May 20, 2010

Hyperparathyroidism: The Changing Face of Parathyroid SurgeryJaymie Claire Go Ang, M.D.

History

• 1850- First description of the parathyroid glands was by the London anatomist and curator of the Natural History Museum, Sir Richard Owen

• 1887- medical student Ivar Sandström described tiny glandular elements in 50 dissected human bodies.

• On a New Gland in Man and Several Animals

• comprehensive description of their appearance, position, size, and blood supply

• rejected by German editors and eventually published in Swedish in the Uppsala Medical Journal.

Tetany and Hypoparathyroidism

• Kocher and Billroth - Late 1900s

• Anton Wölfler gave a full and detailed account of tetany in the first patient who had undergone a total thyroidectomy by Theodor Billroth

• Surgical knowledge about the parathyroids emerged from surgical complications and preceded the discovery of parathyroid function.

Tetany and Hypoparathyroidism

• 1891- French physiologist Eugene Gley clarified the relation between parathyroid gland function and tetany. He described tetany in rats and rabbits as a consequence of the removal of the thyroid and parathyroid glands.

• 1892- First parathyroid autotransplantation was per- formed in 1892 by Anton von Eiselsberg in the preperitoneal space of cats

Tetany and Hypoparathyroidism

• William J. MacCallum at Johns Hopkins, described the use of parathyroid extracts to cure tetany in experimental animals.

• Transferred upcoming knowledge about the role of calcium in nerve conduction and muscle action and formed a hypothesis that the parathyroid glands may play a role in calcium metabolism.

• Later proven in experiments by Carl Voegtlin

• tetany caused by parathyroidectomy could be corrected with parathyroid extract or by injections of calcium

• 1907-William Halsted at Johns Hopkins used parathyroid extract and calcium chloride to treat postoperative tetany

The Case of Capt. Charles Martell• Master mariner of the U.S. merchant marine

• 1918-(22 y/0)- 1.85 m tall

• 1919- severe osteopathy and nephrolithiasis.

• 1926- entered the Massachusetts General Hospital (MGH) for surgery, shrunk by about 18 cm.

• 8 fractures, marked kyphosis, bone deformities

• Two first cervical explorations- Dr. E.P. Richardson were unsuccessful

The Case of Capt. Charles Martell

✄ 1932-third operation by Dr. Russell Patterson in New York City, with no tumor being discovered

✄ Returned to the MGH. Dr. Oliver Cope and Dr. Edward D. Churchill performed three subsequent cervical reinterventions without finding an adenoma.

✄ Seventh operation (Churchill/Cope)- mediastinal encapsulated brown tumor of 3 cm in diameter was found.

✄ excised only 90% of the adenoma, attaching the remnant with its vascular pedicle to the region of the sternal notch.

✄ tetany developed POD3, kidney stone impacted ureter 6 wks postop

✄ Died of laryngospasm

History

• 1928- Isaac Y. Olch performed the first successful operation of a parathyroid gland in the United States.

• Removed a 3 × 3 cm adenoma from the left inferior thyroid pole from a patient at Barnes Hospital of the Washington University School of Medicine in St. Louis, Missouri.

• The definitive breakthrough of parathyroid surgery occurred in the late 1920s and early 1930s

• Fuller Albright studied in detail the pathophysiology of parathyroid bone disease and recognized hyperparathyroidism as a distinct clinical syndrome

History: Technical Innovations

✄ 1959-60- Immunoassay for parathyroid hormone detection in peripheral blood was developed by Yalow and Berson

✄ 1977-DNA sequence of the gene for parathyroid hormone was identified

✄ 1989- A.J. Coakely noticed that technetium sestamibi is rapidly taken up by the parathyroids.

✄ 1988- Nussbaum provided evidence that PTH measures can be produced during the operation and thereby identify success.

✄ Uniglandular disease may well be approached by minimally invasive techniques, such as focused mini-incisions or endoscopy.

Parathyroid Surgery Today✄ Diagnosis of hyperparathyroidism readily made.

✄ Association between elevated PTH and bone disease is well understood

✄ The effects of elevated PTH on the central nervous system needs further investigation.

✄ Parathyroid surgery for primary hyperparathyroidism

✄ success rate close to 99%

✄ operative complications are below 1%

✄ mortality is virtually nil.

Embryology

Ectopic Parathyroid Glands

Anatomy and Histology

Relations

Physiology: Calcium

Hypercalcemia and Hyperparathyroidism

Hypercalcemia and Hyperparathyroidism

Text

Hyperparathyroidism (HPTH)

✄ Primary

✄ Secondary

✄ Tertiary

✄ Multiglandular MEN syndromes

✄ FHH

Primary HPTH

• Most common form of HPTH

• Most frequent explanation for hypercalcemia in the outpatient arena.

