Diagnosis and

Management of
Parathyroid Disease
Nino Zaya, MD
December 1, 2005

Objectives

Review calcium homeostasis

Understand parathyroid anatomy and
histopathology
Review embryo-anatomic relationships in
the central neck
Recognize the clinical features, diagnosis
and surgical/medical management of
hyperparathyroidism
Understand the molecular basis of
localization studies

CALCIUM HOMEOSTASIS AND

PARATHYROID HORMONE
SECRETION AND REGULATION

Parathyroid hormone (PTH) contains

84 amino acids
Degradation into amino(N) and
carboxyl(C)-terminal fragments.
The N-terminal fragment biologically
active and rapidly cleared
C-terminal fragment is biologically
inert and cleared by the kidney

Continued.

PTH release governed by serum ionized

calcium levels.
PTH secreted in response to decrease in
serum-ionized calcium and inhibited by an
increase serum-ionized calcium.
Target end organs: kidneys, skeletal
system, and intestine.
PTH binding to receptor sites results in
cAMP 2nd messenger system activation.
Half-life PTH few minutes.

Continued.

Etiology and Pathogenesis

of Hyperparathyroidism

Parathyroid adenomas (PA) considered

monoclonal or oligoclonal neoplasms.
Propagation through clonal expansion of
cells with altered sensitivity to calcium.
PRAD1 implicated in only some PA.
Another mechanism involves alternation in
tumor suppressor gene expression.

Continued.

Continued.

Parathyroid Anatomy and

Histopathology: The Normal
Parathyroid Gland

Supernumerary fifth parathyroid found

between 0.7%-5.8% patients
5th glands found in the mediastinum
(thymus or related to the aortic arch),
thyrothymic tract

Parathyroid Gland
Location

80% of superior parathyroid glands found at

the cricothyroid junction ~1 cm cranial to
juxtaposition of RLN & ITA.
Inferior parathyroid glands (IPG) variable in
location.
61% of (IPG) near the lower pole of the
thyroid gland and 26% in thyrothymic
ligament.
Incidence of intrathyroidal parathyroid
glands ~0.5% to 3%.

Embryology

Morphologic Characteristics
of Parathyroid Glands

Shape-oval, bean, or teardrop

appearance or flat shape when
juxtaposed to thyroid gland.
Color-yellowish brown to reddish
brown in normal parathyroid glands
and lighter gray tone in pathological
states.

Vascular Anatomy of the

Parathyroid Glands

Normal parathyroid glands most commonly

are supplied by a single dominant artery
(80%).
The length of the dominant artery supplying
glands vary from 1 to 40 mm.
ITA is dominant blood supply to both
superior & inferior parathyroid glands most
of the time.

Histopathology of the
Parathyroid Glands

Parathyroid gland composed of chief cells,

oxyphilic cells and intermediate cells
Solitary parathyroid adenoma ~80%-85%
of patients with primary
hyperparathyroidism
Variations in parathyroid adenoma includes
other subtypes (oncocytic adenoma,
lipoadenoma, large clear cell adenoma,
water-clear cell adenoma, and atypical
adenoma).

Continued.

Primary parathyroid hyperplasia-proliferation

of parenchymal cells with increase in weight
in multiple glands with absence of stimulus
for parathyroid hormone secretion.
Two types of parathyroid hyperplasia are
seen: the common chief cell hyperplasia and
the rare water cell or clear cell hyperplasia.

Continued.

Parathyroid carcinoma (PC) ~0.1% to 5.0% cases

of primary hyperparathyroidism.
PC tend to be large tumors, (30% to 50% palpable
presentation).
May measure up to 6 cm in diameter, mean ~3 cm.
Lesion adheres to surrounding tissues including soft
tissues of the neck (thyroid gland, strap muscles,
trachea & recurrent laryngeal nerve).
Regional metastasis rare.
Pulmonary metastasis most common distant
metastasis site.

Continued.

PC tends to be an indolent tumor.

