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Summary Table

Category	Detail
Risk Factors	Recent thyroid or parathyroid surgery (most common cause), autoimmune polyglandular syndrome, DiGeorge syndrome (22q11.2 deletion), history of neck irradiation, hypomagnesemia
Etiology	Deficient or absent parathyroid hormone (PTH) secretion leading to hypocalcemia and hyperphosphatemia
Patient Presentation	Perioral numbness, tingling of fingers and toes, muscle cramps, carpopedal spasm, seizures in severe cases
Classic Physical Exam	Chvostek sign (facial muscle twitching on tapping the facial nerve), Trousseau sign (carpal spasm after inflating BP cuff above systolic for 3 minutes)
Key Diagnostic Results	Low serum calcium, low PTH, elevated serum phosphate, low urine calcium, prolonged QT interval on ECG
Management	IV calcium gluconate for acute symptomatic hypocalcemia; oral calcium + active vitamin D (calcitriol) for long-term replacement
Keywords	"Post-thyroidectomy numbness," "perioral tingling," "carpopedal spasm," "low calcium with low PTH," "Chvostek and Trousseau positive"

1. Pathophysiology

Parathyroid hormone (PTH) is the principal regulator of serum calcium. It acts on three target organs: bone, kidney, and gut (indirectly via vitamin D activation). When PTH is deficient, all three calcium-raising mechanisms fail simultaneously, producing the hallmark biochemical profile of hypocalcemia with hyperphosphatemia.

In bone, PTH normally stimulates osteoclastic resorption to release calcium and phosphate into the bloodstream. Without PTH, this resorption is diminished, reducing one major source of calcium influx. In the kidney, PTH promotes calcium reabsorption in the distal convoluted tubule and phosphate excretion in the proximal tubule. Loss of PTH therefore causes inappropriate urinary calcium wasting (relative to the low serum calcium) and renal phosphate retention, driving serum phosphate upward. The high phosphate further depresses ionized calcium through formation of calcium-phosphate complexes.

PTH also stimulates 1-alpha hydroxylase in the kidney, which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol), the active form. Without this conversion, intestinal calcium absorption falls dramatically. This is why calcitriol, not cholecalciferol, is the replacement vitamin D form used in hypoparathyroidism.

The resulting hypocalcemia increases neuromuscular excitability. Calcium normally stabilizes voltage-gated sodium channels. When extracellular calcium drops, the threshold potential shifts closer to the resting membrane potential, making neurons fire with less provocation. This explains tetany, muscle spasms, paresthesias, and seizures. The same mechanism prolongs the QT interval on ECG by extending the ST segment, which represents delayed ventricular repolarization.

The most common cause by far is iatrogenic injury or inadvertent removal of the parathyroid glands during thyroid surgery. The onset is typically within 24 to 72 hours postoperatively. Autoimmune destruction of the parathyroid glands occurs either in isolation or as part of autoimmune polyglandular syndrome type 1 (APS-1), which classically presents with hypoparathyroidism, mucocutaneous candidiasis, and adrenal insufficiency. In children, DiGeorge syndrome (22q11.2 microdeletion) causes aplasia or hypoplasia of the parathyroid glands and thymus, resulting in both hypoparathyroidism and T-cell immunodeficiency.

One frequently tested concept is the role of magnesium. Severe hypomagnesemia (serum Mg below 1.0 mg/dL) impairs both PTH secretion and PTH receptor sensitivity. This creates a state of functional hypoparathyroidism that will not respond to calcium replacement until magnesium is corrected first.

