Hypoparathyroidism Part 1

• Hypoparathyroidism (hypoPT):
  • Is the most common complication of bilateral and re-operative thyroid operations
• The true incidence of postoperative hypoPT is debatable:
  • Because of significant heterogeneity in how it has been studied:
    • Different time points after surgery, diverse electrolyte supplementation protocols, thyroid operations of variable aggressiveness, by surgeons of varying expertise, and for a broad array of indications are further confounded by variable use of clinical criteria (symptomatic vs, asymptomatic hypocalcemia), biochemical criteria (serum parathyroid hormone [PTH] and / or calcium and / or ionized calcium), and treatment criteria (requirement for calcium and / or vitamin D supplementation)
• According to a recent meta-analysis:
  • The median incidence of temporary hypoPT following thyroidectomy ranges from:
    • 19% to 38%
  • The median incidence of permanent hypoPT following thyroidectomy ranges from:
    • 0% to 3%
• It is critically important for the thyroid surgeon to employ strategies for minimizing and preventing hypoPT, including:
  • Carrying out the most appropriate extent of thyroidectomy for a specific patient
• Background:
  • The short half-life of PTH (3 to 5 minutes), along with the fragile nature of the parathyroid glands:
    • Sets the stage for their functional derangement following manipulation
  • The etiology of hypoPT:
    • Is related to dissection or removal of the vulnerable parathyroid glands during central neck operations:
      • Resulting in a decline in circulating PTH 
• Definitions
  • Biochemical hypoPT:
    • Is defined as a low intact PTH level:
      • Below the lower limit of the laboratory standard (usually 12 pg/mL):
        • Ranges of normal PTH values vary:
          • Depending upon the laboratory 
    • Accompanied by hypocalcemia:
      • Hypocalcemia is a total serum calcium level that is less than the lower limit of the center-specific reference range
      • Transient serum calcium values outside the normal reference range:
        • May reflect dynamic changes in electrolytes and state of hydration:
          • Rather than true hypocalcemia
      • Hypocalcemia may occur independent of hypoPT, but untreated hypoPT always leads to hypocalcemia, even though time lag can range from hours to days. 
  • Clinical hypoPT:
    • Is defined as biochemical hypoPT that is accompanied by symptoms and / or signs of hypocalcemia
  • Parathyroid insufficiency, or relative hypoPT:
    • May occur after central neck surgery
    • Typically is manifested by clinical symptoms of hypoPT that require medical treatment:
      • Despite measured laboratory values within normal ranges 
  • Transient or temporary hypoPT:
    • Is defined as occurring for less than six months after surgery:
  • Permanent hypoPT:
    • Is defined as occurring beyond six months after surgery 
• Mechanisms:
  • The mechanisms that underlie hypoPT:
    • Are related to:
      • Disruption of parathyroid gland arterial supply
      • Disruption of parathyroid gland venous drainage
      • Mechanical injury
      • Thermal or electrical injury
      • Intentional or inadvertent partial or complete removal
  • Normal parathyroid function requires a rich blood supply:
    • A normal parathyroid gland is composed of up to 30% capillary cells
  • Parathyroid blood supply is both delicate and complex:
    • Requires close attention during thyroidectomy to ensure its preservation
  • While the inferior thyroid artery is typically the dominant blood vessel that supplies the parathyroid glands:
    • Laser Doppler flowmetry has shown that:
      • The superior thyroid artery and vessels within the thymo-thyroid cord (ligament) can dominate in some individuals 
  • Impaired PTH secretion results in postoperative hypocalcemia through:
    • Inhibition of bone resorption
    • Reduction of 1,25-dihyroxyvitamin D synthesis by the kidneys
    • Reduced intestinal absorption of calcium
• Symptoms and signs:
  • Hypocalcemia causes:
    • Neuromuscular excitability and cardiac electrical instability:
      • Due to a reduced nerve and muscle cell depolarization threshold
  • Its most common early symptoms are:
    • Paresthesias, or numbness and tingling, of the perioral region and the fingertips
    • Muscle stiffness, cramps, and spasms are also common
    • Neuropsychiatric symptoms include:
      • Confusion, anger, depression, lightheadedness, and irritability
    • More sustained muscle contraction may lead to:
      • Laryngospasm
    • More severe neural excitability:
      • May lead to seizures
  • Signs of hypocalcemia include:
    • Observed or elicited tetany:
      • Classic bedside findings are:
        • A positive Chvostek sign:
          • Facial muscle twitching upon tapping the preauricular region over the facial nerve:
            • Present at baseline in up to 25% of people
        • A positive Trousseau sign:
          • Flexion of the wrist, thumb, and metacarpophalangeal joints and hyperextension of the fingers, upon brachial artery occlusion by inflation of a blood pressure cuff above systolic blood pressure)
    • Cardiovascular signs observed with progressive hypocalcemia include:
      • Prolongation of the QT interval that can result in torsades de pointes:
        • A form of ventricular tachycardia that may degenerate into ventricular fibrillation.

