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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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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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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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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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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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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

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