2. Classification and Clinical Manifestation

Classification	Mechanism	Key Clinical Features
Postsurgical	Damage or removal of parathyroid glands during thyroidectomy, parathyroidectomy, or radical neck dissection	Onset within 24-72 hours postop; perioral tingling, muscle cramps, carpopedal spasm; may be transient (recovers in weeks) or permanent
Autoimmune	Antibody-mediated destruction of parathyroid tissue; isolated or part of APS-1	Gradual onset; associated with chronic mucocutaneous candidiasis, adrenal insufficiency, alopecia; childhood or young adult onset
DiGeorge Syndrome	Congenital absence or hypoplasia of parathyroid glands due to 22q11.2 deletion	Neonatal hypocalcemia, tetany, seizures; associated with conotruncal cardiac defects (tetralogy of Fallot, truncus arteriosus), cleft palate, thymic aplasia
Hypomagnesemia-induced	Severe Mg depletion impairs PTH secretion and end-organ response	Refractory hypocalcemia despite IV calcium; PTH level is inappropriately low or normal; common in alcoholism, chronic diarrhea, aminoglycoside or PPI use
Infiltrative/Depositional	Iron (hemochromatosis, thalassemia with transfusion overload), copper (Wilson disease), or metastatic disease replaces parathyroid tissue	Gradual onset; look for signs of the underlying storage disease (bronze skin, hepatomegaly, KF rings)

Clinical Manifestations by Severity

Severity	Manifestations
Mild	Perioral numbness, acral paresthesias (fingertips, toes), fatigue, anxiety
Moderate	Carpopedal spasm, muscle cramps, Chvostek sign positive, Trousseau sign positive, QT prolongation
Severe	Laryngospasm (stridor), generalized seizures, refractory arrhythmias, heart failure; can be life-threatening
Chronic	Basal ganglia calcifications (seen on CT), cataracts (posterior subcapsular), dental enamel hypoplasia, dry and coarse skin, brittle nails

3. Diagnostic Workup

Test	Role	Expected Finding
Serum calcium (total and ionized)	Best initial test	Low total calcium (below 8.5 mg/dL); low ionized calcium confirms true hypocalcemia
Serum albumin	Correction factor	Must correct calcium for albumin: $Ca_{corrected} = Ca_{measured} + 0.8 \times (4.0 - Albumin)$
Intact PTH level	Confirmatory test, distinguishes cause	Low or inappropriately normal (this is the hallmark that separates hypoparathyroidism from other causes of hypocalcemia)
Serum phosphate	Supporting	Elevated (due to loss of PTH-mediated renal phosphate excretion)
Serum magnesium	Must check in every case	Low magnesium indicates functional hypoparathyroidism; must correct Mg before calcium will respond
25-OH vitamin D	Rule out deficiency	Normal in primary hypoparathyroidism (distinguishes from vitamin D deficiency where PTH is high)
1,25-dihydroxyvitamin D	Supporting	Low (due to absent PTH stimulation of 1-alpha hydroxylase)
Urine calcium (24-hour)	Monitoring during treatment	Low at baseline; used to monitor for hypercalciuria during calcium/calcitriol replacement
ECG	Acute assessment	Prolonged QT interval (risk for torsades de pointes)
CT head	Chronic cases	Bilateral basal ganglia calcifications (Fahr syndrome pattern)

The workup begins with serum total calcium and albumin. Because roughly 40% of circulating calcium is bound to albumin, hypoalbuminemia (common in hospitalized patients) can falsely lower total calcium. The corrected calcium formula or direct measurement of ionized calcium resolves this ambiguity. If ionized calcium is low, the next step is to measure intact PTH.

The PTH level is the critical branch point. In hypoparathyroidism, PTH is low or inappropriately normal in the face of hypocalcemia. A normal PTH when calcium is low is abnormal because the parathyroid glands should be maximally stimulated by low calcium. This distinguishes hypoparathyroidism from other causes of hypocalcemia such as vitamin D deficiency, chronic kidney disease, or pseudohypoparathyroidism, all of which present with elevated PTH (secondary hyperparathyroidism).

Always check serum magnesium alongside calcium. This is one of the most tested points. If magnesium is severely depleted, PTH secretion is impaired and PTH action at the receptor is blunted. The clinical picture mimics hypoparathyroidism with low calcium and low PTH, but the treatment is entirely different: IV magnesium replacement must come first.