• Risk factors:
  • HypoPT may follow any simultaneous or staged bilateral central neck operation
  • Risk factors for both temporary and permanent hypoPT are presented in the following Table:

• A prior partial thyroid operation creates a potentially increased risk of hypoPT during completion thyroidectomy:
  • Due to unknown status (presence or viability) of the parathyroid glands in the previously operated neck
  • The most straightforward way to avoid hypoPT:
    • Is to limit the extent of thyroidectomy to a unilateral approach
  • Though the historical rationale for a near-total or subtotal thyroidectomy
    • Instead of a total thyroidectomy, is in part preservation of the parathyroid glands:
      • It has never been adequately studied whether this actually reduces the risk of hypoPT
  • Parathyroid autotransplantation (PA):
    • At the time of thyroidectomy has been associated with an increased risk of temporary hypoPT
    • Paradoxically, routine PA may be associated with a reduced risk of permanent hypoPT
    • While data supporting propyhylactic PA are not definitive:
      • The risk of permanent hypoPT is very low in patients who have undergone autotransplantation of at least one parathyroid gland
• Preoperative vitamin d deficiency:
  • When the planned thyroid operation is bilateral:
    • Preoperative testing of baseline serum calcium, PTH, and 25-hydroxy vitamin D blood levels can be helpful
  • If the baseline calcium is low normal, or below normal:
    • The risk of hypoPT is increased:
      • It may be appropriate to initiate scheduled oral calcium supplementation preoperatively
  • If the baseline calcium level is elevated:
    • Then the PTH level should be measured in order to evaluate for occult primary hyperparathyroidism, which could be definitively treated during thyroidectomy
  • A preoperatively elevated PTH level is commonly due to secondary hyperparathyroidism from vitamin D deficiency:
    • Vitamin D increases the absorption of calcium from the intestinal tract, and supplementation may be helpful to patients with hypoPT:
      • Assuming no underlying malabsorptive condition is present
    • Vitamin D also increases bone resorption and decreases renal excretion of calcium and phosphate
    • Vitamin D deficiency can be:
      • Severe – below the lowest recordable level, less than 10 ng/mL
      • Moderate – 10 to less than 20 ng/ mL
      • Mild (20 to 30 ng/mL
  • To optimize postoperative oral calcium absorption:
    • It is prudent to treat vitamin D deficiency preoperatively:
      • The Food and Drug Administration (FDA) approved regimen is:
        • 50,000 IU of vitamin D3 (cholecalciferol) weekly or 6000 IU daily for eight weeks
      • More aggressive regimens and other vitamin D supplements are available, but their utilization should be considered off-label
  • Not all studies have substantiated improved postoperative calcium levels with higher preoperative vitamin D levels:
    • Lang et al. found the rate of clinically significant hypocalcemia after total thyroidectomy to be similar in patients with severe, moderate, and mild vitamin D deficiency, whereas Al-Khatib et al. found that severe 25-hydroxyvitamin D deficiency was an independent predictor of hypoPT in patients undergoing total thyroidectomy:
      • However, a large meta-analysis reported that the perioperative PTH level, the preoperative vitamin D level, and postoperative changes of calcium were biochemical predictors of post-thyroidectomy hypocalcemia
    • Given the present evidence, it would appear preferable to diagnose vitamin D deficiency and initiate appropriate corrective supplementation prior to surgery
    • In cases of elective bilateral thyroid surgery:
      • It may be prudent to delay surgery in order to correct severe vitamin D deficiency
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