Principles in Surgical Management of Primary Hyperparathyroidism

In this chapter, we discuss the current approach to preoperative workup for primary hyperparathyroidism (primary HPT), determine appropriate surgical candidacy, review parathyroid surgical anatomy, and detail a comprehensive search algorithm for surgical exploration.

Preoperative Evaluation

Background

Primary HPT is a common cause of hypercalcemia with approximately 100,000 new cases diagnosed in the United States each year. This number may be an underestimation due to the prevalence of undiagnosed and untreated primary HPT in the general population. Most cases of primary HPT are due to excess parathyroid hormone (PTH) secretion from a single adenoma (80% to 85%), followed by four-gland hyperplasia (10% to 15%), multiple adenomas (5%), and carcinoma (< 1%). Primary HPT must be distinguished from other causes of hypercalcemia before surgical exploration because operating for incorrect reasons will not cure the patient and may even worsen the situation. The differential diagnosis for hypercalcemia includes malignancy, multiple myeloma, primary HPT, granulomatous disease, calcium/vitamin D supplementation, thiazide diuretics, lithium, benign familial hypocalciuric hypercalcemia, and Paget’s disease.

Clinical Manifestations

Primary HPT can be associated with a wide range of symptoms as summarized by the colorful phrase “renal stones, painful bones, abdominal groans, psychic moans, and fatigue overtones.” Hyperparathyroidism (HPT) complications consist of a spectrum of bony (bone/joint pain, fractures, osteitis fibrosa cystica), renal (nephrolithiasis, polyuria, renal insufficiency), gastrointestinal (nausea, vomiting, peptic ulcer disease, constipation, pancreatitis), neuropsychiatric (lethargy, “brain fog,” depression, psychosis), soft tissue (calcinosis, calciphylaxis, intractable pruritus), and cardiovascular (left ventricular hypertrophy, conduction abnormalities, endothelial dysfunction, decreased QT interval) manifestations. However, in most modern series in developed regions of the world, patients generally present with asymptomatic forms of primary HPT, which are discovered in routine laboratory tests.

Preoperative History and Physical Examination

Preoperative history should include questions related to the potential etiology, symptoms, and complications of primary HPT.

History

Symptoms of hypercalcemia. Weight loss, polydipsia, fatigue, memory change, depression, renal stones, hypertension, bone-joint-muscle pain, arthritis, gout, fractures, bone disease, nausea, vomiting, constipation, peptic ulcer, and pancreatitis.
Time course of hypercalcemia. Gradual onset is consistent with primary HPT. More rapid onset occurs in the setting of malignancy. Hypercalcemia associated with malignancy usually occurs in relatively advanced, clinically apparent disease. Multiple myeloma is an exception where hypercalcemia might be the initial symptom. Lifelong and stable hypercalcemia is observed in benign familial hypocalciuric hypercalcemia (BFHH).
Age of onset. Sporadic HPT usually occurs in older patients. Some familial HPT syndromes may present at an earlier age (see the primary HPT genetic section presented later in the chapter).
History related to drugs and conditions that mimic HPT. Intake of oral calcium, vitamins D and A, thiazide diuretics, lithium, and anticonvulsants. History of vitamin D deficiency, rickets, adrenal insufficiency, hyperthyroidism, prolonged immobilization, sarcoidosis, known malignancy.
History of radiation exposure. Low-dose radiation exposure can increase the risk of HPT threefold.
Family history. Hypertension, endocrine tumors, calcium disorders.

Six-question panel for MEN 1 Assessment. Yip et al. suggested that a six-question panel assessment for possible multiple endocrine neoplasia 1 (MEN 1) can be used to screen for MEN 1 in apparent sporadic primary HPT. The assessment question panel includes the following: have any blood relatives had (1) Neck surgery? (2) Kidney stones? (3) Brain tumors? (4) Ulcers? (5) High calcium levels? (6) Pancreatic tumors?

