Management of Parathyroid Disorders PDF

123 123 Management of Parathyroid Disorders Lisa M. Reid, Dipti Kamani, Gregory W. Randolph KEY POINTS Most patients diagnosed with primary hyperparathyroidism are asymptomatic or are only mildly symptomatic, compared with the classic descriptions of patients with hyperparathyroidism. Calcium levels...

123 123 Management of Parathyroid Disorders Lisa M. Reid, Dipti Kamani, Gregory W. Randolph KEY POINTS Most patients diagnosed with primary hyperparathyroidism are asymptomatic or are only mildly symptomatic, compared with the classic descriptions of patients with hyperparathyroidism. Calcium levels are regulated by the actions of parathyroid hormone (PTH), vitamin D, and calcitonin on the intestines, bone, and kidneys. Knowledge of parathyroid anatomy and embryology is key in finding diseased parathyroid glands in both their normal and abnormal locations. An elevated calcium with an elevated PTH level is diagnostic of primary hyperparathyroidism. Similarly a high normal calcium with a nonsuppressed PTH level suggests primary hyperparathyroidism. Single adenomas are seen in 80% to 85% of cases of primary hyperparathyroidism. Four gland hyperplasia accounts for another 10% to 15% of cases. There are many localization studies that can be obtained before parathyroid surgery to aid in localization intraoperatively. A negative localization test is not a contraindication to surgery if the patient otherwise has clear-cut surgical indication. The revised NIH consensus guidelines are used to help decide which patients are appropriate surgical candidates. PTH has a very short half-life of 3 to 5 minutes, so intraoperative PTH measurement can provide an adjunct during surgery. In the absence of definitive preoperative identification of a parathyroid adenoma, bilateral neck exploration remains the classic approach for parathyroid surgery. However, if during surgery parathyroid resection is associated with a drop in the intraoperative rapid PTH assay by 50% with entry into the normal range, surgical exploration may be halted. Intraoperative nerve monitoring for the recurrent laryngeal nerve is a useful adjunct during parathyroid surgery. Having at least two localizing studies prior to reoperative parathyroid surgery is beneficial. The management of parathyroid disorders has evolved over time with the progressive knowledge that has improved the diagnosis, as well as preoperative and intraoperative management of the disorder. HISTORY OF THE PARATHYROID GLANDS British anatomist Sir Richard Owen is generally acknowledged as being the first to describe the existence of the parathyroid glands in 1852.1 The glands were discovered at autopsy of the Zoological Society of London’s Indian rhinoceros. In 1877, Swedish medical student Ivar Sandstrom reported the existence of distinct glandular tissue adjacent to the thyroid in a dog, and in 1880 he reported the discovery of a similar organ in humans (glandulae parathyroideae).2 The earliest reports of clinical hyperparathyroidism (HPT) involved bone disease, or osteitis fibrosa cystica, as termed by von Recklinghausen, although the association with HPT was not discovered until later.3 Halsted was motivated to find the parathyroid blood supply based on his experience with patients after thyroidectomy.4 Gley made the association with tetany after parathyroidectomy.5 Rasmussen and Craig isolated parathyroid hormone (PTH) in 1959.6 Berson and Yalo earned the Nobel prize for developing an assay to measure PTH levels in serum.7 Autoanalyzing systems that rapidly measure calcium levels nowadays allow patients with HPT to be diagnosed before they are symptomatic or develop complications. Olsch performed the first successful parathyroidectomy in the United States in 1928 at Barnes Hospital of Washington University by removing a large parathyroid adenoma, precipitating a profound decline in serum calcium requiring massive doses of parathyroid extract and IV calcium to save the patient.8,9 One of the most famous patients to have suffered from HPT is Captain Charles Martell, who was a merchant marine. He had a total of seven operations and was ultimately found to have a mediastinal parathyroid adenoma.10 He unfortunately died soon after the successful operation from complications related to kidney stones. CALCIUM PHYSIOLOGY Although laboratory values may vary somewhat, the normal range for calcium in the blood is between 8.5 and 10.2 mg/dL. Calcium exists in two forms, bound to protein (55%) or in a free ionized state (45%). The nonionized form is mostly bound to albumin so significant changes in albumin will change the total calcium level. The most common formula to obtain a corrected calcium level is that for every 1.0 mg/dL decrease in albumin there is a 0.8 mg/ dL decrease in calcium. Ionized calcium ranges between 4.5 and 5.0 mg/dL in most laboratories and is inexpensive and easy to obtain. It is affected by blood pH, so both should be measured together. Ionized calcium will be decreased by 0.36 mmol/L for every one unit increase in pH. PTH is secreted in response to low serum ionized calcium levels and is inhibited via a feedback mechanism when the serum ionized calcium level is high. Intact PTH is an 84–amino acid protein that is the biologically active form of the hormone. It has a half-life of only 3 to 5 minutes.9 Calcium homeostasis is affected by the interplay between PTH, calcium, and vitamin D on the gastrointestinal tract, bone, and kidneys.11 The target end organs of PTH are the kidneys, intestines, and bones. In the kidneys, PTH increases the rate of conversion of 25-hydroxyvitamin D3 (calcifediol) to 1,25-dihydroxyvitamin D3 (calcitriol), increases calcium reabsorption, and decreases phosphorus reabsorption in the tubules.12 Calcium and phosphorus reabsorption are increased in the intestines, whereas the effects on bone are via a PTH receptor on the osteoblasts resulting in