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Hyperparathyroidism
Anatomy/Embryology
• endoderm of pharyngeal pouches III and IV• inferior parathyroid glands arise from pouch III
– migrate down with the thymus– usually located at inferior pole of the thyroid– associated with most variability in location
• superior parathyroid glands arise from pouch IV – located just above the intersection of recurrent
laryngeal nerve and the inferior thyroid artery
• usually 4 glands, supernumerary glands in 15%
Anatomy/Embryology
• parathyroid glands typically located posterolateral to the thyroid
• arterial supply: inferior thyroid artery (superior thyroid, throidea ima)
• venous drainage: inferior, middle, superior thyroid veins
• adult parathyroid gland 50% parenchyma 50% fat• cell types:
chief cells (water clear cells)oxyphil cells
Parathyroid Hormone
• secreted by chief cells
• Release of PTH
Increased by: low serum calcium
Decreased by: high serum calcium,
low magnesium,
1,25 dihydroxy vitamin D
vitamin D3 25-OH vitamin D 1,25 OH2 vitamin D
skin liver kidney
Parathyroid Hormone• Type I PTH receptors present in bone, kidney and intestine
Bone • + osteoclasts - osteoblasts• increased bone resorption • calcium and phosphorus release
Kidney• increased calcium resorption• increased phosphorus excretion• increased conversion of 25 hydroxy vitamin D to
1,25 dihydroxy vitamin D
Intestines (indirect effect through vitamin D)• increased calcium absorption
Hypercalcemia
Calcium intakeHyperparathyroidismHyperthyroidismImmobilizationMilk Alkali SyndromePaget’s DiseaseAdrenal InsufficiencyNeoplasm
Bone mets, bone tumorsPTH related peptide secreting tumors (small cell lung cancer) Blast crisisPrimary malignancies
Zollinger Ellison (MEN I Syndrome)Elevated Vitamin DElevated Vitamin ASarcoid and other granulomatous
disordersFamilial hypocalciuric hypercalcemiaLithiumThiazide Diuretics
Hyperparathyroidism
• 100,000 new cases per year in the US
• 2:1 female:male ratio
• average age at diagnosis 55
• 2/1000 people over the age 60
Primary Hyperparathyroidism
• High serum calcium (ionized calcium)
• High or high normal PTH levels
• Solitary Parathyroid Adenoma ~85%
• Multiple Adenomas, hyperplasia ~15%
• Parathyroid Carcinoma ~1%
Manifestations of Primary Hyperparathyroidism
• Hypercalcemia
• Hypercalciuria
• Increased rate of bone turnover
Manifestations of Primary Hyperparathyroidism
• neurobehavioral symptoms: fatigue and weakness• nephrolithiasis 20%• cardiac calcification and LV hypertrophy• osteopenia • most patients asymptomatic although fatigue and
weakness are undercounted as symptoms• 25% of asymptomatic patients have progressive
disease
Hereditary Primary Hyperparathyroidism
• MEN I: parathyroid, pancreatic (Zollinger Ellison), pituitary (prolactinoma)
tumor suppressor MENI gene, autosomal dominant inheritance
• MEN 2A: parathyroid, pheochromocytoma, medullary thyroid cancer
RET proto-oncogene, autosomal dominant inheritance
• Familial Hypocalciuric Hypercalcemia: autosomal dominant, surgery not indicated, PTH normal
• Neonatal Severe Hyperparathyroidism • Hyperparathyroidism- Jaw Tumor Syndrome
Surgical Intervention in Primary Hyperparathyroidism
NIH Criteria for Parathyroidectomy (1991, 2002)Any of the following:• serum calcium > 1mg/dL above normal• history of life threatening hypercalcemia• abnormal serum Cr• elevated urine calcium, > 400mg/day• kidney stones• < 50 years old• bone density less than two standard deviations below
the norm• neuromuscular symptoms
Surgical Intervention in Primary Hyperparathyroidism
• NIH criteria leave out patients who would benefit from parathyroidectomy
• ParathyroidectomyBenefits– neurobehavioral symptoms improve – bone mass increases – safe in patients over 70 years old– bilateral neck exploration cures 95-99% of
patients with a 1-3% complication rate
Preoperative Evaluation
• neck ultrasound
• MRI
• thallium-technetium dual isotope scintigraphy
• technetium-99m sestamibi scan
