Hyperparathyroidism

http://apexiondental.com/
 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 intake Zollinger Ellison (MEN I Syndrome)
Hyperparathyroidism Elevated Vitamin D
Hyperthyroidism Elevated Vitamin A
Immobilization Sarcoid and other granulomatous
Milk Alkali Syndrome disorders
Paget’s Disease Familial hypocalciuric hypercalcemia
Adrenal Insufficiency Lithium
Neoplasm Thiazide Diuretics
Bone mets, bone tumors
PTH related peptide secreting
tumors (small cell lung cancer)
Blast crisis
Primary malignancies
 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 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 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