increased production of cAMP, which in turn stimulates the osteoclasts.13–15 Calcitonin is secreted by the parafollicular C cells in the thyroid and has a smaller role in calcium regulation. It is stimulated by 1899 Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. CHAPTER 123 Management of Parathyroid Disorders1899.e1 Abstract Keywords The management of parathyroid disorders has evolved over time due to the improved knowledge that has aided in the diagnosis, as well as preoperative and intraoperative management, of the disorder. parathyroidectomy PTH recurrent laryngeal nerve hypocalcemia hyperparathyroidism parathyromatosis hyperplasia Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 123 1900 PART VI Head and Neck Surgery and Oncology BOX 123.1 Causes of Hypercalcemia of Malignancy Parathyroid hormone–related protein secretion by lung, esophagus, head and neck, renal cell, ovary, bladder, and pancreatic cancers; thymic carcinoma; islet cell carcinoma; carcinoid; and sclerosing hepatic carcinoma Ectopic parathyroid hormone secretion by small cell lung cancer, small cell ovarian carcinoma, squamous cell lung carcinoma, ovarian adenocarcinoma, thymoma, papillary thyroid carcinoma, hepatocellular carcinoma, and undifferentiated neuroendocrine tumor Ectopic 1,25-dihydroxyvitamin D production by B-cell lymphoma, Hodgkin disease, and lymphomatoid granulomatosis Lytic bone metastases caused by multiple myeloma, lymphomas, breast cancer, and invasive sarcoma Tumor production of other cytokines by T-cell lymphomas/ leukemias, non-Hodgkin lymphoma, and other hematologic malignancies high calcium levels and inhibits bone resorption; however, it does not alter calcium levels significantly. This is illustrated in medullary thyroid carcinoma. In this condition very high levels of calcitonin are present, yet these patients do not have hypocalcemia.16,17 Several endogenous substances—including peptides, steroid hormones, and amines—influence PTH release.18,19 However, calcium represents the most potent regulator of PTH secretion. Even minor alterations within the physiologic plasma calcium range can induce considerable secretory responses: reduction of ionized plasma calcium by 0.04 mmol/L may elevate serum PTH by 100% or more. The rapid effect of extracellular calcium on PTH release suggests that calcium directly interferes with the release process, but the nature of this interference has been only partly clarified. Intact PTH 1-84 is rapidly cleared from the human circulation and has a half-life of only a few minutes.20 PTH clearance occurs in the liver and kidney. Clinical analysis with immunometric PTH assays usually discriminates hypercalcemic patients with HPT from patients with other causes of hypercalcemia. Nonparathyroid tumors that produce intact PTH are exceptionally rare. These include ovarian and small cell carcinomas and thymoma21–23 (Boxes 123.1 and 123.2). PARATHYROID ANATOMY Normal parathyroid glands are small, 30 to 50 mg, and yellow to brown in color. Their shape can be described as oval or beanlike. The glands appear different with age: darker in younger patients and more yellow in older patients, which is affected by the fat content which increases with age.17,24–26 Most people have four parathyroid glands.27 There are two superior and two inferior glands. Multiple autopsy studies have found four glands 84% to 87% of the time, and three glands in 3% to 6% of patients.17,24–26 Supernumerary glands can be found, with studies showing up to 12 glands.28,29 These account for a small proportion of cases of persistent HPT after surgery. Studies with a large series of patients showed that a supernumerary gland is the cause of disease in only 0.7% (15 out of 2015 patients).30 Most of these fifth-gland tumors were located in the mediastinum (Fig. 123.1). In a similar series of 762 patients with primary HPT, the supernumerary gland was close to the thymus and accounted for 0.8% of patients.31 Discerning an abnormal gland from a normal gland relates to the experience of the surgeon. The glands are normally found posterior to the thyroid. The location relative to the recurrent BOX 123.2 Causes of Nonparathyroid Hormone-Mediated, Nonmalignant Hypercalcemia BENIGN TUMORS Parathyroid hormone–secreting ovarian dermoid cyst or uterine fibroid ENDOCRINE DISEASE Thyrotoxicosis Pheochromocytoma Addison disease Islet cell pancreatic tumors VIPoma GRANULOMATOUS DISORDERS Sarcoidosis Wegener granulomatosis Berylliosis Silicone-induced and paraffin-induced granulomatosis Eosinophilic granuloma Tuberculosis (focal, disseminated, mycobacterium avium complex in AIDS) Histoplasmosis Coccidioidomycosis Candidiasis Leprosy Cat-scratch disease DRUGS Vitamin D excess (oral or topical) Vitamin A excess Thiazide diuretics Lithium Estrogens and antiestrogens Androgens Aminophylline, theophylline Ganciclovir Recombinant growth hormone treatment of AIDS patients Foscarnet 8-Chloro-cyclic adenosine monophosphate MISCELLANEOUS Familial hypocalciuric hypercalcemia Immobilization with or without Paget disease of bone End-stage liver failure Total parenteral nutrition Milk-alkali syndrome Hypophosphatasia Systemic lupus erythematosus Juvenile rheumatoid arthritis Recent hepatitis B vaccination Gaucher disease with acute pneumonia Aluminum intoxication (long-term hemodialysis) Manganese intoxication Primary oxalosis AIDS, Acquired immunodeficiency syndrome; VIPoma, vasoactive intestinal polypeptide–secreting tumor. laryngeal nerve (RLN) is usually constant, so the superior glands are usually dorsal (deep) to the RLN, while the inferior glands are ventral (superficial) to the nerve32 (Fig. 123.2). Most superior glands are found near the tracheoesophageal groove, just cranial to the point where the inferior thyroid artery and the RLN cross and are very intimate with, but not typically within the thyroid capsule.29 The superior parathyroid glands, which are intimately associated