Skip to content

PARATHYROID [Schwartz]

Historical Background

  • 1849: Sir Richard Owen, curator of the London Zoological Gardens, provided the first accurate description of the normal parathyroid gland after autopsy examination of an Indian rhinoceros.
  • 1879: Ivar Sandström, a medical student in Uppsala, Sweden, grossly and microscopically described human parathyroids and suggested they be named glandulae parathyroideae.
  • 1903: Recognition of the association between hyperparathyroidism (HPT) and osteitis fibrosa cystica (described by von Recklinghausen).
  • 1909: Calcium measurement became possible, establishing the link between serum calcium levels and the parathyroid glands.
  • 1925: Felix Mandl performed the first successful parathyroidectomy on a patient with advanced osteitis fibrosa cystica.
  • 1926: At Massachusetts General Hospital, Edward Churchill and Oliver Cope operated on Captain Charles Martell for severe primary HPT (PHPT).
  • 1928: Isaac Y. Olch performed the first successful parathyroidectomy for HPT in the U.S. on a patient who developed postoperative tetany requiring lifelong calcium supplementation.

Embryology

  • Superior parathyroid glands derive from the fourth branchial pouch, along with the thyroid gland.
  • Inferior parathyroid glands derive from the third branchial pouch, along with the thymus.
  • Position of superior glands:
    • 80% near the posterior aspect of the upper and middle thyroid lobes at the level of the cricoid cartilage.
    • ~1% in the paraesophageal or retroesophageal space.
    • Enlarged glands may descend in the tracheoesophageal groove.
  • Position of inferior glands:
    • Most common near where the inferior thyroid artery and recurrent laryngeal nerve (RLN) cross.
    • 15% found in the thymus.
    • Variable positions due to longer migratory path.
    • Undescended glands may be near the skull base or angle of the mandible.
  • Intrathyroidal glands: Frequency of about 2%.

image.png

image.png

Anatomy and Histology

  • Typical number: Most patients have four parathyroid glands.
  • Superior glands: Usually dorsal to the RLN at the level of the cricoid cartilage.
  • Inferior glands: Located ventral to the RLN.
  • Appearance:
    • Gray and semitransparent in newborns.
    • Golden yellow to light brown in adults.
    • Embedded in surrounding fat and may be difficult to discern.
  • Size and weight:
    • Ovoid, up to 7 mm in size.
    • Weigh 40–50 mg each.
  • Blood supply:
    • Primarily from branches of the inferior thyroid artery.
    • 20% of upper glands from the superior thyroid artery.
    • Additional supply from the thyroidea ima and vessels to the trachea, esophagus, larynx, and mediastinum.
  • Venous drainage: Ipsilaterally by the superior, middle, and inferior thyroid veins.
  • Variations in gland number:
    • 84% have four glands.
    • 13% have supernumerary glands, commonly in the thymus.
    • 3% have fewer than four glands.
  • Histology:
    • Composed of chief cells and oxyphil cells within a stroma of adipose cells.
    • Chief cells produce parathyroid hormone (PTH).
    • Oxyphil cells appear around puberty and increase in adulthood.
    • Water-clear cells are derived from chief cells and are rich in glycogen.

Parathyroid Physiology and Calcium Homeostasis

  • Calcium: Most abundant cation with critical extracellular and intracellular functions.
  • Extracellular calcium functions:
    • Muscle contraction.
    • Nervous system transmission.
    • Blood coagulation.
    • Hormone secretion.
  • Intracellular calcium functions:
    • Cell division.
    • Motility.
    • Membrane trafficking.
    • Secretion.
  • Calcium levels:
    • Extracellular levels are 10,000-fold higher than intracellular levels.
    • Ionized calcium: ~50% of serum calcium; active component.
    • Serum calcium ranges:
      • Total: 8.5–10.5 mg/dL (2.1–2.6 mmol/L).
      • Ionized: 4.4–5.2 mg/dL (1.1–1.3 mmol/L).
  • Albumin and calcium:
    • Alterations in serum albumin affect total serum calcium.
    • For each 1 g/dL change in albumin above or below 4.0 mg/dL, total calcium changes by 0.8 mg/dL.

Parathyroid Hormone (PTH)

  • Regulation:
    • Parathyroid cells use the calcium-sensing receptor (CASR) to regulate PTH secretion.
    • PTH secretion stimulated by low levels of 1,25-dihydroxy vitamin D, catecholamines, and hypomagnesemia.
  • Synthesis:
    • PTH gene on chromosome 11.
    • Produced as preproPTH, cleaved to proPTH, then to PTH (84 amino acids).
  • Metabolism:
    • Half-life of 2–4 minutes.
    • Metabolized in the liver into active N-terminal and inactive C-terminal fragments.
    • C-terminal fragment excreted by the kidneys.
  • Actions of PTH:
    • Bone: Stimulates osteoclasts to release calcium and phosphate.
    • Kidney:
      • Increases calcium reabsorption in the distal convoluted tubule.
      • Inhibits phosphate reabsorption in the proximal convoluted tubule.
      • Inhibits bicarbonate reabsorption.
      • Inhibits Na⁺/H⁺ antiporter, causing mild metabolic acidosis.
      • Enhances 1-hydroxylation of 25-hydroxyvitamin D.
    • Gut: Indirectly increases calcium absorption via active vitamin D.

Calcitonin

  • Produced by thyroid C cells.
  • Functions as an antihypercalcemic hormone by inhibiting osteoclast-mediated bone resorption.
  • Stimulated by:
    • High calcium levels.
    • Pentagastrin.
    • Catecholamines.
    • Cholecystokinin.
    • Glucagon.
  • Effects:
    • Decreases serum calcium when administered intravenously.
    • Increases phosphate excretion by inhibiting renal reabsorption.
  • Clinical relevance:
    • Minimal role in normal calcium regulation.
    • Useful as a marker for medullary thyroid carcinoma (MTC).
    • Used in treating acute hypercalcemic crisis.

