Hypoparathyroidism

Table of Contents

1. How Hypoparathyroidism Upsets Calcium Balance
2. Causes and Risk Factors
3. Signs and Symptoms
4. Chvostek and Trousseau Signs
5. Diagnosis
6. Acute Management
7. Long-Term Treatment
8. Hypomagnesemia as a Reversible Cause
9. Key Research Papers
10. Connections
11. Featured Videos

How Hypoparathyroidism Upsets Calcium Balance

Hypoparathyroidism occurs when the parathyroid glands — four tiny glands embedded in or near the thyroid — fail to secrete adequate amounts of parathyroid hormone. This hormone is the master regulator of calcium homeostasis, and its absence creates a cascade of metabolic problems.

Under normal conditions, parathyroid hormone raises serum calcium through three coordinated mechanisms:

1. Bone resorption: parathyroid hormone activates osteoclasts, releasing calcium and phosphate from the skeletal matrix into the bloodstream.
2. Renal calcium reabsorption: parathyroid hormone stimulates the distal convoluted tubule of the kidney to reabsorb calcium that would otherwise be lost in urine.
3. Vitamin D activation: parathyroid hormone upregulates renal 1-alpha-hydroxylase, the enzyme that converts 25-hydroxyvitamin D into the active form, 1,25-dihydroxyvitamin D (calcitriol). Calcitriol in turn increases intestinal calcium absorption.

When parathyroid hormone is absent or severely reduced, all three mechanisms fail simultaneously. Blood calcium falls, phosphate rises (because parathyroid hormone normally promotes renal phosphate excretion), and the kidney cannot activate vitamin D. The result is a dangerous state of neuromuscular hyperexcitability that can progress to tetany, seizures, and cardiac arrhythmias.

For decades hypoparathyroidism was one of the few hormone-deficiency diseases treated without replacing the missing hormone: treatment relied on calcium pills and active vitamin D. That has changed. Palopegteriparatide, a once-daily injected, slow-release form of parathyroid hormone, received a marketing authorisation valid throughout the European Union on 17 November 2023 (European Medicines Agency), and its United States label lists an initial approval in 2024 for the treatment of hypoparathyroidism in adults (see Long-Term Treatment).

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Causes and Risk Factors

The causes of hypoparathyroidism range from surgical complications to genetic disorders to nutritional deficiencies.

Surgical Hypoparathyroidism (~75% of cases)

The most common cause is inadvertent removal or devascularization of the parathyroid glands during thyroid or parathyroid surgery. Because the parathyroid glands are small (each roughly the size of a grain of rice) and anatomically variable, they are at significant risk during neck surgery. Transient hypoparathyroidism is common after total thyroidectomy and usually resolves within weeks as traumatized glands recover. The 2022 Second International Workshop guideline states that hypoparathyroidism after surgery may be considered permanent if it persists for more than 12 months after the operation.

The same guideline recommends measuring parathyroid hormone 12 to 24 hours after total thyroid removal (thyroidectomy): a level above 10 pg/mL (1.05 pmol/L) virtually excludes long-term hypoparathyroidism. A 2026 review describes surgery-related hypoparathyroidism, about 75% of all cases, as largely preventable, with risk lowered by careful assessment before the operation and by surgical technique.

Autoimmune Hypoparathyroidism

Isolated autoimmune destruction of the parathyroid glands can occur, or it may present as part of Autoimmune Polyglandular Syndrome Type 1 (APS-1), caused by mutations in the AIRE gene on chromosome 21q22. APS-1 presents in childhood with the triad of hypoparathyroidism, primary adrenal insufficiency, and chronic mucocutaneous candidiasis. Anti-CaSR (calcium-sensing receptor) antibodies have also been identified in some autoimmune cases.

Genetic and Developmental Causes

• DiGeorge syndrome (22q11.2 deletion): failure of the third and fourth pharyngeal pouches to develop results in absent or hypoplastic parathyroid glands, along with cardiac defects, thymic aplasia, and palatal abnormalities.
• Familial isolated hypoparathyroidism: mutations in the PTH or GCM2 (also called GCMB) genes cause autosomal dominant or recessive forms.
• Activating mutations of the calcium-sensing receptor (CaSR): the CaSR is tricked into perceiving normal calcium as elevated, suppressing parathyroid hormone secretion.