with the posterior capsule of the Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 1901 CHAPTER 123 Management of Parathyroid Disorders 123 Thyroid cartilage Superior parathyroid gland deep (dorsal) to RLN coronal plane Cricoid cartilage Thyroid Coronal plane of RLN Trachea Inferior parathyroid gland superficial (ventral) to RLN coronal plane Fig. 123.1 Sestamibi scan showing mediastinal parathyroid gland. superior thyroid pole, are usually covered by an extension of the pretracheal fascia that envelopes the thyroid gland and connects it to the hypopharynx, esophagus, and the carotid sheath. The relationship of these superior parathyroid glands with the pretracheal fascia is such that the glands themselves are allowed freedom of movement under this “pseudocapsule.” This feature discriminates parathyroid glands from thyroid nodules that cannot move freely as the true capsule of the thyroid gland envelopes these nodules. When enlarged, the superior parathyroid glands may also be found in the retroesophageal or paraesophageal space. The color of the glands is similar to the esophagus, so maintaining a nonbloody field and being cognizant of this anatomic variant will help in identifying a missing superior parathyroid gland. The inferior parathyroid glands tend to have a more variable location, though most are found near the lower pole of the thyroid gland. As many as 28% of these glands are found within the thymus in the thyrothymic ligament or within the anterior superior mediastinal thymic gland. Intrathyroidal parathyroid glands are uncommon, reported in the 1% to 3% range, and are more common with superior glands.33–36 EMBRYOLOGY For surgeons, knowledge of embryology is key to understanding normal and abnormal parathyroid anatomy. The superior parathyroid glands develop from the fourth pharyngeal pouch, and the inferior parathyroid glands come from the third pharyngeal pouch along with the thymus (Fig. 123.3). The inferior parathyroid glands may then end up in the anterior superior mediastinum, where a third of all missed parathyroid tumors may be found. Other ectopic locations include the carotid sheath, retroesophageal, and the submandibular region. Fig. 123.2 The superior (dorsal) and inferior (ventral) parathyroid gland locations relative to the coronal plane denoted by recurrent laryngeal nerve (RLN) course. (From Randolph GW, editor: Principles in thyroid surgery in surgery of the thyroid and parathyroid glands, ed 2, 2013, Philadelphia, Elsevier, fig. 30.15.) PIV III IV PIII Thyroid Thymus Fig. 123.3 Embryologic derivation and subsequent descent of the parathyroid glands with associated structures. The superior glands are not as likely to be ectopic but may descend into the tracheal esophageal groove at or below the mid or inferior thyroid pole. Vascular Anatomy of the Parathyroid Gland The blood supply for both the superior and inferior parathyroid glands is from the inferior thyroid artery, which branches from the thyrocervical trunk. However, ligation of the inferior thyroid artery during thyroid surgery may not always compromise the blood supply to the parathyroid glands. Abundant arterial anastomoses supply the parathyroid glands and include anastomoses with thyroid arteries and dominant arteries of the larynx, pharynx, esophagus, and trachea. A transient hypoparathyroidism from ischemia may occur in up to 20% of patients after total thyroidectomy. It is treated with oral and IV calcium supplementation as appropriate. Fortunately this effect is transient and usually resolves in a few weeks postoperatively. Ten percent of the inferior Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 1902 PART VI Head and Neck Surgery and Oncology parathyroid glands derived their dominant arterial supply from a branch of the superior thyroid artery. Etiology and Pathogenesis of Hyperparathyroidism Parathyroid adenomas are monoclonal or oligoclonal neoplasms; the mechanism of propagation is believed to be clonal expansion of cells that have an altered sensitivity to calcium.37 Genetic rearrangements of CCND1 or parathyroid adenomatosis 1 oncogene, also known as cyclin D1, have been identified. This protooncogene is located in the vicinity of the regulatory region of the gene for PTH production.38,39 In the case of sporadic parathyroid adenomas, it has been proposed that the etiology may be loss of suppressor gene function on chromosome 1p. Another process for development of these neoplasms is felt to be due to changes in expression of a tumor suppressor gene where a mutation affects both alleles on the gene and both copies of the tumor suppressor gene are inactivated. HPT is a part of the multiple endocrine neoplasia type 1 (MEN1) syndrome.40 Somatic mutations in both gene copies of the MEN1 tumor suppressor gene are seen in 20% of patients with primary HPT.41 Familial hypercalcemic hypocalceuria (FHH) and neonatal severe HPT (NSHPT) are linked to point mutations in the calcium-sensing receptor gene that causes reduced activity.42 There is also evidence to support exposure to ionizing radiation as another cause for the development of HPT.43 Common syndromic HPT entities are described in a later section. Histopathology of the Parathyroid Glands The gross appearance of parathyroid adenomas varies, but generally they are oval or bean shaped, reddish brown in color, and soft in consistency.44,45 Adenomas may be bilobed or multilobulated in conformation. In 70% of adenomas, a rim of normal parathyroid tissue may be found around the hypercellular portion of the replaced normal gland. However, the absence of this characteristic does not exclude the presence of a parathyroid adenoma. Under light microscopy, adenomas appear similar to normal parathyroid glands and exhibit a thin fibrous capsule with a cellular framework arranged in nests and cords invested by a rich capillary network. Other growth patterns include follicular, pseudopapillary, and acinar