Multiple recurrences after resection
common and may occur over a 15- to
20-year period.
Death results from from effects of
excessive PTH secretion and
uncontrolled hypercalcemia rather
than growth of the tumor mass.

Clinical features Primary

Hyperparathyroidism (PH)

Incidence 27 cases annually per

100,000
Prevalence PH general population
0.1%-0.3%
Prevalence women >60 years more
than 1%

CALCIUM HOMEOSTASIS AND

PARATHYROID HORMONE
SECRETION AND REGULATION

Continued.

Osteitis fibrosis cystica

Nephrolithiasis
Hypercalcemic crisis
Osteitis fibrosis occurs ~1% of patients
Renal stones ~10%-20% of patients have renal
stones.
Nonspecific symptoms: malaise, fatigue,
depression, sleep disturbance, weight loss,
abdominal pains, constipation, vague
musculoskeletal pains in the extremities, and
muscular weakness

Continued.

Kidney/Urinary Tract: 4% with nephrolithiasis

and nephrocalcinosis (stone composition, calcium
oxylate or calcium phosphate). Sx of urolithiasis:
renal colic, hematuria, pyuria.
Skeletal System:
1. Osteitis fibrosis cystica (rare)
2. Subperiosteal erosion of the distal phalanges
3. Bone wasting and softening
4. Chondrocalcinosis as a result of bone demineralization
5. Bone pain
6. Pathologic fracture
7. Cystic bone changes
8. Bone loss: cortical bone sites sparing trabecular bone

Continued.

Neuromuscular:
1.
2.

Muscle weakness, (proximal extremity muscle groups

with fatigue and malaise)
Neuromuscular syndrome improves in 80%-90% of
patients.

Neurologic:
1.
2.
3.

Depression, nervousness, and cognitive dysfunction

Deafness, dysphagia, and dysosmia
Many psychiatric symptoms improve after
parathyroidectomy. Fifty percent of patients with
depression or anxiety, or both will improve after
surgery.

Continued.

Cardiovascular
1.
2.

Hypertension (50% of patients)

Parathyroidectomy results in a reduction in BP in
minority of patients.

Hypercalcemic syndrome
1.
2.
3.

polydipsia and polyuria, anorexia, vomiting,

constipation, muscle weakness and fatigue, mental
status changes.
Metastatic calcifications at the corneal/scleral junction,
so-called band keratopathy
Shortened Q-T interval on electrocardiogram, ectopic
calcium deposits, and pruritus.

Continued.

Band Keratopathy

Continued.

Diagnosis:
1. Elevated serum Ca
2. Elevated PTH (suppressed in PTH-rp induced
hypercalcemia)
3. Other:
Albumin
Phosphorous
BUN/Cr
24-hour urine Ca (r/o FHH)
Bone Mineral Density

Localization Studies

Noninvasive preoperative methods

1.
2.
3.
4.
5.
6.

Ultrasonography
Radioiodine or technetium thyroid scan
Thallium-technetium scintigraphy
Technetium-99m sestamibi scintigraphy
Computed tomography scan
Magnetic resonance imaging

1.
2.
3.
4.

Fine-needle aspiration
Selective arteriography or digital subtraction angiography
Selective venous sampling for parathyroid hormone assay
Arterial injection of selenium-ethionine

1.
2.
3.
4.

Intraoperative ultrasonography
Toluidine blue or methylene blue
Urinary adenosine monophosphate
Quick parathyroid hormone intraoperative

Invasive preoperative methods

Intraoperative Methods

Sestamibi-Technetium 99m
Scintography

Sestamibi taken up mitochondria of parathyroid cells greater

than surrounding parenchyma.
Inject 20 to 25 millicuries of technetium-99m sestamibi.
Images obtained at 10-15 minutes then 2-3 hours after the
injection.
Late phase preferable for detecting parathyroid adenomas, as
thyroid nodules clear uptake faster than do parathyroid
neoplasms.
Sensitivity (solitary adenoma) ~100%, Specificity ~90%.
False-positive:
1.
2.
3.
4.

