Hypoparathyroidism, often abbreviated as HPT, refers to a group of clinical syndromes caused by insufficient secretion of parathyroid hormone (PTH) and/or inadequate PTH action. Clinically, its main features include tetany, seizure-like episodes, hypocalcemia, and hyperphosphatemia. Common clinical types include idiopathic hypoparathyroidism, secondary hypoparathyroidism, hypomagnesemic hypoparathyroidism, and neonatal hypoparathyroidism. Rare types include pseudohypoparathyroidism and others.
Etiology and Pathogenesis
Insufficient PTH production, suppressed PTH secretion, or PTH action impairment at its target tissues can result in hypoparathyroidism. Any of these causes may lead to the condition:
Decreased PTH Production
This can be secondary or idiopathic.
Secondary Causes
These often result from surgical damage or destruction of the parathyroid glands during neck surgery or radiation therapy.
Idiopathic Causes
The exact cause is often unclear and may be associated with abnormal PTH biosynthesis or activating mutations in calcium-sensing receptors. Congenital absence of the parathyroid glands is an extremely rare condition. Autoimmune hypoparathyroidism typically presents before the age of 10, and there may be a delay of several years from symptom onset to diagnosis, by which time parathyroid function is generally lost. Patients may have detectable parathyroid antibodies in their blood, as well as antibodies against adrenal cortex, thyroid gland, or gastric parietal cells. Autoimmune hypoparathyroidism may coexist with other autoimmune diseases, such as primary hypothyroidism, pernicious anemia, and Addison's disease. Neonatal hypoparathyroidism is often transient and associated with immature parathyroid gland development.
Suppressed PTH Secretion
Severe hypomagnesemia can transiently suppress PTH secretion, causing reversible hypoparathyroidism. Magnesium ions are essential for PTH release. Hypomagnesemia can also impair the action of PTH on peripheral tissues.
Impaired PTH Action
Resistance to PTH occurs due to defects in PTH receptors or post-receptor signaling pathways. This leads to the inability of PTH to act on its target cells in tissues such as bone or kidney. The resultant parathyroid hyperplasia and overproduction of PTH define pseudohypoparathyroidism. This is a genetic condition and can be associated with Albright's hereditary osteodystrophy in some cases.
Pathophysiology
Hypocalcemia and hyperphosphatemia are the biochemical hallmarks of hypoparathyroidism. PTH deficiency results in the following pathophysiological changes:
Reduced Bone Resorption
Osteoclastic activity is weakened, leading to decreased bone resorption.
Decreased 1,25-(OH)2D3 Synthesis in the Kidney
This causes reduced intestinal calcium absorption.
Decreased Renal Calcium Reabsorption
This leads to increased urinary excretion of calcium. However, when serum calcium levels fall below approximately 1.75 mmol/L, the severe hypocalcemia significantly reduces urinary calcium excretion.
Reduced Renal Phosphorus Excretion
This results in elevated serum phosphate levels, and calcium-phosphate complexes deposit in bones and soft tissues. Some patients may develop increased bone density. However, this is not due to enhanced osteoblast activity or bone formation, as bone turnover slows down, and serum ALP (alkaline phosphatase) remains normal.
Long-Term Hypocalcemia
Chronic hypocalcemia can lead to calcifications in the basal ganglia, as well as damage to ectodermal tissues such as skin, hair, and nails. In children, hypocalcemia may impair intellectual development.
Clinical Manifestations
The symptoms of hypoparathyroidism depend on the severity, rate of decline, and duration of hypocalcemia.
Increased Neuromuscular Excitability Due to Hypocalcemia
Symptoms such as numbness and tingling around the fingertips or mouth may develop. Muscle spasms in the hands, feet, or face can occur, and severe cases may result in tetany (serum calcium levels are usually <2 mmol/L). Typical manifestations include strong adduction of both thumbs, flexion of the metacarpophalangeal joints, extension at the interphalangeal joints, and flexion of the wrist and elbow, creating a "claw-like" or "obstetrician's hand" posture. The feet may occasionally exhibit tonic extension, with flexion at the knee and hip joints. Physical examination may reveal positive Chvostek's sign (facial nerve tapping) and Trousseau's sign (induced carpal spasm with blood pressure cuff inflation).
Neurological and Psychiatric Symptoms
Severe hypocalcemia or acute drops in serum calcium levels may trigger seizures or generalized tonic-clonic spasms resembling epilepsy, often misdiagnosed as epileptic seizures. These episodes can be precipitated by factors such as infection, fatigue, or emotional stress, and are more frequent in women during the perimenstrual period.
