Employ diagnostic testing to distinguish secondary from primary hyperparathyroidism (PHPT).

Utilize the criteria for surgical intervention in PHPT.

Discuss the similarities and differences between bilateral and unilateral exploration of the parathyroid gland.

Practice the techniques commonly used in conventional bilateral exploration of the parathyroid.

Recognize and manage patients with persistently elevated parathyroid hormone after surgery.

Management Guidelines
James Cohen, MD, PhD, Professor of Otolaryngology–Head and Neck Surgery, Multidisciplinary Thyroid and Parathyroid Tumor Program, Oregon Health and Science University, Portland

Role of surgery: successful surgical treatment of primary hyperparathyroidism (PHPT) requires secure diagnosis and understanding of indications for surgery (means understanding natural history and consequences of disease); 3 questions to ask—first, whether patient has PHPT; second, whether patient has indications for surgery; third, localization; previously (before routine screening performed), most patients seen with PHPT had manifestations of disease (indications for surgery; eg, bone disease, renal stones); previously, only bilateral exploration performed

Basic diagnostic testing: includes ionized calcium (Ca) and intact parathyroid hormone (PTH; 7-84 assay); ensure that patient has nonphysiologic secretion of PTH; possible for patient to have normal PTH and normal Ca but out of proportion to one another; caution necessary in area of overlap between PHPT and secondary HPT; other tests—25-hydroxyvitamin D level, which reflects dietary intake; vitamin D deficiency—rampant, due to inadequate sun exposure and diet and coexistent in most patients with PHPT; important to treat before surgery so patient can optimally absorb Ca after surgery; ensure that serum urea nitrogen (BUN) and creatinine not contributing to secondary HPT; occasionally, creatinine clearance necessary; 24-hr urine Ca—to rule out benign familial hypocalciuric hypercalcemia (BFHH) or other forms of secondary HPT; extremely low 24-hr urine Ca may mean presence of BFHH, poor Ca intake, or deficiency in vitamin D causing poor absorption of Ca; extremely elevated 24-hr urine Ca may signify spillover due to PHPT or renal wasting of Ca; if unable to distinguish, temporary trial of thiazide diuretic to decrease Ca excretion and determine whether PTH suppressed (secondary HPT): signs and symptoms of PHPT—absent in majority of patients; study shows that 75% of patients with mild HPT who are asymptomatic by usual criteria will not necessarily progress over time; 25% progress, so monitoring necessary

Primary hyperparathyroidism: renal consequences—renal stones relatively uncommon (15%-20%) in PHPT and indication for surgery; hypercalciuria seen in 30% to 50% of patients and defined as urine Ca >350 to 400 mg/24 hr; no correlation between urinary Ca and presence of renal stones; formation of renal stones complex process; over time, hypercalcemia and hypercalciuria impair renal function; bone consequences—excess of PTH affects cortical bone; standard screening for osteoporosis looks at lumbar spine and hip; bone mineral density (BMD) reported as T score (number of SDs from normal); lumbar spine, however, mostly cancellous bone, and PTH has protective effect on cancellous bone, so not ideal site to look for BMD changes related to PTH; radius (40%-50% cortical bone) ideal site to look for effects of excess PTH; screening for BMD necessary; if BMD decreased, determine whether differentially greater in radius than hip or lumbar spine (useful since many patients older and have osteoporosis for other reasons); BMD testing part of work-up

Surgical management: advantageous for bones in patients with bone changes from PHPT; patients who are cured of disease and who take added Ca and vitamin D can increase BMD 10% within first year of surgery, and bone loss stops; also results in 0% incidence of recurrent nephrolithiasis

Other consequences of PHPT: musculoskeletal pain and bone pain; increased cardiovascular risk, with possible increased incidence of sudden death; in patients with secondary HPT from renal causes or chronic PHPT, proximal muscle weakness and band keratopathy; not conclusive that peptic ulcer disease associated with PHPT or that hypertension exacerbated by PHPT; no link established between PHPT and refractory pancreatitis, gout, and anemia; fatigue, weakness, and depression possibly associated

Criteria for surgical intervention: serum Ca >1 mg/dL above normal range (patients more likely to have dehydration and worsening hypercalcemia); 24-hr urine Ca >400 mg/24 hr; creatinine clearance <30% of age-matched patients; previously, BMD Z score (age-matched number of SDs from normal) 2 SDs below age-matched normal; presently, T score (number of SDs below normal bone) 2.5 times below normal (increased risk for fracture) or decreasing BMD, despite maximum Ca and vitamin D intake; age <50 yr; complications of PHPT or patients who cannot be reliably followed; asymptomatic patients with PHPT must be followed with vitamin D or Ca levels once or twice annually after stabilization, urine Ca initially and BMD every 8 to 12 mo; absolute vs relative indications—surgery not performed if patient has severe medical comorbidities or if against patient’s wishes; decision difficult if patient has multiple relative indications; decision influenced by surgeon’s vs patient’s expectations and by progression of disease