Solid thyroid nodules (adenomas)

Hurthle cell carcinoma
Malignant thyroid lymph node metastases
No false-positive with cystic lesions of the thyroid gland

Continued.

False-negatives
1. Smaller parathyroid adenoma size.
2. Suboptimal dosing of technetium-99m
sestamibi.

Continued.

Four gland hyperplasia

Continued.

Double adenoma

Medical Management

Intravascular volume expansion + loop

diuretics (avoid thiazide diuretics)
Bisphosphonates
Calcitonin
Plicamycin
Estrogens therapy
Oral phosphate salts
Calcimimetic agents (investigational drug R568)

Case 1

65 y.o. male with history of a left

thyroid mass underwent, FNA atypical
follicular lesion. Patient underwent L.
thyroid lobectomy with final diagnosis
of follicular adenoma. Patient had
been noted in past to have
asymptomatic hypercalcemia. PTH
126, 24-hour urine calcium 380mg,
Ionized Ca 1.4

Continued.

Tc-99m
Sestamibi
suggested
parathyroid
adenoma in R
inferior pole of
thyroid gland.

Continued.

Patient taken to OR for MIRP using a

Neoprobe.

Continued.

664 mg right superior parathyroid

gland identified
PTH decreased from 126 to 15

Surgical Management

1.
2.
3.
4.
5.

6.

Clinical indicators for surgery*

Serum calcium is >1.0 mg/dL above the upper
limit of normal.
Creatinine clearance is reduced >30% for age in
the absence of another cause.
Twenty-four hour urinary calcium is >400 mg/dL.
Patients are younger than 50 years of age.
Bone mineral density measurement at the lumbar
spine, hip, or distal radius is reduced >2.5
standard deviations (by T score).
Patients request surgery, or patients are unsuitable
for long-term surveillance.

*Consensus conference held by the National Institutes of Health in 2002

Continued.

1.

2.
3.

Adenoma
Directed unilateral cervical
exploration.
Curative in >95% of patients
Preoperative localization with
technetium-99m sestamibi + IOPTH

Continued.

MEN 1
1. Subtotal vs. total with autotransplantation.

Men 2a1. 100% cure rate with no recurrences

whether total parathyroidectomy,
subtotal parathyroidectomy, or excision
of enlarged glands performed.
2. R/O pheochromocytoma prior to OR trip
(hypertensive crisis).

Continued.

Non-MEN familial
hyperparathyroidism (NMFH).
1. Subtotal or total (autotransplant) with
bilateral cervical thymectomy.

Familial neonatal
hyperparathyroidism.
1. Total (autotransplant) + bilateral
transcervical thymectomy

Continued.

Renal failure-induced hyperparathyroidism.

1.

Subtotal vs. total parathyroidectomy (autotransplant)

with or without cryopreservation.

Parathyroid Carcinoma

1.

2.
3.

en bloc resection of the tumor and areas of potential

local invasion and/or regional metastasis (ipsilateral
central neck contents including the thyroid lobe and
tracheoesophageal soft tissues, lymphatics, and
resection of soft tissues within the superior anterior
mediastinum)
RLN, esophageal wall, or strap muscles may require
sacrifice if the tumor adheres to them.
Not enough data to recommend for or against
chemotherapy or RT.

Continued.

1.
2.

3.

MIRP
Preoperative administration of technetium 99m sestamibi
before operation + intraoperative hand-held gamma probe.
Advantages:

1.
2.
3.
4.

Improved patient comfort postoperatively.

Performance of ambulatory procedures.
Reduced cost.
Avoidance of general anesthetic.

1.

Potential for conversion to bilateral dissection in event of failed

exploration.
Patient anxiety when conversion needed (general anesthesia).

Disadvantages:

2.

Conclusion

No substitute for strong foundation

surgical embryology, anatomy, and
technique for approaching parathyroid
disease.

Bibliography

Cummings Otolaryngology Head and

Neck Surgery. 2005.
Rosen F., Pou A., Parathyroid
Disease. March 2002. UTMB site
http://www.mrcophth.com/corneacom
moncases/bk.html (Image-Band
Keratopathy)