Vitamin D

  • Includes vitamin D₂ and vitamin D₃.
    • Vitamin D₂: Available commercially.
    • Vitamin D₃: Produced from 7-dehydrocholesterol in the skin.
  • Metabolism:
    • Converted in the liver to 25-hydroxyvitamin D.
    • Hydroxylated in the kidneys to 1,25-dihydroxy vitamin D (active form).
  • Functions:
    • Stimulates absorption of calcium and phosphate from the gut.
    • Stimulates resorption of calcium from the bone.

Hyperparathyroidism

Classification

  • Primary Hyperparathyroidism (PHPT):
    • Increased PTH production from abnormal parathyroid glands.
    • Disturbance of normal feedback control by serum calcium.
  • Secondary Hyperparathyroidism (HPT):
    • Compensatory response to hypocalcemic states (e.g., chronic renal failure, GI malabsorption).
    • Reversible with correction of the underlying problem (e.g., kidney transplantation).
  • Tertiary Hyperparathyroidism (HPT):
    • Chronically stimulated glands become autonomous.
    • Persistence or recurrence of hypercalcemia after successful renal transplantation.

Primary Hyperparathyroidism (PHPT)

  • Epidemiology:
    • Affects 100,000 individuals annually in the U.S.
    • Occurs in 0.1%–0.3% of the general population.
    • More common in women (1:500) than in men (1:2000).
  • Pathophysiology:
    • Increased PTH leads to hypercalcemia via:
      • Enhanced GI absorption of calcium.
      • Increased production of vitamin D₃.
      • Reduced renal calcium clearance.
    • Characterized by parathyroid cell proliferation and PTH secretion independent of calcium levels.

Etiology

  • Exact cause unknown.
  • Contributing factors:
    • Low-dose ionizing radiation exposure.
    • Familial predisposition.
    • Certain diets and intermittent sunshine exposure.
    • Renal leak of calcium.
    • Declining renal function with age.
    • Altered sensitivity to calcium suppression.
  • Radiation Exposure:
    • Latency period: 30–40 years post-exposure.
    • Similar clinical presentations but higher PTH levels and incidence of thyroid neoplasms.
  • Lithium Therapy:
    • Shifts the set point for PTH secretion.
    • Causes elevated PTH levels and mild hypercalcemia.
    • Stimulates growth of abnormal parathyroid glands.
  • Causes of PHPT:
    • Parathyroid adenoma (single gland): ~80% of cases.
    • Multiple adenomas or hyperplasia: 15%–20%.
    • Parathyroid carcinoma: 1%.
  • Double Adenomas:
    • Supported by biochemical, intraoperative PTH, molecular, and histologic data.
    • Less common in younger patients; up to 10% in older patients.
  • Important Note:
    • Multiple abnormal glands suggest hyperplasia until proven otherwise.

Genetics

  • Mostly sporadic cases.
  • Associated inherited disorders:
    • MEN1 (Multiple Endocrine Neoplasia Type 1).
    • MEN2A.
    • Isolated familial HPT.
    • Familial HPT with jaw-tumor syndrome.
  • Inheritance Pattern: Autosomal dominant.
  • MEN1:
    • PHPT develops in 80%–100% by age 40.
    • Associated with:
      • Pancreatic neuroendocrine tumors.
      • Pituitary adenomas.
      • Less commonly, adrenocortical tumors, lipomas, carcinoid tumors.
    • Caused by mutations in the MEN1 gene on chromosome 11q12-13.
    • Menin protein interacts with transcription factors JunD and nuclear factor-κB.
  • MEN2A:
    • PHPT in 20% of patients, generally less severe.
    • Mutations in the RET proto-oncogene on chromosome 10.
    • Codon 634 mutations increase HPT risk.
  • Familial HPT with Jaw-Tumor Syndrome:
    • Increased risk of parathyroid carcinoma.
    • Linked to HRPT2 (CDC73 or parafibromin) on chromosome 1.
  • MEN4:
    • Patients without MENIN mutations have mutations in CDKN1B on chromosome 12p13.
    • CDKN1B encodes p27^kip1, involved in cyclin D1 signaling.
  • Sporadic Parathyroid Adenomas:
    • 25%–40% show loss at 11q13 (MEN1 gene site).
    • PRAD1 (CCND1) overexpressed in ~18% of adenomas.
      • Due to rearrangement placing PRAD1 under PTH promoter control.
    • Mutations in cyclin-dependent kinase inhibitor genes (e.g., CDKN1B).
    • Chromosomal deletions at 1p, 6q, 15q.
    • Amplifications at 16p, 19p.
  • Parathyroid Carcinomas:
    • Loss of RB tumor suppressor gene.
    • 60% have HRPT2 (CDC73) mutations.
    • p53 inactivated in 30%.

Clinical Manifestations

  • Historical "Classic" Symptoms:
    • Kidney stones.
    • Painful bones.
    • Abdominal groans.
    • Psychic moans.
    • Fatigue overtones.
  • Current Common Symptoms:
    • Weakness, fatigue.
    • Polydipsia, polyuria, nocturia.
    • Bone and joint pain.
    • Constipation, decreased appetite, nausea, heartburn.
    • Pruritus, depression, memory loss.
  • Quality of Life:
    • Lower scores on health surveys (SF-36).
    • Symptoms improve after parathyroidectomy in most patients.
  • Asymptomatic PHPT:
    • Rare, occurring in <5% of patients.