Chronic hypocalcemia may also lead to extrapyramidal symptoms, including classic manifestations of Parkinson's disease, which may improve with correction of hypocalcemia. Psychiatric symptoms, such as irritability, agitation, depression, or other mental disturbances, can also occur in chronic hypoparathyroidism.
Ectodermal Tissue Dystrophy
Hypocalcemia commonly causes cataracts, which are observed in approximately 50% of individuals with hypoparathyroidism. The progression of cataracts may stabilize upon correction of hypocalcemia. Symptoms such as dental developmental abnormalities, enamel hypoplasia, and defective tooth calcification may also occur. In chronic cases, microvascular spasm and insufficient blood supply may lead to dry, scaly skin; longitudinal ridges on fingernails; coarse, dry, and brittle hair with a tendency to fall out; and increased susceptibility to candidiasis infections.
Other Symptoms
Metastatic calcifications frequently occur in the basal ganglia (e.g., globus pallidus, putamen, and caudate nucleus), often distributed symmetrically. These calcifications may contribute to seizures and represent a characteristic finding of hypoparathyroidism. Calcifications can also appear in other soft tissues, tendons, and paraspinal ligaments. Electrocardiographic findings may include prolonged QT intervals and changes in the ST-T segment. Electroencephalographic studies may exhibit epileptiform wave patterns.
Laboratory Tests
Repeated measurements of serum total calcium below 2.2 mmol/L confirm the presence of hypocalcemia. Symptomatic cases often have serum total calcium levels ≤1.88 mmol/L and free calcium levels ≤0.95 mmol/L. Since 40–45% of blood calcium is bound to proteins, the effect of hypoalbuminemia on serum calcium levels should be considered using the following formula:
Corrected Serum Calcium (mmol/L) = Measured Serum Calcium + 0.02 × [40 − Serum Albumin (g/L)].
Most patients have elevated serum phosphate levels, though some may remain normal. Urinary excretion of calcium and phosphate is reduced. Serum alkaline phosphatase levels are typically normal. Serum PTH levels are often below the normal range, though they may occasionally fall within the normal range. Since hypocalcemia strongly stimulates the parathyroid glands, serum PTH levels should normally increase 5–10 times when serum total calcium levels fall below 1.88 mmol/L. Thus, normal PTH levels under conditions of hypocalcemia are still indicative of hypoparathyroidism. When measuring PTH, concurrent measurement of serum calcium is advised for proper interpretation. In pseudohypoparathyroidism, serum PTH levels are elevated due to PTH resistance.
Diagnosis and Differential Diagnosis
The condition is characterized by recurrent episodes of tetany, with positive Chvostek's and Trousseau's signs. Laboratory findings reveal decreased serum calcium (often <2 mmol/L) and increased serum phosphate (often >2 mmol/L) in the absence of renal failure, supporting the diagnosis. In cases of idiopathic hypoparathyroidism, there is often no evident cause but a possible family history, accompanied by reduced serum PTH levels. Post-surgical hypoparathyroidism typically occurs following thyroid or parathyroid surgery.
Idiopathic hypoparathyroidism must be differentiated from the following conditions:
Pseudohypoparathyroidism (PHP)
This dominant or recessive genetic disorder is characterized by hypocalcemia and hyperphosphatemia and can be classified into type I and type II. Typical patients may present with developmental abnormalities, intellectual disability, short stature, a round face, and shortening of metacarpal or metatarsal bones, particularly the symmetrical shortening of the fourth and fifth metacarpals. Peripheral tissues show resistance to PTH (PTH resistance) due to defects in PTH receptor function or post-receptor signaling, leading to elevated PTH levels. The treatment approach is generally similar to that of idiopathic hypoparathyroidism.
Severe Hypomagnesemia (Serum Magnesium <0.4 mmol/L)
Patients may develop hypocalcemia and tetany, accompanied by reduced serum PTH levels. Correction of hypomagnesemia often restores serum calcium and PTH levels to normal relatively quickly.
Other Conditions
These include metabolic or respiratory alkalosis, vitamin D deficiency, renal insufficiency, chronic diarrhea, and malabsorption of calcium, which should also be considered in the differential diagnosis.
Treatment
Hypoparathyroidism and pseudohypoparathyroidism are lifelong conditions. The treatment goals involve the following: (1) controlling symptoms, including cessation of tetany episodes and restoring serum calcium levels to normal or near-normal; (2) reducing the risk of complications associated with hypoparathyroidism.