Preoperative localization: if glands well localized, surgery likely straightforward and successful, and should be performed; secure localization last of 3 questions

Conventional Parathyroidectomy
Dr. Cohen

Definitions: bilateral exploration involves 4 glands; unilateral exploration involves 2 glands on one side of neck; targeted or directed parathyroidectomy involves only one gland; 2 conventional methods include 1) open approach and 2) endoscopic or video-assisted; “minimally invasive” does not imply use of endoscope, only that overall morbidity less than that of conventional approach; strategy for any parathyroid operation to identify and remove all abnormal tissue; change seen in how abnormal tissue identified; abnormal tissue now identified before patient taken to operating room (OR)

Bilateral exploration: requires great judgment and experience for success; parathyroid glands difficult to locate (look similar to surrounding fat, particularly if some blood staining present) and have variable location; in HPT, normal glands often suppressed (smaller and less vascular); frozen sections not helpful; should ask pathologist only whether tissue is parathyroid; differentiation between normal and abnormal gland by frozen sections extremely difficult; macroscopic appearance of gland relied on to make decision in OR; decision not easy when gland only slightly abnormal; bilateral exploration relies on surgical experience to locate gland and surgical judgment to determine abnormality

Unilateral exploration: 85% to 95% of patients have problem in only one gland; removal of one gland and finding normal gland precludes 4-gland hyperplasia; less morbidity and less risk for recurrent laryngeal nerve injury; requires preoperative localization to determine on which side of neck to operate; requires heavy reliance on surgical experience and judgment

Functional studies: intraoperative PTH assay determines PTH level in OR; if PTH level returns to normal, means abnormal tissue removed; alternative gamma probe, which relies on radionuclide uptake by tissue and absence when tissue removed to make same judgment; led to targeted parathyroidectomy; all operations based on conventional parathyroidectomy

Parathyroid surgery: steep learning curve; finding normal gland difficult; more difficult second time; start and finish one side of neck before working on other side; localization relies heavily on bloodless field; loop magnification used; understanding embryonic roots of parathyroid important, particularly in pediatric patients; based on good exposure, which depends on ability to visualize field by anterior and superior retraction of ipsilateral thyroid lobe (to get into paratracheal and thyroid bed)

Speaker’s technique for conventional bilateral exploration: incision based just below thyroid isthmus, usually at inferior pole; incision usually ≈3.5 cm; action on strap muscles depends on location of gland; for patient with low parathyroid adenoma, traction obtained by taking sternothyroid muscle and retracting entire laryngotracheal complex upward

Position of parathyroid adenoma: determines actions taken; if adenoma at level of sternal notch, section both strap muscles; if strap muscles pulled laterally, distance comes from stretch of strap muscles and from pulling hyoid bone down; if exploring thymic tongue with open technique, strap muscles problematic

Finding inferior gland: first look below thyroid pole; when field maximally exposed with retraction of strap muscles, look around inferior pole of thyroid; parathyroid adenoma often behind draining veins from thyroid; should also look for thyrothymic ligament and thymic tongue; follow ligament upward to where it joins inferior aspect of thyroid lobe, and inferior parathyroid almost always sits on that tract; exercise caution about not placing clamp on parathyroid adenoma

Finding superior gland: thyroid is handle for getting into paratracheal groove and into posterior aspect of thyroid; necessary to mobilize thyroid gland; middle layer of deep cervical fascia sends its investments from thyroid to carotid sheath; incise fascia as high as possible to roll gland forward to obtain good exposure of its posterior aspect; if patient has short neck or big gland, moving gland forward important, as well as taking down superior pole if necessary to obtain exposure; most parathyroid glands located superior and lateral to recurrent laryngeal nerve and inferior thyroid artery cross or to where nerve inserts into larynx; in conventional exploration, should locate recurrent laryngeal nerve, especially if dealing with superior gland; probably not applicable in targeted parathyroidectomy if involving inferior gland located anteriorly in thymic tongue; recurrent laryngeal nerve useful landmark in guiding exploration; inferior gland sits anterior to coronal plane, and superior gland sits posterior to plane; as gland pulled forward, plane shifts