Complications

Renal Disease

  • Renal dysfunction in ~80% of patients.
  • Kidney Stones:
    • Now occur in 20%–25% (previously up to 80%).
    • Composed of calcium phosphate or oxalate.
  • Nephrocalcinosis:
    • Renal parenchymal calcification.
    • Found in <5%.
    • Leads to renal dysfunction.
  • Chronic Hypercalcemia:
    • Causes polyuria, polydipsia, nocturia.
  • Hypertension:
    • Reported in up to 50%.
    • More common in older patients.
    • Correlates with renal dysfunction.
    • Least likely to improve post-parathyroidectomy.

Bone Disease

  • Present in ~15% of patients.
  • Includes osteopenia, osteoporosis, osteitis fibrosa cystica.

  • Osteitis Fibrosa Cystica:

    • Occurs in <5%.
    • Radiologic signs:
      • Subperiosteal resorption (hands).
      • Bone cysts, tufting of distal phalanges.
      • Mottled skull appearance.
    • Elevated alkaline phosphatase.

    image.png

  • Bone Mineral Density (BMD):

    • Loss at cortical sites (e.g., radius).
    • Preservation at cancellous bone (e.g., vertebral bodies).
    • Increased fracture risk.
    • Improvement after parathyroidectomy.
  • Correlation:
    • With serum PTH and vitamin D levels.

Gastrointestinal Complications

  • Associated with peptic ulcer disease.
  • Hypergastrinemia observed in animal studies.
  • Increased incidence of pancreatitis (Ca²⁺ ≥12.5 mg/dL).
  • Increased cholelithiasis due to elevated biliary calcium.

Neuropsychiatric Complications

  • Severe hypercalcemia:
    • Psychosis, obtundation, coma.
  • Mild hypercalcemia:
    • Depression, anxiety, fatigue.
  • Findings:
    • Reduced monoamine metabolites in CSF.
    • EEG abnormalities normalize post-parathyroidectomy.

Other Features

  • Fatigue, muscle weakness (proximal muscles).
  • Due to neuropathy rather than myopathy.
  • Increased incidence of:
    • Chondrocalcinosis.
    • Gout, pseudogout (uric acid and calcium pyrophosphate deposition).
  • Ectopic Calcifications:
    • In blood vessels, cardiac valves, skin.
  • Cardiovascular Manifestations:
    • Changes in endothelial function.
    • Increased vascular stiffness.
    • Possible diastolic dysfunction.
  • Mortality:
    • European studies suggest increased deaths from cardiovascular disease and cancer.

Physical Findings

  • Parathyroid tumors are rarely palpable.
  • Palpable neck mass:
    • Likely a thyroid mass or parathyroid cancer.
  • Band Keratopathy:
    • Calcium deposition in Bowman's membrane of the eye.
    • Associated with high calcium or phosphate levels.
  • Fibro-Osseous Jaw Tumors:
    • Suggest possibility of parathyroid carcinoma.

Differential Diagnosis

image.png

  • Causes of Hypercalcemia:
    • PHPT and malignancy account for >90%.
    • PHPT common in outpatients.
    • Malignancy common in hospitalized patients.
  • Hypercalcemia of Malignancy:
    • Humoral hypercalcemia without bone metastases.
    • Mediated by PTH-related peptide (PTHrP).
    • Associated with solid tumors and hematologic malignancies (e.g., multiple myeloma).
  • Thiazide Diuretics:
    • Decrease renal clearance of calcium.
    • Can unmask or exacerbate PHPT.
  • Familial Hypocalciuric Hypercalcemia (FHH1):
    • Rare, autosomal dominant.
    • Mutations in CASR gene on chromosome 3.
    • Lifelong hypercalcemia not corrected by parathyroidectomy.
  • FHH Types 2 and 3:
    • Mutations in GNA11 (19p13.3) and AP2S1 (19q12.2).
    • Cause hypocalciuric hypercalcemia via CaSR signaling inactivation.
  • Other Causes:
    • Sarcoidosis: Increased 1-hydroxylase activity.
    • Thyrotoxicosis: Bone resorption.
    • Adrenal insufficiency, pheochromocytoma.
    • Vasoactive intestinal peptide–secreting tumors.
    • Milk-alkali syndrome.
    • Vitamin D or A toxicity.
    • Immobilization.

Diagnostic Investigations

Biochemical Studies

image.png

  • Diagnosis:
    • Elevated serum calcium and intact PTH levels.
    • Absence of hypocalciuria.
  • PTH Assays:
    • Use immunoradiometric or immunochemiluminescent techniques.
    • Do not cross-react with PTHrP.
  • Additional Findings:
    • Decreased serum phosphate (~50%).
    • Elevated 24-hour urinary calcium (~60%).
    • Mild hyperchloremic metabolic acidosis (80%).
      • Elevated chloride-to-phosphate ratio (>33).
  • Urinary Calcium Measurement:
    • Not routinely necessary.
    • Important for ruling out FHH:
      • FHH: Low 24-hour urinary calcium (<100 mg/d).
      • Calcium-to-creatinine clearance ratio:
        • <0.01 in FHH.
        • >0.02 in PHPT.
  • Alkaline Phosphatase:
    • Elevated in ~10% of patients.
    • Indicates high-turnover bone disease.
  • Protein Electrophoresis:
    • To exclude multiple myeloma.
  • Normocalcemic PHPT:
    • Due to vitamin D deficiency, low albumin, excessive hydration, high phosphate diet, or low normal blood calcium set point.
    • Elevated PTH with or without increased ionized calcium.
    • Differentiated from renal leak hypercalciuria using thiazide diuretics.