• Overall incidence approximately 4 per 100,000/year.

• Peak incidence is in the fifth to sixth decade of life, with a female to male ratio of approximately 3:2.

• Overall prevalence in the elderly 2–3%

• Most common clinical presentation: asymptomatic mild hypercalcemia

Primary HPTH

• Solitary, benign parathyroid adenoma- 80–85% of patients.

• Two distinct adenomas (double adenoma)- 5%

• Multigland parathyroid hyperplasia- 15–20%

✄ multiple endocrine neoplasia (MEN) type 1 (Wermer syndrome) and type 2A (Sipple syndrome)

• Parathyroid carcinoma- <1% of case

• Hyperparathyroidism–jaw tumor syndrome (HPTH-JT)- rare

• Familial isolated primary HPTH have also been described, outside of MEN1, MEN2A, and HPTH-JT syndromes

Secondary HPTH

• Occurs when decreased circulating calcium concentrations stimulate the increased secretion of PTH

• Most commonly in patients with chronic renal insufficiency (associated with renal osteodystrophy) or in patients with gastrointestinal calcium malabsorption.

• Stimulus for PTH hypersecretion is a reduced extracellular calcium concentration

• hypercalcemia is not present

• never a consideration in the differential diagnosis of hypercalcemia.

Tertiary HPTH✄ Secondary HPTH may, over time, develop one or more enlarged

parathyroid glands (hyperplasia) or a more generalized dysregulation of parathyroid function that actually progresses to hypercalcemia.

✄ Not uncommon in this setting for patients to develop multigland disease, although marked asymmetry is typical.

✄ Leads to hypercalcemia, often severe

✄ Requires parathyroid resection.

✄ Typically encountered in patients with end-stage renal disease on dialysis.

✄ Optimization of serum calcium and phosphate levels and vitamin D status in patients with chronic kidney disease necessary to avoid this complication.

Multiglandular Parathyroid Disease and MEN syndromes

Familial hypocalciuric hypercalcemia (FHH)

✄ Inherited autosomal dominant condition due to a deactivating mutation in the extracellular CaSR

✄ The receptor is subnormally activated by the extracellular calcium concentration

✄ PTH levels are inappropriately normal or slightly elevated, in the face of mild elevation of serum calcium

✄ Urinary calcium excretion is reduced, due to the same defective CaSRs in the nephron, with consequent increased urinary calcium reabsorption

✄ Does not require surgical intervention

✄ Surgical indications in patients with primary hyperparathyroidism

• Significant bone, renal, gastrointestinal, or neuromuscular symptoms typical of primary hyperparathyroidism

• In otherwise asymptomatic patients:

• Elevation of serum calcium by 1 mg/dl or more above the normal range (i.e., ≥11.5 mg/dl in most laboratories)

• Marked elevation of 24-hour urine calcium excretion (e.g., >400 mg)

• Decreased creatinine clearance (e.g., reduced by ≥30% compared with age-matched normal persons)

• Significant reduction in bone density of more than 2.5 standard deviations below peak bone mass at any measured site (hip, lumbar spine, wrist; i.e., “T score” approximately <2.5 at any of these sites)

• Consistent follow-up is not possible or is undesirable because of coexisting medical conditions

• Age younger than 50 years Fromthe2002NationalInstitutesofHealthWork- shop)

Parathyroid imaging

• Traditionally, the standard surgical approach consisted of a bilateral neck exploration with direct visualization of all four parathyroid glands

• Role of preoperative imaging depends upon the surgical approach

• Currently, minimally invasive surgical techniques are advocated for patients with primary HPTH

• Accurate preoperative localization of the parathyroid adenoma must be provided for this approach to be successful

Parathyroid Imaging

• Plays an important role in the preoperative assessment of patients with persistent or recurrent HPTH

• Ultrasound (US) is ideal for eutopic lesions nearby the thyroid gland

• Computed tomography (CT) and magnetic resonance imaging (MRI) are more effective in detecting ectopic parathyroid glands.

• Sestamibi scintigraphy- single most sensitive study for both perithyroidal and ectopic glands, detecting most of the adenomas and a large proportion of hyperplastic glands.

Nuclear Imaging

• Dual-radioisotope combination us- ing thallium-201 (201Tl) and 99mTc pertechnetate (201Tl/99mTc) with the aid of a subtraction program

• Sestamibi-lipophilic cationic complex that is sequestered primarily within the mitochondria and was developed for myocardial perfusion studies

• Combination imaging using 99mTc sestamibi and 123I sodium iodide.

