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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 skin 25-OH vitamin D 1,25 OH2 vitamin D 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 intake Hyperparathyroidism Hyperthyroidism Immobilization Milk Alkali Syndrome Pagets Disease Adrenal Insufficiency Neoplasm Bone mets, bone tumors PTH related peptide secreting tumors (small cell lung cancer) Blast crisis Primary malignancies Zollinger Ellison (MEN I Syndrome) Elevated Vitamin D Elevated Vitamin A Sarcoid and other granulomatous disorders Familial hypocalciuric hypercalcemia Lithium Thiazide 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


thall/techn scintigraphy computed tomography ultrasonography MRI Technetium-99m Sestamibi

Sens 73% 68% 55% 50%


91%

Spec 94% 92% 95% 87%


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 postmanipulation 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 gland selective arteriography selective venous sampling FNA 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 its 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 Schwartzs Principles of Surgery 8th Edition 2005 Duh QY. Whats 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 Surgeons Armamentarium to the Surgical Treatment of Primary Hyperparathyroidism J Surg Onc 2005;89:130-135

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