Radiologic Tests

  • Osteitis Fibrosa Cystica:
    • Rarely demonstrated on hand and skull X-rays today.
  • Bone Mineral Density (BMD) Studies:
    • Use dual-energy absorptiometry.
    • Assess bone effects of PHPT.
  • Current Evaluations:
    • Vertebral imaging (X-ray, VFA, CT scan).
    • Optional trabecular bone score (TBS) measurement.
    • Renal imaging (ultrasound, X-ray, CT scan).
  • Parathyroid Localization Studies:
    • Not for diagnosis confirmation.
    • Aid in identifying the location of offending gland(s).

Management of Primary HPT

Indications for Parathyroidectomy and Role of Medical Management

  • Symptomatic PHPT:
    • Patients with classic symptoms and complications should undergo parathyroidectomy.
  • Asymptomatic PHPT:
    • Treatment is controversial due to differing definitions of asymptomatic.
    • 1990 NIH Consensus:
      • Defined as absence of bone, renal, gastrointestinal, or neuromuscular disorders.
    • Importance of considering natural history of untreated PHPT and outcomes of medical vs. surgical treatments.

Natural History and Guidelines

  • Nonoperative management recommended for patients with mild PHPT based on observational studies.
  • Initial guidelines established for surgery in patients with:
    • End-organ effects.
    • Higher likelihood of disease progression.
  • Silverberg et al. Study:
    • Followed 52 patients with asymptomatic PHPT over 10 years.
    • Biochemical parameters remained stable in most patients.
    • 27% developed new indications for surgery.
    • Age <50 years predictive of progression.
    • Parathyroidectomy led to normalization of calcium and PTH levels and improved BMD.
  • 2002 NIH Workshop:
    • Reassessed guidelines based on new studies.

Further Studies

  • Additional studies (randomized, controlled, prospective) showed:
    • Stability of biochemical indices over 1–3.5 years.
    • Long-term study (15 years) indicated:
      • Calcium levels may rise after 13–15 years.
      • Bone density stable for 8–10 years, then cortical bone density worsened.
      • 60% lost >10% of BMD over 15 years.
    • Fracture risk increased up to 10 years before diagnosis and treatment.

Medical Management

  • Antiresorptive Treatments:
    • Bisphosphonates.
    • Hormone Replacement Therapy (HRT).
    • Selective Estrogen Receptor Modulators (e.g., Raloxifene).
  • Bisphosphonates and HRT:
    • Effective at decreasing bone turnover and increasing BMD.
    • Bisphosphonates preferred due to nonskeletal effects of HRT.
  • Calcimimetics:
    • Modify sensitivity of the CASR.
    • Decrease serum calcium and PTH levels.
    • Bone density does not improve.
    • Not routinely recommended due to lack of long-term data.

Surgical Management

  • Parathyroidectomy:
    • Resolves osteitis fibrosa cystica.
    • Decreases formation of renal stones.
    • Improves BMD:
      • 6%–8% in the first year.
      • Up to 12%–15% at 15 years.
    • Reduces fracture risk by 50% at hip and upper arm, 30% overall.
    • Improves nonspecific symptoms:
      • Fatigue, polydipsia, polyuria, nocturia.
      • Bone and joint pain.
      • Constipation, nausea, depression.
    • May reverse increased death rate.
    • Success rates >95% with minimal morbidity.
    • More cost-effective than medical management.

Guidelines for Parathyroidectomy

  • Recommended for virtually all patients except those with prohibitive operative risks.
  • 2014 Revised Guidelines:
    • Serum calcium >1 mg/dL above upper limit of normal.
    • BMD T-score < –2.5 at any site (radius, spine, or hip).
    • Patients <50 years old.
    • Creatinine clearance <60 cc/minute.
    • Urine calcium >400 mg/day with increased stone risk.
    • Presence of nephrolithiasis or nephrocalcinosis on imaging.
    • Vertebral fracture detected by X-ray, CT, MRI, or VFA.
  • Neurocognitive and cardiovascular aspects remain controversial and are not sole indications for surgery.

  • Follow-up for nonsurgical patients:

    • Annual calcium and serum creatinine measurements.
    • BMD measurements every 1–2 years.

    image.png

Preoperative Localization Tests

  • Purpose: To identify hyperfunctioning parathyroid glands before surgery.
  • Noninvasive Modalities:
    • 99mTc-Sestamibi Scan:
      • Most widely used.
      • Sensitivity >80% for detecting parathyroid adenomas.
      • Delayed washout from hypercellular parathyroid tissue.
    • Neck Ultrasound:
      • Sensitivity >75% in experienced centers.
      • Identifies intrathyroidal parathyroids.
    • Single-Photon Emission CT (SPECT):
      • Superior when combined with CT.
      • Determines adenoma location (anterior/posterior mediastinum).
    • Four-Dimensional CT (4D-CT):
      • Provides functional and anatomic information.
      • Improved sensitivity (88%) over sestamibi and ultrasound.
  • Invasive Modalities:
    • Intraoperative PTH (IOPTH) Monitoring:
      • Introduced in 1993.
      • Positive if PTH drops by ≥50% 10 minutes post-excision.
      • Less reliable in multiglandular disease.

    • Bilateral Internal Jugular Vein Sampling:

      • Used intraoperatively.
      • Less accurate.

      image.png

Operative Approaches

1. Unilateral Parathyroid Exploration

  • Initially used intraoperative staining with Sudan black dye.
  • Advantages over bilateral exploration:
    • Reduced operative times.
    • Fewer complications (RLN injury, hypoparathyroidism).
  • Concerns:
    • Risk of missing a second adenoma.
    • Higher in patients with familial HPT, MEN syndromes, elderly.
    • Difficulty distinguishing single adenoma from asymmetric hyperplasia.
  • Recent Studies:
    • No difference in recurrence rates between unilateral and bilateral exploration.