Biochemical screening to rule out MEN 1 was recommended in HPT patients with multiple positive panel answers. It was noted that young males with multiple positive panel answers have higher chances of MEN 1 than females with positive panel scores or males without positive answers. Age and positive panel answers were associated with increased chance of having MEN 1; however, male sex alone was not. A false positive result of 23% was noted with question panel positivity.

Physical Examination

Physical examination is typically unremarkable. Albright’s dictum states that if a palpable nodule is present in a patient with HPT, it is an unrelated thyroid nodule. However, up to 50% of parathyroid carcinoma patients have a palpable mass. A firm palpable neck mass in the setting of severe hypercalcemia and PTH elevation strongly suggests parathyroid carcinoma.
Preoperative laryngeal examination to assess preoperative vocal cord function should be considered in patients with voice changes, preoperative evaluation suggestive of parathyroid carcinoma, or history of operation that places at risk the innervation of muscles controlling the vocal folds.

Preoperative Laboratory Tests

Serum calcium and intact parathyroid hormone (iPTH)
- High calcium and high iPTH are indicative of primary HPT.
- High calcium and normal PTH. At least 10% of surgically proven primary HPT cases have high normal serum PTH levels. This pattern of elevated calcium and inappropriately elevated PTH in the high normal range is consistent with parathyroid gland autonomy.
- Normal calcium and elevated PTH. Normocalcemic primary HPT is considered a form of parathyroid disease, perhaps an initial form of HPT. Although normocalcemic primary HPT may be associated with symptoms or complications equivalent to those affecting patients with frankly elevated calcium, it is very important to exclude other mimicking diagnoses such as vitamin D deficiency and “renal leak” hypercalciuria as causes for PTH elevation, which in these conditions is secondary (see the discussion on vitamin D and primary HPT and normocalcemic primary HPT presented later).
- Serum calcium of higher than 14 mg/dL raises the specter of parathyroid carcinoma and is typically accompanied by significantly elevated PTH.
Vitamin D-25-OH. Vitamin D should be evaluated in patients being assessed for primary HPT. Conditions associated with vitamin D deficiency should also be considered, including Crohn’s disease, cystic fibrosis, celiac disease, malabsorption after gastric bypass surgery, or renal dysfunction (with decreased ability to synthesize the active dihydroxylated form).
24-hour urine calcium and creatinine. Urine parameters may be measured to assess renal function and help rule out BFHH, which can mimic HPT; the diagnosis is made with low urine calcium/creatinine clearance ratio and total calcium/24-hour urine collection < 100 mg.
Serum phosphate and chloride. Patients with primary HPT typically have a low or low-normal phosphate. An elevated serum chloride level, with a chloride-to-phosphate ratio > 33 was diagnostically helpful for HPT before accurate PTH assays.
Alkaline phosphatase. Alkaline phosphatase levels may be elevated in the setting of bone disease. When elevated preoperatively, surgeons should anticipate that postoperative hypocalcemia (termed hungry bone syndrome ), which can prolong hospitalization, may occur.
Bone density scan. Patients may demonstrate osteopenia or osteoporosis as well as progressive decrease in bone density on serial imaging. Bone loss affecting the distal 1/3 radius is particularly suggestive of parathyroid disease.
Surgeons should be knowledgeable and astute about the biochemical diagnosis of HPT. In the operating room, surgeons should be confident that the diagnosis is accurate; this implies their commitment to explore thoroughly and recognize that ≥ 1 abnormal glands will be amenable to curative resection through a neck incision about 98% of the time ( Box 55.1 ).
Box 55.1

Key Elements of the Biochemical Diagnosis of HPT
- 1.
  High calcium and PTH
- 2.
  Normal creatinine
- 3.
  Low or low normal phosphate
- 4.
  Urinary calcium > 100 mg/24 hours
- 5.
  Normal vitamin D-25-OH

Preoperative Genetic Assessment

Familial Syndromes and Genetic Testing

Primary HPT is predominantly sporadic but may be diagnosed in the context of an inherited syndrome. For surgeons, it is important to distinguish preoperatively if a patient with primary HPT is sporadic or syndromic in nature. The diagnosis of syndromic HPT has implications as to the number of glands involved, the extent of surgery necessary for cure, as well as important implications for family screening. Genetic testing is not recommended on a routine basis. Varying penetrance and incomplete syndromic manifestations can make the diagnosis of syndromic HPT challenging. A clinician must look for clues during initial preoperative evaluation to identify when and which genetic tests should be ordered ( Table 55.1 ).

