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Hyperparathyroidism
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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 recurrentlaryngeal nerve and the inferior thyroid artery
usually 4 glands, supernumerary glands in 15%
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Anatomy/Embryology
parathyroid glands typically located posterolateralto the thyroid
arterial supply: inferior thyroid artery (superiorthyroid, throidea ima)
venous drainage: inferior, middle, superior thyroidveins
adult parathyroid gland 50% parenchyma 50% fat cell types:
chief cells (water clear cells)
oxyphil cells
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Parathyroid Hormone
secreted by chief cells
Release of PTH
Increased by: low serum calciumDecreased by: high serum calcium,
low magnesium,
1,25 dihydroxy vitamin D
vitamin D3 25-OH vitamin D 1,25 OH2vitamin D
skin liver kidney
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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 to1,25 dihydroxy vitamin D
Intestines (indirect effect through vitamin D)
increased calcium absorption
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Hypercalcemia
Calcium intake
Hyperparathyroidism
Hyperthyroidism
Immobilization
Milk Alkali Syndrome
Pagets Disease
Adrenal Insufficiency
Neoplasm
Bone mets, bone tumors
PTH related peptide secretingtumors (small cell lung cancer)
Blast crisis
Primary malignancies
Zollinger Ellison (MEN I Syndrome)
Elevated Vitamin D
Elevated Vitamin A
Sarcoid and other granulomatousdisorders
Familial hypocalciuric hypercalcemia
Lithium
Thiazide Diuretics
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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
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Primary Hyperparathyroidism
High serum calcium (ionized calcium)
High or high normal PTH levels
Solitary Parathyroid Adenoma ~85%
Multiple Adenomas, hyperplasia ~15% Parathyroid Carcinoma ~1%
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Manifestations of Primary
Hyperparathyroidism Hypercalcemia
Hypercalciuria
Increased rate of bone turnover
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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
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Hereditary Primary Hyperparathyroidism
MEN I: parathyroid, pancreatic (Zollinger Ellison),
pituitary (prolactinoma)
tumor suppressor MENI gene, autosomal
dominant inheritance
MEN 2A: parathyroid, pheochromocytoma, medullarythyroid cancer
RET proto-oncogene, autosomal dominant
inheritance
Familial Hypocalciuric Hypercalcemia: autosomal
dominant, surgery not indicated, PTH normal
Neonatal Severe Hyperparathyroidism
Hyperparathyroidism- Jaw Tumor Syndrome
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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 deviationsbelow the norm
neuromuscular symptoms
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Surgical Intervention in Primary
Hyperparathyroidism
NIH criteria leave out patients who wouldbenefit from parathyroidectomy
ParathyroidectomyBenefits
neurobehavioral symptoms improve
bone mass increases
safe in patients over 70 years oldbilateral neck exploration cures 95-99% of
patients with a 1-3% complication rate
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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
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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%
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Technetium-99m Sestamibi Scan
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Technetium-99m Sestamibi Scan
technetium 99m taken up by the thyroid
sestamibi taken up by both the parathyroid andthyroid tissue
sestamibi washes out of the thyroid faster
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Preoperative Evaluation
no consensus on whether preoperative localizationnecessary
preoperative localization can allow for unilateralfocused parathyroidectomy
The combination often used is: sesatmibi for localization
ultrasound for information on size and relationship ofthe abnormal glands to surrounding tissue
sestamibi scanning limited in identifying multipleadenomas and 4 gland hyperplasia
preoperative localization essential in reoperationcases
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Parathyroidectomy
Options:
bilateral neck exploration
unilateral focused parathyroidectomy
endoscopic parathyroidectomy
video assisted parathyroidectomy
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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
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PTH Assay
collection from a peripheral venous sample, IJsampling 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)
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Persistent Hyperparathyroidism
5-10% of patients have persistent disease
Location of the abnormal glands at second
operationneck 30-54%
mediastinum 16-34%
retroesophageal 14-39%upper cervical area 8%
aortic arch area 5%
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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 arteriography
selective venous sampling
FNA and PTH assay Complication rate at reoperation for recurrent
laryngeal nerve injury or hypoparathyroidism
1-2%
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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 dihydroxyvitamin D
First line therapy:
phosphate binders
supplemental vitamin D
Severe or refractory cases of secondaryhyperparathyroidism should undergo surgery
subtotal parathyroidectomy
total parathroidectomy with autotransplantation
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Tertiary Hyperparathyroidism
after renal transplant or as a progression of secondaryhyperparathyroidism
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
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Parathyroid Carcinoma
Occurs in ~1% of patients with hyperparathyroidism
Associated with genes: cyclin D1, MEN1, HRPT2
Risk Factors
neck irradiation
ESRD
familial hyperparathyroidism (not MENsyndromes)
hyperparathyroidism- jaw tumor syndrome
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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%
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Parathyroid Carcinoma
Appearance
Adenoma: round, soft and reddish-brown
Parathyroid carcinoma: lobulated firm andadherent to surrounding tissue
Carcinoma often localized to inferior
parathyroid glands
difficult to distinguish benign and malignant
tumors histologically
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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
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Parathyroid Carcinoma
Postoperatively hungry bone syndrome: symptomatic hypocalcemiafrom calcium and phosphorus deposition into the
bones
if hypocalcemia severe its treated with iv calcium andvitamin 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
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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)
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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 frozensection 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 andautotransplantation
exploration of the contralateral neck ipsilateral thyroid lobectomy and lymph node
dissection
biopsy of all 3 remaining parathyroid glands
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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 frozensection 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 andautotransplantation
exploration of the contralateral neck
ipsilateral thyroid lobectomy and lymphnode dissection
biopsy of all 3 remaining parathyroid glands
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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
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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
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Management of hypercalcemia associated with
recurrence of parathyroid carcinoma could include
administration of any of the following EXCEPT
bisphosphonates
calcitonin plicamycin
gallium nitrate
fluorouracil
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Management of hypercalcemia associated with
recurrence of parathyroid carcinoma could include
administration of any of the following EXCEPT
bisphosphonates
calcitonin plicamycin
gallium nitrate
fluorouracil
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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
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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
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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 ofPrimary Hyperparathyroidism J Surg Onc2005;89:130-135