2. Radio-Guided Parathyroidectomy

  • Utilizes 99mTc-Sestamibi retention by parathyroid tumors.
  • Procedure:
    • Inject 1–2 mCi of isotope preoperatively.
    • Use gamma probe intraoperatively.
  • Advantages:
    • Easier localization, especially in reoperative cases.
    • Possible under local anesthesia with smaller incisions.
  • Current Use:
    • Rarely used now.
    • Little advantage over preoperative sestamibi scans.
    • Increased operative times.
    • Reduced accuracy in multiglandular disease.

3. Endoscopic Approaches

  • Video-Assisted and Total Endoscopic Techniques.
  • Total Endoscopic Parathyroidectomy:
    • First described by Gagner in 1996.
    • Involves CO₂ insufflation to create working space.
  • Advantages:
    • Superior cosmesis.
    • Excellent visualization.
  • Limitations:
    • Increased operating times, personnel, expense.
    • Not suitable for multiglandular disease, large thyroid masses, previous neck surgery.
  • Robotic Approaches:
    • Gasless, transaxillary technique.
    • Advantages:
      • Improved 3D visualization.
      • Refined ergonomic control.
      • Improved cosmetic results.

4. Minimally Invasive Parathyroidectomy

  • Candidates:
    • Patients with sporadic PHPT.
    • Sestamibi scan and neck ultrasound identify the same enlarged gland.
  • Approach:
    • Focused neck exploration.
  • Standard Bilateral Exploration indicated if:
    • Localization studies or IOPTH not available.
    • Localization studies fail or identify multiple abnormal glands.
    • Family history of PHPT, MEN1, or MEN2A.
    • Concomitant thyroid disorder requires bilateral exploration.
  • In MEN1 Patients:
    • HPT should be corrected before treating gastrinomas.

Conduct of Parathyroidectomy (Standard Bilateral Exploration)

  • Surgeon Expertise:
    • Thorough knowledge of parathyroid anatomy and embryology.
    • Meticulous technique crucial for success.
  • Anesthesia:
    • Performed under general anesthesia.
  • Patient Positioning:
    • Supine with neck extended.
  • Incision:
    • 3–4 cm incision below the cricoid cartilage.
  • Dissection:
    • Strap muscles separated in midline.
    • Dissection maintained lateral to the thyroid to preserve blood supply.

Identification of Parathyroids

  • Importance of a bloodless field.
  • Middle thyroid veins ligated and divided.
  • Thyroid lobe retracted medially and anteriorly.
  • Space between carotid sheath and thyroid opened.
  • Recurrent Laryngeal Nerve (RLN) identified.
  • Parathyroid Gland Locations:
    • Upper glands: Superior and dorsal to RLN-inferior thyroid artery junction.
    • Lower glands: Inferior and ventral to RLN.
  • Distinguishing Parathyroid Tissue:
    • From fat, thyroid nodules, lymph nodes, ectopic thymus.
    • Intraoperative PTH assays or frozen section may assist.

Location of Parathyroid Glands

  • Lower Glands:
    • Near the lower thyroid pole.
    • If not found, mobilize thyrothymic ligament and thymus.
  • Upper Glands:
    • Near junction of upper and middle thirds of thyroid gland at level of cricoid cartilage.
    • Ectopic Locations:
      • Carotid sheath.
      • Tracheoesophageal groove.
      • Retroesophageal.
      • Posterior mediastinum.
  • Intrathyroidal Glands:
    • May require intraoperative ultrasound, thyroid capsule incision, or thyroid lobectomy.

Treatment Based on Number of Abnormal Glands

  1. Single Adenoma:
    • 80% of PHPT cases.
    • One abnormal gland, others normal.
    • Excision of adenoma without fracturing it.
    • Avoid rupture to prevent parathyromatosis.
    • Biopsy normal glands if uncertainty exists.
  2. Double and Multiple Adenomas:
    • Double adenomas: Two abnormal, two normal glands.
    • Triple adenomas: Three abnormal, one normal gland.
    • More common in patients >60 years old.
    • Excision of abnormal glands after confirming normality of remaining glands.
  3. Parathyroid Hyperplasia:
    • Occurs in ~15% of patients.
    • All glands enlarged or hypercellular.
    • Treatment Options:
      • Subtotal parathyroidectomy: Leave a 50 mg remnant.
      • Total parathyroidectomy with autotransplantation.
    • Autotransplantation:
      • Parathyroid tissue transplanted into nondominant forearm.
      • Cryopreservation recommended.
      • Failure rate of autotransplanted tissue: ~5%.

Indications for Sternotomy

  • Sternotomy usually not recommended at initial operation.
  • Preferred approach:
    • Biopsy normal glands.
    • Close neck and obtain localizing studies.
  • Mediastinal Glands:
    • Lower glands may migrate to anterior mediastinum.
    • Often approached via cervical incision.
  • Sternotomy Needed in ~5% of cases:
    • For glands in posterior mediastinum or inaccessible locations.
    • Performed via partial sternotomy to the third intercostal space.
    • Extended as needed.

