Primary hyperparathyroidism

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Primary hyperparathyroidism

• ?????
• 2004/4/7

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Treatment of primary hyperparathyroidism

• Primary hyperparathyroidism is the third most
  common endocrine disorder.
• behind diabetes and thyroid disorders,
• the second most common cause of hypercalcemia.
• Current prevalence 1200 to 11000, depending on
  the type of population surveyed
• More common in postmenopausal women (with a ratio
  of 231)

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Varieties of primary hyperparathyroidism

• Sporadic benign adenoma 80-85
• Primary parathyroid hyperplasia 15-20
• Familial syndromes
• MEN 1
• MEN 2a
• isolated familial
• Jaw-tumor-PHPT syndrome
• Parathyroid cancer lt0.1

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Pathogenesis

• Genetic mutations
• Loss of vitamin D and calcium-sensing receptors
• External radiation to the head and neck
• Long-term thiazide and lithium therapy
• Chronic vitamin D depletion

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Clinical manifestations

• Severe life-threatening hypercalcemia
• Moderate hypercalcemia with classic bone lesions
  of osteitis fibrosa cystica
• Mild hypercalcemia with recurrent
  nephrolithiasis.
• Euphemism the disease of stones, bones, groans,
  and psychic overtones.

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The sweep effect Changing patterns of
presentation of primary hyperparathyroidism
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Relation between parathyroid adenoma weight and
age at the time of parathyroidectomy
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Diagnosis of primary hyperparathyroidism

• Sustained hypercalcemia
• intermittent hypercalcemia occurs over a period
  of 2 to 4 years
• Elevated or nonsuppressed serum parathyroid
  hormone (PTH)
• intact PTH assays measured both biologically
  active 1-84 and its N-terminally truncated 7-84
  biologically inactive fragment

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Minimal laboratory evaluation in patients with
primary hyperparathyroidism
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Management of contemporary primary
hyperparathyroidism the decision-making process

• Balance the risks and benefits of
  parathyroidectomy versus medical management
• Parathyroidectomy is the treatment of choice
• symptomatic hypercalcemia,
• overt bone disease or decreased bone density
• metabolical active kidney stones
• asymptomatic status
• continued accelerated bone loss, increased risk
  of fractures , nephrolithiasis or renal failure
  or both , increased CV mortality

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NIDDK workshop guidelines for parathyroidectomy
in asymptomatic primary hyperparathyroidism

• Age lt 50
• Serum calcium gt1.0 mg/dl above the reference
  range
• Bone density T-score gt -2.5 SD at any site
• Creatinine clearance reduced by 30
• Metabolically active kidney stone disease

J Bone Miner Res 2002
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Management of contemporary primary
hyperparathyroidism the decision-making process

• Medical therapy
• Raloxifene and bisphosphonates increase bone
  density
• the effect on serum calcium level is not
  consistent
• Calcimimetic agents,
• act through parathyroid cell calcium-sensing
  receptors,
• inhibit PTH secretion and lower serum calcium
  levels

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Oral Phosphate

• Low the serum calcium by up to 1 mg/dl.
• Limited G-I tolerance, possible further increase
  in parathyroid hormone levels, and the
  possibility of soft tissue calcifications, after
  long term use.
• This agent is no longer advisable as a chronic
  treatment for primary hyperparathyroidism.

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Bisphosphonates

• Reduce serum and urinary calcium levels but do
  not affect parathyroid hormone secretion
  directly.
• Risedroante lowered the serum and urinary calcium
  as well as the hydroxyproline excretion
  significantly while the parathyroid hormone
  concentration rose.

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Estrogen

• Reduce 0.5 to 1.0 mg/dl reduction in total serum
  calcium levels in postmenopausal women with
  primary hyperparathyroidism
• although parathyroid hormone levels do not change
  
• Raloxifene has been associated with modest
  reductions in serum calcium concentration.

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Calcimimetics

• A family of molecules that act on the parathyroid
  cell calcium sensing receptor
• Interact at an allosteric site on the calcium
  receptor
• Mimic the effect of extracellular calcium and act
  as agonists
• Lead to an increase in intracellular calcium and
  inhibit parathyroid cell function

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Calcimimetics

• Phenylalkylamine (R)-N-(3-methoxy-alpha-phenylethy
  l)-3-(2-chlorophenyl)-1- propylamine R-568
• increase cytoplasmic calcium and reduce
  parathyroid hormone secretion in vitro
• AMG 073
• Such an agent might be effective in inducing
  sustained reductions in parathyroid hormone and
  the serum calcium without the need for
  parathyroidectomy.

