Hyperparathyroidism Diagnosis

• 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 1^st 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 2^nd 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

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 (2^nd generation PTH assay) or PTH 1-84 assays (3^rd 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

• 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

Ultrasonography

• 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)

• 2^nd-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:
  
  • ^{- 201}Thallous 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