patterns. Chief cells are the major parenchymal cells present in parathyroid glands. Oxyphil cells are also present; although fewer and larger, they have more mitochondria and thus are more likely to concentrate technetium 99m (Tc99m).46,47 They take up eosinophilic stain more than the chief cells. Besides the classic adenomas, a few subtypes have been described. Oncocytic adenomas are composed primarily of oxyphil cells.48,49 They are mostly nonfunctional and are likely to be seen in older women. Lipoadenomas are composed of primarily chief cells with a few oxyphil cells and have a large amount of adipose tissue.50 They can be functional. Water clear cell adenomas and large clear cell adenomas have also been described in case reports.51,52 Due to the difficulty in diagnosing parathyroid cancer, some lesions are described as atypical adenomas. Although they appear atypical, they lack the more concerning features of invasion seen in malignancy.53 Although primary HPT is the most common cause of hypercalcemia, there are other disorders such as certain malignancies and granulomatous disease that also cause hypercalcemia. Treatment of Hypercalcemia Some patients may present with profoundly high calcium levels, also known as hypercalcemic crisis. Urgent treatment is needed to prevent arrhythmias and worsening neurologic status, even coma. Initial management includes hydration using normal saline to increase intravascular volume. Caution should be used in patients with a history of cardiac disease so as not to fluid overload the patient. All medications contributing to the hypercalcemic state must be discontinued. These include calcium supplements and thiazide diuretics. The next line of treatment should be a loop diuretic, which will inhibit renal calcium absorption. Bisphosphonates inhibit osteoclast activity and will cause a profound drop in calcium level.54,55 Other medications include glucocorticoids and calcitonin. Glucocorticoids lower the calcium level by inhibiting vitamin D, inhibiting osteoclasts, and decreasing intestinal absorption and renal excretion of calcium. The additive effect of calcitonin and glucocorticoids on osteoclasts will also lower the calcium level. PRIMARY HYPERPARATHYROIDISM The incidence of primary HPT is 1/1000 and is more common in women than men, with a predilection for postmenopausal women.56–58 The diagnosis of HPT is a biochemical diagnosis based on calcium and PTH level. In most cases, both calcium and PTH levels are elevated, although normocalcemic primary HPT is currently an accepted entity. Normocalcemic Primary Hyperparathyroidism Normocalcemic primary HPT is a recently acknowledged entity where total and ionized serum calcium concentrations are normal but PTH levels are consistently elevated in the absence of secondary cause of HPT.59 This entity was officially recognized at the Third International Workshop on the Management of Asymptomatic Primary HPT.60 Before making the diagnosis of normocalcemic primary HPT, a thorough search for causes of secondary HPT should be performed, especially vitamin D deficiency. Many patients in whom normocalcemic PHPT is suspected may actually have hypercalcemic primary HPT with coexisting vitamin D deficiency. Renal leak hypercalciuria is another entity that should be ruled out; it can be done simply by giving a trial course of thiazide. In general, normocalcemic primary HPT is considered a nascent form of HPT. Normocalcemic primary HPT should be under regular monitoring for progression of the disease, with surgery considered for development of symptoms. Syndromic Hyperparathyroidism Multiple Endocrine Neoplasia Type 1 MEN1 is an autosomal dominant disorder associated with MEN1 gene (encoding menin). Often HPT is the first manifestation, presenting in the third or fourth decade which is earlier compared with sporadic HPT. Almost 95% of MEN1 patients develop HPT by the age of 50. Multiple Endocrine Neoplasia Type 2A Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant condition with RET gene mutation. Approximately 30% of MEN2A patients have parathyroid tumors. Hyperparathyroidism–Jaw Tumor Syndrome Hyperparathyroidism–jaw tumor syndrome (HPT-JT) is an autosomal dominant tumor linked to HRPT2 (CDC73) gene. The most common manifestation is the presence of parathyroid tumors, frequently developing asynchronously. Other manifestations include parathyroid carcinoma (15% to 20%), ossifying mandibular or maxillary fibromas and renal cysts or hamartomas. Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. CHAPTER 123 Management of Parathyroid Disorders Autosomal Dominant Mild Hyperparathyroidism This is a very rare autosomal dominant syndrome associated with CASR gene, presenting with hypercalcemia and hypercalcuria.61 Familial Hypercalcemic Hypocalciuria FHH must be distinguished from HPT, because it is not treated surgically. It is an autosomal dominant disorder that is caused by abnormalities in the calcium-sensing receptor. Patients with FHH present with asymptomatic nonprogressive lifelong hypercalcemia with 100% penetrance.62 Although calcium and PTH level are elevated, 24-hour urine calcium will be low in FHH, typically less than 100. The other helpful test is the 24-hour urine calcium to creatinine clearance ratio (Ca/Cr). In FHH the ratio is less than 0.01, whereas in HPT the ratio is greater than 0.01. Neonatal Severe Hyperparathyroidism NSHPT is the homozygous form of FHH, manifesting either at birth or within the first 6 months of life. These babies present with severe symptomatic hypercalcemia with skeletal manifestations. It requires immediate total parathyroidectomy. Familial Isolated Hyperparathyroidism FIHPT is a rare autosomal dominant syndrome, where manifestation is limited to HPT. The genetic understanding of FIHPT is still evolving. Symptoms Presently, the classic stone, bones, and groans is no longer typical; many patients are diagnosed on routine blood