Serum phosphate is elevated in hypoparathyroidism because PTH normally promotes phosphaturia. The combination of low calcium + high phosphate + low PTH is the classic biochemical triad. In contrast, vitamin D deficiency causes low calcium + low phosphate + high PTH, because PTH is still functioning and driving renal phosphate wasting.

4. Management and Treatment

Setting	Treatment	Details
Acute symptomatic hypocalcemia (tetany, seizures, laryngospasm, QT prolongation)	IV calcium gluconate	1-2 ampules (10-20 mL of 10% solution, providing 93-186 mg elemental calcium) diluted in 50-100 mL D5W, infused over 10-20 minutes; follow with continuous drip (calcium gluconate 10 ampules in 1L D5W at 50 mL/hr) titrated to symptoms and calcium levels
Acute, if central line available	IV calcium chloride	Contains 3x more elemental calcium per mL than gluconate; preferred through central line (causes tissue necrosis if extravasated peripherally)
Correct magnesium first	IV magnesium sulfate	1-2 g IV over 15-30 min, then continuous infusion if needed; hypocalcemia will not correct until magnesium is repleted
Chronic replacement	Oral calcium carbonate or calcium citrate	1-3 g elemental calcium daily in divided doses (2-3 times daily with meals)
Chronic replacement	Calcitriol (1,25-dihydroxyvitamin D)	0.25-2 mcg daily; this is the active form and bypasses the need for PTH-dependent renal hydroxylation
Refractory or difficult cases	Recombinant PTH (teriparatide or PTH 1-84)	Used when patients cannot maintain adequate calcium on conventional therapy; reduces the calcium and calcitriol dose needed
Monitoring	Serum calcium, phosphate, creatinine, 24-hour urine calcium	Every 3-6 months; target serum calcium in the low-normal range (8.0-8.5 mg/dL); monitor urine calcium to avoid nephrocalcinosis

Acute Management

The first priority in a symptomatic patient (tetany, seizures, arrhythmia, stridor) is IV calcium gluconate. Calcium gluconate is preferred over calcium chloride for peripheral IV access because chloride is highly caustic to veins and can cause tissue necrosis on extravasation. One to two ampules of 10% calcium gluconate are infused slowly over 10-20 minutes with cardiac monitoring, because rapid infusion can cause bradycardia or cardiac arrest. After the bolus, a continuous calcium gluconate drip is maintained and titrated to keep the patient symptom-free while oral therapy is initiated.

Before giving calcium, always check magnesium. If magnesium is low, administer IV magnesium sulfate first. This step is non-negotiable. A patient with combined hypomagnesemia and hypocalcemia will remain refractory to calcium replacement until the magnesium deficit is corrected.

Chronic Management

The mainstay of long-term therapy is oral calcium supplements combined with calcitriol. Calcitriol is chosen over regular vitamin D (cholecalciferol or ergocalciferol) because patients with hypoparathyroidism lack the PTH needed to activate 1-alpha hydroxylase. Giving inactive vitamin D would be ineffective since the conversion step is impaired. Calcitriol has a rapid onset (1-2 days) and short half-life, allowing easier dose titration.

The target for serum calcium during chronic management is deliberately set in the low-normal range (approximately 8.0-8.5 mg/dL). The rationale is that without PTH, the kidney cannot adequately reabsorb calcium. Pushing serum calcium to mid-normal or high-normal levels will result in hypercalciuria, which leads to nephrolithiasis and nephrocalcinosis over time. This is why 24-hour urine calcium is monitored regularly; the target is below 300 mg/day.

Thiazide diuretics may be added as adjunctive therapy in patients with persistent hypercalciuria, because thiazides enhance distal tubular calcium reabsorption and reduce urinary calcium excretion.

Contraindications and Cautions

Avoid loop diuretics (furosemide) in hypoparathyroidism patients because they increase renal calcium wasting and worsen hypocalcemia. This is in direct contrast to their use in hypercalcemia, where the calciuric effect is desirable. If a patient with hypoparathyroidism needs a diuretic, use a thiazide instead.

