Parathyroid Glands, Hyperparathyroidism, and Hypoparathyroidism: Causes, Symptoms, and Treatment

What are the Parathyroid Glands?

The parathyroid glands are four small endocrine glands located on the posterior surface (back) of the thyroid gland in the neck:

• Two superior parathyroid glands
• Two inferior parathyroid glands

The term “endocrine” means that these glands secrete their products, hormones, directly into the bloodstream or lymphatic circulation, rather than through a duct.

In healthy individuals, each parathyroid gland is remarkably small:

• Weight: approximately 35 mg in men and 30 mg in women
• Dimensions: approximately 6 mm tall × 4 mm wide × 2 mm deep

They are so small that they cannot be felt on physical examination of the neck under normal circumstances.

Although the parathyroid glands share their blood supply, venous drainage, and lymphatic drainage with the thyroid gland, this anatomical proximity is where the similarities end. The parathyroids are functionally completely independent from the thyroid and serve an entirely different purpose.

The Role of Parathyroid Hormone (PTH)

The sole function of the parathyroid glands is to produce and secrete parathyroid hormone (PTH), a single-chain polypeptide composed of 84 amino acids. PTH is the master regulator of calcium and phosphorus metabolism in the body, exerting its effects primarily on two target organs:

1. The Kidneys:

• Promotes calcium reabsorption (retaining calcium in the body rather than excreting it in urine)
• Promotes phosphorus excretion (increases phosphorus loss in urine)
• Activates vitamin D (converting it to its biologically active form, calcitriol), which in turn increases calcium absorption from the intestine

2. The Bones:

• Promotes bone resorption, stimulating osteoclast activity to release calcium stored in bone tissue into the bloodstream.

The net effect of PTH is to raise blood calcium levels. It is therefore released in response to low blood calcium (hypocalcemia) as part of a finely tuned feedback loop:

• Low blood calcium → parathyroids detect this → PTH is secreted → calcium rises → PTH secretion decreases

This elegant regulatory system maintains blood calcium within a very narrow normal range, essential for:

• Nerve conduction
• Muscle contraction (including the heart)
• Blood clotting
• Bone integrity

When Parathyroid Function Goes Wrong

If the parathyroid glands produce incorrect amounts of PTH, the consequences are felt throughout the body through calcium dysregulation:

• Excess PTH production → Hyperparathyroidism: Blood calcium rises (hypercalcemia). In most cases, the cause is a benign tumor (adenoma) making one gland overactive; less commonly, all glands are enlarged (hyperplasia); rarely, a malignant tumor is responsible.

• Insufficient PTH production → Hypoparathyroidism: Blood calcium falls (hypocalcemia) and phosphorus rises (hyperphosphatemia). Causes include gland injury, autoimmune destruction, or congenital conditions.

In both cases, treatment aims to restore normal calcium and phosphorus balance.

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Hyperparathyroidism

Hyperparathyroidism is the condition characterized by abnormally elevated production of parathyroid hormone (PTH) by the parathyroid glands. It is classified into three distinct types based on the underlying mechanism:

Types of Hyperparathyroidism

1. Primary Hyperparathyroidism Caused by an intrinsic problem within the parathyroid gland or glands themselves, the condition most commonly arises from:

• Parathyroid adenoma (80–85% of cases): A single benign tumor that autonomously overproduces PTH regardless of blood calcium levels
• Parathyroid hyperplasia (10–15% of cases): Enlargement and overactivity of all four glands
• Parathyroid carcinoma (<1% of cases): A rare malignant tumor

Primary hyperparathyroidism can occasionally have a hereditary basis, particularly when linked to the Multiple Endocrine Neoplasia (MEN) syndromes, such as MEN1 and MEN2A.

2. Secondary Hyperparathyroidism This is a reactive condition in which the parathyroid glands hypersecrete PTH in response to an external stimulus that causes chronically low blood calcium (hypocalcemia). The most common cause is chronic kidney disease (CKD), where impaired renal function reduces vitamin D activation and calcium absorption. This, in turn, chronically stimulates PTH production.