Management of Acute Hypocalcemia
When tetany, laryngospasm, bronchospasm, seizures, or generalized tonic-clonic spasms occur, intravenous administration of 10–20 ml of 10% calcium gluconate within 10–15 minutes is recommended. Repeat administration may be necessary in 4–6 hours, with 1–3 injections per day depending on the severity. Continuous intravenous infusion of 100 ml of 10% calcium gluconate (containing 900 mg elemental calcium diluted in 500–1,000 ml of normal saline or dextrose solution) may also be used; the infusion rate should not exceed 4 mg/kg of elemental calcium per hour. Serum calcium levels should be monitored regularly to avoid hypercalcemia, which can result in life-threatening arrhythmias. For severe episodes, intramuscular administration of diazepam or phenytoin may be used as a short-term intervention to rapidly control spasms and cramps.
Maintenance Therapy
A combination of vitamin D and calcium supplementation is typically recommended.
Calcium Supplementation
Long-term calcium supplementation is necessary. Patients are usually given 1–3 g of elemental calcium daily, taken orally in divided doses. Calcium carbonate is a commonly used form, with 2.5 g of calcium carbonate providing 1 g of elemental calcium. Other options include 7.7 g of calcium lactate, 11 g of calcium gluconate, or 3.7 g of calcium chloride for the same dose of elemental calcium. Calcium levels should be maintained to approach normal. Dosage can be adjusted for pregnant or breastfeeding women and children. With the elevation of serum calcium, the renal phosphate threshold decreases, and urinary phosphate excretion increases, often resulting in a natural reduction in serum phosphate without the need for phosphate-lowering medications. Attention to a diet rich in calcium and low in phosphate is advisable.
Vitamin D and Its Derivatives
Since hypoparathyroidism patients lack PTH, the production of active vitamin D is impaired, requiring supplementation with active forms of vitamin D to quickly correct intestinal calcium absorption deficiencies. Commonly used forms include:
1,25-(OH)2D3 (Calcitriol)
This is administered at a dosage of 0.25–2.0 μg/day, divided into multiple doses; serum calcium elevation can typically be observed 1–3 days after starting treatment.
1α-(OH)D3 (Alfacalcidol)
This is administered at 0.5–3.0 μg/day. After absorption, it is converted into 1,25-(OH)2D3 in the liver, which exerts its effect.
Standard Vitamin D (Vitamin D2 or D3)
In hypoparathyroidism, renal 1α-hydroxylase function is reduced, impairing the conversion of exogenous vitamin D into active forms. Therefore, higher doses are required. Conversion in the liver to 25-(OH)D helps stabilize serum calcium levels.
In hypoparathyroidism, renal tubular calcium reabsorption is impaired, and urinary calcium excretion increases, resulting in significant hypercalciuria. The aim of treatment with calcium and vitamin D (or its derivatives) is to alleviate and control symptoms rather than fully restore serum calcium levels to the normal range. Serum calcium is ideally maintained between 2.0–2.25 mmol/L to prevent tetany while avoiding excessive urinary calcium excretion, which could lead to kidney stones or nephrocalcinosis. Additionally, maintaining this range helps prevent vitamin D toxicity. If serum calcium approaches normal levels but urinary calcium excretion remains elevated, thiazide diuretics may be used orally to reduce the risk of kidney stone formation.
Magnesium Supplementation
For patients with hypomagnesemia, correction through magnesium supplementation is required. This may involve intravenous infusion of 10–20 ml of 25% magnesium sulfate diluted in 500 ml of 5% glucose solution, with the dosage adjusted based on the severity of hypomagnesemia. Hypocalcemia may also improve following the correction of hypomagnesemia.
Recombinant Human Parathyroid Hormone (rhPTH)
Even with high doses of calcium and active vitamin D, some hypoparathyroidism patients fail to achieve target serum calcium levels. Furthermore, long-term use of large doses of calcium and vitamin D can lead to side effects such as hypercalciuria and kidney stones. PTH replacement therapy offers the advantage of correcting hypocalcemia while significantly reducing urinary calcium levels, thereby avoiding complications like hypercalciuria. Recombinant human PTH, identical to natural PTH, has been approved in some countries as an adjunctive treatment for hypoparathyroidism. However, its high cost has limited widespread use. The typical regimen involves subcutaneous injections of 50 µg every 1–2 days.
Prevention
During thyroid and parathyroid surgery, care should be taken to avoid injury to or excessive removal of the parathyroid glands to prevent the development of postoperative hypoparathyroidism.