Table 55.1

Disorders, Characteristics, and Genetic Tests

Disorder	Age of Onset	HPT Penetrance	Associated Features	Gene Involved (Chromosomal Location)	Genetic Tests	Commercially Available Tests	Typical Appropriate Surgery
MEN 1	< 30 years (usually 20–25 years)	High (90%–100%)	Pituitary adenomas; Pancreatic tumors (gastrinomas causing Zollinger-Ellison syndrome)	MEN 1 (11q13)	MEN 1	Yes	Multi-gland excision
MEN 2A	> 30 years	Low (15%–30%)	MTC and pheochromocytoma	RET (10q21)	RET	Yes	Enlarged glands only
HPTJT	> 30 years (Av age 32 years)	High (80%) Increased risk of parathyroid carcinoma	Fibro-osseous tumors of maxilla or mandible, increased risk of renal tumors (nephroblastomas, hamartomas, or Wilms’ tumors), and uterine tumors	HRPT2 (also known as CDC73) (1q 21–32)	HRPT2	Yes	Multi-gland excision
ADMH	40–48 years	High (100%)	h/o unsuccessful parathyroid surgeries	CASR (3q21–24)	CASR	Yes	Multi-gland excision
FHH (heterozygous form)	Young (before 10 years)	High	Asymptomatic mild hypercalcemia with relative hypocalciuria, hypermagnesemia in half of the patients, low calcium/creatinine ratio with total calcium /24-hour urine collection < 100 mg	CASR (3q21–24)	CASR	Yes	Asymptomatic, no treatment
NSHPT (homozygous form)	Birth-6 months	Low (12%–14%)	Infants present with lethargy, hypotonia, failure to thrive, bony undermineralization, multiple fractures, severe skeletal deformities; if left untreated, can lead to florid rickets, devastating neurodevelopmental disorders, and often fatality	CASR (3q21–24)	CASR	Yes	Multi-gland excision

Multiple Endocrine Neoplasia Type 1 (MEN 1)

MEN 1 is an autosomal dominant disorder of the MEN 1 gene (encoding menin) and is also known as Wermer’s syndrome. It presents with tumors predominantly of the parathyroid, pancreas, and pituitary glands. HPT is the most frequent endocrine expression of MEN 1, occurring in 95% by 50 years of age. MEN 1–associated HPT presents at an earlier age, on average at 20 years, which is 30 years younger than for typical nonsyndromic primary HPT. Yip found that MEN 1 is more common in young males presenting with primary HPT; he proposed a six-question panel (described on Expert Consult website).

Multiple Endocrine Neoplasia Type 2A (MEN 2A)

MEN 2A is an autosomal dominant disorder resulting from mutations in the RET gene. It is also known as Sipple’s syndrome and typically consists of medullary thyroid cancer, pheochromocytoma (in 50% of MEN 2A patients), and HPT (in 10% to 30% of MEN 2A patients).

Hyperparathyroidism Jaw Tumor Syndrome (HPTJT)

This rare autosomal dominant condition is associated with the HRPT2 gene (also known as the CDC73 gene). HPT is the most common manifestation, which often presents with asynchronous development of multiple adenomas. Parathyroid carcinoma occurs in about 15% to 20% cases. Ossifying mandibular or maxillary fibromas, uterine polyps, and renal cysts or hamartomas also occur.