3. Tertiary Hyperparathyroidism This occurs when parathyroid glands, which have been chronically overstimulated and are now experiencing secondary hyperparathyroidism, begin to function autonomously. In this state, they continue secreting excess parathyroid hormone (PTH), even after the original cause, such as hypocalcemia, has been resolved. For example, this can happen following a kidney transplant. The glands essentially “forget” how to regulate their own activity relative to blood calcium.

Hyperparathyroidism Symptoms

The symptom pattern depends on the type of hyperparathyroidism.

Primary and Tertiary Hyperparathyroidism: Symptoms of Hypercalcemia

In primary hyperparathyroidism, approximately 50% of patients are completely asymptomatic at diagnosis (the condition is often discovered incidentally on routine blood tests showing elevated calcium). The remaining 50% exhibit classic symptoms of hypercalcemia, which can be memorized using the clinical mnemonic “Bones, Stones, Groans, and Psychic Moans”:

General and neuromuscular symptoms:

• Fatigue and weakness (asthenia)
• Lethargy
• Difficulty concentrating and cognitive impairment
• Muscle aches and pains, especially in muscles close to the trunk (proximal myopathy)
• Depression

Gastrointestinal symptoms:

• Loss of appetite (anorexia)
• Nausea and vomiting
• Constipation

Renal symptoms:

• Polyuria (increased urine production)
• Polydipsia (increased thirst and fluid intake)

Complications of Primary and Tertiary Hyperparathyroidism

When hypercalcemia is prolonged or severe, the following complications can develop:

• Nephrolithiasis: Formation of kidney stones (typically calcium oxalate or calcium phosphate stones), which can cause severe renal colic and obstruct the urinary tract
• Nephrocalcinosis: Abnormal calcium deposits within the kidney tissue itself, impairing renal function and closely related to nephrolithiasis
• Acute or chronic kidney failure.
• Osteoporosis: A progressive condition involving the loss of bone mass and structural integrity. It results from chronic PTH-driven bone resorption, which raises the risk of fragility fractures. These fractures most commonly affect the hip, spine, and wrist.
• Peptic ulcer disease: Hypercalcemia stimulates gastric acid secretion, increasing the risk of gastritis and peptic ulcers.
• Chondrocalcinosis (pseudogout): This condition involves the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in joints and connective tissues. It typically causes acute inflammatory arthritis, often affecting the knee, shoulder, and ankle.
• Arterial hypertension: Due to vascular stiffening caused by calcium deposits in arterial walls.
• Acute pancreatitis: Hypercalcemia can trigger pancreatic enzyme activation and inflammation.
• Cardiac effects: QT interval shortening on ECG and, in severe hypercalcemia, potentially life-threatening ventricular arrhythmias.

Secondary Hyperparathyroidism: Symptoms of Elevated PTH Without Hypercalcemia

In secondary hyperparathyroidism, the blood calcium is low or normal (because elevated PTH is the compensatory response to hypocalcemia, not its cause). Therefore, the symptoms are not those of hypercalcemia, but rather of chronic PTH excess acting on bone:

• Rickets: In children, rickets occurs when bones fail to mineralize properly. This leads to soft, deformable bones; skeletal deformities; and impaired growth.
• Osteomalacia: This condition affects adults and is characterized by bone pain, tenderness, and muscle weakness. These symptoms result from inadequate bone mineralization.
• Renal osteodystrophy: A spectrum of bone disorders arising specifically in the context of chronic kidney disease
• Osteitis fibrosa cystica: An advanced form of PTH-induced bone disease featuring fibrous replacement of bone marrow, cyst-like “brown tumors”, and markedly increased fracture risk (today uncommon due to earlier detection and treatment)

All of these conditions predispose to bone fractures and skeletal deformities, particularly if chronic secondary hyperparathyroidism remains untreated over years.

Hyperparathyroidism Diagnosis

The clinical suspicion of hyperparathyroidism is raised by the history and physical examination findings. However, definitive confirmation requires blood tests, specifically the measurement of PTH and calcium levels.

Blood Test Profiles

Distinguishing Primary from Tertiary Hyperparathyroidism

The clinical history is the key differentiator: patients with tertiary hyperparathyroidism have a documented history of chronic kidney disease and prior secondary hyperparathyroidism. In some cases, tertiary hyperparathyroidism may also show elevated phosphorus if significant chronic kidney damage persists.

