Preoperative Evaluation

Surgical Indications

Primary hyperparathyroidism (primary HPT) can be associated with a wide range of symptoms and complications. These consist of a spectrum of bone disease (bony pain, fractures, osteitis fibrosa cystica), renal (nephrolithiasis, nephrocalcinosis, polyuria, renal insufficiency), gastrointestinal (nausea, vomiting, peptic ulcer disease, constipation, pancreatitis), neuropsychiatric (lethargy, decreased cognitive and social function, depression, psychosis), soft tissue (calcinosis, calciphylaxis, intractable pruritus), and cardiovascular (left ventricular hypertrophy, conduction abnormalities, endothelial dysfunction and decreased QT interval) manifestations.² Hyperparathyroidism complications have been summarized by the familiar phrase “renal stones, painful bones, abdominal groans, psychic moans (depression), and fatigue overtones.” In most modern series in developed regions of the world, patients generally present with asymptomatic forms of primary HPT or nonspecific symptoms such as fatigue, mild depression, or cognitive impairment, and classic symptoms of hypercalcemia are uncommon.²

Generally, parathyroidectomy benefits symptomatic patients by halting or stabilizing the progression of most complications of primary HPT (see Chapter 56, Primary Hyperparathyroidism: Pathophysiology, Surgical Indications, and Preoperative Workup). Most agree surgery is clearly indicated in symptomatic primary HPT. However, some controversy exists regarding surgical indications in asymptomatic primary HPT. Indications for surgery in asymptomatic primary HPT were originally defined by the first Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism, sponsored by the National Institutes of Health, in 1990. A second international conference, in 2002, and a third, in May 2008, have revised consensus guidelines for surgical indications in asymptomatic primary HPT.^3,4 The most recent (2008) guidelines are summarized and discussed next (see also Table 58-1).

Table 58-1 Comparison of New and Old Guidelines for Parathyroid Surgery in Asymptomatic primary HPT*³

Preoperative Genetic Assessment

Familial Syndromes and Genetic Testing

Primary hyperparathyroidism (HPT) is predominantly sporadic but may be seen as part of an inherited syndrome. For a surgeon, it is important to distinguish preoperatively if a patient with primary hyperparathyroidism is sporadic or syndromic in nature. The diagnosis of syndromic HPT has implications as to the number of glands involved and hence on the aggressiveness of surgery necessary 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 58-2).

Table 58-2 Disorders, Characteristics, and Genetic Tests

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, pancreatic, and pituitary glands. Hyperparathyroidism is the most frequent endocrine expression of MEN 1, occurring in 95% by age 50. MEN 1–associated HPT presents at earlier age, on average at 20 years, 30 years younger than for typical nonsyndromic primary HPT (see Chapter 67, Parathyroid Management in the MEN Syndromes).¹⁸ Yip et al. found that MEN 1 is more common in young males presenting with primary HPT and proposed a six-question panel (described on Expert Consult website).¹³

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%), and HPT (in 10% to 30%) cases (see Chapter 67, Parathyroid Management in the MEN Syndromes).

Hyperparathyroidism-Jaw Tumor Syndrome (HPTJT)

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

Autosomal Dominant Mild Hyperparathyroidism (ADMH)

This is a rare autosomal dominant syndrome presenting with hypercalcemia and hypercalciuria. It is associated with CASR gene mutation.¹⁹ This syndrome presents in an older age group, usually after 40 years of age, and hyperparathyroidism is seen in all cases. History of failed parathyroid surgery is noted in many patients. Multigland excision is the treatment of choice.²⁰

Familial Hypocalciuric Hypercalcemia (FHH)

This is a rare autosomal dominant disorder presenting with asymptomatic nonprogressive lifelong hypercalcemia with 100% penetrance.^21,22 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 and 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 and a diagnostic low calcium/creatinine clearance ratio (usually below 0.01) with total calcium for a 24-hour urine collection of typically < 100 mg. FHH is the phenotype when this gene is heterozygous, whereas neonatal severe hyperparathyroidism is present phenotypically when the gene 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.

