Hyperparathyroidism Diagnosis
Classification
- 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
History
- 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
- 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
Imaging
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)
- 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
Screening
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
Complications
- 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