12/5/19: SCORE LECTURE PARATHYROID

I. Anatomy and Embryology

a. Superior parathyroid glands derived from 4rth branchial pouch (same as thyroid)
b. Inferior parathyroid glands from 3rd branchial pouch
c. Superior glands = posterior/dorsal to RLN
d. Inferior glands = ventral/anterior to RLN

e. Parathyroid gland blood supply from Inferior Thyroid Artery

f. Venous drainage ipsilaterally by superior, middle, and inferior thyroid
g. Histo: Composed of CHIEF cells and Oxyphil cells
i. Chief cells = produce PTH!!
h. Ectopic Parathyroid Glands
i. Ectopic Superior  posterior at tracheoesophageal groove and retroesophageal
ii. Ectopic Inferior  commonly mediastinum (thymus), carotid sheath, thyroid gland
iii. Note: Most common location of a MISSED Parathyroid gland is within its usual
anatomic position
II. Physiology of Calcium
a. PTH  increases serum Ca2+ by 3 ways
i. Increased bone resorption by stimulation of Osteoclasts

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 ii. Increased Calcitriol (activate 1,25-(OH)2D )  more Ca2+ absorbed in Small
intestine
iii. Decreased Urinary Ca2+ excretion by stimulating Ca2+ reabsorption in distal
convoluted tubule (DCT)
b. PTH = inhibits phosphate reabsorption at proximal convoluted tubule (PCT)
i. Secretion regulated by GPCR CASR (Ca2+ sensing receptor)
ii. Also stim by LOW 1,25-Dihydroxy Vitamin D, catecholamines, HypoMag
iii. Secreted PTH = half life of 2-4 mins
iv. PTH metabolized in LIVER

c.

d. Calcitonin = produced by Thyroid C cells, LOWERS Ca2+ (“tones down”)

e. Vitamin D  metabolized by LIVER to primary circulating form, 25-Hydroxy Vit D
i. Kidney, gets hydroxylated  1,25-Dihydroxy Vit D ; most metabolic form
III. Hyperparathyroidism

a. Primary HyperPTH
i. one or more PTH glands autonomously secreting high levels PTH
ii. most commonly: Parathyroid Adenoma (80%)
iii. Genetic causes: MEN1 and MEN2A
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 1. MEN1 or MEN2A = 4-gland hyperplasia usually b/c gene expressed all 4
iv. Parathyroid cancer (rare)
v. Diagnostic signs can also includes:
1. Chloride : Phosphate ratio > 33
2. Hyperchloremic metabolic acidosis
vi. Osteitis fibrosa cystica (Brown tumors)
1. Bone lesions from Ca2+ resorption
b. Secondary HyperPTH = b/c LOW Ca2+ leads to HIGH PTH
i. Caused by LOW Vit D or chronic renal failure  increased PTH b/c losing Ca2+
1. Parathyroid hyperplasia in response to persistent low Ca2+
ii. Most usually DO NOT need surgery
iii. Secondary HyperPTH  indications for parathyroidectomy include:
1. Severe HyperCa
2. Bone dx
3. Refractory pruritus
4. Calciphylaxis
5. Unexplained myopathy
iv. Tx: Ca2+ supplement, Vitamin D, restrict phosphate diet, phosphate binders
1. Cinacalcet = inhibits PTH from parathyroid glands by mimic Ca2+
2. Surgery is usually total parathyroidectomy with autotransplantation
c. Tertiary HyperPTH
i. Most commonly in postrenal transplant pts after long-standing PTH stim from Low
Ca2+
ii. Leads to autonomous PTH secretion
iii. Tx: subtotal (3.5 glands) resection or total parathyroidectomy with
autotransplantation

