms. Thiazide diuretics and injectable PTH have been used with variable results

Acquired hypoparathyroidism can be either surgical or nonsurgical

Surgical resection of thyroid (cancer, Grave’s disease, head and neck cancer) or parathyroid (adenoma or hyperplasia) glands is the most common cause of hypoparathyroidism in adults

Transient hypocalcemia is extremely common after surgery because of Ca²⁺ uptake by bones (hungry bone syndrome). This syndrome is seen in hyperparathyroid patients with severe hypercalcemia. Patients need i.v. calcium gluconate or chloride and active vitamin D₃ to improve symptomatic hypocalcemia

Nonsurgical causes include infiltrative diseases such as hemochromatosis, thalassemia major, Wilson’s disease, infections or metastatic cancers. Irradiation to the neck also presents with hypoparathyroidism

PsHPT is a condition of PTH resistance. The first documented cases were described by Albright and colleagues in 1942. These patients were hypocalcemic and hyperphosphatemic and failed to respond to infusion of bovine PTH. These patients had several facial and skeletal abnormalities, including obesity, short stature, brachydactyly, and mental retardation. Subsequent studies have shown that these patients have elevated PTH levels. These features are now considered characteristics of the disorder called Albright’s hereditary osteodystrophy (AHO)

AHO results from loss-of-function mutation of the GNAS1 gene, which encodes the stimulatory G protein α-subunit

PsHPT is considered heterogeneous with different clinical and biochemical features and is classified into types Ia, Ib, II, and pseudo-PsHPT

Patients with type Ia PsHPT are similar to those of AHO

Type Ib PsHPT patients have normal appearance, but have resistance to PTH action

Patients with type II PsHPT have normal developmental features, but hypocalcemic. PTH infusion causes normal excretion of cAMP, but urinary excretion of phosphate is decreased

Pseudo-PsHPT patients have characteristics similar to those of type Ia PsHPT, but without PTH resistance, because urinary excretions of cAMP and phosphate are normal to PTH infusion

Urinary cAMP response to the infusion of synthetic PTH is used to establish the diagnosis of PTH resistance

Vitamin D deficiency may be due to an absolute deficiency of vitamin D or an abnormality in vitamin D metabolism

Absolute deficiency is generally related to inadequate oral intake, lack of sun exposure, use of sunscreens, or fat malabsorption as vitamin D absorption is dependent on fat intake. Elderly are at particular risk for vitamin D deficiency

Altered metabolism due to medications and disease conditions seems to be the common cause of vitamin D deficiency (Table 18.1)

Vitamin D-dependent rickets in children or osteomalacia in adults is a rare inborn error of vitamin D metabolism, resembling vitamin D deficiency

Type I disease is inherited as an autosomal recessive disorder, which is due to defective activity of 1α-hydroxylase, caused by mutations in the gene of this enzyme. Patients are hypocalcemic with low calcitriol (1,25(OH)₂D₃) levels and respond to calcitriol

Type II disorder is characterized by increased calcitriol levels, but fails to respond to pharmacologic doses of calcitriol. These patients, therefore, have hypocalcemia due to calcitriol resistance. This resistance is caused by mutations in the vitamin D receptor

Obtain surgical history and good history regarding nutrition, medications, inherited and developmental anomalies

Physical examination should focus on blood pressure (usually hypotension), bradycardia, and neurologic and ocular (cataracts) changes

Rule out pseudohypocalcemia following magnetic resonance imaging (MRI) with contrast agents

Establish true hypocalcemia by determining serum ionized Ca²⁺

Determine serum albumin, and correct Ca²⁺ for normal albumin concentration

Measure serum Mg²⁺ and phosphate. Correct hypomagnesemia and hyperphosphatemia

Review medications that alter 25(OH)D₃ (calcifediol) metabolism, and change or choose alternative medications

Check liver and renal function

Determine serum PTH and vitamin D status. Start vitamin D preparations for vitamin D deficiency

If PTH is elevated, evaluate parathyroid glands. If PTH resistance is suspected, measure urinary cAMP levels in response to PTH infusion. Figure 18.1 shows the suggested diagnostic work-up of a patient with hypocalcemia