Special Situations

1. Normocalcemic Hyperparathyroidism

  • Definition:
    • Elevated PTH levels with repeatedly normal calcium (including ionized calcium) levels.
  • Prevalence:
    • Ranges from 0.5% to 16% in clinical practice.
  • Diagnosis:
    • Rule out secondary causes of elevated PTH:
      • Vitamin D deficiency
      • Osteomalacia
      • Hypercalciuria (renal leak)
      • Renal insufficiency
  • Natural History:
    • Limited data available.
    • Lowe et al. Study (37 patients):
      • 19% became hypercalcemic within 3 years.
      • 57% developed osteoporosis.
      • 11% had fragility fractures.
      • 14% developed nephrolithiasis.
  • Implications:
    • May represent a variant of symptomatic PHPT.
    • Parathyroidectomy may be unsuccessful.
  • Management:
    • No established guidelines.
    • Conservative approach unless:
      • Progression to hypercalcemia
      • Development of nephrolithiasis
      • Reduced bone mineral density
      • Occurrence of fragility fractures

2. Parathyroid Carcinoma

  • Incidence:
    • Accounts for ~1% of PHPT cases.
  • Clinical Features:
    • Suspected preoperatively by:
      • Severe symptoms
      • Serum calcium levels >14 mg/dL
      • Significantly elevated PTH levels (five times normal)
      • Palpable parathyroid gland
  • Invasion and Metastasis:
    • Local invasion common
    • 15% have lymph node metastases
    • 33% have distant metastases at presentation
  • Intraoperative Findings:
    • Large, gray-white to gray-brown parathyroid tumor
    • Adherent to or invasive into surrounding tissues:
      • Muscle
      • Thyroid
      • Recurrent Laryngeal Nerve (RLN)
      • Trachea
      • Esophagus
    • Enlarged lymph nodes may be present
  • Diagnosis:
    • Frozen sections generally unreliable
    • Requires histologic examination
    • Major diagnostic criteria:
      • Vascular or capsular invasion
      • Trabecular or fibrous stroma
      • Frequent mitoses
    • Note: Classic findings may not always be present and can occur in benign adenomas
  • Treatment:
    • Neck exploration with en bloc excision of:
      • The tumor
      • Ipsilateral thyroid lobe
      • Contiguous lymph nodes (tracheoesophageal, paratracheal, upper mediastinal)
    • Recurrent nerve preserved unless directly involved
    • Resection of adherent soft tissue structures
    • Modified radical neck dissection if lateral lymph node metastases present
    • Prophylactic neck dissection is not advised
  • Postoperative Management:
    • Reoperation for locally recurrent or metastatic disease
    • Adjuvant radiation therapy considered for:
      • High risk of local recurrence (close or positive margins, invasion, tumor rupture)
      • Unresectable disease or palliation of bone metastases
    • Chemotherapy generally ineffective
  • Medical Therapies:
    • Bisphosphonates for hypercalcemia
    • Cinacalcet hydrochloride (calcimimetic) reduces PTH levels
    • Experimental approaches:
      • Antiparathyroid hormone immunotherapy
      • Octreotide
      • Telomerase inhibitor azidothymidine

3. Familial Hyperparathyroidism

  • Associated Syndromes:
    • MEN1
    • MEN2A
    • Isolated familial HPT (non-MEN)
    • Familial HPT with jaw tumors
  • Diagnosis:
    • Known or suspected in ~85% of patients preoperatively
  • Clinical Features:
    • Higher incidence of:
      • Multiglandular disease
      • Supernumerary glands
      • Recurrent or persistent disease
  • Management:
    • Not candidates for focused surgical approaches
    • Preoperative imaging (sestamibi scan, ultrasound) may identify ectopic glands
    • Standard bilateral neck exploration with bilateral cervical thymectomy
    • Surgical Options:
      • Subtotal parathyroidectomy
      • Total parathyroidectomy with autotransplantation
      • Parathyroid tissue cryopreservation
    • If an adenoma is found:
      • Resection of adenoma and ipsilateral normal parathyroid glands
      • Contralateral glands biopsied and marked
  • Special Considerations in MEN2A:
    • Require total thyroidectomy and central neck dissection for MTC
    • Only abnormal parathyroid glands resected
    • Normal glands marked with a clip

4. Neonatal Hyperparathyroidism

  • Presentation:
    • Severe hypercalcemia
    • Lethargy
    • Hypotonia
    • Mental retardation
  • Cause:
    • Homozygous mutations in the CASR gene
  • Management:
    • Urgent total parathyroidectomy with:
      • Autotransplantation
      • Cryopreservation
      • Thymectomy
    • Subtotal resection associated with high recurrence rates

5. Parathyromatosis

  • Definition:
    • Multiple nodules of hyperfunctioning parathyroid tissue throughout the neck and mediastinum
  • Etiology:
    • Unknown
    • Theories include:
      • Overgrowth of congenital parathyroid rests (ontogenous parathyromatosis)
      • Seeding during surgery from:
        • Rupture of parathyroid tumors
        • Subtotal resection of hyperplastic glands
  • Clinical Significance:
    • Rare cause of persistent or recurrent HPT
    • Identified intraoperatively
  • Management:
    • Aggressive local resection may achieve normocalcemia
    • Rarely curative
    • Some studies suggest association with low-grade carcinoma

6. Postoperative Care and Follow-Up

  • Monitoring:
    • Calcium level checks at:
      • 2 weeks postoperatively
      • 6 months
      • Then annually
  • Recurrence Rates:
    • Generally rare (<1%)
    • Higher in patients with familial HPT
    • In MEN1 patients:
      • 15% recurrence at 2 years
      • 67% recurrence at 8 years