Familial Isolated Hyperparathyroidism (FIHPT)

This is rare autosomal dominant syndrome, which is actually a phenotypic subgroup resulting from incomplete expression of MEN 1, FHH, HPTJT, or some other syndromic cause where syndromic manifestation is limited to HPT. Hannan et al. have reported on two cases of FIHPT, one with symptomatic hypercalcemia and the other asymptomatic.²³ They suggest that if a detailed family history shows that first-degree relatives are affected, then genetic analysis should be performed to rule out MEN 1, MEN 2, FIHPT, or BFHH.

Vitamin D and primary HPT

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 as we evaluate patients. 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 will have normal calcium and elevated PTH, which may initially look quite similar to pure vitamin deficiency.

Second, vitamin D deficiency is common and so may coexist in patients with primary HPT. Interestingly, vitamin D deficiency and insufficiency seem to be more prevalent in patients with primary hyperparathyroidism than in geographically matched populations.²⁶ Primary hyperparathyroidism seems to be more severe in those with concomitant vitamin D deficiency presenting with advanced disease phenotype, at least biochemically.^26–30 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 like Crohn’s disease, cystic fibrosis, celiac disease, or past gastric bypass surgeries, or inability to synthesize the active dihydroxylated compound as in renal dysfunction.¹⁷

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 hyperparathyroidism.²⁶ A postoperative rise in PTH is more likely in patients with preoperative vitamin D deficiency. Vitamin D supplementation following parathyroidectomy for primary hyperparathyroidism reduces the incidence of this postoperative eucalcemic PTH elevation.³¹

It may be difficult to treat vitamin D deficiency in the setting of primary hyperparathyroidism, and close monitoring of serum and urine calcium levels is essential, as limited data suggest that those levels may increase in some patients in response to vitamin D replacement therapy.²⁷ Current guidelines recommend measurement of serum levels of 25-hydroxy vitamin D (25-OH vitamin D) in all patients with primary HPT, and repletion if the levels are less than 50 mmol/L (20 ng/mL). If vitamin D is to be given, it should be done with care, close follow-up, and at low doses. Preliminary data on vitamin D repletion in patients with mild primary hyperparathyroidism suggest that, in some cases, vitamin D deficiency may be corrected without worsening the underlying hypercalcemia.^26,30

Normocalcemic Primary Hyperparathyroidism

Normocalcemic primary HPT is a newly recognized entity in which patients have normal total serum calcium concentrations but present with parathyroid hormone levels that are consistently elevated in the absence of a secondary cause of hyperparathyroidism.³² Although total calcium levels are normal, ionized levels may be elevated in these patients.

A rigorous search for the causes of secondary hyperparathyroidism must be done before diagnosing normocalcemic primary HPT; importantly, vitamin D deficiency has to be ruled out as does renal leak hypercalciuria. A course of thiazide helps one to differentiate renal leak hypercalciuria and primary HPT. In renal leak patients, the thiazide reduces renal calcium loss; serum calcium and PTH tend to normalize. In primary HPT, thiazide will tend to produce hypercalcemia and PTH levels will be stable.

Patients with true normocalcemic primary HPT are largely asymptomatic. Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in primary HPT, and over time these changes tend to progress. These patients usually seek medical attention in the context of an evaluation for decreased bone mass.³³ A certain percentage of patients who have normocalcemic primary hyperparathyroidism will progress to overt hypercalcemic primary hyperparathyroidism. It seems evident, however, that progression to hypercalcemia is not inevitable, nor is there any uniform time course for the development of hypercalcemia. Many of patients with normocalcemic primary HPT continue to show normal concentrations of the serum calcium over time.³² Some have suggested these patients may represent an early form of symptomatic primary HPT.³⁴ It is suggested that patients with normocalcemic primary HPT should be monitored regularly for progression of their disease. If the disease is worsening, then a proactive, surgical approach would seem to be appropriate.³² Data on normocalcemic primary HPT are limited, and further research on this entity is warranted (see also Chapter 56, Primary Hyperparathyroidism: Pathophysiology, Surgical Indications, and Preoperative Workup).