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Surgical management

• minimally invasive parathyroidectomy
• All glands must be explored on both sides of the
  neck, along the entire length of the carotid
  sheath and para-esophageal grooves, and the
  superior mediastinum.
• 5 to 15 of patients have more than or fewer
  than four glands, up to 35 may have
  multiglandular disease, especially in mild
  disease.

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Surgical management

• A histologic distinction between adenoma and
  hyperplasia is not always possible.
• Minimally invasive parathyroidectomy (MIP) is
  gaining popularity and accounts for approximately
  50 of the parathyroidectomies in the United
  States since its introduction in 1996.
• Preoperative localization is not required for
  standard bilateral neck exploration, accurate
  localization of parathyroid adenoma is a
  prerequisite for successful MIP.

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Surgical management

• Combined with intraoperative rapid PTH assay,
  gamma probe, or videoscope MIP offers curative
  surgery.
• The success of MIP depends heavily on
  preoperative localization of an adenoma, and
  therefore the cure rate is still less than 80,
  the sensitivity of most imaging procedures.

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Surgical management

• lt 2 for temporary or permanent recurrent
  laryngeal nerve palsy
• lt than 2 for postoperative hypoparathyroidism,
• 2 to 3 for reoperation because of either
  persistent or recurrent disease

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conservative management

• Adequate hydration to avoid hypercalcemic crises,
  particularly during the summer months and
  intercurrent illnesses.
• Adequate calcium intake may actually attenuate
  the effects of PTH on bone by partially
  suppressing PTH secretion.

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Secondary Hyperparathyroidism

• A physiologic response to renal failure with the
  accompanying 1)decrease in gut absorption of Ca
  (secondary to uremia) 2) decrease in 1-25 vit D
  production, 3) elevated serum phos. secondary to
  decreased excretion.
• The elevation in phosphate causes increased
  tissue deposition.

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Secondary Hyperparathyroidism

• The parathyroids attempt to make up for the
  decreased Ca levels and have compensatory
  hyperplasia.
• Treatment consists of management of each of the
  above three measures.
• Calcium carbonate, bisphosphonates, avoidance of
  aluminum.

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Secondary Hyperparathyroidism

• Only 5 of patients will develop either 1) an
  overshoot phenomenon or 2) severe symptoms
  (renal osteodystrophy, spontaneous fractures,
  intractable pruritis, headaches, malaise, soft
  tissue calcificications and psychoneurologic
  disorders) and require surgical excision of
  hyperplastic gland.
• Most others do not benefit from surgery.

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Tertiary Hyperparathyroidism

• Tertiary hyperplasia occurs when secondary
  hyperparathyroidism goes away.
• Basically the hyperplasia becomes monoclonal and
  adenomas will form which are resistant to normal
  feedback and require excision in patients able to
  tolerate this.

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Radioguided Tumorectomy in the Management of
Parathyroid Adenomas

• Sidiropoulos, Nikoletta MSII Vento, John MD
  Malchoff, Carl MD Whalen, Giles MD
• Volume 138(7)   July 2003  p 716720

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Introduction

• Bilateral neck exploration emerged as the gold
  standard treatment of primary hyperparathyroidism
  during a time when reliable preoperative
  localization did not exist.
• By 1990, localize the abnormal parathyroid glands
  preoperatively were compiled and reviewed by a
  National Institutes of Health (NIH) consensus
  panel.

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Introduction

• The reported false-positive rates of 15 and
  true-positive rates of 60 compared with the
  general success rate of 95 demonstrated by
  experienced parathyroid surgeons who performed
  bilateral neck exploration.
• More recent reports of high sensitivity and high
  specificity of preoperative localization with
  sestamibi suggest that the test might have
  potential value in the operative management of
  patients with primary hyperparathyroidism.