If gland not found after inferior and superior exploration: explore thymic tongue as far down as possible; anterior mediastinal exploration not arbitrary removal of block of fat from anterior or superior mediastinum; plane of recurrent laryngeal nerve important in determining where to explore; vascular pedicles important for gland localization; if still unable to locate abnormal gland, explore carotid sheath (open and search); parathyroid adenomas usually located in proximity to vagus nerve; as last resort, thyroid lobe removed if other side explored and gland(s) not found

Biopsy: whether to biopsy normal glands to prove them normal controversial, due to morbidity of bilateral exploration and risk for hypoparathyroidism (although usually temporary); routine biopsy of gland not necessary, except if exploration unsuccessful; in all decision making, treat every parathyroid gland as last one; should not make final decision about excision until involvement of other glands determined; operative note—should reflect actions performed, findings, and tissues sent, based on frozen section, particularly in unsuccessful exploration

PTH Elevation After Parathyroid Surgery
Keith S. Heller, MD, Professor of Surgery, New York University School of Medicine, and Chief, Division of Endocrine Surgery, New York University, Langone Medical Center, New York, NY

Persistently elevated PTH: incidence 10% to 40% and same whether bilateral or focused exploration performed; article by Silverberg—patients seen in referral center with normocalcemic PHPT have more substantial skeletal involvement than typically seen in PHPT and develop more symptoms and complications over time; may represent earliest form of symptomatic PHPT; relatively normal Ca does not mean that PHPT relatively insignificant; explanations—most common one states that actually reactive secondary HPT after surgery, particularly in northern parts of country, where vitamin D deficiency almost rule, not exception; in some patients, impaired renal hydroxylation of vitamin D proposed; other studies demonstrate decreased peripheral sensitivity to PTH; speaker’s concern whether patients actually have persistent PHPT and whether disease significant; if due to vitamin D deficiency and bone re-mineralization, expected that over time, persistent elevations of PTH would resolve; study data—show that 50% to almost 100% of patients return to normal; in group with persistent elevation, 3% developed frank recurrent disease with hypercalcemia; small series showed that 14% with persistently elevated PTH developed recurrent HPT; in 3 other studies with similar design, in which intraoperative PTH measured, no intraoperative decisions made based on measurements; on bilateral exploration, 15% of patients had multigland disease which would have been missed by imaging and intraoperative PTH measurement

Speaker’s study: 816 participants; all had preoperative sestamibi scanning and intraoperative PTH measurements; criteria for persistently elevated PTH calcium 10.2 mg/dL and PTH >65 pg/mL at postoperative visits; 2% failure rate, with all having persistently elevated postoperative Ca and PTH, despite fact that imaging showed one abnormal gland and intraoperative PTH met criterion of 50% drop into normal range; 15% had normocalcemic elevated PTH postoperatively; compared to groups cured postoperatively, group with persistently elevated PTH tended to have elevated (50% higher) preoperative PTH level, less likely to have undergone bilateral exploration, and less likely to have multiple abnormal glands identified; final intraoperative PTH slightly higher in group with persistently elevated PTH; postoperatively, slightly lower Ca level in PHPT group and statistically significant lower vitamin D levels; some patients clearly had secondary form of HPT postoperatively; group with persistently elevated PTH divided into those with low-normal Ca (<9.6 mg/dL) and those with high-normal Ca, with no difference found; group whose PTH normalized tended to have Ca that increased more, compared to group with persistently elevated PTH (also true for vitamin D); in group with normal Ca and PTH postoperatively, none developed recurrent HPT, although some developed slightly elevated PTH levels; no patients with persistently elevated PTH but relatively low Ca went on to develop recurrent disease; 3 of 47 developed frank HPT if Ca levels higher normal

Speaker’s more recent study: 176 participants with PHPT; 70% underwent focused single-gland exploration, 7% unilateral exploration, and 15% bilateral exploration, based on imaging; 7% started as focused exploration but converted to bilateral exploration because intraoperative PTH did not decrease; ≈15% of patients with PHPT have multigland disease, but imaging studies detect only ≈ 50% of these; outcome—11% had persistently elevated PTH; final intraoperative PTH—in group with PTH <10 pg/mL (14%), none had persistently elevated PTH postoperatively; in group with PTH <20 pg/mL, 2 had persistently elevated PTH postoperatively but had low Ca levels; as numbers increase, percentage of patients with persistently elevated PTH increases (all met 50% criteria); in group with PTH >40 pg/mL, approximately one-third had persistently elevated PTH and in 4 of 7, Ca in high range; possible way of selecting patients who require more careful follow-up; conclusions—important to follow PTH; in most cases, persistently elevated PTH related to vitamin D deficiency; concern about patients who have high-normal Ca; high final intraoperative PTH possibly more accurate predictor of persistent disease than 10-min intraoperative PTH; follow patients’ BMD (shown that if HPT improved, BMD improves)