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
- Decreased Bone Resorption: PTH normally stimulates osteoclasts. Without PTH, there is minimal release of calcium into the bloodstream.
- 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.
- Excess Phosphate Retention: Without PTH, the renal tubules reabsorb phosphate excessively, elevating serum phosphate. High Pi itself also depresses serum calcium.
- Diagnostic Triad
- Low serum calcium
- High serum phosphate
- Normal serum alkaline phosphatase (in the absence of renal failure or malabsorption)
CAUSES OF PTH DEFICIENCY
- 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).
- 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.
- Developmental or Regulatory Defects
- Abnormal parathyroid gland embryologic development or PTH synthesis.
- Mutations affecting regulation of PTH production, secretion, or action.
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).
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.
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.).