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d.
e. For pts with HyperCalcemia…
i. most common cause in OUTPATIENT = Primary HyperPTH
ii. most common cause in INPATIENT = Hypercalcemia of Malignancy
f. Diagnosis and workup
i. Labs showing: Elevated PTH and Elevated Ca2+ is diagnostic of primary hyperPTH
1. In 10-20% of pts, PTH minimally elevated; 24-hr urinary Ca2+ levels can be
useful to differentiate Primary HyperPTH vs Familial Hypocalciuric
Hypocalcemia
2. HYPOphosphatemia
3. Chloride : Phosphate ratio >33
ii. Imaging
1. Sestamibi scan = can localize hyperactive gland
a. BUT poor isolating multiple lesions
b. Best if Sestamibi combined w/3D-SPECT
2. Ultrasound = useuful in locating, esp if combined w/Sestamibi
3. Chest imaging to search for bony mets, sarcoidosis, tumors (looking for PTHrP
source)
4. Secretory urogram  search for nephrolithiasis
5. Serum protein electrophoresis can help r/o multiple myeloma
6. Hand + Skull XRays to eval for osteitis fibrosa cystica (not commonly done)
g. Operative Treatment of Primary Hyperparathyroidism (PHPT)
i. All symptomatic disease (ex: kidney stones, fractures, bone pain, etc)

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 ii.
1. some asymptomatic pts followed by bone mineral density scans
2. 95% of pts with Primary hyperPTH experience cure from surgery
iii. 85% of pts have single gland disease and can undergo resection with focused
parathyroid exploration
1. focused parathyroidectomy focuses incision near affected gland
2. “minimally invasive”
3. this approach requires extensives preoperative localization
iv. 10-11% of pts have MORE than 1 adenoma, <10% have hyperplasia of ALL 4 glands
1. Multigland disease  Bilateral parathyroid exploration
2. If 4-gland hyperplasia Subtotal parathyroidectomy
a. All but a small well-vascularized portion of 1 enlarged gland is
removed
b. Alternatively, Total parathyroidectomy with autotransplantation of
parathyroid tissue into forearm
v. Common complications of parathyroidectomy
1. RLN injury in 0.5-1% of parathyroid resections
2. Transient HYPOCa2+
3. HypoMag, HypoPhoph
4. Bleeding in 0.5% of pts w/parathyroidectomy
IV. Parathyroidectomy
a. Indications
i. Any symptomatic pt w/classic symptoms as mentioned above
ii. For asymptomatic pt with PHPT, refer to NIH Consensus
1. Age<50
2. Serum Ca2+ >1mg/dL above normal
3. BMD T-Score <-2.5
4. Vertebral fractures
5. 24-hr urine Ca2+ >400mg/d
6. Creatinine Clearance<60
b. Preoperative Planning
i. Imaging to localize abnormal glands: sestamibi, ultrasound, and/or CT
ii. Preop PTH levels checked

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 iii. Minimally invasive parathyroidectomy = for pts w/PHPT with ONE abnormal gland
seen on BOTH sestamibi scan + ultrasound
iv. 4-gland exploration if preoperative testing is inconclusive, multiple abnormal glands,
or MEN syndromes
c. Operative steps overview

