Parathyroid Adenoma

1
Parathyroid Adenoma

• Chou Chien-Wen M.D.
• Endocrine Metabolism Section
• Chi-Mei Medical Center
• 10 Jan 2003

2
Case Report

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3
Present Illness Past History

• 62-year-old female, general twitching, painful
  sensation bothered her for months.
• Gout (), HTN ()
• Operation history
• (1)R't renal stone s/p ESWL (1993 Sep)
• (2)Fail back surgery syndrome with HIVD with
  stenosis of L4-5 s/p disectomy of L5-S1
  laminectomy of L4-5 L5-S1 (91-07-17)
• (3)HIVD with lumbar stenosis of L4-5, left s/p
  disectomy with laminectomy of L4-5
  (91-08-28)

4
Laboratory Data

• BUN/Cr 22.8/1.17 (91-12-12)
• Na/K 138.1/4.72 (91-12-12)
• Serum Ca
• 13.7 (91-11-18)
• 11.6 (91-12-14)
• 12.3 (91-12-30)
• 8.8 (92-01-02) postoperation
• Free-Ca 5.6 (91-12-18)
• P 2.7 (91-12-3)
• Alk P-tase 216 (91-12-3)
• i-PTH 223.7 pg/ml (91-12-2)

5
(No Transcript)
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Operation Pathology

• Operation
• Parathyroidectomy, right
• Partial central LNs dissection
• Pathology
• Parathyroid adenoma, right lower parathyroid gl
  , parathyroidectomy
• Nodular goiter, bilateral thyroid, bilateral
  subtotal thyroidectomy

7
Introduction

• The estimated incidence is 1 case per 1000 men
  2 to 3 cases per 1000 women.
• The severe complications of hyperparathyroidism,
  osteitis fibrosa cystica nephrocalcinosis, are
  rarely seen today.
• Distinguishing primary hyperparathyroidism from
  malignancy, the next most common cause of
  hypercalcemia,
• Minimally invasive surgery is now available, in
  addition to standard bilateral neck exploration,
  as curative therapy for primary
  hyperparathyroidism.

(Mayo Clinic Proceedings Volume 77(1) January
2002 pp 87-91)
8
Etiologic Factors Pathogenesis (1)

• Sporadic, benign parathyroid adenomas 80-85
• Postmenopausal women, average age of 55 years
• External neck irradiation
• Lithium therapy 5
• Multiple parathyroid glands may be abnormal,
  hyperparathyroidism may persist after
  discontinuation of the drug.
• Hereditary disorders 10, including familial
  hyperparathyroidism or MEN type 1 2A
  hyperparathyroidism-jaw tumor syndrome.
• MEN 1 95
• present at a younger age, more severe disease
• Associated tumors include pancreatic (30-80)
  pituitary (15-50) adenomas.
• The gene responsible for MEN 1, menin (chromosome
  11), has been identified cloned with tumor
  suppressor function.

9
Etiologic Factors Pathogenesis (2)

• MEN 2A
• A milder form, resection of only enlarged glands
  compared to subtotal resections in patients with
  other forms of multigland disease.
• MCT is a universal component of this syndrome.
• Pheochromocytoma 50 primary hyperparathyroidism
  10.
• Mutations of the ret proto-oncogene.
• Hyperparathyroidism-jaw tumor syndrome
• Early, relatively severe hypercalcemia in
  teenagers or young adults is the common
  presentation.
• The pathologic finding is usually a single
  adenoma. Bone lesions of the jaw appear as cystic
  punched-out regions on x-ray films.
• Frequent association with Wilms tumors or renal
  cysts.
• A familial disorders

10
Etiologic Factors Pathogenesis (3)

• Parathyroid carcinoma lt 0.5 of cases
• Severe hypercalcemia, extremely high PTH levels,
  a palpable neck mass.
• Benign familial hypocalciuric hypercalcemia (FHH)
  
• an autosomal dominant disorder, hypercalcemia
  relative hypocalciuria.
• The degree of hypercalcemia is generally mild.
  Normal PTH levels but in 5 to 10 of patients,
  modestly elevated.
• Most kindreds have an inactivating mutation of Ca
  sensing receptor, resulting in a mild increase in
  the set point for Ca suppression of PTH
  secretion.
• The Ca clearance-Cr clearance ratio with a cutoff
  of .01 distinguishing from primary
  hyperparathyroidism.
• This disorder results in hypercalcemia at birth
• Surgery or further medical evaluation is not
  indicated because it is a benign condition
  without progressive complications.