Autosomal Dominant Mild Hyperparathyroidism (ADMH)

This is a rare autosomal dominant syndrome presenting with hypercalcemia and hypercalciuria. It is associated with calcium-sensing receptor (CASR) gene mutation. This syndrome usually presents in patients > 40 years of age, and HPT is seen in all cases. History of failed parathyroid surgery is noted in many patients. Multi-gland excision is the treatment of choice.

Familial Hypocalciuric Hypercalcemia (FHH)

This is a rare autosomal dominant disorder presenting with asymptomatic, nonprogressive lifelong hypercalcemia with 100% penetrance. It is typically diagnosed in families by the presence of hypercalcemia and relative hypocalciuria with variable PTH elevation. This represents a renal calcium set point disorder and is not managed with parathyroid surgery but needs to be preoperatively distinguished from primary HPT. It is the main reason for checking a 24-hour urine collection for total calcium and creatinine in patients preoperatively. Almost half of FHH patients have increased serum magnesium, a diagnostically-low calcium/creatinine clearance ratio (usually below 0.01), and total calcium for a 24-hour urine collection < 100 mg.

FHH is the phenotype when this gene abnormality is heterozygous, whereas neonatal severe HPT is the phenotype when the gene abnormality is homozygous.

Neonatal Severe Hyperparathyroidism (NSHPT)

This is a homozygous form of FHH that manifests at birth or within the first 6 months of life. There is severe symptomatic hypercalcemia with skeletal manifestations. Treatment involves prompt total parathyroidectomy.

Vitamin D and Primary Hyperparathyroidism

Consideration of vitamin D levels is important in the preoperative evaluation of patients with presumptive HPT. First, vitamin D deficiency must be considered in the differential diagnosis. Vitamin D deficiency results in low or normal serum calcium and high PTH. In primary HPT, both calcium and PTH are high, and vitamin D levels are normal. However, normocalcemic HPT can have normal calcium and elevated PTH, which may be quite similar to vitamin D deficiency.

Second, vitamin D deficiency is common and can coexist in patients with primary HPT. Interestingly, vitamin D deficiency and insufficiency seem to be more prevalent in patients with primary HPT than in geographically matched populations. Primary HPT seems to be more severe in those with concomitant vitamin D deficiency presenting with advanced disease phenotype, at least biochemically. Coexisting vitamin D deficiency may cause the serum calcium level to fall into the normal range, which may lead to diagnostic uncertainty. The cause of vitamin D deficiency is usually multifactorial, resulting from either inadequate exposure to ultraviolet radiation, inadequate vitamin D intake (dietary), vitamin D malabsorption due to certain medical conditions such as Crohn’s disease, cystic fibrosis, celiac disease, or past gastric bypass surgeries, or in the inability to synthesize the active dihydroxylated compound as in renal dysfunction.

Vitamin D–deficient patients undergoing parathyroidectomy are also at increased risk of postoperative hypocalcemia and “hungry bone syndrome,” which underscores the importance of a preoperative assessment of vitamin D status in all patients with primary HPT. A postoperative rise in PTH is more likely in patients with preoperative vitamin D deficiency. Vitamin D supplementation after parathyroidectomy for primary HPT reduces the incidence of this postoperative eucalcemic PTH elevation. It may be difficult to treat vitamin D deficiency in the setting of primary HPT, and close monitoring of serum and urine calcium levels is essential because limited data suggest that those levels may increase in some patients in response to vitamin D replacement therapy. If vitamin D is to be given, it should be done with care, with close follow-up, and at low doses. Data on vitamin D repletion in patients with mild primary HPT suggest that vitamin D deficiency may be corrected without worsening the underlying hypercalcemia.