i. Low transverse collar incisions

ii. Past platysma, raise sub-platysmal flaps extending superiorly to thyroid cartilage and
inferiorly to sternal notch
iii. Divide fascia btwn strap muscles midline and separate Sternohyoid from
Sternothyroid muscle
1. After strap muscles separated, choose one side for neck exploration
iv. Note: dissection is done LATERAL to thyroids
1. Avoid disturbing BLOOD supply (which run medial)
2. Easier to ID parathyroid glands
v. Dissect Sternothyroid off thyroid
vi. Mobilize right lobe of thyroid  find middle thyroid vein and RLN
1. Middle thyroid veins ligated and divided
vii. Locating the Parathyroid Glands
1. ~85% of Parathyroid glands within 1cm of junction of Inferior Thyroid
Artery and RLN
2. Superior parathyroids  usually POSTERIOR to this junction
3. Inferior parathyroids  usually ANTERIOR to this junction
viii. Find parathyroid adenoma  ligate vascular pedicle  remove gland  send PTH
after 10 mins
1. PTH level should drop >50% decrease after removal
2. Failure of PTH reduction >50%  further exploration
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 d. Complications and Treatment
i. Recurrent laryngeal nerve injury
1. Most injuries transient, some take months to heal
2. Vocal cord palsy; permanent = >6 months persistence
ii. Significant post-op bleeding (rare)
1. Immediate operative intervention to alleviate tracheal compression
2. Air way compromise  immediate wound opening + evac hematoma
iii. Unsuccessful exploration
1. Reconfirm diagnosis of PHPT, imaging for localization
2. Make sure rule out FHH w/24-hr urine calcium
3. If recurring symptoms of HYPERCa2+, reexploration is necessary
a. Redo exploration, gland likely to be in ECTOPIC areas
4. Reoperation assoc w/increased risk of RLN injury and permanent
hypoparathyroidism
iv. Hypocalcemia
1. Temporary as long as viable parathyroid tissue remains
2. Persistent HypoCa2+  check PTH level to make sure functioning
parathyroid tissue remains
e. Long-Term Follow-up
i. Ca2+ checks 2 weeks post-op, then 6 months, then annually
ii. Recurrence rare (<1%) except in familial HPT
iii. MEN1 recurrence is 15% at 2 years, 67% at 8 years
V. Parathyroid Cancer
a. Epidemiology
i. <1% of all cases of PHPT
ii. incidence is EQUAL in men & women
iii. pts with Hyperparathyroidism jaw tumor syndrome = increased risk of parathyroid
carcinoma
1. associated w/HRPT2 mutations
b. Presentation
i. Serum Ca2+ GREATER than 14 mg/dL
ii. PTH is 3x to 15x the upper limit
iii. Symptoms are more severe than w/pts with PHPT
1. Profound lethargy, weakness, falls, nausea, anorexia, pancreatitis,
dehydration, palpitations, short QT segments
iv. Hypercalcemic crisis = Parathyroxicosis  possible association
1. Rare condition, multiple nodues of HYPERfunctioning parathyroid tissue
2. Usually s/p previous parathyroidectomy
3. Cause unknown but could be from overgrowth of tissue OR seeding from
rupture of parathyroid tumor
4. Serum Ca2+ > 16
v. Other Symptoms
1. A PALPABLE neck mass (up to 70%)
2. Paralyzed RLN = ADVANCED and invasive disease
3. Dysphagia or dyspnea secondary to mass effect of tumor

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c. Diagnosis
i. Labs
1. Ca2+ > 14, PTH = 3-15x higher, elevated ALP
ii. Imaging
1. NECK ULTRASOUND = imaging study of choice
2. Features: lobulated, HYPOechoic appearance, gland enlargement, ill-defined
borders
3. Local infiltration, calcification, thick capsule
iii. Sestamibi scan CANNOT differentiate Adenoma vs Carcinoma
iv. 4D-CT or MRI can be considered if ultrasound is unrevealing
v. DO NOT do FNA
vi. Pathology
1. Vascular or capsular invasion
2. Trabecular or fibrous stroma, frequent mitoses
d. Operative Treatment
i. En bloc resection + adherent structures (ipsilateral thyroid lobe) with grossly
negative margins
ii. If lymph nodes involved  therapeutic ipsilateral cervical compartment lymph node
dissection
1. Prophylactic lymph node dissection NOT indicated for clinic uninvolved nodes
iii. Avoid capsule rupture  prevent parathyromatosis
e. Postoperative
i. Decrease in hypercalcemia within 24 hrs
ii. STRICT serum Ca2+ monitoring for Hungry Bone Syndrome
1. Hungry bone = severe HypoCa and HypoPhoph
iii. Complications
1. RLN injury, hypoPTH, hypoCa, neck hematoma
f. Long-Term Follow-up
i. Serial Ca + PTH measurements
ii. If elevated, workup for recurrence
iii. Likely site of recurrence = local due to incomplete resection or intraop tumor spillage
1. Local recurrence = rexplore + resect
iv. Most common sites of mets
1. Lungs, Liver, Bone
2. Resection recommended to tx assoc HyperCa

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 g. Prognosis of Parathyroid Carcinoma
i. No chemotherapy is effective
ii. 10-year survival rate = ~70%
iii. Disease recurrence = at least 50% cases
1. Mean time = 2.5-4.8 yrs
iv. Mortality related to HyperCa
v. Usually radioresistant, but can be for palliative

