Parathyroid anatomy
- 4 symmetrically arranged glands. Can vary from 2 to 6
- 10-20% mostly inferior are aberrant
- Supernumerary glands: 7-10% of population
- Weight: up to 50 grams. Size < 7mm.
- Yellowish-brown in color and each one is about the size of a split pea.
Histology of parathyroid
Fat cells
- Young: few sparse but increase gradually until 30 y, 10-25% of glandular volume, after which remain constant.
Parenchymal cells
- Chief cells: Calcium homeostasis, have calcium sensing receptor (CaSR) to detect small changes in serum Ca level. Normal level 2.2 – 2.6mmol/L, produce PTH (T1/2 - 2-3mins)
- Oxyphilic cells: unknown function, usually inactive. May produce PTH
Primary Hyperparathyroidism
Excessive PTH secretion with resulting abnormal Ca2+ homeostasis with normal renal function due to:
Solitary Adenoma (80-90%)
- Microadenoma: Adenoma with rim of normal tissue. Nuclear pleomorphism – differentiate adenoma from hyperplasia
Double adenoma (2-5%)
Parathyroid Hyperplasia(MGD) (10 – 15%) - Mainly chief cells in diffuse pattern. Asymmetrical involvement
Parathyroid carcinoma (<1%) - Not capsulated, lobulated, firm with adhesion.
Familial syndromes (MEN 1 & 2a), Familial isolated hyperparathyroidism (FIHPT).
Supernumerary in Thymus : 1% - Prof Chaon
Epidemiology of pHPT
- Prevalence: 0.1-2.0%, highest in post-menopausal women.
- Most common cause of hypercalcemia.
- Age: Peak at 50 – 60 years old.
- F : M = 4 : 1
- Majority sporadic, < 5% familial (MEN 1, MEN 2A)
Presentation of pHPT
Asymptomatic - Hypercalcemia detected by routine blood test for unrelated complaints.
Symptomatic
- MOAN: Fatigue, depression, anxiety, decreased working memory and concentration, as well as irritability. (probably due to dehydration)
- STONE: Renal calculi (15-20%), Nephrocalcinosis (calcium oxalate and calcium phosphate deposition in renal parenchyma - 10.2%).
- GROAN: Pancreatitis (related to the severity of hypercalcemia rather than to hyperparathyroidism), peptic ulcer
- BONE: bone pain, pathological fracture. Osteitis fibrosa cystica rare, specific for PHPT
- CVS: HPT, Valvular calcification, Calciphylaxis (Ca2+ deposit in small vessels → blood clots, painful skin ulcers, infection), left ventricular hypertrophy, aortic valve calcification, increased aortic stiffness and increased intimal media thickness. Reduced QT interval ( Tacycardic)
- Nephrogenic DI → polyuria → thirst.
Investigation of pHPT
Blood Investigations: Serum total Calcium, and 24-hour urinary calcium level PTH, Creatinine, and 25-hydroxyvitamin D levels.
X-ray - Hands, Clavicle & Skull: look for resorption signs & cystic formation, punched out skull lesion. Pelvis to screen for silent nephrolithiasis or nephrocalcinosis.
CTU / USG - to detect renal stone.
Dual-energy X-ray absorptiometry (DXA) - Bone mineral density should be measured at the lumbar spine, hip, and distal radius. ( T score < -2.5 suggestive of osteopososis)
Summary of Localization technique ( Non invasive vs invasive) Sensitivity/ Specificity
diagnositic criteria for pHPT
Diagnostic : ↑ Ca2+ (corrected for albumin or ionized (≥2.6 mmol/L)), ↑ iPTH, ↓ or normal PO4
Normal values of iPTH are 10 to 55 picograms per milliliter (pg/mL)
- ↓ or normal iPTH indicates possible malignancy, vitamin D intoxication or thyrotoxic
- Cl : PO4 ratio: > 33 very suggestive of hyperparathyroidism with hypercalcemic acidosis.