5. Differential Diagnosis and Distractors

Differential	Why It Looks Similar	Key Discriminator
Pseudohypoparathyroidism (Albright hereditary osteodystrophy)	Hypocalcemia, hyperphosphatemia, tetany, seizures	PTH is elevated (end-organ resistance to PTH, not deficiency); short stature, round face, brachydactyly (short 4th and 5th metacarpals), subcutaneous calcifications
Vitamin D deficiency	Hypocalcemia, tetany, muscle weakness	PTH is elevated (secondary hyperparathyroidism); phosphate is low or normal (not elevated); look for osteomalacia (bone pain, proximal weakness, Looser zones on X-ray)
Chronic kidney disease (renal osteodystrophy)	Hypocalcemia, hyperphosphatemia	PTH is elevated (secondary hyperparathyroidism); elevated BUN and creatinine; phosphate retention is renal, not due to PTH deficiency
Hungry bone syndrome	Hypocalcemia post-parathyroid surgery	Occurs after parathyroidectomy for hyperparathyroidism; PTH may be low or normalizing; profound hypocalcemia due to rapid bone uptake of calcium; distinguished by prior hyperparathyroidism history
Hypomagnesemia	Low calcium, low PTH, neuromuscular irritability	Serum magnesium is severely depressed; calcium will not respond to replacement until magnesium is corrected first; common in alcoholics, patients on PPIs or aminoglycosides
Acute pancreatitis	Hypocalcemia, abdominal symptoms	Severe epigastric pain radiating to the back, elevated lipase; calcium drop is due to saponification (calcium binding to necrotic fat), not PTH deficiency; PTH is appropriately elevated

The most important differential on exams is pseudohypoparathyroidism versus hypoparathyroidism. Both present with low calcium and high phosphate. The single discriminating feature is the PTH level: low in hypoparathyroidism, high in pseudohypoparathyroidism. The physical phenotype of Albright hereditary osteodystrophy (short stature, round face, shortened metacarpals) is a strong vignette clue pointing toward pseudohypoparathyroidism.

6. Traps and High-Yield Pearls

The most common trap with hypoparathyroidism questions involves the postsurgical setting. A vignette describes a patient 24-48 hours after total thyroidectomy who develops perioral tingling and a positive Chvostek sign. Students who do not connect thyroid surgery to parathyroid gland injury may fail to recognize this as postsurgical hypoparathyroidism and instead attribute the symptoms to anxiety or hyperventilation. The key is that hyperventilation-induced hypocalcemia causes respiratory alkalosis (which shifts calcium onto albumin), whereas postsurgical hypoparathyroidism causes true hypocalcemia with low PTH.

Another frequent pitfall is the magnesium trap. A patient presents with refractory hypocalcemia despite adequate IV calcium. The vignette may mention a history of chronic alcohol use, prolonged PPI therapy, or aminoglycoside use. If you do not check magnesium and correct it first, the calcium will not budge. Test-writers love this scenario because it tests whether you understand that magnesium is required for PTH secretion and action.

Students also confuse the direction of phosphate across different causes of hypocalcemia. In hypoparathyroidism, phosphate is high (no PTH to excrete it). In vitamin D deficiency, phosphate is low (PTH is high and driving phosphaturia). This phosphate level is often the fastest way to differentiate between the two on a timed exam.

For treatment questions, remember that calcitriol is chosen over cholecalciferol because the 1-alpha hydroxylase step is PTH-dependent. If a question offers cholecalciferol as an answer choice alongside calcitriol, always pick calcitriol. Similarly, the target serum calcium is intentionally kept in the low-normal range to prevent hypercalciuria and renal stones, and this counterintuitive "don't normalize the calcium" concept is a favorite testing point.

Finally, know the ECG finding: prolonged QT interval due to lengthening of the ST segment. This is distinct from other causes of QT prolongation (such as hypokalemia, which prolongs QT by producing U waves and flattened T waves). Hypocalcemia-related QT prolongation is caused by delayed phase 2 of the cardiac action potential and predisposes to torsades de pointes.

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