Normocalcemic Primary Hyperparathyroidism

Normocalcemic primary HPT is a condition in which patients have normal serum calcium concentrations, but present with PTH levels that are consistently elevated in the absence of a secondary cause of HPT. Some have suggested that patients with these conditions may have an early form of symptomatic primary HPT. Although total calcium levels are normal, ionized levels may be elevated in these patients. A rigorous search for the causes of secondary HPT must be done before diagnosing normocalcemic primary HPT; importantly, vitamin D deficiency must be ruled out as does renal leak hypercalciuria. A course of thiazide diuretics helps one differentiate renal leak hypercalciuria from primary HPT. In renal leak patients, the thiazide reduces renal calcium loss and PTH levels tend to normalize. In primary HPT, thiazides will tend to produce hypercalcemia and PTH levels will be stable.

Patients with true normocalcemic primary HPT are largely asymptomatic but may have more substantial skeletal involvement than is typical. These patients usually seek medical attention in the context of an evaluation for decreased bone mass. Although some patients eventually progress to overt hypercalcemic primary HPT, this transition is not inevitable, nor is there any uniform time course for the development of hypercalcemia. Many patients with normocalcemic primary HPT continue to show normal concentrations of serum calcium over time. Careful monitoring of these patients is recommended, and a proactive, surgical approach should be considered when appropriate. Data suggest that patients with normocalcemic primary HPT demonstrate improvement in bone mineral density after successful parathyroidectomy.

Primary Hyperparathyroidism Surgical Guidelines

Once the diagnosis of primary HPT is made, parathyroidectomy can benefit symptomatic patients by halting or stabilizing the progression of most complications of primary HPT. Although many agree that surgery is indicated in symptomatic primary HPT, controversy exists regarding surgical indications in asymptomatic primary HPT. Surgical guidelines for patients with asymptomatic primary HPT were originally defined in 1990 by the first Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism, which was sponsored by the National Institutes of Health (NIH). Subsequent conferences have revised consensus guidelines for surgical indications in asymptomatic primary HPT. The most recent (2013) guidelines are summarized and discussed in the following (see also Table 55.2 ):

1.
Degree of hypercalcemia. Serum calcium at more than 1 mg/dL above the upper limits of normal.
2.
Degree of hypercalciuria. In the 1990 and 2002 guidelines, hypercalciuria above 400 mg/dL was considered an indication for surgery in asymptomatic primary HPT. In the absence of renal stones, hypercalciuria was not regarded as an indication for parathyroid surgery in 2008. The basis for this change in recommendation was that hypercalciuria had not been established as a risk factor for kidney stones in primary HPT. In 2013, the guidelines changed to recommend surgery in the presence of hypercalciuria above 400 mg/dL and increased stone risk by biochemical analysis. Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound, or computed tomography (CT) was also added as a surgical indication.
3.
Renal dysfunction. Glomerular filtration rate (GFR) reduced to < 60 mL/min. In earlier guidelines, surgery was indicated if creatinine clearance was reduced by 30% compared with age-matched normal controls.
4.
Bone density reduction. Reduction in the bone density in women and in men over 50 years of age, with a T score of ≤–2.5 at lumbar spine, femoral neck, total hip, or distal radius. In the 2013 guidelines, vertebral fracture was added as a surgical indication.
5.
Age. Age less than 50 years. Surgery is offered to asymptomatic young patients because multiple studies show that approximately 25% of such patients will develop complications of their disease, some of which are irreversible.
6.
Other important management factors. Surgery is also indicated in patients for whom medical surveillance and follow-up is difficult, not desired, or not possible.

Table 55.2

Comparison of New and Old Guidelines for Parathyroid Surgery in Asymptomatic primary HPT *

Measurement	1990	2002	2008	2013
Serum calcium	> 1.5 mg/dL above normal	> 1 mg/dL above normal	> 1 mg/dL above normal	> 1 mg/dL above normal
24-hour urine calcium	> 400 mg/dL	> 400 mg/dL	Not indicated	> 400 mg/dL
Renal function	Creatinine clearance reduced by 30%	Creatinine clearance reduced by 30%	GFR < 60 mL/min	GFR < 60 mL/min
BMD	Z score <–2 in forearm	T score <–2.5 at any site ^†	T score <–2.5 at any site ^† or previous fracture fragility	T score <–2.5 at any site ^† , previous fracture fragility, or vertebral compression fracture
Age (yr)	< 50	< 50	< 50	< 50

* Surgery is also indicated in patients for whom medical surveillance is neither desired nor possible.