Other Causes

• Neck irradiation: external beam radiation for head and neck cancers can damage parathyroid tissue.
• Infiltrative diseases: iron overload (hemochromatosis), copper accumulation (Wilson's disease), and granulomatous diseases (sarcoidosis, tuberculosis) can destroy parathyroid tissue.
• Hypomagnesemia: a reversible functional cause — low magnesium impairs both parathyroid hormone secretion and peripheral parathyroid hormone action (see dedicated section below).
• Metastatic malignancy: rare; tumor infiltration of all four glands.

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Signs and Symptoms

Symptoms arise primarily from hypocalcemia-induced neuromuscular irritability, though chronic disease produces distinct structural changes. The severity correlates with the degree and rate of calcium decline — a rapidly falling calcium is more symptomatic than a chronically low but stable level.

Neuromuscular Symptoms

• Paresthesias: tingling or numbness around the mouth (perioral), in the fingertips, and in the feet — often the earliest symptom.
• Muscle cramps and stiffness: particularly in the hands, feet, and calves.
• Tetany: sustained, painful muscle spasms, often involving the hand (carpopedal spasm — wrist flexion with finger extension).
• Laryngospasm: spasm of the vocal cords causing stridor and potentially respiratory arrest — a medical emergency.
• Bronchospasm.
• Seizures: focal or generalized, particularly in children; may be the presenting manifestation.

Cardiac Symptoms

• QT prolongation on electrocardiogram (ECG): hypocalcemia prolongs the action potential plateau phase. This increases the risk of ventricular arrhythmias, including torsades de pointes.
• Heart failure can occur in severe, prolonged hypocalcemia (hypocalcemic cardiomyopathy).

Chronic and Structural Changes

• Cataracts: calcium deposits in the lens (lenticular calcifications), often bilateral, are a well-known complication of longstanding hypoparathyroidism.
• Basal ganglia calcifications: calcium deposits in the brain's basal ganglia are visible on computed tomography (CT) or plain skull X-ray; may cause extrapyramidal movement disorders (parkinsonism-like features) or cognitive changes.
• Dental abnormalities: enamel hypoplasia, delayed tooth eruption, and shortened tooth roots from calcium deprivation during development.
• Dry skin and brittle nails: reflecting impaired epithelial function in the absence of normal calcium signaling.
• Psychological effects: depression, anxiety, and cognitive impairment are reported even in well-treated patients, suggesting parathyroid hormone has direct effects on the brain beyond calcium regulation.

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Chvostek and Trousseau Signs

Two classic bedside signs are used to detect latent (subclinical) tetany in patients with suspected hypocalcemia. Both reflect the increased excitability of peripheral nerves when extracellular calcium is low.

Chvostek Sign

To elicit the Chvostek sign, the examiner taps the facial nerve as it exits the parotid gland, approximately 2 cm anterior to the tragus of the ear. A positive result is ipsilateral twitching of the facial muscles — ranging from a subtle twitch of the corner of the mouth to contraction of the entire half of the face in severe hypocalcemia.

Sensitivity and specificity: The Chvostek sign is sensitive but not specific. It is present in 10–25% of normocalcemic individuals and can be absent even in proven hypocalcemia. On its own it is not a reliable basis for diagnosis.

Trousseau Sign

The Trousseau sign is elicited by inflating a blood pressure cuff on the upper arm to 20 mmHg above the patient's systolic blood pressure and maintaining it for 3 minutes. Occlusion of the brachial artery creates local ischemia and hypocalcemia, which provokes carpopedal spasm in a susceptible patient — the hand assumes a characteristic posture with wrist flexion, finger extension at the metacarpophalangeal joints, and thumb adduction (the "accoucheur's hand").

Sensitivity and specificity: The Trousseau sign is more specific than the Chvostek sign for true hypocalcemia. It is positive in approximately 94% of hypocalcemic patients and in only 1% of normocalcemic individuals. It is the preferred bedside test when hypocalcemia is clinically suspected.