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Etiologic Factors Pathogenesis (4)

• Insufficient Vit D /or insufficient Ca intake
• Mild secondary hyperparathyroidism
• Normal serum Ca level an elevated PTH level
• Measurement of 25-hydroxyvitamin D 24-hour
  urinary Ca level is helpful
• Such patients often have intermittent elevations
  of ionized Ca levels with documented stone
  disease /or osteoporosis.
• ESRD
• most common cause of secondary hyperparathyroidism
  .
• PTH secretion is stimulated by hypocalcemia,
  which results from low concentrations of
  1,25-dihydroxy-vitamin D due to decreased renal
  production, by hyperphosphatemia.
• Prevention with supplementation with
  1,25-dihydroxyvitamin D Ca control of
  hyperphosphatemia
• Tertiary hyperparathyroidism
• Prolonged abnormalities can evolve into a state
  of autonomous PTH secretion hypercalcemia,

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Evaluation

• The total Ca level can be "corrected" by adding
  0.8 mg/dL for every 1.0 g/dL by which the serum
  albumin concentration is lower than 4.0 g/dL.
• All patients will have increased ionized Ca
  levels.
• Hypercalcemia, an elevated or inappropriately
  high-normal PTH level is diagnostic
• Malignancy is associated with suppressed levels
  of PTH.
• Modern intact PTH assays have no cross-reactivity
  with PTH-related protein.
• FHH in young patients with mild hypercalcemia
  normal or slightly elevated PTH levels.
• The urinary Ca clearance-Cr clearance ratio,
  previous Ca levels, family history are helpful.
  
• Evaluation for other endocrine disorders
  associated with one of the MEN syndromes
• Appropriate genetic testing for MEN
• BMD is usually measured, cortical sites such as
  the distal one-third radius.
• A 24-hour urinary Ca measurement radiological
  evaluation for the presence of kidney stones

13
Radiographic manifestations of PHP.
Asubperiosteal resorption of radial side of
middle phalanges distal turfs B"Brown
tumour" (arrow) in the proximal tibia
Cresorption tapering of distal
clavicle Dcystic changes in head of humerus
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Technetium-99m sestamibi/iodine scans in planar
(A), coronal (B), sagittal (C) views.
Aincreased uptake of the radiotracer in right
lower parathyroid adenoma thyroid in
early image (after 20 min) Bafter 2 h,
concentration of radiotracer in parathyroid
adenoma with disappearance of thyroid
uptake Cconfirms concentrations in parathyroid
adenoma
15
Management (1)

• Institution of therapy for hypercalcemia depends
  on the degree of hypercalcemia the presence or
  absence of clinical symptoms.
• Mild hypercalcemia usually have no symptoms,
  require no Ca-lowering agents
• Moderate hypercalcemia symptoms probably
  benefit from hypocalcemic agents.
• Severe hypercalcemia require hospitalization
  therapy.
• The combination of altered mental status,
  anorexia, nausea, defective urine-concentrating
  ability results in dehydration. Iv fluids are the
  initial therapy for severe hypercalcemia.
• Diuretic therapy with furosemide (20 mg) should
  not be instituted until euvolemia is achieved.
• Correction of fluid deficits alone can produce a
  decrease in the Ca level but rarely restores
  normocalcemia

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Management (2)

• Hypocalcemic agents, calcitonin (4-8 IU/kg im or
  sc q 6-8 hrs) has the most rapid onset of action.
  
• Resistance to its hypocalcemic effects develops
  limits its use to 24 to 48 hrs of therapy.
• Calcitonin alone rarely normalizes serum Ca
  levels but is useful in addition to
  bisphosphonates.
• Iv bisphosphonate therapy with pamidronate (60-90
  mg)
• The onset of action for pamidronate is 24 to 48
  hours after infusion, with nadir Ca at about 7
  days.
• Duration of treatment effect varies from weeks to
  months.
• Plicamycin, gallium nitrate, etidronate, used
  in the past to treat severe hypercalcemia are
  rarely used today.
• H/D in severe hypercalcemia with impaired renal
  function.

17
Management (3)

• Glucocorticoids hypercalcemia due to lymphoma or
  granulomatous diseases but have no role in
  managing hypercalcemia due to hyperparathyroidism.
  