Localization Testing

Please see the Expert Consult website for more discussion of this topic. See also Chapter 57, Guide to Preoperative Parathyroiod Localization Testing.

Localization Testing

Localization testing is necessary if one is to offer unilateral or minimal access surgery (see Chapter 57, Guide to Preoperative Parathyroid Localization Testing). Our preference is for 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.³⁵ Sestamibi scanning appears to be the most sensitive preoperative test modality available, and when oblique views plus single-photon emission computed tomography (SPECT) imaging are incorporated, it is often sufficient without the addition of ultrasound. Most researchers feel that it is less accurate in the setting of multiglandular disease, revision surgery, mediastinal lesions, and morbid obesity. Although ultrasound is inexpensive and noninvasive, it is operator dependent and can miss lesions because of acoustic shadowing behind the larynx and trachea and in the mediastinum. Primary hyperparathyroid patients with preoperative positive MIBI and negative ultrasound (US) are more likely to have posterior located upper gland adenomas.³⁶

A 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.^37,38

Single photon emission computed tomography/computed tomography (SPECT/CT) offers the advantage of combining function and anatomy for exact localization of ectopic parathyroid adenomas. SPECT/CT may provide more reliable localization of ectopic adenomas.³⁹

Uniglandular versus Multiglandular Disease

Primary hyperparathyroidism results from exuberant autonomous parathyroid glandular growth. Traditionally we have recognized two discrete forms of abnormal parathyroid growth: uniglandular disease and multiglandular disease. In certain circumstances, however, it is difficult to differentiate between these two entities. The actual definitions of uniglandular and multiglandular disease have varied. In multiglandular disease, all four glands are involved synchronously or asynchronously. The size of each hyperplastic gland can vary considerably, so that some of the affected hyperplastic glands may be quite small at operation. Adding further complexity to this issue is a controversial, but generally accepted, discrete hybrid entity of “double adenoma.”

Single-gland enlargement with three remaining uninvolved glands represents the underlying pathology in—depending on the exact definition used—80% to 95% of patients with primary hyperparathyroidism. 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. They may be described as normal or atrophic if sampled. This uniglandular enlargement represents a benign neoplasm of primarily chief cells.

In four-gland hyperplasia, all four glands are hyperplastic and some, or all, may be enlarged. The individual glands affected by hyperplasia, as just stated, may vary 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 (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, with gland lobulation and thick-walled vessels), it is generally accepted that adenomas and hyperplastic glands cannot be segregated based on histologic criteria.⁴⁰ DeLellis has shown that only 50% of known adenomas have the “normal rim” sign.⁴¹ Further, some hyperplastic glands affected with nodular hyperplasia may have pseudo rims.⁴² Given these histologic findings, the diagnosis of single-gland disease versus four-gland hyperplasia has traditionally been made with a combination of gross surgical and histologic findings (see Chapter 70, Surgical Pathology of the Parathyroid Glands).

Asynchronous Multiglandular Disease

The occurrence of asynchronous multiglandular disease is supported by multiple studies that show that the rates of recurrent (not persistent) hyperparathyroidism after initial biochemical cure range from 1% to 16%.^50–54 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.⁵³ In such patients with asynchronous multiglandular disease, it appears that although they have a four-gland process, the polyclonal hyperplastic tendency is weak and not clinically manifest at least initially and in some may never develop clinically. With this construct in mind, it is interesting to note that several milder forms of primary hyperparathyroidism (including single adenoma and some forms of multiglandular disease, such as double adenoma, hyperparathyroidism in MEN 2A, and sporadic noninherited hyperplasia) are well treated, with 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. Within other forms of multiglandular disease in primary hyperparathyroidism (such as 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 initially successful subtotal parathyroidectomy.⁵⁵ A higher recurrence rate after aggressive parathyroid exploration and resection is also noted in neonatal hyperparathyroidism, familial hyperparathyroidism, and secondary hyperparathyroidism. Four-gland disease can be thought of as a spectrum of disease with varying degrees of penetrance and clinical aggressiveness (Figure 58-1). Changes may evolve over time, leading to recurrence through asynchronous changes in different glands. In more clinically virulent forms of multiglandular disease, even supernumerary glands develop and become clinically manifest.^41,56 Excision of these supernumerary glands may require bilateral thymectomy and resection of adipose tissue surrounding the parathyroid glands.