Both signs are most useful for identifying patients at risk for symptomatic tetany before full-blown symptoms develop, particularly in the postoperative setting after thyroid or parathyroid surgery.

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Diagnosis

The biochemical diagnosis of hypoparathyroidism is straightforward once the clinician measures the right panel of tests. The key diagnostic triad is: low calcium + low parathyroid hormone + high phosphate.

Core Laboratory Tests

• Serum total calcium: corrected for albumin (add 0.8 mg/dL for every 1 g/dL albumin below 4.0 g/dL). Normal: 8.5–10.5 mg/dL. In hypoparathyroidism, typically below 8.0 mg/dL.
• Ionized calcium: the physiologically active fraction; preferred in critically ill patients or when albumin is abnormal. Normal: 1.12–1.32 mmol/L.
• Intact parathyroid hormone (iPTH): low or inappropriately normal (in the lower half of the reference range despite hypocalcemia, when it should be elevated). This is the key differentiating test — in all other causes of hypocalcemia (vitamin D deficiency, malabsorption, pseudohypoparathyroidism), parathyroid hormone is elevated as the glands respond normally.
• Serum phosphate: elevated (parathyroid hormone normally promotes renal phosphate wasting; without parathyroid hormone, phosphate accumulates). Normal: 2.5–4.5 mg/dL; in hypoparathyroidism, often 5–8 mg/dL.
• Serum magnesium: low magnesium (hypomagnesemia) can cause a functional, reversible hypoparathyroidism, so it is checked and corrected before permanent disease is diagnosed; the 2025 best-practice recommendations list correction of abnormalities in serum magnesium as part of conventional therapy.
• 25-hydroxyvitamin D: assess baseline vitamin D status; deficiency worsens hypocalcemia; the 2025 best-practice recommendations include correction of vitamin D inadequacy in conventional therapy.
• 24-hour urine calcium: important for monitoring treatment. Target is below 300 mg/day (men) or 250 mg/day (women) to avoid hypercalciuria, nephrolithiasis, and nephrocalcinosis — common complications of calcitriol therapy.

Differentiating from Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) presents with identical biochemistry (low calcium, high phosphate, high parathyroid hormone) but the cause is end-organ resistance to parathyroid hormone action rather than parathyroid hormone deficiency. PHP type 1a is associated with Albright's hereditary osteodystrophy (short stature, obesity, short fourth metacarpal, round face). Parathyroid hormone levels are elevated (not low), distinguishing it from true hypoparathyroidism.

Imaging

Computed tomography of the brain may reveal basal ganglia calcifications in chronic disease. An electrocardiogram is used to assess the QT interval. Renal ultrasound or computed tomography is warranted in patients with longstanding disease or when nephrocalcinosis/nephrolithiasis is suspected.

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Acute Management

Acute symptomatic hypocalcemia — presenting with tetany, seizures, laryngospasm, or QT prolongation — is a medical emergency requiring prompt intravenous calcium replacement.

Intravenous Calcium Gluconate

The preferred intravenous (IV) preparation is calcium gluconate (not calcium chloride, which is more irritating and causes tissue necrosis if extravasated). The standard acute protocol:

1. Bolus: 1–2 grams of calcium gluconate (10–20 mL of 10% solution) infused over 10–20 minutes, with continuous cardiac monitoring. Too rapid an infusion can cause vasodilation, hypotension, or cardiac arrhythmia.
2. Maintenance infusion: follow the bolus with a continuous infusion of 0.5–1.5 mg elemental calcium per kg per hour, typically in D5W or normal saline, titrated to keep ionized calcium in the low-normal range (1.0–1.12 mmol/L).
3. Overcorrection risk: targeting a serum calcium above 9 mg/dL without parathyroid hormone action leads to marked hypercalciuria and rapid stone formation.

Cardiac Monitoring

Intravenous calcium is given with continuous cardiac telemetry (heart-rhythm monitoring). The QT interval typically normalizes within hours of calcium repletion. Hypomagnesemia prolongs QT through independent mechanisms and is corrected at the same time.