• SPECT sestamibi scan: allows for 3-D localization but is expensive
Preoperative Study Comparison
Sens Spec
thall/techn scintigraphy 73% 94%
computed tomography 68% 92%
ultrasonography 55% 95%
MRI 50% 87%
Technetium-99m Sestamibi 91% 99%
Technetium-99m Sestamibi Scan
Technetium-99m Sestamibi Scan
• technetium 99m taken up by the thyroid
• sestamibi taken up by both the parathyroid and thyroid tissue
• sestamibi washes out of the thyroid faster
Preoperative Evaluation
• no consensus on whether preoperative localization necessary
• preoperative localization can allow for unilateral focused parathyroidectomy
• The combination often used is:– sesatmibi for localization – ultrasound for information on size and relationship of
the abnormal glands to surrounding tissue
• sestamibi scanning limited in identifying multiple adenomas and 4 gland hyperplasia
• preoperative localization essential in reoperation cases
Parathyroidectomy
Options:
• bilateral neck exploration
• unilateral focused parathyroidectomy
• endoscopic parathyroidectomy
• video assisted parathyroidectomy
Intraoperative Considerations
• Radioguided surgery: timing dependent • Intraoperative ultrasound• Intraopertive internal jugular PTH samples• PTH assay:
most widely used intraoperative test
provides an efficient means of determining adequacy of resection
allows for determination of the need for four gland exploration
PTH Assay
• collection from a peripheral venous sample, IJ sampling may be inaccurate
• baseline measures are pre-incision and post-manipulation
• propofol will interfere with the assay• samples sent at fixed time intervals after resection• Different standards for what constitutes a
successful resection – Drop of at least 50% from highest baseline value– Return of PTH level to normal (used at DHMC)
Persistent Hyperparathyroidism
• 5-10% of patients have persistent disease
• Location of the abnormal glands at second operation
neck 30-54%
mediastinum 16-34%
retroesophageal 14-39%
upper cervical area 8%
aortic arch area 5%
Persistent Hyperparathyroidism
• localization studies necessary prior to reoperation• sestamibi, MRI and ultrasound together identify
abnormal glands in 87% of patients• Invasive studies used if non-invasive methods
cannot localize the abnormal glandselective arteriographyselective venous samplingFNA and PTH assay
• Complication rate at reoperation for recurrent laryngeal nerve injury or hypoparathyroidism
1-2%
Secondary Hyperparathyroidism
• Hypocalcemia in chronic renal failure stimulates PTH secretion and parathyroid gland growth
• Hypocalcemia in CRF caused by hyperphosphatemia and decreased renal production of 1,25 dihydroxy vitamin D
• First line therapy: • phosphate binders • supplemental vitamin D
• Severe or refractory cases of secondary hyperparathyroidism should undergo surgery
• subtotal parathyroidectomy• total parathroidectomy with autotransplantation
Tertiary Hyperparathyroidism
• after renal transplant or as a progression of secondary hyperparathyroidism
• hyperparathyroidism and hypercalcemia• 1/3 of transplant patients• hyperclacemia can threaten the graft• usually subsides within months to years• 1-3% of patients require parathyroidectomy
• subtotal parathyroidectomy• total parathyroidectomy with autotransplantation
Parathyroid Carcinoma
• Occurs in ~1% of patients with hyperparathyroidism
• Associated with genes: cyclin D1, MEN1, HRPT2
• Risk Factors• neck irradiation• ESRD• familial hyperparathyroidism (not MEN
syndromes)• hyperparathyroidism- jaw tumor syndrome
Parathyroid Carcinoma
• more severe hypercalcemia 3-4 mg/dl above normal
• nephrolithiasis 56%• renal insufficiency 84%• pathologic fractures or radiographic evidence of
bone disease 40%• palpable neck mass 50%• hypercalcemic crisis 10%
Parathyroid Carcinoma
Appearance• Adenoma: round, soft and reddish-brown• Parathyroid carcinoma: lobulated firm and
adherent to surrounding tissue• Carcinoma often localized to inferior