Figure 58-1 Spectrum of clinical virulence in hyperparathyroidism.

Treating the less virulent forms of multiglandular disease with conservative resection of only grossly enlarged glands results in a high cure rate and is supported by the work of Badder and Harrison, which has emphasized the clinical insignificance of microscopic hyperplasia.^57–59 A more aggressive subtotal resection in these patients can lead to rates of hypoparathyroidism of more than 20%.⁶⁰

Intraoperative PTH: A Functional Criteria for Uniglandular versus Multiglandular Disease

In the past and to some degree today, uniglandular disease was distinguished from multiglandular disease (MGD) with a combination of gross surgical and histologic findings. If the surgeon judged that a given gland was greater than normal size and if the pathologist judged 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, multiglandular disease was judged to be present in approximately 15% of patients with primary hyperparathyroidism. In fact, in the past it was suggested that most patients with primary hyperparathyroidism had hyperplasia and that all these patients should be treated with subtotal parathyroidectomy.⁶¹ A new alternate test, intraoperative PTH (iPTH), is available to the surgeon to facilitate the diagnosis of MGD. There are two options for diagnosing MGD after the first enlarged gland is removed: the identification of additional grossly enlarged glands that are histologically hyperplastic, or through intraoperative 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 15% to 30% (see Chapter 59, Standard Bilateral Parathyroid Exploration). The later approach using iPTH as a biochemical test for additional hyperfunctional glands also has its advocates and claims rates of MGD closer to between 4% and 5%⁶² (see Chapter 63, Intraoperative PTH Monitoring during Parathyroid Surgery). Advocates of both approaches claim success for their respective algorithms. It does appear that with obligatory bilateral exploration some enlarged glands are found but some of these glands may not be functionally active and their excision may not be necessary because iPTH-guided parathyroidectomy is highly successful and to date is not associated with a higher incidence of recurrent HPT.⁶³ Those favoring iPTH as the diagnostic tool believe that all enlarged or hyperplastic glands may not be clinically significant. Harrison has shown that the finding of microscopic hyperplasia in normal-sized glands is of no clinical significance and that the removal of such glands is unnecessary.⁵⁸ Badder has also proposed that microscopically hyperplastic glands do not have functional significance.⁵⁷ Questions have been raised regarding the functionality of oncocytic adenomas as well as glands affected by clear-cell hyperplasia.^41,64,65 Dawkins has shown that the concentration of PTH per milligram of fresh tissue is 1000 times less in clear-cell hyperplastic glands than in normal glands or in chief-cell adenomas. The clinical significance of this finding is unclear.⁶⁵

Histology

Please see the Expert Consult website for more discussion of this topic.

Histology

The typical histologic picture for an adenoma or hyperplastic gland is an increased number of chief cells with scattered oncocytes and decreased glandular fat (see Chapter 70, Surgical Pathology of the Parathyroid Glands). Bondeson has noted that some hyperplastic glands, although overall reduced in fat, may have patchy, prominent fat deposits.⁶⁶ Different histologic categories of adenomas have been identified, including the oncocytic and lipoadenomatous variants. Oncocytic adenomas are uncommon, with one series showing only 6.3% of 160 adenomas being oncocytic.⁶⁷ Controversy exists regarding whether such oncocytic adenomas are truly functional.^36,47,41,64 Lipoadenomas represent a proliferation of parenchymal and stromal elements and are generally associated with clinical hyperparathyroidism.^1,41 Histologic variants of four-gland hyperplasia have been described, including clear-cell (Wasserhelle) hyperplasia. Cases of clear-cell hyperplasia were described early in the study of hyperplasia, but subsequent work has shown that this histologic form is rare.¹

Molecular Genetics of Primary Hyperparathyroidism

Please see the Expert Consult website for more discussion of this topic.

