Hyperparathyroidism is a condition wherein there is an excessive production of parathyroid hormone (PTH).

Primary hyperparathyroidism is the most common endocrine disorder and an important cause of hypercalcemia in ambulatory patients.

Classic signs and symptoms include bone disease, kidney stones and hypercalcinosis.

Primary goal of pharmacological therapy is to normalize calcium levels.


Hyperparathyroidism Diagnosis


Primary Hyperparathyroidism (PHPT)
  • An autonomous parathyroid hormone (PTH) overproduction resulting from either an adenoma or hyperplasia of parathyroid tissue
  • 2 molecular defects in sporadic parathyroid adenoma
    • Cyclin D1 gene inversions - leads to cyclin D1 overexpression causing cell proliferation
    • MEN1 mutations - accounts for approximately 20-30% of sporadic parathyroid tumors & found in familial parathyroid adenomas
  • Genetic syndromes associated w/ familial parathyroid adenomas
    • Multiple endocrine neoplasia, type 1 (Werner’s syndrome) & 2 (Sipple’s syndrome) - due to germline mutations of MEN1 & RET
    • Familial hypocalciuric hypercalcemia - a rare autosomal dominant disorder caused by loss-of-function mutation in parathyroid calcium-sensing receptor gene (CASR) leading to decreased extracellular calcium sensitivity
    • Neonatal severe PHPT - rare disorder developing shortly after birth affecting either homozygous or heterogenous mutation of the calcium-sensing receptor gene
    • Hyperparathyroidism-jaw tumor syndrome
      • Affects adults; an autosomal dominant disorder characterized by fibrosseous jaw tumors & parathyroid adenoma; Polycystic kidney disease, renal hamarthomas & Wilms tumor can also be observed in affected patients
    • Familial isolated hyperparathyroidism- has no specific features but are thought to be an occult expression of MEN type I
  • May occur during pregnancy
    • Causes spontaneous abortion, intrauterine growth restriction, supravalvular aortic stenosis, still birth & neonatal tetany
    • Neonatal tetany is a result of fetal parathyroid gland suppression by high levels of maternal circulation which readily crosses the placenta during pregnancy & most common initial sign of maternal hyperparathyroidism
    • Functional hypoparathyroidism occurs after birth in infants of mothers w/ PHPT due to hypercalcemic states while in utero
    • Affected infants can develop hypocalcemia & tetany in 1st few days of life
    • Initial symptoms: Abdominal symptoms, muscle weakness, disorientation, coma & death
    • Other complications: Prematurity, spontaneous abortion, intrauterine growth restriction, still birth
    • Decreased risk of obstetric complication has been seen in patients who undergo surgery for hyperparathyroidism
    • Surgical intervention can be done around 2nd trimester
  • Clinical manifestations:
    • Musculoskeletal: Bone disease & bone pain secondary to bone fractures weakened by osteopenia, osteoporosis or osteitis fibrosa cystics, Brown tumors/cysts, muscle aches, weakness, fatigue
    • Renal: Nephrocalcinosis, nephrolithiasis w/ attendant pain & obstructive uropathy, chronic renal insufficiency & renal function abnormalities leading to polyuria & secondary polydipsia
    • Gastrointestinal: Abdominal pain, constipation, nausea, vomiting, peptic ulcers, pancreatitis & gallstones
    • Neurocognitive: Depression, lethargy, seizure, anxiety, depression, cognitive dysfunction, nervousness, mild emotional disturbances, frank psychosis
    • Cardiac: Aortic &/or mitral valve calcifications, hypertension

Secondary Hyperparathyroidism

  • Caused by any condition giving rise to chronic hypocalcemia leading to compensatory PTH overactivity
  • Other causes: Inadequate dietary calcium intake, steatorrhea, vitamin D deficiency
  • In cases of chronic renal insufficiency, decrease in phosphate excretion leads to elevation of serum phosphate levels which directly depresses serum calcium levels eventually leading to parathyroid gland stimulation
  • Clinical manifestations: Renal osteodystrophy, calciphylaxis

Tertiary Hyperparathyroidism

  • Persistence of autonomous hypersection of parathyroid hormone after secondary hyperparathyroid hormone is corrected
  • Development of hypercalcemia refractory to medical management in patients w/ secondary hyperparathyroidism

Transient Neonatal Hyperparathyroidism

  • Occurs in infants of mothers w/ idiopathic or surgically-induced hypoparathyroidism or pseudo­hypoparathyroidism
  • Caused by chronic intrauterine exposure to hypocalcemia which results to fetal parathyroid gland hypoplasia


  • Complete history & physical examination including surgical procedures, medical conditions & medications
  • Check for thiazide diuretic & Lithium intake