† Lumbar spine, total hip, femoral neck, or distal third of the radius.

Controversy also exists regarding surgery for asymptomatic patients older than 50 years of age. Talpos, reviewing SF36 Health Survey results, reported that “asymptomatic” patients do benefit from surgery. Silverberg has shown that asymptomatic patients enjoy improved and sustained lumbar spine and femoral neck (cancellous) bone density after surgery. Pasieka demonstrated that surgically corrected HPT was associated with improved disease-specific symptoms, and patient reported health-related quality of life. Zanocco demonstrated, by cost-effectiveness analysis, that parathyroid surgery was the optimal strategy for asymptomatic patients > 50 years of age. Currently, the trend is a much more “pro-surgery” attitude.

Localization Testing

Localization testing is necessary if one is to offer unilateral or minimal access surgery. Preferences have changed over time because imaging technology and experience have improved. Some surgeons prefer a combination of sestamibi and ultrasound analysis. These two studies provide a complementary functional (sestamibi) and structural (ultrasound) assessment and have been shown to be extremely reliable, even in the reoperative setting. Ultrasound is useful for ruling out concomitant thyroid disease. Primary HPT patients with preoperative positive sestamibi and negative ultrasound are more likely to have posterior-located upper gland adenomas. Negative sestamibi imaging is often suggestive of multiglandular disease (MGD). Four-dimensional computed tomography (4D-CT) may provide greater sensitivity than sestamibi imaging and ultrasonography for precise (quadrant) localization of hyperfunctioning parathyroid glands and should be considered if initial localization studies are negative. For patients undergoing reoperative exploration for recurrent or persistent parathyroid disease, 4D-CT appears to offer improved preoperative planning.

Uniglandular Versus Multiglandular Disease

Primary HPT results from autonomous parathyroid glandular growth. Traditionally, clinicians have recognized two discrete forms of abnormal parathyroid growth: uniglandular and MGD. In certain circumstances, it is difficult to differentiate between these two entities. Adding further complexity to this issue is a controversial, but generally accepted, hybrid entity of “double adenoma.”

Uniglandular enlargement, with three remaining uninvolved glands, represents the underlying pathology in most patients (80% to 85%) with primary HPT. The affected gland is enlarged and hypercellular, with decreased intracellular and intercellular fat. The three remaining glands are normal to small in size, not hypercellular, and have abundant fat mixed into the gland. This uniglandular enlargement represents a benign neoplasm of primarily chief cells (see Chapter 65 , Surgical Pathology of the Parathyroid Glands).

In multiglandular hyperplasia, all four glands are hyperplastic and some, or all, may be enlarged. The individual glands affected by hyperplasia may vary considerably from normal size to markedly enlarged. Glands affected with hyperplasia, like single-gland adenomas, are hypercellular with decreased fat. Although histologic differences between adenomas and hyperplastic glands have been proposed (e.g., adenomas having a normal rim of parathyroid tissue around the adenoma and hyperplastic glands having a thick capsule, greater cellular atypia, a more mixed cellularity of chief cells, and oncocytes), it is generally accepted that adenomas and hyperplastic glands cannot be segregated based on histologic criteria. DeLellis has shown that only 50% of known adenomas have the “normal rim” sign. Further, some hyperplastic glands affected with nodular hyperplasia may have pseudo rims. Given these histologic findings, the diagnosis of uniglandular versus multiglandular hyperplasia has generally been made with a combination of gross surgical and histologic findings (see Chapter 65 , Surgical Pathology of the Parathyroid Glands).