VI. Multiple Endocrine Neoplasias (MEN) Syndromes

a. Genetics
i. ALL MEN types are AUTO-DOMINANT
ii. MEN1 = on 11q13, produces menin protein
iii. MEN2A = RET proto-oncogene on 10q11.21
iv. MEN2B = also associated w/RET
b. MEN1 with Parathyroid hyperplasia
i. Hypercalcemia = first sign in 85% of pts w/FHx of MEN1 syndrome
ii. Nearly 100% penetrance, multiglandular dx
1. Develops in 80-100% of MEN1 pts by 40 years old
iii. Pancreatic tumors include neuroendocrine tumors:
1. Gastrinomas 54%
a. PUD, diarrhea
2. Insulinomas 15-18%
a. Whipple triad: sx of hypoglycemia, hypoglycemia, and immediate relief
w/IV glucose
3. Glucagonomas 3%
a. Necrolytic migratory erythema, cheilitis, DM, venous thrombosis,
diarrhea
4. VIPomas 3%
a. Watery diarrhea, hypokalemia, hypochlorhydia
5. Somatostatinomas 1%
iv. Diagnosis of MEN1
1. Indications of genetic test include: 2 or more MEN1-associated endocrine
tumors
2. First-degree relative w/MEN1 mutation
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 3. With a pancreatic endocrine neoplasm, workup for Gastrinoma
a. Serum gastrin levels can be falsely high in pts w/PPIs
b. Secretin stimulation test necessary
i. Measure serum gastrin BEFORE and AFTER IV admin of
secretin
ii. Gastrin increase >120pg/mL over fasting = positive
4. Localization techniques
a. CT, octreotide scan, arterial stim w/hepatic venous sampling
b. CT shows arterial enhancement
c. Octreotide scan b/c gastrinomas, glucagonomas, and other
nonfunctioning pancreatic tumors express high levels of Somatostatin
receptors
i. Insulinomas express little Somatostatin receptors
v. Preoperative Evaluation
1. Same indications for parathyroidectomy in MEN1 as PHPT
2. Imaging not required b/c BILATERAL exploration is required
vi. Operative Treatment of MEN1 Hyperparathyroidism
1. Subtotal vs total parathyroidectomy w/autotransplantation
2. Bilateral neck exploration
3. Cervical thymemectomy may be needed if 4 glands not localized
4. In Zollinger-Ellison Syndrome with MEN1, surgery controversial, not curative
c. MEN2A
i. Common manifestations
1. Medullary Thyroid Cancer (100% penetrance)
2. Pheochromocytoma (50% penetrance)
3. Hyperparathyroidism (10-25% penetrance)
ii. Work-up
1. Work up for medullary thyroid cancer
a. Diarrhea = most common symptom
b. Bilateral
c. #1 cause of death of MEN2A pts
2. In medullary thyroid pts, test for RET oncogene and screen for Pheo
a. Pheo = often bilateral
iii. Preoperative evaluation
1. Neck ultrasound needed to assess local + regional disease
2. Pheo MUST be excluded or managed prior surgery
a. Want to avoid fatal hypertensive crisis
d. MEN2B
i. Common Manifestations
1. Medullary Thyroid cancer
2. Pheochromocytoma
3. Marfanoid habitus
4. Mucosal neuromas
ii. Work-up and Preoperative eval
1. Similar to MEN2A, work up for and screen for pheochromocytoma
2. Serum calcitonin + CEA (medullary tumor markers) baseline
a. Calcitonin = sensitive for persistent and recurrent disease
3. Serum Ca2+ & PTH

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 4. Plasma metanephrines or 24-hr urinary excretion of metanephrines +
catecholamines for Pheo
e. Operative Treatment for MEN2A and MEN2B
i. Prophylatic thyroidectomy if confirmed RET mutation
1. Patients with high risk mutations, prophy thyroidectomy in first year of life or
year of diagnosis
ii. Central compartment lymph node dissections
1. Recommended ONLY for pts with established tumors or those with highest
risk RET mutations
iii. MEN-2 is multiglandular parathyroid hyperplasia  bilateral exploration

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