Laboratory Tests

Urine tests

24-hour Urinary Calcium Level Measurement

  • Performed to exclude familial hypocalciuric hypercalcemia (FHH)
  • Used in renal complication risk assessment for asymptomatic PHPT
  • Elevated levels in young patients should raise suspicion on multiple endocrine neoplasia (MEN) syndrome & familial endocrinopathies
  • <200 mg/day (5.0 mmol/day) urinary calcium excretion - FHH or PHPT w/ concomitant vitamin D deficiency is possible
  • <100 mg/day urinary calcium excretion - seen in approximately 75% of FHH patients

Urinary Calcium Excretion

  • Helpful in renal complication risk assessment for asymptomatic PHPT patients

Serum Test

Total Serum Calcium Concentration

  • Used for initial & repeat serum calcium measurements
  • Preferrably done on a fasted patient w/ minimal venous occlusion
  • Being done together w/ serum albumin measurement because it may influence the accuracy of total serum calcium concentration
  • Adjusted to reflect any abnormality in albumin
  • Compute for corrected calcium
    • Corrected calcium (mg/dL) = Measured total serum calcium (mg/dL) + 0.8 x (4.0 - serum albumin concentration(Patient)(g/dL)
    • Corrected calcium (mg/dL) = Measured calcium (mg/dL) - measured albumin (g/dL) +4

Ionized Serum Calcium

  • Preferred for patients w/ asymptomatic PHPT in patients w/ normal serum albumin concentrations & absence of acid base imbalance
  • It has the advantage of not being affected by albumin levels
  • Adjunct to diagnosis in patients w/ presumed normocalcemic PHPT
  • Longstanding asymptomatic hypercalcemia is suggestive of PHPT

Serum Parathyroid Hormone (PTH) Concentration

  • Uses an intact PTH (2nd generation PTH assay) or PTH 1-84 assays (3rd generation)
  • Concomittantly measured w/ serum calcium to diagnose hyperparathyroidism
  • Elevated PTH - 80-90% of PHPT patients
  • PTH w/ normal range - 24-hour urinary calcium excretion measurement should be done to help distinguish PHPT from FHH
  • PTH lower end of normal range - investigate for non-PTH-mediated cause of hypercalcemia
Serum Phosphorus
  • May be in the lower normal range or decreased in cases of PHPT
  • Some patients may present w/ mild hyperchloremic acidosis

Serum 25-hydroxyvitamin D (25(OH)D)

  • Useful to distinguish PHPT from other conditions
  • Insufficiency (<20 ng/dL) or frank deficiency (<10 ng/dL) indicates a more active disease
  • Evidence showed PTH level reduction can occur in cases of insufficient correction of 25(OH)D
  • Increased urinary calcium excretion w/ vitamin D repletion - seen in mild PHPT w/ concomitant vitamin D deficiency, elevated serum PTH & calcium w/ normal or low 24-hour urine calcium excretion
  • Low 25-hydroxyvitamin D is noted in secondary hyperparathyroidism due to vitamin D deficiency

Serum Creatinine

  • Diminished by hypercalcemia
  • eGFR of 60 mL/min - chronic kidney disease threshold for deciding which asymptomatic PHPT patient will benefit from early surgical management

Bone Markers

  • Eg Collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase
  • Upper normal value or mildly elevated in asymptomatic PHPT
  • Severe cases presents w/ elevated bone markers

Genetic Testing

  • Performed in patients suspected w/ familial form of PHPT, young patients & those w/ family history of PHPT, multigland involvement or clinical finding suspicious for multiple endocrine neoplasia type 1 (MEN1)
  • Approximately 10% patients w/ PHPT will have 1 out 11 genes mutation



  • Highly operator-dependent & high subjectivity in interpretation
  • Vital information for diagnosis can be detected when correlated w/ scintigraphy findings
  • Cervical ultrasonography is utilized for excellent anatomic information but not for lesion identification
  • Parathyroid adenoma appears as a homogenous well-demarcated mass, hypoechoic in contrast to hyperechoic thyroid tissue
  • Enlarged inferior parathyroid adenomas are found immediately adjacent to the inferior pole of the thyroid lobes, thyrothymic ligament or upper cervical portion of the thymus
  • Enlarged superior parathyroid adenomas are usually found adjacent to posterior thyroid lobe which tends to migrate posteriorly & inferiorly

Single-proton Emission Computed Tomography (SPECT/CT)

  • 2nd-line modality in identification of ectopic glands
  • Most valuable in identifying ectopic adenoma (except those located in the lower neck at the level of the shoulders & lesions close to or within the thyroid gland) hyperfunctioning gland not identified during initial surgery
  • More successful modality in detecting retrotracheal, retro-esophageal & mediastinal adenoma
  • Mediastinal view - utilized to locate ectopic glands in the thorax
  • Jaw view - to locate undescended glands

Magnetic Resonance Imaging (MRI)