Hypomagnesemia Correction Comes First

If serum magnesium is below 0.7 mmol/L, intravenous magnesium sulfate is given before or alongside calcium. Hypocalcemia refractory to calcium replacement is almost always due to unrecognized hypomagnesemia. Parathyroid hormone secretion is magnesium-dependent — the signaling pathway cannot function without adequate intracellular magnesium.

Transition to Oral Therapy

Once symptomatic control is achieved and the patient can tolerate oral medications, treatment moves to calcitriol plus oral calcium supplements (see Long-Term Treatment below). Abrupt discontinuation of intravenous calcium before adequate oral supplementation leads to rebound hypocalcemia.

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Long-Term Treatment

Long-term management of hypoparathyroidism focuses on maintaining serum calcium in a safe range while minimizing the complications of therapy — primarily hypercalciuria, nephrolithiasis, and nephrocalcinosis that result from treating hypocalcemia without parathyroid hormone's renal calcium-conserving effect.

The 2022 Second International Workshop guideline lists the complications linked with hypoparathyroidism: calcium deposits in the kidneys (nephrocalcinosis) and kidney stones (nephrolithiasis), reduced kidney function (renal insufficiency), cataracts, seizures, heart rhythm problems (cardiac arrhythmias), ischemic heart disease, depression and a higher risk of infection. For chronic hypoparathyroidism its panel suggests conventional therapy, calcium plus active vitamin D, as first-line treatment (a weak recommendation based on low-quality evidence), and considers parathyroid hormone when conventional therapy is unsatisfactory.

Calcitriol (Active Vitamin D)

Calcitriol (1,25-dihydroxyvitamin D3) is the cornerstone of long-term therapy. Because parathyroid hormone is absent, the kidney cannot activate vitamin D — therefore only the already-active form (calcitriol) is effective. Ergocalciferol or cholecalciferol alone are insufficient.

• Typical dose: 0.25–2.0 mcg per day, divided twice daily (calcitriol has a short half-life of 4–6 hours).
• Serum calcium is checked frequently during dose titration (weekly initially, then every 3–6 months when stable).
• 24-hour urine calcium is measured to detect hypercalciuria before clinical complications develop.

Calcium Supplements

Oral elemental calcium (1,000–1,500 mg/day in divided doses) is taken with calcitriol:

• Calcium carbonate (40% elemental calcium) is the most cost-effective but requires gastric acid for absorption — it is absorbed best with meals and poorly in people taking proton pump inhibitors (PPIs).
• Calcium citrate (21% elemental calcium) is absorbed independently of gastric acid and is preferred in patients with achlorhydria, on proton pump inhibitors, or with a history of kidney stones.

Serum Calcium Targets

Target serum total calcium in the low-normal range: 8.0–8.5 mg/dL. This is deliberately below the middle of the reference range (8.5–10.5 mg/dL) because without parathyroid hormone-driven renal calcium reabsorption, any increment in serum calcium is filtered freely by the kidney, leading to hypercalciuria. Keeping calcium at 8.0–8.5 mg/dL maintains symptom control while limiting urinary calcium excretion.

Hydrochlorothiazide

Thiazide diuretics reduce urinary calcium excretion by promoting proximal tubular reabsorption. Adding hydrochlorothiazide (12.5–50 mg/day) allows higher calcitriol and calcium supplementation doses in patients who develop hypercalciuria or nephrolithiasis despite conservative targets.

Recombinant Parathyroid Hormone (1-84)

In 2015, the U.S. Food and Drug Administration (FDA) approved recombinant human parathyroid hormone (1-84) for adults with hypoparathyroidism inadequately controlled with conventional therapy. Administered by daily subcutaneous injection, it reduces calcitriol and calcium supplement requirements, better mimics physiological parathyroid hormone action (including renal calcium conservation), and is associated with improved quality of life in clinical trials. It carries a boxed warning for osteosarcoma risk (seen in rodent studies at supratherapeutic doses) and is available only through a restricted program (REMS). The European Medicines Agency reports that the European Commission withdrew its European Union marketing authorisation on 1 July 2026, at the request of the maker, which had decided to permanently stop marketing the product because of unresolved supply problems specific to it.