Double Adenoma

In primary HPT, there appears to be a third, distinct, pathologic entity—double adenoma—that takes the middle ground between single-gland adenoma and four-gland hyperplasia. When explored, some patients are found to have only two enlarged glands and are durably cured upon resection of these two glands alone. Double adenoma may be considered a form of asynchronous four-gland hyperplasia, but the high, long-term cure rate associated with two-gland resection would argue toward the existence of double adenoma as a separate legitimate entity. Szabo and others have shown that the recurrence rate after initial successful surgery for double adenoma is equivalent to that after successful single-adenoma surgery (approximately 1% to 2%), with both single-gland and double adenoma recurrence rates being significantly lower than for MGD (approximately 9.2% recurrence rate). In a series reviewing 1962 patients with primary HPT, Edis reported finding two large glands and two normal-sized glands in 1.9% of patients. These patients were rendered eucalcemic through resection of only the two large glands. Most believe that double adenoma accounts for 2% to 5% of patients with primary HPT.

Asynchronous Multiglandular Disease

The occurrence of asynchronous MGD is supported by multiple studies showing that the rates of recurrent (not persistent) HPT after initial biochemical cure range from 1% to 16%. Worsey’s series of 371 patients with 15-year follow-up showed that when disease recurred, it did so on average 3.8 years after an initially successful operation. In such patients with asynchronous MGD, it appears that, although they have a four-gland process, the polyclonal hyperplastic tendency is weak; it is not clinically manifest, at least initially, and in some may never develop clinically. With this in mind, it is interesting to note that several milder forms of primary HPT (including single adenoma and some forms of MGD, such as double adenoma, HPT in MEN 2A, and sporadic hyperplasia) are well treated and have low recurrence rates when only grossly enlarged glands are excised. Thus, in some subset of these patients with a four-gland process, asynchronous changes may be so gradual as to never become clinically manifest; so, a conservative initial surgical plan seems optimal.

Within other forms of MGD in primary HPT (e.g., MEN 1), the tendency for all four glands to proliferate and form clones is considerably stronger. This translates into a much more aggressive clinical course, as evidenced by a 50% recurrence rate in patients with MEN 1 at 12 years after successful initial subtotal parathyroidectomy. A higher recurrence rate after aggressive parathyroid exploration and resection is also noted in neonatal HPT, familial HPT, and secondary HPT. Four-gland disease can be thought of as a spectrum of disease with varying degrees of penetrance and clinical aggressiveness ( Figure 55.1 ). Changes may evolve over time, leading to recurrence through asynchronous changes in different glands. In more clinically virulent forms of MGD, even supernumerary glands develop and become clinically manifest. Excision of these supernumerary glands may require bilateral thymectomy and resection of adipose tissue surrounding the parathyroid glands.

Fig. 55.1, Spectrum of clinical virulence in hyperparathyroidism.

Intraoperative PTH: Functional Criteria for Uniglandular Versus Multiglandular Disease

In the past, and to some degree today, uniglandular disease was distinguished from MGD with a combination of gross surgical and histologic findings. If the surgeon found that a given gland was greater than normal size and the pathologist reported there was increased cellularity and decreased stromal fat, the gland was judged to be diseased and therefore clinically significant. With these gross surgical/histologic criteria, MGD disease was found in approximately 10% to 15% of patients with primary HPT.

A new alternate test, intraoperative PTH, is available to the surgeon to facilitate the diagnosis of MGD (see Chapter 59 , Intraoperative PTH Monitoring During Parathyroid Surgery). There are two options for diagnosing MGD after the first enlarged gland is removed: (1) the identification of additional grossly enlarged glands that are histologically hyperplastic, or (2) through PTH. The former is the traditional gross and histologic definition approach that requires bilateral exploration and has its advocates and claims rates of MGD of as high as 15% to 30%. The latter approach, using PTH as a biochemical test for additional hyperfunctional glands, also has its advocates and claims rates of MGD closer to 5%. Those favoring PTH as the diagnostic tool believe that all enlarged or hyperplastic glands may not be clinically significant.

Histology

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