work early in the disease process and are relatively asymptomatic. Symptoms that are currently more common include fatigue, depression or anxiety, insomnia, joint and muscle pain, and constipation. Hypercalcemic patients should be questioned about history of kidney stones, which are present in 10% to 20% of the cases.63–65 The stones are mostly calcium oxalate and less likely calcium phosphate. Osteoporosis is suggested by a history of broken bones without major trauma and is detected by DEXA scan. The World Health Organization (WHO) uses a T score of −2.5 to classify osteoporosis. The bone loss is most common in cortical bone. The distal forearm is particularly susceptible and should be included on DEXA study. The term asymptomatic HPT has been commonly applied when the disorder is detected during health screenings and population studies or coincidentally during medical examinations. The usual presenting abnormality in these patients is an abnormally elevated serum calcium detected on routine blood chemistry screening. Despite the lack of obvious abnormalities noted at the time of diagnosis, caution should be exercised before declaring that a patient is asymptomatic. Many seemingly asymptomatic patients may manifest subtle or even “silent” sequelae of HPT, such as emotional complaints, muscular fatigue, constipation, bone and joint pain, and silent objective findings such as asymptomatic renal calculi and decreased bone mineral density. In most patients with asymptomatic or minimally symptomatic HPT, these symptoms are subtle and so common in the general population that they preclude establishment of a causal relationship to primary HPT. Gland Pathology Most cases of primary HPT are caused by abnormal growth and function of a single gland. Single gland adenomas account for primary HPT 80% to 85% of the time. The second most common 1903 BOX 123.3 NIH Consensus Guidelines for Asymptomatic Hyperparathyroidism Age younger than 50 years Calcium greater than 1 mg/dL (0.25 mmol/L) above upper limit of normal DEXA revealing T score greater than −2.5 at the lumbar spine, total hip, femoral neck, or distal radius Vertebral fracture on imaging Kidney stone or nephrocalcinosis on imaging Creatinine clearance less than 60 mL/min 24-hour urine calcium greater than 400 mg/d and increased stone risk on stone analysis Adapted from Bilzekian JP, Brandi ML, Eastell R, et al: Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 99(10):3561–3569, 2014. finding (10% to 15%) is four-gland hyperplasia, where all four glands are enlarged and hyperfunctioning. This may be associated with MEN1 and MEN2A, although most cases of four-gland hyperplasia are sporadic. Less commonly, multiple adenomas are found (2% to 5%), and even less common is parathyroid cancer (1%).66,67 Parathyroid cancers are difficult to diagnose pathologically and are not always diagnosed at the time of surgery. The only clear indicator of malignancy is metastatic disease, which is not typically apparent at the time of surgery. SURGICAL MANAGEMENT The NIH consensus guidelines are widely utilized in the decision for surgery, but surgeons and endocrinologists need to employ their clinical judgment in surgical decision making. The guidelines are based on risk/benefit ratio of surgery versus nonoperative management and favor operations in young, healthy patients or patients older than 50 years with sequelae of disease (Box 123.3). Preoperative Evaluation Diagnosis is made based on blood work revealing an elevated calcium and PTH level. An elevated PTH level with a high normal calcium level is termed normocalcemic HPT. Other tests include vitamin D level to rule out a secondary HPT and 24-hour urine if there is a concern for FHH. It is essential preoperatively to not only differentiate syndromic from sporadic HPT but also to identify the probable syndrome so that appropriate genetic testing can be carried out. Overall, the presence of syndromic HPT impacts the extent of surgery offered and the recommendations for family screening. The surgeon/physician must look for suspicious findings during history and physical exam. Age of onset (third or fourth decade in MEN1, birth to 6 months in NSHPT), history of frequent renal stones specifically at younger age, family history of severe hypertension, calcium disorder or coexistent endocrine disorder, and, lastly, history of syndrome-specific manifestations such as jaw tumors, uterine polyps, or parathyroid cancer in HPTJT cases, should prompt appropriate genetic testing.68 Localization Once a clear diagnosis is made and a patient is deemed an appropriate surgical candidate, efforts are made to localize the abnormal gland(s). There are several procedures that can be used preoperatively to find the diseased gland(s), and these include noninvasive Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 123 1904 PART VI Head and Neck Surgery and Oncology as well as invasive tests. These include ultrasound, technetium-99m sestamibi (99mTc), thallous chloride (201TI), CT, MRI and PET CT, angiography, venous sampling, and fine-needle aspiration (FNA). Preoperative localization affords patients the option of minimally invasive surgery with local or regional anesthesia, allowing for same day surgery. Adequate localization is particularly important for reoperative parathyroidectomy, and many surgeons favor two confirming localization procedures prior to revision surgery. Noninvasive Localization Sestamibi is the most accurate and commonly used study for localization preoperatively. Sensitivity has been reported to be as high as 100% and specificity at 90%, although there is marked institutional variability in the test. The addition of single-photon emission computed tomography (SPECT) increases the sensitivity of the test, particularly with smaller adenomas.69–71 It was incidentally noted that 99mTc used for cardiac studies also concentrated in thyroid and parathyroid glands, although