• Treating the underlying cause of hypercalcemia is
  necessary.
• Ca sensing receptor agonists (calcimimetics) have
  been studied in a small number of patients but
  are not available clinically.
• Estrogen replacement therapy for postmenopausal
  women can attenuate bone resorption results in
  modest reduction in serum Ca levels.
• Older bisphosphonates did not sustain reductions
  in serum Ca levels.
• Surgery is the only curative therapy for primary
  hyperparathyroidism

18
Management (4)

• Up to 25 of patients develop an indication for
  surgery during medical observation.
• Increases in BMD of both the hip the spine
  after surgical cure of hyperparathyroidism
• Avoidance of drugs that could worsen
  hypercalcemia, especially thiazides.
• Modest Ca intake is generally recommended because
  low Ca intake could theoretically stimulate more
  PTH production.
• Estrogen therapy can be considered in
  postmenopausal women.
• Yearly measurement of bone density, 24-hour
  urinary Ca values, serum Ca levels is advised,
  as is monitoring for nephrolithiasis.
• Preventing tertiary hyperparathyroidism by
  controlling serum phosphate levels, replacing
  1,25-dihydroxyvitamin D, maintaining Ca levels
  to decrease stimulation of PTH secretion
  parathyroid gland growth.

19
Management (5)

• The doses of calcitriol needed to suppress serum
  PTH levels can lead to hypercalcemia or
  hyperphosphatemia.
• New vitamin D analogues, 22-oxacalcitriol,
  19-nor-1,25-dihydroxyvitamin D2 (paricalcitol),
  1-alpha-hydroxyvitamin D2 (doxercalciferol), have
  the advantages of suppressing PTH a reduced
  tendency to increase serum Ca phosphate levels
• After tertiary hyperparathyroidism has developed,
  calcitriol must be used carefully because it can
  worsen hypercalcemia.
• Sevelamer is a polymer-based phosphate binder
  that can be used in place of Ca-based phosphate
  binders to decrease hyperphosphatemia in patients
  with hypercalcemia.
• Surgery is often necessary to control
  hypercalcemia in patients with tertiary
  hyperparathyroidism.
• Indications for surgery in secondary
  hyperparathyroidism due to renal failure include
  severe metabolic bone disease (renal
  osteodystrophy, fractures), intractable bone pain
  pruritis, rarely necrotizing skin ulcers
  (calciphylaxis) not responding to dialysis
  medical therapy.

20
Surgery (1)

• An experienced endocrine surgeon cures gt 95
  undergoing initial bilateral neck exploration
  incurs lt 1 perioperative morbidity.
• Reoperations for persistent or recurrent primary
  hyperparathyroidism are less successful (about
  80 cure) much higher incidence of
  complications.
• 25 of patients remained either hypercalcemic
  (13) or permanently hypocalcemic (12), a
  reflection of previously failed procedures.
• Preoperative localization of the abnormal
  parathyroid gland(s) is unnecessary for initial
  bilateral neck exploration.
• In patients who have had prior neck surgery,
  preoperative localization is essential because
  scar tissue altered anatomy make surgical
  exploration more challenging.
• Sestamibi imaging of the parathyroid gland has
  the best specificity sensitivity (90-95
  80-85, respectively)
• In sporadic cases of primary hyperparathyroidism,
  a single adenomatous gl is usually found
  removed.

21
A New, Practical Intraoperative Parathyroid
Hormone Assay (1)

• PTH measurement by immuno-chemiluminometric assay
  (ICMA) is a nonradioisotopic technique that is
  more practical for use during parathyroidectomy.
• Sixteen patients had multiple samples taken
  during parathyroidectomy.
• PTH levels measured 5 minutes after excision of a
  suspected abnormal gland were compared with
  pre-operative or preexcision samples either
  confirmed complete excision or indicated the need
  for more exploration in each patient.
• Correlation of 88 ICMA samples with standard
  24-hour IRMA controls was excellent (r equals
  0.9218, P lt0.0001).
• The sensitivity of the test in predicting
  postoperative Ca levels was 94 percent.