Ultrasound

• Complementary role

• Unique role in preoperative fine-needle aspiration (FNA) of extrathyroidal masses

• More detailed anatomic information

• Able to assess concurrent thyroid disease, which is estimated to be present in approximately 40% of patients, and is able to guide percutaneous FNA to confirm the diagnosis.

• Less value in identifying ectopic parathyroid glands outside of the neck, particularly in the mediastinum and retrotracheal or retroesophageal areas

✄ classic appearance of an adenoma on US examination: homogeneously hypoechoic extrathyroidal oval mass ranging in size from 0.8 to 1.5 cm in length with a clear fat plane separating the adenoma from the thyroid gland

CT scan/ MRI

• effective method for the detection of ectopic lower parathyroid adenomas, especially in the ant. mediastinum, sensitivity- 92%

• MRI provides a higher sensitivity at identifying ectopic parathyroid adenomas than does CT scan

• Parathyroid gland localization by MRI are 71–83%, for the adenomas (87%) but less for parathyroid hyperplasia (75%)

Contrast-enhanced CT scan of the upper mediastinum shows a hyperdense lesion surrounded by the mediastinal fat during arterial contrast dye phase

Invasive Localization Test

• Almost exclusively indicated in the preoperative work-up for repeat surgery

• Used only if the advanced noninvasive tests as sonography, scintigraphy, CT, and/or MRI have been negative or inconclusive.

• Selective Parathyroid Venous Sampling (SVS)

• First described by Reitz and colleagues.

• If positive, it can indicate the side and the cervical or thoracic location of a PTH-producing lesion

Venous PTH levels

Conventional Surgical Management: Single adenoma

• Bilateral neck exploration- remained the conventional treatment of choice for primary HPTH for many decades, until more recently, when minimally invasive parathyroidectomy has been popularized.

• “Gold” standard to which all other procedures are compared.

• Success rate >95% in the hands of experienced endocrine surgeons

• Surgical failures occur due to the inability to locate an ectopic parathyroid adenoma, unrecognized multiple gland hyperplasia, or supernumerary glands.

✄ Fibrotic, enlarged PTH elicits a desmoplastic reaction, and is adherent to other neck structures or the thyroid gland, ?malignancy-resect en bloc with hemithyroidectomy

Conventional: Multiglandular

• 10–30% of patients with primary HPTH

• incidence of recurrent or persistent hypercalcemia highest for patients with multiglandular hyperplasia

• sporadic (5-10%)

• MEN syndromes (20-40%)

• Gland hyperplasia- subtotal parathyroidectomy (3.5) + cryopreservation of one gland

Conventional: Double adenoma

• 2% of patients with primary HPTH

• ?represents a distinct entity or merely asymmetrical diffuse hyperplasia.

• Controversial surgical approach:

• “hyperplasia theory” recommend subtotal parathyroidectomy or total parathyroidectomy with autotransplantation

• separate disease entity, remove only clinically enlarged glands

Conventional: Ectopic gland

• Found in ectopic locations along their embryologic migration path. Noted in 15–20% of autopsy studies

• Standard neck exploration

• 20% of patients may have parathyroid glands extending into the mediastinum- cervical thymectomy.

• Direct mediastinal exploration required in only 1–2% of cases.

• Subcarinal parathyroid adenomas may be accessed via a partial or complete median sternotomy

• Posterior mediastinal parathyroid adenomas may require a thoracotomy

Minimally Invasive Parathyroidectomy (MIP): Intro✄ Targeted surgery using unilateral neck exploration under regional or local anesthesia

has been developed and evaluated since 1995 for single adenoma

✄ Standard of care in an ever-increasing number of specialized centers.

✄ Unilateral surgery for primary HPTH (1975), side to be explored chosen based on palpation, esophagram, venography, or angiography. If both an enlarged and normal gland were found on the initial side, then contralateral exploration was aborted.

✄ Lund University surgeons advocated unilateral parathyroidectomy.

✄ excised tissue studied microscopically during surgery with oil- red-O

✄ decision to stop the operation at this stage was based on demonstration of a reduction in intracytoplasmic fat droplets in the excised adenomatous parathyroid tissue.

MIP: Indications

• Same as those for traditional cervical exploration

• Rarely employed when preoperative localization of the parathyroid tumor has not been performed, is negative, or is consistent with multiglandular enlargement.

• Rare cases when parathyroid carcinoma is diagnosed or suspected preoperatively should undergo radical resection at the initial operation

MIP: Technique

✄ Awake

✄ Semi-Fowler position

MIP: Technique

• Lo Gerfo, et al

• Bilateral neck exploration under regional anesthesia can be performed safely and effectively in patients with coexisting thyroid disease and a non-localized adenoma.