Additional Investigations

• Imaging studies are used to localize abnormal parathyroid tissue when surgery is planned:

  • Sestamibi parathyroid scintigraphy (nuclear medicine scan): The most accurate imaging for localizing a single adenoma
  • Neck ultrasound: Used alongside scintigraphy; useful for identifying enlarged glands and evaluating the thyroid
  • 4D-CT (four-dimensional CT): Increasingly used when other modalities are inconclusive
  • MRI: May be used in specific situations (e.g., ectopic parathyroid tissue)

• DEXA bone density scan: To assess the degree of bone loss and guide treatment decisions, especially in asymptomatic primary hyperparathyroidism

• Renal imaging (ultrasound or CT): To assess for nephrolithiasis and nephrocalcinosis

• 24-hour urine calcium excretion: This essential test helps differentiate primary hyperparathyroidism from a benign familial condition, Familial Hypocalciuric Hypercalcemia (FHH). In FHH, calcium levels are high, but urinary calcium remains disproportionately low. Surgery is not indicated in these cases.

Hyperparathyroidism Treatment

Primary Hyperparathyroidism

The only curative treatment for primary hyperparathyroidism is surgery (parathyroidectomy). The surgical approach varies according to the underlying cause:

• Single adenoma (most common): Minimally invasive parathyroidectomy is typically performed. The surgeon removes only the affected gland after confirming complete removal through intraoperative verification that PTH levels drop appropriately. This can often be performed as day surgery through a small incision, guided by preoperative localization imaging.

• Multiglandular hyperplasia: Two surgical options exist:

  • Subtotal parathyroidectomy: Complete removal of three glands plus partial removal of the fourth, leaving a remnant of approximately 50 mg of functional tissue in situ.
  • Total parathyroidectomy with autotransplantation: All four glands are removed, and a small portion of one gland is transplanted into the muscles of the forearm or into the sternocleidomastoid muscle in the neck, where it can continue to produce PTH at a regulated level.

• Parathyroid carcinoma (rare): This condition requires more aggressive surgery. The procedure involves removal of all four glands, plus ipsilateral hemithyroidectomy, since the tumor may have invaded the adjacent thyroid tissue. In some cases, lateral cervical lymph node dissection is also necessary.

For asymptomatic primary hyperparathyroidism: Current international guidelines define specific criteria for when surgery is recommended even in the absence of symptoms:

• Blood calcium ≥1.0 mg/dL above the upper limit of normal
• Estimated GFR <60 mL/min (kidney function impairment)
• DEXA T-score ≤ −2.5 at any site, or previous fragility fracture
• Age <50 years
• 24-hour urinary calcium >400 mg/day

Medical management (for patients who cannot or will not undergo surgery):

• Cinacalcet (calcimimetic agent): A drug that mimics calcium’s action on parathyroid cells. It suppresses PTH secretion and lowers blood calcium. While effective at controlling hypercalcemia, it does not eliminate the underlying adenoma.
• Bisphosphonates (e.g., alendronate): To protect bone density in patients with osteoporosis who are not surgical candidates
• Adequate hydration and avoidance of thiazide diuretics (which increase calcium reabsorption) and immobilization

Secondary Hyperparathyroidism

Treatment is directed at correcting the underlying cause of chronic hypocalcemia:

• For CKD-related secondary HPT:
  • Active vitamin D analogs, such as calcitriol and paricalcitol, help improve calcium absorption.
  • Phosphate binders, which help reduce elevated phosphorus levels.
  • Cinacalcet, which directly suppresses PTH production.
  • Adequate dialysis in patients with ESRD.

Tertiary Hyperparathyroidism

Management is complex and must be handled by an endocrinology specialist. Since the parathyroid glands have become autonomous, medical therapy alone is often insufficient. Surgical total parathyroidectomy (with autotransplantation) is typically the definitive treatment, particularly when hypercalcemia becomes severe or symptomatic.

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Hypoparathyroidism

Hypoparathyroidism is the condition characterized by insufficient production of parathyroid hormone (PTH), leading to low blood calcium (hypocalcemia) and high blood phosphorus (hyperphosphatemia). It is less common than hyperparathyroidism.