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Introduction

• Experience with sestamibi scanning as a reliable
  preoperative localization tool for single
  parathyroid adenomas, in addition to the widely
  accepted prevalence rate of 80 to 85 of single
  adenomas as the cause of hyperparathyroidism, led
  surgeons to incorporate minimally invasive
  techniques.
• We have selectively undertaken a minimally
  invasive, probe-directed tumorectomy in patients
  with primary hyperparathyroidism and a solitary
  adenoma found by sestamibi scanning.

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Introduction

• We review our results and test the hypothesis
  that a clearly localizing sestamibi scan
  identifies individuals in whom minimally invasive
  radioguided parathyroidectomy can be performed
  successfully.
• Secondary hypotheses are that radioguided
  parathyroidectomy will reduce operating room
  time, can be performed without increased
  morbidity, and will shorten hospital stay.

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METHODS

• Sixty-five patients underwent parathyroidectomy
  from January 1, 1998, to June 30, 2002.
• Fifty-five of these underwent sestamibi scanning
  at this institution and form the basis of the
  present study.
• Forty patients had a clearly positive sestamibi
  scan result, and 31 of these underwent minimally
  invasive radioguided parathyroidectomy.
• The remaining 24 underwent standard bilateral
  neck exploration.

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METHODS

• Two patients in each group underwent redo
  operations.
• There were 9 patients with a clearly positive
  sestamibi scan result in whom a minimally
  invasive parathyroidectomy was not performed
• in 4 patients the surgeon did not have the
  appropriate expertise,
• in 1 patient logistic obstacles precluded the
  procedure,
• in 1 patient there was a known thyroid
  abnormality,
• in 1 patient there was a positive family history
  that suggested multiglandular disease,
• in 2 patients the delay between preoperative
  sestamibi injection and the operation exceeded 3
  hours.

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METHODS

• In these last 2 patients, the minimally invasive
  procedure had been planned but was abandoned in
  favor of a standard approach, because after 3
  hours there was no longer increased radioactivity
  in the parathyroid adenoma.

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METHODS

• The criteria used in selecting patients
• a secure biochemical diagnosis of primary
  hyperparathyroidism
• an elevated plasma ionized calcium concentration,
  a nonsuppressed plasma parathyroid hormone
  concentration, and urinary calcium excretion of
  more than 100 mg/24 h (2.50 mmol/d) or kidney
  stones
• a clearly localizing sestamibi scan from our
  institution
• unequivocally identified a solitary focus of
  technetium Tc 99m sestamibi uptake that was
  clearly distinguishable from the iodine uptake
  into the thyroid gland
• absence of clinical suspicion of multiglandular
  disease.

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METHODS

• Cure of hyperparathyroidism was defined as
  normalization of ionized calcium on the follow-up
  visits to the surgeon and referring
  endocrinologists.
• Sestamibi scanning is performed via dual
  simultaneous isotope acquisition and subtraction
  analysis.

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METHODS

• Patients ingested approximately 0.5 mCi (18.5
  MBq) of sodium iodide I 123 in the capsule form
  and then were injected intravenously with
  approximately 25 mCi (925 MBq) of technetium Tc
  99m sestamibi.
• Four images of the iodine and sestamibi uptake
  were obtained simultaneously.
• A pinhole collimator was used to obtain anterior,
  right anterior oblique, and left anterior oblique
  images.
• A low-energy, high-resolution parallel hole
  collimator was used to obtain a chest view.

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METHODS
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METHODS

• We aimed to begin the operation 1.5 to 2 hours
  after a preoperative injection with approximately
  25 mCi (925 MBq) of technetium Tc 99m sestamibi.
• General anesthesia was used for most patients,
  although local anesthesia was used in 2 cases.
  Patients were positioned so that the neck was
  fully extended, and a collar incision was marked.
  
• Counts were taken at all 4 poles before incision.
  
• A small, midline, horizontal incision was made
  down the strap muscles, which were split open to
  enter the deep visceral compartment.

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METHODS

• The nature of the specimen was confirmed by
  radioactive counts ex vivo and by frozen section.
  
• After specimen removal, counts were taken to
  ensure that the radiation in all 4 quadrants and
  the operative bed decreased to levels below those
  recorded preoperatively.
• Analysis of variance included, such as the size
  of the adenoma, the time since the preoperative
  sestamibi injection, the dose of sestamibi, and
  the difference in counts between the background
  and target area.