Palopegteriparatide (Long-Acting Parathyroid Hormone)

Palopegteriparatide is a parathyroid hormone analog (PTH[1-34]) released slowly from a once-daily injection; a 2026 review gives its half-life as 60 hours. The European Union authorised it on 17 November 2023, and its United States label (initial approval 2024) lists it for the treatment of hypoparathyroidism in adults. The label states that it was not studied for acute hypoparathyroidism straight after surgery, and that it is not recommended for people at increased risk of osteosarcoma (a bone cancer). The 2025 best-practice recommendations describe it as an important option, especially when conventional therapy is inadequate or not tolerated.

• One year (PaTHway trial): in this phase 3 trial (82 adults randomized, 78 completing week 52), 81% (63 of 78) had normal blood calcium while free of conventional therapy, and 95% (74 of 78) no longer needed therapeutic calcium doses or active vitamin D; none needed active vitamin D. Average 24-hour urine calcium fell from 376 to 195 mg/day. Most side effects were mild or moderate.
• 3.5 years (week 182): of 73 participants still in the trial, 96% (70) were free of therapeutic calcium doses, 100% (73) were free of active vitamin D and 89% (65) had normal blood calcium. Early normalization of urine calcium, gains in kidney filtering function (eGFR) and improvements in patient-reported outcomes held through week 182; most side effects were mild to moderate.

Monitoring Schedule

• Serum calcium, phosphate, magnesium, creatinine: every 3–6 months when stable.
• 24-hour urine calcium and creatinine: annually.
• Renal imaging (ultrasound): every 1–2 years to screen for nephrocalcinosis.
• Eye examination: baseline slit-lamp exam for cataracts; repeat every 2–3 years.
• Brain computed tomography: if neuropsychiatric symptoms emerge (basal ganglia calcification surveillance).

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Hypomagnesemia as a Reversible Cause

Hypomagnesemia is one of the most commonly overlooked and most important reversible causes of functional hypoparathyroidism. Understanding this relationship can spare patients from a lifelong diagnosis of permanent hypoparathyroidism when the true problem is correctable magnesium deficiency.

The Mechanism

Magnesium plays a dual role in parathyroid function:

1. Parathyroid hormone secretion: The parathyroid cell releases parathyroid hormone via a magnesium-dependent exocytosis process. Intracellular magnesium is required for G-protein signaling downstream of the calcium-sensing receptor. When magnesium is severely depleted, this signaling fails and parathyroid hormone secretion is suppressed regardless of how low serum calcium drops.
2. Peripheral parathyroid hormone resistance: Even if some parathyroid hormone is secreted, target tissues (kidney and bone) cannot respond normally to parathyroid hormone without adequate magnesium, because the adenylate cyclase cascade that parathyroid hormone activates is also magnesium-dependent. This creates end-organ resistance identical to pseudohypoparathyroidism.

Common Causes of Hypomagnesemia

• Alcohol use disorder: poor dietary intake plus alcohol-induced urinary magnesium wasting.
• Proton pump inhibitors: long-term proton pump inhibitor (PPI) use impairs intestinal magnesium absorption via TRPM6 channel inhibition.
• Loop diuretics (furosemide, ethacrynic acid): cause renal magnesium wasting.
• Malabsorption syndromes: celiac disease, Crohn's disease, short bowel syndrome.
• Type 2 diabetes: osmotic diuresis promotes urinary magnesium loss.
• Cisplatin chemotherapy: nephrotoxic injury to the renal magnesium-conserving mechanism.
• Hypomagnesemia with secondary hypocalcemia (HSH): a rare autosomal recessive disorder caused by TRPM6 mutations, presenting in infancy with profound hypomagnesemia and secondary hypocalcemia.