Causes

The main causes of hypoparathyroidism include:

**1. Acquired (Surgical): The Most Common Cause

• Post-thyroid surgery: Inadvertent removal or devascularization of the parathyroid glands during thyroidectomy (for thyroid cancer, goiter, or Graves’ disease) is the most common cause of hypoparathyroidism worldwide.
• Post-parathyroid surgery: Hypoparathyroidism is the main complication of total parathyroidectomy, when insufficient parathyroid tissue remains or the autotransplant fails to function.
• Post-radiation: Radiation therapy to the neck (e.g., for head and neck cancers) can damage parathyroid tissue.

2. Congenital and Genetic Syndromes

• DiGeorge Syndrome (22q11.2 deletion): Congenital absence (agenesis) of both the thymus and parathyroid glands, often associated with cardiac malformations and immune deficiency
• Barakat Syndrome (HDR syndrome): Hypoparathyroidism, deafness, and renal disease
• Autoimmune Polyglandular Syndrome Type 1 (APS-1 / APECED): Hypoparathyroidism combined with chronic mucocutaneous candidiasis and autoimmune adrenal insufficiency (Addison’s disease)
• Activating mutations of the calcium-sensing receptor (CaSR): These cause the parathyroid gland to be inappropriately suppressed even at normal calcium levels

3. Metabolic Causes

• Hypomagnesemia (low magnesium levels): Magnesium is required for both PTH secretion and peripheral PTH action. Severe magnesium deficiency can cause functional hypoparathyroidism that is refractory to calcium replacement until magnesium is corrected.

4. Autoimmune Destruction

• Isolated autoimmune hypoparathyroidism occurs when the immune system produces antibodies against parathyroid tissue. Over time, this process progressively destroys gland function.

5. Infiltrative Diseases

• Conditions such as hemochromatosis (iron deposition), Wilson’s disease (copper deposition), sarcoidosis, or metastatic cancer can infiltrate and destroy parathyroid tissue

6. Idiopathic

• No identifiable cause is found in a minority of cases

Hypoparathyroidism Symptoms

Patients with hypoparathyroidism exhibit the characteristic symptoms of hypocalcemia (low blood calcium). The clinical manifestations vary in severity, from mild tingling to life-threatening seizures, depending on the degree and rapidity of the calcium drop.

Neuromuscular Excitability (Tetany)

Calcium plays a critical role in stabilizing nerve membranes. When blood calcium falls, nerves and muscles become abnormally excitable, producing the spectrum of symptoms collectively called tetany:

• Muscle spasms and cramps, particularly in the hands, feet, and face.
• Hyperreflexia: exaggerated deep tendon reflexes.
• Trousseau’s sign (carpal spasm): When a blood pressure cuff is inflated above systolic pressure on the upper arm for 3 minutes, the wrist flexes, the fingers extend, and the thumb adducts. This results in the classical “obstetrician’s hand” posture. This is a reliable bedside test for latent tetany.
• Chvostek’s sign: Tapping the facial nerve just anterior to the ear, over the parotid gland, causes ipsilateral facial muscle twitching. This is another bedside marker of hypocalcemia.
• Laryngospasm: A life-threatening spasm of the laryngeal muscles that causes stridor and airway obstruction. This is a medical emergency.
• Bronchospasm.

Neurological Symptoms

• Seizures: Can occur in severe hypocalcemia, potentially indistinguishable from epileptic seizures.
• Paresthesias: Abnormal tingling, numbness, or “pins and needles” sensations. These usually occur in the hands, feet, and around the mouth, known as circumoral paresthesia.
• Cognitive symptoms: Irritability, anxiety, difficulty concentrating, and in severe or chronic cases, more significant cognitive impairment.

Cardiovascular Effects

• Prolonged QT interval on ECG, a marker of increased risk of potentially dangerous cardiac arrhythmias, should be carefully monitored.
• Cardiac arrhythmias, including ventricular fibrillation in severe cases,

Psychiatric Manifestations

• Anxiety
• Depression
• Psychosis (in severe or chronic cases)

Dermatological and Other Chronic Manifestations

• Dry, scaly skin.
• Brittle nails.
• Alopecia (hair loss).
• Dental abnormalities (if onset occurred in childhood, such as hypoplastic tooth enamel).
• Cataracts: Chronic hypocalcemia causes lens opacification; this is an important long-term complication of inadequately treated hypoparathyroidism.
• Persistent fatigue and weakness (asthenia)
• Basal ganglia calcifications: Chronic hypocalcemia can lead to calcium deposits in the basal ganglia, visible on brain CT, potentially causing extrapyramidal movement disorders.