at higher concentration in the parathyroid. This is currently known to be due to the high mitochondrial concentration in these adenomatous or hyperplastic parathyroid glands with a rich blood supply and increased activity.72–74 There are two phases to the test. Once the patient is injected with technetium, images are done at 10 minutes and again at 2 hours. A hyperplastic or adenomatous gland has persistent uptake at the 2-hour period, while the thyroid activity which is prevalent on the initial scans has washed out. Although sestamibi has been proven to be very sensitive for parathyroid adenomas, it is not as helpful for multigland hyperplasia because it infrequently reveals the location of all four glands. Another limitation is that uptake in a thyroid nodule or even a lymph node can cause false positives47,75,76 (Fig. 123.4). A neck ultrasound is a useful adjunct to sestamibi. Neck ultrasound is helpful in finding abnormal parathyroid glands preoperatively and has the added benefit of identifying any coexisting thyroid pathology. The ability to find parathyroid pathology preoperatively is operator dependent, and it has been advocated that surgeons themselves become skilled at ultrasound. The added knowledge of the intraoperative appearance and normal anatomy gives surgeons an advantage in examining the images. Recently, Thimmappa et al., in their single institutional study, reported that a surgeon-performed ultrasound is overall more accurate and has better positive predictive value than sestamibi scan or radiologyperformed ultrasound.77 Adenomas appear as a hypoechoic lesion usually inferior or posterior to the thyroid. Ultrasound can also be used intraoperatively and is particularly helpful for ruling out A cases of an intrathyroidal parathyroid adenoma.78,79 Although ultrasound is inexpensive and decreases radiation exposure, it is not helpful for finding mediastinal adenomas (Fig. 123.5). MRI and CT are less commonly used as routine preoperative imaging but can be helpful for glands that are in unusual anatomic locations. The glands have to be larger to get picked up. MRI has the advantage of not requiring iodinated contrast, and the lesions are usually hyperintense on the T2 images.80 Lubitz et al. reported that a 4D-CT scan detects more than half of abnormal parathyroid glands missed by traditional imaging and recommend it especially if sestamibi and ultrasound exams are negative or discordant.81 PET CT has also been used but is not standard. Invasive Localization FNA can be utilized in cases where there is uncertainty if a lesion is thyroid or parathyroid in origin, in cases of ectopic glands, and also for reoperative surgery. The addition of PTH assessment on the FNA needle rinsing helps differentiate between parathyroid and thyroid.82–84 Fig. 123.4 Two-hour delayed technetium 99m sestamibi nuclear scan in a patient with hyperparathyroidism secondary to double parathyroid adenomas. Nuclear uptake is shown bilaterally, indicating the location of both adenomas confirmed at surgery. B Fig. 123.5 (A) Sagittal ultrasonography showing a small but hyperfunctioning parathyroid adenoma that is completely within the thyroid gland. (B) Doppler ultrasonography showing a discrete blood supply for the parathyroid adenoma that is different from the more diffuse perinodular vascular supply for a thyroid adenoma. Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. CHAPTER 123 Management of Parathyroid Disorders 1905 Selective venous sampling has also been used to check PTH for lateralization. Carneiro has reported on this for in-office jugular vein measurement in the preoperative period.85 123 Intraoperative Parathyroid Hormone Measurement A rapid PTH assay is available to confirm removal of the correct gland or adequate glandular tissue. The run time is approximately 9 minutes but can be as long as 30 minutes depending on the assay. Multiple studies have shown that a 50% drop is predictive of cure.86–88 Initial intact PTH level is obtained at the beginning of the case prior to any manipulation, from blood drawn either peripherally or from a central vein adjacent to the operative site. Although the half-life of PTH is only 3 to 5 minutes, the second PTH level is drawn 10 to 15 minutes after the removal of the adenoma because a “spike” in the PTH level is known to occur with manipulation of the parathyroid gland. Norman and colleagues have advocated radiation-guided parathyroid gland identification and removal.89,90 This is done with the addition of sestamibi on the day of surgery. The use is limited with the wide availability of intraoperative PTH measurements. SURGICAL TREATMENT In the past, the standard surgical approach to parathyroidectomy was bilateral neck exploration with visualization of all parathyroid glands. This operation has a very high rate of cure and a low complication rate. However, with accessibility of adjuncts such as intraoperative PTH measurement and better preoperative and intraoperative localization, including surgeon-directed ultrasound, there has been a paradigm shift towards less invasive, unilateral approaches. Several leading organizations, including the American Association of Endocrine Surgeons and American Head and Neck Society (AHNS), have published recommendations that with appropriate preoperative imaging and intraoperative PTH assessment more focused minimally invasive procedures are equally successful in rendering cure.91,92 Minimally invasive/alternate approach procedures include endoscopic, video assisted, and robotic parathyroidectomy. Anesthesia Anesthesia choices include general, local, or regional anesthesia. Local and regional anesthesia is ideal for patients who have adequate preoperative localization, preferably by two modalities, most commonly sestamibi and ultrasound.93,94 Standard Neck Exploration The patient is positioned in a supine position with gentle hyperextension of the neck. The arms are