Magnesium Check Before a Permanent Diagnosis

Serum magnesium is checked and corrected before permanent hypoparathyroidism is diagnosed. If serum magnesium is below 0.7 mmol/L (1.7 mg/dL), it is replaced with intravenous magnesium sulfate (2–4 g over 2–4 hours), and parathyroid hormone and calcium are rechecked 24–48 hours later. In true hypomagnesemia-induced functional hypoparathyroidism, parathyroid hormone and calcium normalize after magnesium repletion — no further treatment is needed. This diagnostic step is especially critical in patients with alcohol use disorder admitted for any reason, as hypomagnesemia-induced tetany is common and easily corrected.

Oral Magnesium for Maintenance

Once the acute deficit is corrected, the underlying cause is looked for and treated. Where ongoing losses are unavoidable (e.g., persistent proton pump inhibitor use, loop diuretics), oral magnesium supplementation (magnesium glycinate or malate; 200–400 mg elemental magnesium daily) helps maintain levels. Magnesium oxide is poorly absorbed. Magnesium has a dose-dependent laxative effect.

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Key Research Papers

Key peer-reviewed studies and guidelines on hypoparathyroidism:

1. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of Hypoparathyroidism: Present and Future. J Clin Endocrinol Metab. 2016;101(6):2313-2324. — PubMed PMID: 26938200
2. Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008;359(4):391-403. — PubMed PMID: 18650515
3. Mannstadt M, Bilezikian JP, Thakker RV, et al. Hypoparathyroidism. Nat Rev Dis Primers. 2017;3:17055. — PubMed PMID: 28857066
4. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658-5671. — PubMed PMID: 11739416
5. Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1(4):275-283. — PubMed PMID: 24622413
6. Cusano NE, Rubin MR, McMahon DJ, et al. The effect of PTH(1-84) on quality of life in hypoparathyroidism. J Clin Endocrinol Metab. 2013;98(6):2356-2361. — PubMed PMID: 23596139
7. Vadiveloo T, Donnan PT, Leese GP. A Population-Based Study of the Epidemiology of Chronic Hypoparathyroidism. J Bone Miner Res. 2018;33(3):478-485. — PubMed PMID: 29087618
8. Khan AA, Bilezikian JP, Brandi ML, et al. Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop. J Bone Miner Res. 2022;37(12):2568-2585. — PubMed PMID: 36054621
9. Khan AA, Ali DS, Bilezikian JP, et al. Best practice recommendations for the diagnosis and management of hypoparathyroidism. Metabolism. 2025;171:156335. — PubMed PMID: 40581321
10. Ali DS, Perrier ND, Khan AA. Hypoparathyroidism Post Thyroidectomy: Prevention, Evaluation, Management, and Application of Recent Guidelines. Thyroid. 2026;36(6):582-596. — PubMed PMID: 42170800
11. Clarke BL, Khan AA, Rubin MR, et al. Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial. J Clin Endocrinol Metab. 2025;110(4):951-960. — PubMed PMID: 39376010
12. Khan AA, Clarke BL, Rubin MR, et al. Palopegteriparatide in Adults With Hypoparathyroidism: 3.5-Year Results From the Phase 3 PaTHway Trial. J Clin Endocrinol Metab. 2026 (online ahead of print). — PubMed PMID: 42935168

PubMed Topic Searches

1. PubMed: Hypoparathyroidism
2. PubMed: Hypocalcemia treatment
3. PubMed: PTH replacement therapy
4. PubMed: Surgical hypoparathyroidism
5. PubMed: Calcitriol hypocalcemia
6. PubMed: Chvostek Trousseau sign
7. PubMed: Magnesium PTH secretion
8. PubMed: Hypoparathyroidism QT prolongation
9. PubMed: Magnesium deficiency and PTH secretion
10. PubMed: Hypoparathyroidism in pregnancy and the newborn period
11. PubMed: Hypoparathyroidism incidence
12. PubMed: Thyroid surgery and hypoparathyroidism risk

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Connections

• Endocrinology
• Calcium Control: Parathyroid Hormone, Vitamin D & Your Blood Level — interactive animation
• Hyperparathyroidism
• Hypothyroidism
• Thyroid Disorders
• Diabetes
• Addison's Disease
• Calcium
• Magnesium
• Vitamin D3
• Lab Tests

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