7. Persistent and Recurrent Hyperparathyroidism

  • Definitions:
    • Persistence:
      • Hypercalcemia that fails to resolve after parathyroidectomy
    • Recurrence:
      • HPT occurring after at least 6 months of documented normocalcemia
  • Incidence:
    • Persistent HPT more common than recurrent HPT
    • Both occur more frequently in familial HPT and MEN1
  • Common Causes:
    • Ectopic parathyroids
    • Unrecognized hyperplasia
    • Supernumerary glands
  • Less Common Causes:
    • Parathyroid carcinoma
    • Missed adenoma in normal position
    • Incomplete resection
    • Parathyromatosis
    • Inexperienced surgeon
  • Common Ectopic Sites:
    • Paraesophageal: 28%
    • Mediastinal: 26%
    • Intrathymic: 24%
    • Intrathyroidal: 11%
    • Carotid sheath: 9%
    • High cervical/undescended: 2%
  • Evaluation:
    • Confirm diagnosis with necessary biochemical tests
    • Rule out other causes of elevated PTH (e.g., renal insufficiency, renal calcium leak)
    • Detailed family history to screen for familial disease
    • Perform 24-hour urine collection to rule out FHH
  • Management Considerations:
    • Re-exploration for significant symptoms:
      • Recurrent kidney stones
      • Markedly elevated calcium levels
      • Ongoing bone loss
    • Conservative management for minimal or equivocal symptoms
  • Localization Studies:
    • Routine preoperative localization:
      • Sestamibi scan
      • Ultrasound
      • 4D-CT scans
    • If studies are negative or discordant:
      • Ultrasound-guided aspirate of suspicious lesions
      • Selective venous catheterization for PTH levels
  • Surgical Approach:
    • Focused exploration
    • Lateral approach via previous incision
    • Early identification of the RLN
    • Routine cryopreservation of parathyroid tissue
    • Use of adjuncts like intraoperative PTH measurements
    • Additional techniques if needed:
      • Bilateral internal jugular vein sampling
      • Thyroid lobectomy on side of missing gland
      • Cervical thymectomy
      • Ligation of ipsilateral inferior thyroid artery
    • Blind mediastinal exploration is not recommended

  • Medical Management:

    • Cinacalcet may be considered for patients unsuitable for surgery

    image.png

8. Hypercalcemic Crisis

  • Presentation:
    • Acute nausea, vomiting
    • Fatigue, muscle weakness
    • Confusion, decreased level of consciousness
  • Causes:
    • Severe hypercalcemia from uncontrolled PTH secretion
    • Worsened by:
      • Polyuria
      • Dehydration
      • Reduced kidney function
    • May occur with other hypercalcemic conditions
  • Calcium Levels:
    • Markedly elevated (16–20 mg/dL)
  • Risk Factors:
    • Large or multiple parathyroid tumors
    • Parathyroid cancer
    • Familial HPT
  • Treatment:
    • Lower serum calcium levels followed by surgery
    • Mainstay of therapy:
      • Rehydration with 0.9% saline solution
      • Maintain urine output >100 cc/h
    • After rehydration:
      • Diuresis with furosemide (increases renal calcium clearance)
    • If unsuccessful:
      • Other drugs to lower serum calcium levels
    • In life-threatening cases:
      • Hemodialysis may be beneficial

Secondary Hyperparathyroidism

Causes

  • Chronic Renal Failure:
    • Most common cause of secondary HPT.
  • Hypocalcemia due to:
    • Inadequate calcium or vitamin D intake
    • Malabsorption

Pathophysiology

  • Chronic Renal Failure:
    • Hyperphosphatemia leading to hypocalcemia.
    • Deficiency of 1,25-dihydroxy vitamin D due to loss of renal hydroxylation.
    • Low calcium intake and decreased calcium absorption.
    • Abnormal parathyroid cell response to extracellular calcium and vitamin D.
  • Other Factors:
    • Aluminum hydroxide (phosphate binder) contributes to osteomalacia.

Clinical Features

  • Calcium Levels:
    • Generally hypocalcemic or normocalcemic.
  • Osteomalacia:
    • Associated with aluminum hydroxide use.
  • Calciphylaxis:
    • Painful, violaceous, mottled lesions on extremities.
    • May progress to necrotic ulcers, gangrene, sepsis, and death.
    • Skin biopsy can aid diagnosis.

Medical Management

  • Dietary Modifications:
    • Low-phosphate diet.
  • Phosphate Binders:
    • Use of non-aluminum-based binders to avoid osteomalacia.
  • Calcium and Vitamin D:
    • Adequate calcium intake.
    • Supplementation with 1,25-dihydroxy vitamin D.
  • Dialysis Modifications:
    • High-calcium, low-aluminum dialysis bath.
  • Calcimimetics:
    • Control parathyroid hyperplasia.
    • Decrease plasma PTH and calcium levels.

Indications for Parathyroidectomy

  • Traditional Criteria:
    • Bone pain
    • Pruritus
    • Calcium-phosphate product ≥70
    • Calcium >11 mg/dL with markedly elevated PTH
    • Calciphylaxis
    • Progressive renal osteodystrophy
    • Soft tissue calcification and tumoral calcinosis
  • KDOQI Recommendations:
    • Severe HPT (PTH >800 pg/mL)
    • Hypercalcemia
    • Osteoporosis or pathologic bone fractures
    • Symptoms and signs:
      • Pruritis
      • Bone pain
      • Severe vascular calcifications
      • Myopathy
    • Calciphylaxis
  • Additional Considerations:
    • Parathyroid mass >1 cm on ultrasound indicates potential refractoriness to medical management.

