Hypoparathyroidism

PATHOPHYSIOLOGY OF HYPOPARATHYROIDISM

• Key Biochemical Findings
  • Low serum calcium (usually <7 mg/dL)
  • High serum inorganic phosphorus (Pi) (typically >5 mg/dL)
  • Decreased urinary excretion of both calcium and phosphate
  • Absence of PTH actions explains these laboratory results.
• Underlying Mechanisms
  1. Decreased Bone Resorption: PTH normally stimulates osteoclasts. Without PTH, there is minimal release of calcium into the bloodstream.
  2. Diminished Calcium Absorption: PTH deficiency → decreased renal 1α-hydroxylation of 25-hydroxyvitamin D (25[OH]D) to 1,25-dihydroxyvitamin D (1,25[OH]₂D) → reduced GI calcium absorption.
  3. Excess Phosphate Retention: Without PTH, the renal tubules reabsorb phosphate excessively, elevating serum phosphate. High Pi itself also depresses serum calcium.
• Diagnostic Triad
  1. Low serum calcium
  2. High serum phosphate
  3. Normal serum alkaline phosphatase (in the absence of renal failure or malabsorption)
  This triad is essentially pathognomonic for hypoparathyroidism.

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CAUSES OF PTH DEFICIENCY

1. Postsurgical Hypoparathyroidism (Most Common)
   • Neck Surgery: Subtotal or total thyroidectomy, parathyroid surgery, or other neck cancer surgery.
   • Often transient if some viable parathyroid tissue remains or if the parathyroid glands recover from surgical trauma.
   • Permanent if all parathyroid tissue was removed or irreversibly damaged.
   • Hungry Bone Syndrome: Occurs after removal of a hyperfunctioning parathyroid adenoma (bone avidly takes up calcium postoperatively).
2. Autoimmune Hypoparathyroidism
   • Autoimmune Destruction of parathyroid glands, often associated with polyglandular autoimmune syndrome type 1 (with adrenal insufficiency + chronic mucocutaneous candidiasis).
   • Rarely, activating autoantibodies to the Ca²⁺-sensing receptor (CaSR) can cause hypoparathyroidism.
3. Developmental or Regulatory Defects
   • Abnormal parathyroid gland embryologic development or PTH synthesis.
   • Mutations affecting regulation of PTH production, secretion, or action.

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GENETIC CAUSES OF HYPOPARATHYROIDISM

• Abnormal Parathyroid Development
  • X-linked or autosomal recessive mutations (e.g., GCM2 gene, encoding a key transcription factor).
• PreproPTH Gene Mutations
  • Defects in the PTH precursor protein → no biologically active PTH.
• Autosomal Dominant Activating Mutations of the CaSR
  • Lower calcium set point for PTH release → PTH not secreted until hypocalcemia is severe.
  • High urinary calcium excretion (unlike other forms of hypoparathyroidism, which generally show low urinary calcium).

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PSEUDOHYPOPARATHYROIDISM (HYPOCALCEMIA DESPITE HIGH PTH)

• Definition: Serum PTH is high, but hypocalcemia persists because of end-organ (bone, kidney) resistance or other defects in vitamin D metabolism.
• Key Features:
  • Inadequate PTH-induced bone resorption
  • Decreased renal 1,25(OH)₂D production
  • Hypocalcemia remains despite elevated PTH.

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CLINICAL MANIFESTATIONS OF ACUTE HYPOCALCEMIA

• Range of Symptoms
  • Minor: Anxiety, mild muscle spasms or cramps, perioral and acral paresthesias
  • Severe: Tetany, seizures, laryngospasm, papilledema, heart failure
• Acute Tetany
  • Neuromuscular Irritability: Early signs include perioral numbness, tingling (hands/feet), muscle cramps, hyperreflexia, photophobia, diplopia.
  • Advanced symptoms:
    • Carpopedal Spasm (adduction of thumb, finger extension, wrist flexion)
    • Laryngospasm (stridor due to glottic spasm)
    • Seizures (grand mal, petit mal, focal)
• Clinical Tests
  • Trousseau Sign: Carpopedal spasm induced by inflating a blood pressure cuff above systolic BP for ~3 minutes.
  • Chvostek Sign: Ipsilateral facial muscle contraction when tapping the facial nerve below the zygoma. (Not fully specific for hypocalcemia; can also be positive in alkalosis.)
• Other Findings
  • Chronic Hypocalcemia: Cataracts, basal ganglia calcification, extrapyramidal issues, abnormal dentition (enamel/dental hypoplasia).
  • Skin/Hair Changes: Brittle nails with transverse grooves, dry/coarse skin, sparse/coarse scalp hair.
  • Cardiac Effects: Prolonged Q-T interval on ECG, possible arrhythmias (e.g., torsades de pointes), heart failure in severe cases.
• Common Causes
  • Postsurgical hypoparathyroidism remains the leading cause of severe acute hypocalcemia.
  • Diagnosis: Recognized as an endocrine emergency → prompt IV calcium therapy to prevent life-threatening complications (seizures, laryngospasm, etc.).