Hypoparathyroidism Diagnosis

As with hyperparathyroidism, the diagnosis of hypoparathyroidism requires clinical suspicion based on history and symptoms, confirmed by characteristic blood test findings.

Blood Test Profile in Hypoparathyroidism

Additional Investigations

• ECG: To assess QT interval prolongation and identify arrhythmia risk
• Brain CT scan: To detect basal ganglia calcifications (a chronic complication)
• Ophthalmological examination: To detect cataracts
• Bone density (DEXA): Unlike hyperparathyroidism, long-standing hypoparathyroidism is associated with increased bone density. This occurs because PTH normally promotes bone resorption; without it, bones become denser but less remodeled.
• Genetic testing: Recommended in young patients or those without an obvious surgical cause, to identify hereditary syndromes
• Renal function and urinary calcium: Essential for monitoring, as calcium supplementation increases the risk of hypercalciuria and nephrolithiasis in hypoparathyroid patients

Hypoparathyroidism Treatment

Treatment strategy differs based on whether hypoparathyroidism is acute (sudden onset) or chronic:

Acute Hypoparathyroidism (e.g., immediately post-surgery)

Emergency intravenous calcium:

• Calcium gluconate IV (the preferred preparation due to lower tissue irritation risk) administered as a slow infusion, with continuous cardiac monitoring (calcium infusions can cause bradycardia and arrhythmias if given too rapidly)
• Once symptoms resolve and oral intake is possible, transition to oral calcium supplementation

Chronic Hypoparathyroidism

Standard long-term management:

• Oral calcium supplementation: Calcium carbonate or calcium citrate at doses sufficient to maintain blood calcium in the low-normal range (targeting the lower end of normal to avoid hypercalciuria). Taken with meals (for carbonate) or without meals (for citrate, preferred in patients with low stomach acid).
• Active vitamin D (calcitriol or alfacalcidol): Essential because PTH normally activates vitamin D in the kidneys; without PTH, this activation is impaired. Active vitamin D (bypassing the renal activation step) dramatically improves intestinal calcium absorption.

Monitoring: Regular monitoring of blood calcium, phosphorus, magnesium, and 24-hour urinary calcium is essential to:

• Maintain serum calcium in the low-normal range (avoiding both symptomatic hypocalcemia and treatment-induced hypercalciuria)
• Prevent the development of nephrocalcinosis and kidney stones from excessive calcium in the urine
• Monitor for cataract formation and basal ganglia calcification

Emerging therapy: Recombinant PTH

• Recombinant human PTH (rhPTH 1-84, brand name Natpara®/Yorvipath®): A subcutaneously injected PTH replacement therapy, approved for patients with chronic hypoparathyroidism who cannot be adequately controlled on conventional calcium and vitamin D supplementation. It more physiologically replicates the actions of natural PTH, particularly by reducing urinary calcium excretion. This helps lower the risk of kidney complications. Its use is currently reserved for patients inadequately controlled on standard therapy.

Management of hypomagnesemia: If hypomagnesemia is contributing to or causing hypoparathyroidism, magnesium replacement (oral or IV) is essential and must be corrected before calcium therapy will be effective.

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Sources and Bibliography

• Rugarli C., Medicina Interna Sistematica, 2000
• Harrison, Principles of Internal Medicine, 18th ed., McGraw-Hill, 2012
• National Institutes of Health (NIH) – MedlinePlus: Hypoparathyroidism
• National Institutes of Health (NIH) – MedlinePlus: Hyperparathyroidism
• European Society of Endocrinology (ESE) – Guidelines for hypoparathyroidism
• American Association of Clinical Endocrinology (AACE) – Guidelines for primary hyperparathyroidism (2022)
• Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism – JCEM (2014)
• Bilezikian JP et al. – Primary Hyperparathyroidism. NEJM 2018