Surgical Management

  • Preoperative Preparation:
    • Routine dialysis the day before surgery to correct electrolyte abnormalities.
    • Localization studies are optional but can identify ectopic glands.
  • Operative Approach:
    • Bilateral neck exploration:
      • Identify all parathyroid glands.
      • Characterized by asymmetric enlargement and nodular hyperplasia.
    • Surgical Options:
      • Subtotal Parathyroidectomy:
        • Leave about 50 mg of the most normal gland.
      • Total Parathyroidectomy with Autotransplantation:
        • Autotransplant parathyroid tissue into the brachioradialis muscle.
        • Cryopreservation of parathyroid tissue recommended.
      • Total Parathyroidectomy without Autotransplantation:
        • Preferred in patients with calciphylaxis.
        • Contraindicated in patients eligible for renal transplant.
  • Postoperative Care:
    • Monitor calcium levels.
    • Manage potential hypocalcemia.

Calciphylaxis

  • Definition:
    • Rare, limb- and life-threatening complication of secondary HPT.
  • Characteristics:
    • Painful, violaceous, mottled lesions on extremities.
    • Progression to necrotic ulcers, gangrene, sepsis.
  • Diagnosis:
    • Skin biopsy.
  • Management:
    • Parathyroidectomy may relieve symptoms.
    • Not all patients with calciphylaxis have high PTH; surgery should be based on documented hyperparathyroidism.

Additional Notes

  • Calcimimetics:
    • Effective in controlling biochemical parameters.
    • Reduce risk of fractures and cardiovascular complications.
  • Parathyroidectomy Outcomes:
    • Maintains biochemical targets for up to 5 years.
    • Improves bone density, fracture risk, calcinosis, hemoglobin levels, and long-term survival.

Tertiary Hyperparathyroidism

  • Definition:
    • Development of autonomous parathyroid gland function after treatment of secondary HPT, often following renal transplantation.
  • Clinical Features:
    • Similar to PHPT:
      • Pathologic fractures
      • Bone pain and worsened bone disease
      • Renal stones
      • Peptic ulcer disease
      • Pancreatitis
      • Mental status changes
    • Transplanted Kidney at risk from:
      • Tubulointerstitial calcification
      • Volume depletion
  • Management:
    • Medical Treatment:
      • Cinacalcet:
        • Effective and well-tolerated.
        • Decreases serum calcium and PTH levels.
        • Bone density does not improve.
        • Not routinely recommended except for poor operative candidates or those refusing surgery.
    • Surgical Treatment:
      • Parathyroidectomy indicated if:
        • Autonomous PTH secretion persists >1 year post-transplant.
        • Presence of:
          • Hypophosphatemia
          • Low BMD/severe osteopenia
          • Symptoms and signs: Fatigue, pruritis, bone pain, peptic ulcer disease, nephrocalcinosis.
      • Operative Approach:
        • Identify all parathyroid glands.
        • Subtotal or total parathyroidectomy with autotransplantation.
        • Some suggest excision of only enlarged glands, but recurrence risk higher.

Complications of Parathyroid Surgery

  • Overview:
    • Parathyroidectomy generally successful in >95% of patients.
    • Minimal mortality and morbidity when performed by experienced surgeons.
  • Specific Complications:
    • Vocal Cord Palsy:
      • Transient and permanent forms.
    • Hypoparathyroidism:
      • Transient or permanent.
      • More likely in cases of:
        • Four-gland exploration with biopsies.
        • Subtotal resection with inadequate remnant.
        • Total parathyroidectomy with autotransplantation failure.
      • Risk Factors:
        • High-turnover bone disease (elevated preoperative alkaline phosphatase).
      • Management:
        • Oral Calcium Supplements: Up to 1–2 g every 4 hours.
        • 1,25-Dihydroxy Vitamin D (Calcitriol [Rocaltrol], 0.25–0.5 µg twice daily).
        • Intravenous Calcium: Rarely needed, only in severe cases.
    • Permanent Complications:
      • Vocal Cord Paralysis and hypoparathyroidism if symptoms persist >6 months.
      • Incidence: Approximately 1% in surgeries by experienced surgeons.
  • Other Complications:
    • Hypocalcemia resulting from various conditions (see Hypoparathyroidism section).
    • DiGeorge Syndrome: Congenital absence of parathyroid glands, lack of thymus, and lymphoid system.

Hypoparathyroidism

  • Causes:

    • Congenital:

      • DiGeorge Syndrome:

        • Congenital absence of parathyroid glands.
        • Associated with lack of thymic development and lymphoid system.

        image.png

    • Surgical:

      • Thyroid Surgery:
        • Particularly total thyroidectomy with central neck dissection.
        • Common cause of hypoparathyroidism.
      • Parathyroid Surgery:
        • More likely if undergoing subtotal resection or total parathyroidectomy with autotransplantation.
    • Clinical Features:
    • Acute Hypocalcemia:
      • Decreased ionized calcium leading to increased neuromuscular excitability.
      • Symptoms:
        • Circumoral numbness
        • Fingertip tingling
        • Anxiety
        • Confusion
        • Depression
      • Physical Signs:
        • Chvostek’s Sign:
          • Contraction of facial muscles elicited by tapping the facial nerve anterior to the ear.
        • Trousseau’s Sign:
          • Carpopedal spasm elicited by occluding blood flow to the forearm with a blood pressure cuff for 2–3 minutes.
      • Tetany:
        • Tonic-clonic seizures
        • Carpopedal spasm
        • Laryngeal stridor
        • May be fatal if not treated.
    • Management:
    • Oral Calcium Supplements:
      • Up to 1–2 g every 4 hours.
    • Vitamin D Supplements:
      • 1,25-Dihydroxy Vitamin D (Calcitriol [Rocaltrol], 0.25–0.5 µg twice daily).
    • Intravenous Calcium Supplementation:
      • Rarely needed.
      • Reserved for severe, symptomatic hypocalcemia.