The parathyroid gland secretes 1-84 and 7-84 parathyroid hormone (PTH) fragments, and its regulation is dependent on stimulation of the extracellular calcium-sensing receptor. While the intact PTH (iPTH) system detects both PTH fragments, the whole PTH system detects the 1-84PTH but not the 7-84PTH.
Rule out Familial Hypocalciuric Hypercalcemia (FHH):
- Patients usually asymptomatic.
- 24 h urine Calcium to Creatinine Clearance Ratio (CCCR) (24-hour urine calcium/ plasma total calcium)/(24-hour urine creatinine/plasma creatinine)- <0.01 in 80% is diagnostic.
- pHPT CCCR - > 0.02
- 20% of individuals with FHH have a CCCR between 0.01 and 0.02 and can overlap with pHPT.
- Autosomal dominant, due to mutation of Ca2+sensing receptor gene (CaSR) → will not benefit from parathyroidectomy.
Differential diagnosis for hypercalcaemia
Management of pHPT
Divided into:
Surgical
Medical
Surgery is definitive cure for pHPT.
- Surgery does not correct CVS abnormalities in hyperparathyroidism, and whether it alleviates psychiatric and cognitive deficits is a subject of controversy.
Medical management
- Correction of dietary calcium and vitamin D insufficiency.
- Cinacalcet (increase the sensitivity (affinity) of the CaSR receptor in parathyroid to activation by extracellular calcium) lowers lower PTH and thus lower the serum calcium levels but does not affect rates of bone loss.
- Bisphosphonates (Alendronate 10 mg daily) improve bone density, but whether they reduce the risk of fracture is unknown.
IV Zoledronate (Zometa) 4mg given over 15 min 3 monthly
IV pamidronate 60mg in 100cc NS run over 2 hours for malignant
How to manage Hypercalcemia?
🍋Giving hydration ( 2-4L) because normally patient with hyperparathyroidism will be dehydrated:
Patients with hypercalcemia often become dehydrated due to the following mechanisms:
🍎Increased Urinary Calcium Excretion:
* High levels of calcium in the blood lead to increased calcium filtration through the kidneys. The kidneys try to excrete the excess calcium, which requires additional water to flush it out, resulting in increased urine output (polyuria).
🍏Inhibition of Kidney’s Ability to Concentrate Urine:
* Hypercalcemia interferes with the kidney’s ability to concentrate urine by affecting the function of antidiuretic hormone (ADH). High calcium levels reduce the kidney’s response to ADH, leading to increased water loss in the urine (nephrogenic diabetes insipidus-like effect). This contributes to dehydration.
Additional medication for hypercalcemia:
Denosumab ( RANK Ligand inhibitor) - inhibit bone resorption
Surgical management of pHPT
( Indication)
Indication for Surgery
- Serum Ca2+ - > 1mg/dl or >2.85 mmol/L (Corrected Ca = serum Ca level (mg/dL) + 0.8 × (4 − serum albumin [g/dL])).
- Hypercalciuria, urine Ca2+ >10 mmol/day
- Impaired renal function, Creatinine clearance ≤70% of age matched normals (< 60ml /min)
- Osteoporosis (bone density T score < –2.5) and fragility fractures
- < 50 years of age
- Nephrolithiasis or Nephrocalcinosis.
- Patients for whom medical surveillance is not possible or desirable
Surgical management of pHPT ( Pre operative Localization)
Localization can be divided into:
- 🍏Preoperative ( subdivided into Non invasive and invasive)
- 🍎Intraoperative
🔥Non-Invasive:
USG
- Accuracy: 70-90% of enlarged glands.
- ↓ Sensitivity in intra thyroid, ectopic & mediastinal parathyroid gland.
- Seen as homogenous well defines mass, hypoechoic with extrathyroidal feeding vessel.
- FNAB of a suspicious lesion is discouraged to prevent parathyroid seeding.
99mTc-MIBI scintigraphy (Sestamibi scan)
- Accuracy: 75% of parathyroid adenoma & 50% abnormal gland.
- Taken up by mitochondria in both thyroid & parathyroid gland.
- Uptake into parathyroid per gram lower than thallium, but thyroid : parathyroid ratio higher because thyroid has higher washout (less mitochondria)
- Initial scan & 2 hour later.