  • Same as single-proton emission computed tomography (CT)
  • Indicated in pregnant patients w/ noninformative ultrasound results & identification of ectopic parathyroid tissue

4D Computed Tomography (CT)

  • Powerful modality in identifying missed parathyroid glands & localization
  • Provides anatomic & function (perfusion) information
  • Axial views from jaw to aortic arch & perfusion studies should be included
  • Differentiates between perfusion characteristics, hyperfunctioning parathyroid gland, & status of parathyroid glands & other neck structures are visualized
  • When used w/ ultrasound shows 94% sensitivity & 90% specificity in lateralizing hyperfunctioning parathyroid glands & 82% sensitivity in localizing to the correct quadrant of the neck

Parathyroid Positron Emission Tomography (PET)

  • Tracers utilized:
    • 18F-fluorodeoxyglucose - used for the identification of pituitary adenomas
    • 11C-methionine - utilized in cases of problematic identification of parathyroid site w/ conventional scintigraphy

Double-tracer Parathyroid Scintigraphy

  • Also known as subtraction scanning
  • Parathyroid tracers are non-specific & absorbed by the thyroid gland as well; also used as myocardial perfusion tracers
  • Comparison w/ a second tracer is necessary
  • Application:
    • Detection of recurrent & persistent disease both in primary & secondary hyperparathyroidism
    • Improvement in initial surgical results in PHPT
    • Selection of appropriate surgical management for patients w/ PHPT
  • Parathyroid localization tracers utilized:
    • - 201Thallous chloride (201Tl) - first agent used to successfully visualize parathyroid glands in 1980s
    • 99mTc-sestamibi - used for parathyroid localization involving subtraction technique using 123I; Vitamin D therapy might reduce tracer uptake
    • 99mTc-tetrofosmin - an alternative to 99mTc-sestamibi for parathyroid subtraction scanning
  •  Thyroid scan tracers utilized:
    • 99mTc-pertechnetate
    • 123I - trapped & organified by the thyroid; stable within the thyroid gland for long periods of time; uses at least 2 hours for adequate uptake by the thyroid gland


Bone Mass Density

  • Determine reductions in bone density in PHPT patients
  • Essential part of disease management
  • Aids in confirmation of trabecular involvement in asymptomatic PHPT
  • Approaches: Dual-energy x-ray absorptiometry (DXA), vertebral X-ray, vertebral fracture assessment (VFA), trabeculaar bone score (TBS) by DXA or high-resolution peripheral quantitative computed tomography (HRpQCT)
  • Bones to be assessed: Spine, hip & distal ⅓ of forearm

Invasive Methods

Selective Venous Sampling (SVS)

  • Most sensitive localization procedure
  • Highly operator-dependent
  • Catheterization of common femoral vein or iliac vein to obtain PTH baseline values & internal jugular vein or multiple veins (neck & mediastinum) for lateralization
  • Venograms should be obtained in 2 planes to delineate the precise anatomic location of sampled vessels
  • 2-fold elevation in PTH value compared to baseline denotes a positive localization study
  • Limited by procedure cost, adverse reactions (ie renal failure & anaphylactic reaction to contrast medium), & operative complications (ie bleeding, infection, pseudoaneurysm & AV fistula)

Ultrasound-guided Fine Needle Aspiration/Biopsy

  • Cytologic confirmation & PTH biochemical assay should be done to samples
  • Confirms the presence of PTH & differentiate it from other structures
  • Useful in the differential diagnosis of intrathyroidal parathyroid adenoma from a thyroid nodule
  • Positive PTH FNA, surgical reexploration should be done
  • Preoperative FNA of parathyroid glands should not be done due to theoretical risk of parathyroid cell seeding


  • Parathyroid crisis
    • Also known as acute PHPT, parathyroid poisoning, parathyroid intoxication, parathyroid storm, hypercalcemic crisis
    • Excessive fluid loss or severely limits the amount of fluid they can consume
    • Sudden onset of life-threatening hypercalcemic episodes
    • Clinical manifestations are severe hypercalcemia-associated
    • Nephrocalcinosis or nephrolithiasis is frequently seen
    • Radiologic finding: Subperiosteal bone resorption
    • Laboratory findings: Very high serum calcium levels, 20x above normal PTH levels
    • Aggressive fluid resuscitation at a rate of at least 200 mL/hr of normal saline to promote renal calcium excretion & intravascular volume restoration
    • Once rehydrated, diuresis or dialysis w/ no or low calcium-containing dialysate may be added to inhibit reabsorption of calcium, as long as blood pressure remains stable
  • Impaired renal function
  • Nephrolithiasis
  • Bone disease - increased risk of bone fracture, osteopenia, osteoporosis or osteitis fibrosa cystica
  • Rheumatic symptoms - gout or calcification of wrist or knee cartilage
  • Other chemical imbalance - decreased blood phosphate level or slightly increased magnesium level
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