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RESULTS

• The average age of the patients was 62 years
  (range, 37-88 years).
• The study group consisted of 45 women (82) and
  10 men (18).
• Ninety-five percent of the patients had a secure
  biochemical diagnosis of primary
  hyperparathyroidism.
• In the patients who did not have a secure
  biochemical diagnosis, we were unable in the
  retrospective review to find a documented 24-hour
  urinary calcium value.

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RESULT

• Of the 31 patients undergoing radioguided
  parathyroidectomy, 30 successfully completed the
  procedure without conversion to a standard
  procedure and with cure of the hyperparathyroidism
  .
• One patient's operation was converted to an open
  procedure, since the parathyroid adenoma was too
  large to reach through a small incision.
• One patient had 2 adenomas at the site of
  sestamibi uptake.

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RESULT

• A clearly positive sestamibi scan result predicts
  that a minimally invasive parathyroidectomy can
  be completed in 97 of patients.
• 6 of the patients in this group and 13 of the
  standard group experienced transient hoarseness.
• No patients had recurrent laryngeal nerve injury.
  
• There were no intraoperative complications in
  either group.

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RESULT

• 3 other benefits of minimally invasive
  radioguided tumorectomy
• did not experience any difficulties were
  discharged from the recovery room.
• incisions were shorter, averaging 3.3 0.7 cm in
  length
• operative times were 41 shorter
• Average minimally invasive, probe-directed
  operative time was converted to standard
  exploration was 75 29 minutes (range, 40-180
  minutes) vs 183 82 minutes (range, 40-390
  minutes) of standard parathyroidectomy.

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RESULT

• The average time spent in the operating room for
  the minimally invasive procedures vs the standard
  procedures was 128 minutes and 224 minutes,
  respectively, which is a 57 reduction in the
  time spent in the operating room.

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RESULT

• 73 of the scans were interpreted as suggesting a
  single adenoma.
• 5 of the scans showed more than one area of
  uptake, and 22 of the scans showed no uptake.
• In the patients with no uptake on the scan, a
  solitary adenoma was found 83 of the time.
• Overall sensitivity and specificity were 81 and
  86, respectively.

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RESULT

• In the 40 patients with a clearly positive
  sestamibi scan result, 39 (98) had a single
  parathyroid adenoma at the site predicted by the
  scan.
• One patient had a superior parathyroid adenoma
  descend behind and immediately adjacent to the
  lower pole parathyroid that was a second smaller
  adenoma.
• Both adenomas in this patient were at the site
  predicted by the sestamibi scan.

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RESULT

• Preoperative injection of technetium Tc 99m
  sestamibi generally occurred approximately 2
  hours before the initial incision (114 32
  minutes).
• At that time, preoperative counts at the 4 pole
  positions correlated with the scan findings, but
  the counts were not necessarily dramatically
  higher in the target area.
• Surgery was delayed more than 180 minutes
  following the preoperative sestamibi injection in
  2 patients.
• Consequently, radioguided localization of the
  adenoma, given the appropriate timing, exhibited
  increased radioactive counts did not occur.

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RESULT

• Successful use of the probe requires aiming for
  the hottest spot, not the hot spot, and awareness
  that the count increase over background counts
  might be subtle compared with expectations.
• The average bump in counts over the target area
  was only 20 over background, and this ranged
  from a low of 7 to a high of 70.
• The size of the difference in counts between the
  target area and background did not correlate with
  the size of the adenoma, the amount of sestamibi
  injected, or the time between injection and
  measurement.

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COMMENT

• Reliable technology is available that can improve
  efficiency in localizing diseased glands,
  minimize dissection, and probably lessen patient
  discomfort associated with a collar incision.
• A clearly localizing sestamibi scan is a highly
  reliable preoperative localization tool in
  patients with a secure biochemical diagnosis of
  primary hyperparathyroidism and no other reasons
  to suspect multiglandular disease.

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COMMENT

• learned 3 important lessons
• timing is important
• wash out the thyroid gland faster than the
  parathyroid adenoma
• a 3-hour delay between preoperative injection and
  incision was too long
• large adenomas in difficult locations remain
  difficult to remove through small incisions with
  prolong operative times
• aim at the hottest spot and trust the probe