- Inaccurate in parathyroid hyperplasia, small adenoma, coexisting thyroid disease, Ca2+channel blocker usage.
SPECT scan (Single-photon emission CT)
- Sestamibi should be carried out with the SPECT technique or in combination with CT, accuracy: ↑ 85% detection of PT gland.
- 3D 99mTc-MIBI scan with higher resolution & improved performance.
- Improve detection of ectopic PT gland & illustration of depth
- Advantage for retro-tracheal, retro-esophagus and mediastinal adenoma
MRI
- Accuracy: 40 – 85%
- PT gland low signal on T1 & high intensity on T2.
- Cervical LN show similar findings.
U/S & SPECT CT
- combination has 90-94% detection rate
🔥Invasive
Selective venous sampling for iPTH
- 80% Sensitivity for redo cases, does not localize but use gradient to lateralize to the affected side. Sampling done from internal jugular and brachiocephalic veins
- 2 x increase iPTH compared to peripheral venous sampling.
- Indicated when noninvasive localization failed or when re do surgery.
DSA/ Conventional Arteriography
- Selective radiography of thyrocervical trunks, both Internal mammary arteries, both Common Carotid arteries. Blush following injection of contrast indicate presence of hyper vascular gland.
SPEC CT and Sestamibi scan
SPECT-CT and Sestamibi scans are not exactly the same, but they are often used together in nuclear medicine imaging, particularly for parathyroid imaging.
1. What is a Sestamibi Scan
A Sestamibi scan is a nuclear medicine scan that uses Technetium-99m sestamibi (Tc-99m MIBI), a radiotracer that is absorbed by parathyroid adenomas or thyroid tissue. It is commonly used for:
Parathyroid imaging (to locate overactive parathyroid glands in primary hyperparathyroidism).
Myocardial perfusion imaging (to assess blood flow in heart disease).
Breast tumor imaging (in some cases).
2. What is SPECT-CT?
SPECT (Single Photon Emission Computed Tomography) is a 3D nuclear imaging technique that detects gamma rays from a radiotracer.
CT (Computed Tomography) is an X-ray-based imaging technique that provides anatomical detail.
SPECT-CT combines both: SPECT gives functional information (where the tracer is), and CT gives anatomical detail (precise location of the tracer uptake).
3. How are They Related?
A Sestamibi scan can be done with or without SPECT-CT.
Planar Sestamibi Scan (2D) provides only functional imaging.
SPECT-CT Sestamibi Scan provides more precise 3D localization of parathyroid adenomas, helping distinguish them from lymph nodes or thyroid tissue.
4. When is SPECT-CT Preferred?
Difficult cases (e.g., ectopic or small parathyroid adenomas).
Pre-surgical localization for parathyroidectomy.
Better differentiation of parathyroid vs. thyroid or lymph nodes.
Summary
🔹 Sestamibi Scan = Uses Tc-99m sestamibi to detect parathyroid, cardiac, or breast abnormalities.
🔹 SPECT-CT = A hybrid functional + anatomical imaging technique that improves localization.
🔹 Sestamibi Scan + SPECT-CT = More accurate in identifying parathyroid adenomas than a standalone Sestamibi scan.
Latest advancement for Localization of parathyroid
Several articles have reported the high sensitivity of 18F-fluorocholine PET-CT for the detection of parathyroid adenomas. Choline PET-CT can detect elusive parathyroids, including ectopic glands, and may be considered in the management of persistent or recurrent disease when other scans are negative
sensitivity near 100%
Surgical management of pHPT ( Intra operative Localization)
Need to expose & inspect all 4 glands before removing any abnormal gland.
Intra-operative PTH assay (IOPTH)
- Sensitivity 90%, PPV 90%
- Stop propofol at least 5 min before analysis
- Ipsilateral IJV and peripheral vein cannulated, make sure no IV on sampling side.
