Diagnosis and Management of Parathyroid Disease

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Diagnosis and Management of Parathyroid Disease

• Nino Zaya, MD
• December 1, 2005

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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

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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

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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.

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Continued.
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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.

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Continued.
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Continued.
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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

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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.

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Embryology
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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.

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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.

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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).

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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.

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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.

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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.

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Clinical features Primary Hyperparathyroidism (PH)

• Incidence 27 cases annually per 100,000
• Prevalence PH general population 0.1-0.3
• Prevalence women gt60 years more than 1

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CALCIUM HOMEOSTASIS AND PARATHYROID HORMONE
SECRETION AND REGULATION
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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

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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
• Osteitis fibrosis cystica (rare)
• Subperiosteal erosion of the distal phalanges
• Bone wasting and softening
• Chondrocalcinosis as a result of bone
  demineralization
• Bone pain
• Pathologic fracture
• Cystic bone changes
• Bone loss cortical bone sites sparing trabecular
  bone

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Continued.

• Neuromuscular
• Muscle weakness, (proximal extremity muscle
  groups with fatigue and malaise)
• Neuromuscular syndrome improves in 80-90 of
  patients.
• Neurologic
• 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.

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Continued.

• Cardiovascular
• Hypertension (50 of patients)
• Parathyroidectomy results in a reduction in BP in
  minority of patients.
• Hypercalcemic syndrome
• 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.

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Continued.

• Band Keratopathy

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Continued.

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

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Localization Studies

• Noninvasive preoperative methods  
• Ultrasonography 
• Radioiodine or technetium thyroid scan  
• Thallium-technetium scintigraphy  
• Technetium-99m sestamibi scintigraphy  
• Computed tomography scan  
• Magnetic resonance imaging
• Invasive preoperative methods  
• Fine-needle aspiration  
• Selective arteriography or digital subtraction
  angiography  
• Selective venous sampling for parathyroid hormone
  assay 
• Arterial injection of selenium-ethionine
• Intraoperative Methods
• Intraoperative ultrasonography  
• Toluidine blue or methylene blue  
• Urinary adenosine monophosphate  
• Quick parathyroid hormone intraoperative

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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
• Solid thyroid nodules (adenomas)
• Hurthle cell carcinoma
• Malignant thyroid lymph node metastases
• No false-positive with cystic lesions of the
  thyroid gland

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Continued.

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

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Continued.

• Four gland hyperplasia

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Continued.

• Double adenoma

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Medical Management

• Intravascular volume expansion loop diuretics
  (avoid thiazide diuretics)
• Bisphosphonates
• Calcitonin
• Plicamycin
• Estrogens therapy
• Oral phosphate salts
• Calcimimetic agents (investigational drug R-568)

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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

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Continued.

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

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Continued.

• Patient taken to OR for MIRP using a Neoprobe.

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Continued.

• 664 mg right superior parathyroid gland
  identified
• PTH decreased from 126 to 15

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Surgical Management

• Clinical indicators for surgery
• Serum calcium is gt1.0 mg/dL above the upper limit
  of normal.
• Creatinine clearance is reduced gt30 for age in
  the absence of another cause.
• Twenty-four hour urinary calcium is gt400 mg/dL.
• Patients are younger than 50 years of age.
• Bone mineral density measurement at the lumbar
  spine, hip, or distal radius is reduced gt2.5
  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
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Continued.

• Adenoma
• Directed unilateral cervical exploration.
• Curative in gt95 of patients
• Preoperative localization with technetium-99m
  sestamibi IOPTH

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Continued.

• MEN 1
• Subtotal vs. total with autotransplantation.
• Men 2a-
• 100 cure rate with no recurrences whether total
  parathyroidectomy, subtotal parathyroidectomy, or
  excision of enlarged glands performed.
• R/O pheochromocytoma prior to OR trip
  (hypertensive crisis).

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Continued.

• Non-MEN familial hyperparathyroidism (NMFH).
• Subtotal or total (autotransplant) with bilateral
  cervical thymectomy.
• Familial neonatal hyperparathyroidism.
• Total (autotransplant) bilateral
  transcervical thymectomy

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Continued.

• Renal failure-induced hyperparathyroidism.
• Subtotal vs. total parathyroidectomy
  (autotransplant) with or without
  cryopreservation.
• Parathyroid Carcinoma
• 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.

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Continued.

• MIRP
• Preoperative administration of technetium 99m
  sestamibi before operation intraoperative
  hand-held gamma probe.
• Advantages
• Improved patient comfort postoperatively.
• Performance of ambulatory procedures.
• Reduced cost.
• Avoidance of general anesthetic.
• Disadvantages
• Potential for conversion to bilateral dissection
  in event of failed exploration.
• Patient anxiety when conversion needed (general
  anesthesia).

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Conclusion

• No substitute for strong foundation surgical
  embryology, anatomy, and technique for
  approaching parathyroid disease.

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Bibliography

• Cummings Otolaryngology Head and Neck Surgery.
  2005.
• Rosen F., Pou A., Parathyroid Disease. March
  2002. UTMB site
• http//www.mrcophth.com/corneacommoncases/bk.html
  (Image-Band Keratopathy)