tucked on the side of the patient or placed on the torso in a “mummy style.” The back of the bed can be raised or the patient placed in reverse Trendelenburg position to decrease venous congestion in the operative field. The standard incision is a small transverse collar incision (Kocher) in a natural skin crease at the level of the thyroid isthmus, or two fingerbreadths above the sternal notch. The length of the incision is surgeon directed but typically approximately 4 cm. Then subplatysmal flaps are raised. The flaps do not need to be as extensive as those made in thyroid surgery. A preexcision PTH level from the anterior jugular vein may be obtained. If not feasible due to particularly small veins, the internal jugular vein is used. Blood can also be obtained peripherally for intraoperative PTH measurement, either venous or arterial with an arterial line. The strap muscles are divided in the midline and the appropriate lobe of the thyroid mobilized based on the localization studies. As the thyroid lobe is mobilized anteromedially, the middle thyroid vein can be ligated to help get adequate exposure of the parathyroid Fig. 123.6 Exposure achieved through anteromedial rotation of the thyroid gland with demonstration of superior and inferior parathyroid gland positions. glands behind the thyroid. Care to maintain hemostasis during this exposure is key to maintaining a bloodless field making it easier to identify the subtle color of the parathyroid glands (Fig. 123.6). Knowledge of normal parathyroid anatomy and embryology helps guide the exploration. The inferior parathyroid glands can be found at the inferior aspect of the thyroid or within the thyrothymic ligament. These glands are almost always ventral to the RLN. The superior parathyroid glands are found dorsal to the nerve along the posterior capsule of the thyroid. The glands can be differentiated from normal fat by their brown/tan color. They also can be seen sliding within a thin pseudocapsule. Most of the dissection is done bluntly. An abnormal gland is enlarged and has a dark brown color typically. The finding of an ipsilateral normal appearing gland is helpful in making a presumed diagnosis of parathyroid adenoma. This is confirmed with frozen section after removal of the abnormal gland, and the use of the intraoperative PTH level will help guide the decision to explore the contralateral neck. The diseased gland should be removed completely and intact so as to avoid persistent HPT and parathyromatosis after surgery. The RLN should also be visualized so that further dissection can progress safely. If neither parathyroid gland is enlarged, both look the same, or the PTH level fails to fall after removal of the presumed adenoma, a bilateral neck exploration should be done to rule out four-gland hyperplasia or multiple adenomas. When all four glands cannot be found in the case of four-gland hyperplasia or the missing gland is thought to be the adenomatous gland, a systematic search for the missing gland should be done. Approaches involve mobilization and removal of the thymic tissue via the cervical incision, checking the retroesophageal area, the area above the superior pole, the carotid sheath, and removal of a thyroid lobe if indicated. Because almost all missing glands will be found in the neck, opening of the chest is not recommended in the absence of a positive localization test. Once the involved gland(s) is removed, the wound is irrigated, hemostasis ascertained, and the incision is closed. A drain is not needed. Minimally invasive parathyroidectomy is usually done with regional or local anesthesia in patients with localization typically by two methods. The incision is similar, although it can be done directly over the diseased gland. Intraoperative PTH measurement is used as an adjunct.95,96 Video-assisted parathyroidectomy has had good results with quick patient recovery and satisfaction. It uses a small amount of insufflation at the beginning of the case via a separate small incision. It is usually performed with general anesthesia.97,98 Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 1906 PART VI Head and Neck Surgery and Oncology Fig. 123.7 Ectopic parathyroid adenoma inferior to left submandibular gland. Endoscopic parathyroidectomy also has been used with good success and is appealing due to the cosmesis with placement of the ports laterally along the sternocleidomastoid or posteriorly. Definitive preoperative localization is needed for a patient with single gland disease99 (Fig. 123.7). Postoperative Care Parathyroidectomy can be done on an outpatient basis, regardless of the choice for surgical approach. The expected drop in serum calcium level can be treated by placing the patient on calcium supplements. Patients should be cautioned about the symptoms of hypocalcemia, which peaks at 48 hours after surgery. This includes perioral and fingertip numbness and tingling, which can progress to muscle cramps and carpopedal spasm. Patients with low vitamin D and osteoporosis are at higher risk for symptomatic hypocalcemia. The lack of vitamin D inhibits intestinal absorption of calcium. Vitamin D levels should be checked preoperatively and supplementation initiated in patients who are deficient. Patients with osteoporosis may develop “hungry bone,” when the deprived bones take all available calcium from the serum. Oral supplementation with calcium is effective in treating postoperative hypocalcemia and preventing progression to tetany, which requires IV replacement. Intraoperative Adjuncts RLN monitoring is routinely used to help identify and preserve the RLN functional integrity during parathyroid surgery.100 Although the risk of injury is 1% to 2%, it is particularly helpful in a bilateral neck exploration when knowledge of ipsilateral nerve injury can help avoid a bilateral nerve injury. In reoperative cases, it may also be used to aid in identifying the RLN in a potentially