• 236 patients

• 62% had a non-localizing sestamibi scan preoperatively or no scan at all

• 4 required conversion to general anesthesia

• 23 percent had a simultaneous procedure performed for thyroid disease

• 85% underwent a bilateral neck exploration

✤ Superficial cervical block

Lo Gerfo P (1999) Bilateral neck exploration for parathyroidectomy under local anesthesia: a viable technique for patients with coexisting thyroid disease with or

without sestamibi scanning. Surgery 126:1011–1014; discussion 1014–1015

MIP: Technique

✄ Focused exploration (based on preop localization)

Intraoperative assay• reduced operating time.

• 1988 first reported employment of the assay

• refined significantly since then by George Irvin

• rapid PTH immunometric assay utilizes chemiluminescence, acridinium esters as a label in the presence of hydrogen peroxide and sodium hydroxide triggers

• In their presence, the acridinium esters are oxidized to an excited state, and it is the subsequent return to the ground state that causes an emission of light that is quantified.

• amount of bound labeled antibody is directly proportional to the concentration of PTH in the sample

• results of the assay are available within 12 minutes

Intraoperative assay: Technique

• Blood specimens: peripheral intravenous line (best), ipsilateral internal jugular vein, or (rarely) arterial catheter

• Drawn before exploration, intraoperatively immediately after resection of the enlarged gland, 5 and 10 minutes after the excision of the incident adenoma.

• 50% reduction in the quick PTH value from the baseline level= predictive of cure 96% of cases

• Ex vivo intraoperative needle aspiration of suspected parathyroid tissue measurement of intraoperative PTH is a useful alternative to frozen section for parathyroid gland identification

Conventional vs MIP

• Success of MIP has been confirmed by evidence of cure and complication rates that are at least as good as those achieved by conventional bilateral exploration

• 656 consecutive parathyroidectomies (401 standard fashion and 255 MIP) between 1990 and 2001

• no significant differences in complication (3.0% and 1.2%) or cure rates (97% and 99%

• MIP was associated with an approximately 50% reduction in operating time (1.3 hours for MIP versus 2.4 hours for standard operation)

• sevenfold reduction in length of hospital stay (0.24 days MIP versus 1.64 days standard operation

Udelsman R (2002) Six hundred and fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 235:665–670

Endoscopic Parathyroidectomy

• M. Gagner (1996) first endoscopic parathyroidectomy (Gagner M (1996) Endoscopic parathyroidectomy (letter). Br J Surg 83:87)

• Primary HPTH appears to be an ideal disease to be approached endoscopically for several reasons:

• (1) the tumor giving rise to the hyperfunction is almost always benign,

• (2) it rarely exceeds 2–3 cm in size

• (3) there is no need for any surgical reconstruction after the small mass removal.

• Indications: mostly indicated for sporadic disease characterized by the presence of a single, well-localized adenoma harbored in a virgin neck.

• Main advantage: cosmesis

Endoscopic Parathyroidectomy

Conclusion

• History of Parathyroid Surgery interesting path

• Function and form elucidated, coupled with technological innovation has converted parathyroid surgery into an ambulatory procedure

• Success of MIP has been confirmed by evidence of cure and complication rates that are at least as good as those achieved by conventional bilateral exploration

Resource

• Oertli, D., Udelsman, R., Surgery of the Parathyroid and Parathyroid Glands,C2007

• Roth SI, Wang CA, Potts JT Jr (1975) The team approach to primary hyperparathyroidism. Hum Pathol 6:645–64

• Wang CA (1985) Surgical management of primary hyper- parathyroidism. Curr Probl Surg 22:1–50

• Tibblin S, Bondeson AG, Ljungberg O (1982) Unilateral parathyroidectomy in hyperparathyroidism due to single adenoma. Ann Surg 195:245–25

• Udelsman R, Donovan PI, Sokoll LJ (2000) One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 232:331–339

• Bilezikian J, Potts JJ, Fuleihan G-H, Kleerekoper M, Neer R, Peacock M, Rastad J, Silverberg S, Udelsman R, Wells S (2002) Summary statement from a workshop on asymp- tomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 87:5353–5361

• Rastad J, Joborn C, Akerstrom G, Ljunghall S (1992) Inci- dence, type and severity of psychic symptoms in patients with sporadic primary hyperparathyroidism. J Endocrinol Invest 15:149–156

• Silverberg SJ (2002) Non-classical target organs in pri- mary hyperparathyroidism. J Bone Miner Res 17(suppl 2): N117–N125