parathyroid glands• difficult to distinguish benign and malignant
tumors histologically
Parathyroid Carcinoma
Management• en bloc resection: ipsilateral thyroid lobe, overlying
strap muscles and involved soft tissue
• examination of all four parathyroid glands
• modified radical neck dissection if lymph nodes involved (5% of the time)
• intraoperative PTH monitoring
• 90% long term survival
• if microscopic features of parathyroid carcinoma show up in post-op path reoperation is not indicated
Parathyroid Carcinoma
Postoperatively• hungry bone syndrome: symptomatic hypocalcemia
from calcium and phosphorus deposition into the bones
• if hypocalcemia severe it’s treated with iv calcium and vitamin D
• metastatic disease: cervical nodes, lung > liver> bone
• metastatic disease should be resected decreased tumor burden
• no role for chemotherapy or XRT as primary therapy
• XRT may be useful in the postoperative setting
Parathyroid Carcinoma
Hypercalcemia• biggest problem in disseminated parathyroid
carcinoma
• acute management of hypercalcemia consists of :
normal saline
diuretic
osteoclast inhibitor (calcitonin, bisphosphonates)
calcimimetic agent (cinacalcet)
A 45 yo man with preoperative diagnosis of primary hyperparathyroidism has a neck exploration. A large right lower parathyroid gland is removed and sent for frozen section examination. The specimen is identified as a parathyroid carcinoma.The next step should be.
• modified radical neck dissection• removal of the remaining 3 parathyroid glands and
autotransplantation• exploration of the contralateral neck• ipsilateral thyroid lobectomy and lymph node
dissection• biopsy of all 3 remaining parathyroid glands
A 45 yo man with preoperative diagnosis of primary hyperparathyroidism has a neck exploration. A large right lower parathyroid gland is removed and sent for frozen section examination. The specimen is identified as a parathyroid carcinoma.The next step should be.
• modified radical neck dissection• removal of the remaining 3 parathyroid glands and
autotransplantation• exploration of the contralateral neck
• ipsilateral thyroid lobectomy and lymph node dissection
• biopsy of all 3 remaining parathyroid glands
In addition to calcium replacement, which of the following will promote correction of acute hypocalcemia after resection of a large parathyroid adenoma?
• phosphate binding acids• salt restriction• magnesium• zinc• calcitonin
In addition to calcium replacement, which of the following will promote correction of acute hypocalcemia after resection of a large parathyroid adenoma?
• phosphate binding acids• salt restriction
• magnesium• zinc• calcitonin
Management of hypercalcemia associated with recurrence of parathyroid carcinoma could include administration of any of the following EXCEPT
• bisphosphonates• calcitonin• plicamycin• gallium nitrate• fluorouracil
Management of hypercalcemia associated with recurrence of parathyroid carcinoma could include administration of any of the following EXCEPT
• bisphosphonates• calcitonin• plicamycin• gallium nitrate
• fluorouracil
Intraoperative parathormone assay.
• allows confirmation of removal of an adenoma• decreases operating time• decreases complications• is superior to preoperative localization with
sestamibii scan• is inferior to gamma probe localization
Intraoperative parathormone assay.
• allows confirmation of removal of an adenoma
• decreases operating time• decreases complications• is superior to preoperative localization with
sestamibii scan• is inferior to gama probe localization
References
• Greenfield, Surgery 3rd Edition 2001• Schwartz’s Principles of Surgery 8th Edition 2005• Duh QY. What’s New in General Surgery:
Endocrine Surgery. J. Am Coll Surg. November 2005; 201(5): 746-753
• Mittendorf EA, McHenry CR. Parathyroid Carcinoma. J Surg Onc 2005;89:136-142
• Lee JA, Inabnet WB. The Surgeon’s Armamentarium to the Surgical Treatment of Primary Hyperparathyroidism J Surg Onc 2005;89:130-135