(American Journal of Surgery Volume
168(5) November 1994 pp 466-468)
22
Intraoperative monitoring (with
immunochemiluminometric assay ICMA) identified 11
patients with single-gland involvement by a
marked decrease in intraoperative (QPTH) levels
after excision.
Four patients who had minimal decreases in (PTH)
required excision of a second hyperfunctioning
gland before an adequate decrease in PTH
predicted a return to normocalcemia. One patient
with an unusual tumor had a delayed (20 min) fall
in QPTH.
23
Surgery (2)

• Hereditary multigland disease, more aggressive
  initial surgery is performed, usually a subtotal
  or a total parathyroidectomy with
  autotransplantation.
• Recurrence of primary hyperparathyroidism due to
  remnant gland or autotransplanted tissue is
  common in patients with MEN 1 renal failure.
• Because of improvements in preoperative
  localization imaging of the parathyroid glands
  with sestamibi scintigraphy high-resolution
  ultrasonography coupled with intraoperative rapid
  PTH assay, minimally invasive techniques are
  feasible.
• Minimally invasive parathyroidectomy refers to
  one of several procedures, including
  video-assisted or endoscopic, radioguided,
  unilateral image-guided explorations.
• Abnormal parathyroid gland must be located
  preoperatively on imaging studies, usually
  sestamibi imaging.
• Patients with known or suspected multigland
  disease or prior neck surgery are not generally
  candidates for this procedure.
• Cure rates are no better than those with
  traditional bilateral neck exploration.
• Improved cosmetic appearance, less pain,
  shorter operative time.
• Procedures performed with local anesthesia are
  associated with fewer GI adverse effects.

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Minimal InvasiveAdenectomy
(Ann of Surgery Volume 231(4) April 2000  pp
559-565)
25
Changes in the pattern of clinical presentation
of primary hyperparathyroidism
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Indications for surgery in asymptomatic patients
with hyperparathyroidism

• (1) serum Ca level gt 1 mg/dL above reference
  range
• (2) any complications such as nephrolithiasis or
  bone disease
• (3) an episode of life-threatening hypercalcemia
• (4) severe hypercalciuria (gt400 mg/24 h)
• (5) reduced bone mass, especially of distal
  radius (T score less than -2)
• (6) age younger than 50 years

27
Role of surgery in mild primary
hyperparathyroidism in the elderly

• The usual reasons for advising surgery in an
  'asymptomatic' or minimally symptomatic patient
  are to prevent complications such as
  nephrolithiasis, deterioration in renal function,
  accelerated bone loss and fracture
• Elderly patients with primary HPT present more
  often with indistinct psychiatric and
  musculoskeletal symptoms, and these are the
  symptoms most likely to be improved by operation
• Morbidity and mortality rates related to neck
  exploration in the elderly are similar to those
  in younger age groups

(British Journal of Surgery Volume
87(12) December 2000 pp 1640-1649)
28
Success of Cervical Exploration for Patients with
Asymptomatic Primary Hyperparathyroidism

• 61 patients were identified. 19 (31) had no
  symptoms, 21 (34) had subjective symptoms, 21
  had associated conditions
• Average preop postop Ca levels were 11.5 mg
  8.5 mg, respectively.
• Average PTH levels fell from 142 pg/mL to 49
  pg/mL after surgery.
• Preop postop Ca PTH levels for the three
  groups showed no significant differences.
• The success of surgery in identifying pathology
  ranged from 90.5 to 95, again showed no
  difference among the three groups.
• Long-term morbidity (gt6 months) in all groups
  was 0.
• Cervical exploration parathyroidectomy for
  asymptomatic primary hyperparathryoidism is safe
  has similar success rates in identifying
  pathology correcting biochemical abnormalities
  compared with patients with symptomatic disease.

( Am J Surg. 199917769-74).
29
Ethanol Ablation

• The abnormal parathyroid gland(s) must be
  detectable by ultrasonography confirmed by
  fine-needle aspiration for cytology PTH
  measurement before this approach.
• Large parathyroid adenomas are difficult to cure
  by ethanol injection.
• Patients who have undergone a subtotal
  parathyroidectomy for multigland disease have
  recurrent hyperparathyroidism due to the remnant
  gland are cidates for ethanol ablation.
• Hypoparathyroidism recurrent laryngeal nerve
  damage are rarely seen.
• Cure rates are much lower than those with
  surgery.

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Angiographic Ablation of Mediastinal Parathyroid
Adenomas

• 3 patients with likely mediastinal parathyroid
  adenomas that had single feeding arteries
  underwent attempted arteriographic ablation with
  a slow continuous infusion of contrast medium.
• All 3 patients were cured (follow-up 22 to 68
  months) with no long-term complications.

(American of medicine Volume 97(6) December
1994 pp 529-534)