- Sample taken per:
- Pre skin incision
- Pre excision (post dissection pre ligation of vessels of gland)
- 10 minutes post excision,
- 20 mins post excision
- Vienna Criteria - ≥ 50% ↓ from baseline (pre incision) to 10 mins after excision
Intra-operative U/S ± FNA
- Differentiate colloid goiter and parathyroid gland, can guide FNA with PTH assay. After resection, do IOPTH assay.
- Assay of aspirate > 1900 pg/ml (10-fold of serum) for confirmation of parathyroid gland.
Frozen section
- Intraoperative frozen section can help to identify parathyroid tissue, but it cannot differentiate between hyperplastic tissue and parathyroid adenoma.
- Biopsy of normal parathyroid glands should be deferred as it can compromise their vascularization and function
- If auto transplantation is planned and surgeon is uncertain about parathyroid origin, a small biopsy can be examined with frozen sections.
Operative Options for pHPT
Operative options:
Minimal invasive or focused parathyroidectomy (current gold standard)
- Reduce incision length, provide a focused exploration, enable surgery under local anesthesia, and reduce postoperative discomfort.
- Some centers do as a day care procedure
- Must have positive pre-operative localization
- IOPTH is recommended to confirm adequate resection.
- Nonsurgical techniques utilized – Ethanol injection, transcatheter ablation, Laser photocoagulation, USG guided RFA ablation.
Bilateral neck exploration
- Had been the standard procedure for pHPT surgery
- Signs of multiglandular disease in pHPT:
- Negative preoperative imaging procedures,
- Inhomogeneous results of localization studies,
- Visualization of several enlarged or hyperfunctioning parathyroids,
- History of familiar disease or lithium medication.
- Identify all 4 glands & excise the single adenoma (>95% cure in experience hand)
- In MGD subtotal PTH excision & implant ½ a gland under brachioradialis muscle.
Unilateral neck exploration
- Only in solitary adenoma after pre operative localization.
- May miss MGD, double adenoma, hyperplasia if inaccuracy of pre-operative localization.
Endoscopic / video assisted parathyroidectomy
- OMIP - Open Minimally Invasive Parathyroidectomy
- MIVAP - Minimally Invasive Video-Assisted Parathyroidectomy
- TOEPVA - Transoral Endoscopic Parathyroidectomy Vestibular Approach
Excision ± Auto Transplant
- Single gland adenoma (80-85%): abnormal gland removed (adenoma), confirmed by frozen section.
- 2 glands enlarged (2 -5%) : Removed the enlarged 2, normal gland biopsied & clipped.
- 3 glands enlarged: Removed the enlarged 3, normal biopsied & clipped.
- 4 glands enlarged (MGD) 10-15% – 2 options:
- Removed 3½ gland with thymectomy (due to supernumerary glands), or
- Removed all 4 with thymectomy and implant ½ or cryopreservation.
If Failure to identify parathyroid during intraoperative
- Open and inspect thyroid capsule; palpate the gland/ intraoperative USG
- Mobilize pharynx and esophagus to look in parapharyngeal, retropharyngeal and esophageal spaces, digital exploration of post mediastinum, capsulotomy of upper thyroid lobe to look for subcapsular intra-thyroidal gland (for missing superior PTG) look around the inferior pole.
- Dissect superior thymic / paratracheal tissue, thyro-thymic ligament & thymus; complete a cervical thymectomy (for missing inferior PTH gland)
- Open carotid sheath and expose common carotid throughout its course in the neck; inspect for potential PTH glands.
- Ligate ipsilateral inferior thyroid artery and/ or perform a thyroid lobectomy.
- If still cannot find, DO NOT do sternotomy the first time around, close & come out.
- Record location of all confirmed glands identified
- Terminate; follow patient for evidence of persistent hypercalcemia.
- Re-image for evidence of ectopic PTH adenomas
Post operative management
- Monitor for cervical hematoma. If secondary hemorrhage is suspected, immediate airway management and decompression required.
- Postoperative parathyroid function on first postoperative day (Calcium, PTH), to rule out hypoparathyroidism.
- Oral calcium according to symptoms.
- Vitamin D supplementation in deficient patients.
- 50% develop early hypocalcemia, in 10%, hungry bone syndrome is the cause - Prophylactic supplementation with oral calcium and vitamin D.