Molecular Genetics of Primary Hyperparathyroidism

Despite new insights into the genetics of hyperparathyroidism, many questions remain unanswered (see also Chapter 70, Surgical Pathology of the Parathyroid Glands). Does the primary genetic defect result in cellular proliferation or a change in calcium/PTH set point, with cellular proliferation occurring secondarily? What is the exact relationship between parathyroid changes and known genetic lesions in MEN 1 (i.e., MENIN) and MEN 2A (i.e., ret oncogene)? Why is there such variable penetrance among the various forms of inherited primary hyperparathyroidism? What are the genetic changes underlying oncogenesis in sporadic disease and parathyroid carcinoma?

Parathyroid Surgical Anatomy

Parathyroid Gland Characteristics: the “Gliding Sign”

Understanding parathyroid gland embryology and intraoperative attention to detail facilitates the identification of normal and abnormal parathyroids. Parathyroid glands can be seen as distinct from surrounding neck tissues through recognition of a number of different characteristics (see Table 22-4). The color of the parathyroid gland is typically light brown to reddish tan and is often described as mahogany. This color relates to the fat content, vascularity, and percent of oxyphil cells.¹⁰³ In obese persons, the fat content of parathyroid glands is higher. As a result, they assume a more yellowish color, which is only slightly different from surrounding fat.⁴¹ In infants younger than 3 months of age, the normal parathyroid gland looks grayish and semitranslucent. In children the normal parathyroid gland, which has scant fat, is darker (a pinkish brown) compared with that of adults. The normal adult parathyroid gland has greater fat content than that of a child and is more yellow. With increasing adult age, the parathyroid gland darkens.¹⁰⁴ In adults, hypercellular glands with less fat are browner. Large glands associated with secondary hyperparathyroidism can be grayish. A gland involved by parathyroid carcinoma can appear white, hard, and irregular, with a surrounding fibrotic change associated with local invasion.^102,105 Fat, in contrast, is bright yellow. The thyroid is firmer and mottled reddish brown, whereas lymph nodes vary from gray to tan to red and are generally firmer than parathyroid glands. Parathyroid glands also have a distinct hilar vessel (a “vascular strip”) that can be seen if surrounding fat does not obscure its hilum. The parathyroid gland has a discrete, encapsulated, smooth surface as opposed to the more lobular surface of the thyroid and the more mottled, pitted surface of lymph nodes. The parathyroid gland is softer to palpation than thyroid or nodal tissue. Parathyroid shape is also unique and most often leaflike or beanlike.⁹³ The dissection of a small nodule on the surface of the thyroid gland mistaken for a parathyroid gland results in hemorrhage, whereas the dissection of a parathyroid gland closely related to the thyroid capsule does not result in significant hemorrhage when performed with meticulous loupe-assisted dissection. The most important distinguishing feature is that the parathyroid, being a discrete, encapsulated organ, has a characteristic motion when surrounding fat is gently manipulated. The discrete edge of the parathyroid gland can be seen as this fat is dissected. As the surrounding fat is manipulated, the parathyroid gland demonstrates a discrete gliding motion within the fat, like that of a rowboat riding on a wave of water. As Wang has written of the superior parathyroid gland, “The absence of capsular fixation permits an impression of mobility uniquely characteristic of the parathyroid.”⁹³ This “gliding sign” is a tremendously helpful clue in parathyroid recognition during central compartment surgery.