Hungry Bone Syndrome
Prolonged hypocalcemia with normal PTH due to a rapid decrease in bone formation with increased skeletal calcium requirement and is mostly diagnosed between the 5th and 7th postoperative days.
Risk factors:
- Older age,
- Preoperative calcium > 3.0 mmol/L,
- Preoperative osteoporosis
- Vitamin D deficiency
- Elevated alkaline phosphatase
what is persistent hyperparathyroidism
Elevated serum calcium and PTH levels present for more than 6 months post parathyroidectomy.
Cause:
- Failure to identify or remove the parathyroid adenoma
- Failure to identify or remove all adenomatous or hyperplastic parathyroid tissue
- Inadequate subtotal resection in four-gland hyperplasia (MGD)
- Subtotal resection of a parathyroid adenoma
- Residual or metastatic parathyroid carcinoma
- Parathyromatosis - Implantation of cells containing parathyroid adenoma or hyperplastic parathyroid cells – due to tumor capsule rupture.
- Failed percutaneous ablation techniques
What is recurrent hyperparthyroidism
Calcium and PTH decrease postoperatively to normal range and rise again after 6 months or later
Need TRO MEN
Cause:
- Regrowth of hyperplastic parathyroid tissue (especially in familial HPTH)
- Regrowth of auto transplanted parathyroid tissue
- Recurrent or metastatic parathyroid carcinoma
- Parathyromatosis
Approach to Persistent or Recurrent Hyperparathyroidism
Approach to Persistent or Recurrent Hyperparathyroidism
- Full history, examination.
- Family history of endocrinopathies, including MEN, familial primary hyperparathyroidism.
- Review of previous localization results.
- Review of previous HPE
- Communicate with the surgeon operated on before.
Investigations
Biochemical
- Inappropriately ↑ PTH level with hypercalcemia & normal renal function.
- ↑ PTH with normal calcium: not persistent hyperparathyroidism. Causes include hungry bone syndrome, low Vit D, impaired renal function.
- ↑ Calcium with ↑ PTH appropriately: concomitant malignancy.
Preoperative Localization
Need 2 concordant studies
- USG Localization
- SPECT MIBI scan
- CT & MRI – To look for ectopic gland
- Selective venous sampling of iPTH.
- U/S with FNAC of suspicious gland then sends the aspirate for PTH assay: 10-X ↑ in PTH compared to serum level confirm the parathyroid tissue.
Indication for Re Operation
- Ongoing Nephrolithiasis
- Worsening renal function
- Worsening bone disease as evidenced by bone mineral density scores
- Associated neuromuscular symptoms
- Associated psychiatric symptoms
- Worrisome progressive hypercalcemia
Patho Slide
Identification of Parathyroid glands
- Rim of fat
- Moves away on touch
- Color changes with age (Young - grey)
- Encapsulated
- Homogenous on cross section
- Wangs’ test ( Density Study done in 1978 in US by wang,)
- Tiny blood vessels running on surface
- Soft to touch
- Globular
Wang’s Test ( Density Test)
These data show that the Density Test is useful in the intraoperative diagnosis of a diseased from a normal parathyroid tissue. Tissue that sinks within the density range of 1.049and1.069 is without exception diseased and should therefore be either partially or completely excised even if the gland is of average size or only of slight enlargement. If it does not sink, it is virtually certain to be normal and should be spared.
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🫶Differentiated Thyroid Cancer (DTC) + Hyperthyroidism + Thyroglossal cyst84
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🪢Medullary Thyroid Ca9
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☠️🤕Anaplastic Thyroid carcinoma11
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🌊Thyroid Lymphoma + Lymphoma17
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🏀Primary Hyperparathyroidism23
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🏈Secondary and Tertiary Hyperparathyroidism12
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🛰️Adrenal Incidentaloma12
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🛟🥌Pheochromocytoma22
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🌝Cushing Syndrome14
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⭐️Primary Hyperaldosteronism (Conn)15
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☄️Adrenocortical Carcinoma (ACC)9