hostile neck.101 SECONDARY HYPERPARATHYROIDISM Secondary HPT is most commonly seen in patients with renal failure. The chronic hypocalcemia results in hyperplasia of all four parathyroid glands. These patients are also often vitamin D deficient again from the renal failure, which further affects the parathyroid glands. Unlike primary HPT, all four glands are always affected, although it can be to varying degrees. Surgical treatment is indicated after the failure of medical management by cinacalcet, a calcimimetic which activates the calcium receptor on the parathyroid gland, keeping the PTH level at an appropriate level. If patients cannot tolerate the side effects of medication or fail to maintain a PTH level less than an acceptable level, then parathyroidectomy is indicated.102–104 One choice of operation for patients expecting renal transplantation is 3 1 2 gland excision. The gland chosen to leave part as remnant is removed first and monitored as the others are removed, so if the remnant becomes ischemic, another gland can be chosen. A four-gland parathyroidectomy may be performed with reimplantation of a 30- to 50-mg portion of parathyroid tissue into a vascularized bed, usually the forearm, sternocleidomastoid, strap muscles, or pectoralis muscles if no renal transplantation is expected. Failure to achieve cure can occur due to residual tissue, usually in the thymus. This parathyroid tissue hypertrophies from the hypocalcemic stimulus. Thus cervical thymectomy is recommended at initial operation. There is controversy about the role of preoperative imaging for localization in these patients. Even though all the parathyroid glands may not be seen on sestamibi or ultrasound, sestamibi is helpful in identifying ectopic glands. Finding of a mediastinal or undescended gland will change the operative approach.105 TERTIARY HYPERPARATHYROIDISM Tertiary HPT occurs in patients who have undergone renal transplant, but due to long-standing stimulation, the parathyroid glands are functioning autonomously and fail to return to normal function even though the renal function and thus hypocalcemia is treated. The surgical management is the same as for secondary HPT.105–108 Parathyroid Cancer Parathyroid cancer is a rare cause of hypercalcemia and is found in less than 1% of patients with HPT. Patients usually have very high calcium levels. The tumors are usually larger and are sometimes palpable on initial presentation, which is unusual for a benign adenoma. The intraoperative findings that are concerning are a large size tumor that is firm, whiter than typical glands, and adherent to surrounding structures, such as the thyroid, trachea, RLN, and strap muscles. Adjacent lymphadenopathy may be seen. The frozen section may reveal evidence of fibrous bands. Because the diagnosis is difficult to make at the time of surgery, if there is concern, an ipsilateral thyroid lobectomy, lymphadenectomy, and resection of adherent surrounding structures are advocated. Pathologic examination is difficult, although the presence of fibrous bands and increased mitoses raises the concern for parathyroid cancer. The only definitive way to diagnose is when patients present with metastatic disease or recurrence in the resection bed. Sites of metastases include lung, cervical nodes, bone, and liver.109,110 Parathyroid Cysts Parathyroid cysts are rare, accounting for 1% to 5% of all neck masses.111 Parathyroid cysts can be mistaken for a thyroid cyst and are generally nonfunctional. They may, if large enough, present as a neck mass and compressive symptoms are not common. Parathyroid cysts present diagnostic challenges; ultrasound and FNA may be helpful.112 Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. CHAPTER 123 Management of Parathyroid Disorders 1907 Management of Asymptomatic Primary Hyperparathyroidism 123 As mentioned earlier, asymptomatic primary hyperparathyroid patients should be evaluated carefully, provided optimal management, and if surgery is not indicated or possible should be monitored actively. The International Workshop on the Management of Asymptomatic PHPT revised the guidelines for management in 2014.113 These guidelines (1) recommend a more extensive evaluation approach for asymptomatic PHPT patients, especially the skeletal and renal system evaluations, (2) suggest specific skeletal and renal criteria for surgery, and (3) provide a specific algorithm for monitoring those patients who do not meet the guidelines for parathyroid surgery.113 Persistent Hyperparathyroidism When the calcium and PTH level fail to return to normal after parathyroidectomy, it is considered persistent HPT. This may occur when the diseased adenomatous parathyroid gland is not removed or multigland hyperplasia is missed. Fig. 123.8 Ultrasound in patient with recurrent hyperparathyroidism after two previous neck operations for hyperparathyroidism. Biopsy of this hypoechoic right thyroid bed lesion confirmed hypercellular parathyroid tissue, confirmed on histology as parathyroid hyperplasia, after a third operation. Recurrent Hyperparathyroidism The definition of recurrent disease is when patients have a normal calcium and PTH level initially after surgery but have evidence of elevated calcium and PTH levels more than 6 months after surgery. Reoperative Parathyroid Surgery Reoperative parathyroid surgery is associated with lower cure rates, higher complication rates due to increased scarring in the central neck from the previous surgery, and increased cost.114–117 The rate of unilateral vocal cord paralysis from parathyroid surgeries ranges from 6.8% to 8%, with some studies reporting a rate of 1.3% for bilateral cord paralysis.117,118 In fact, recently published joint multidisciplinary consensus guidelines of the AHNS and the British Association of Endocrine and Thyroid Surgeons (BAETS) suggest that reoperative parathyroid surgery should be avoided if possible.92 Furthermore, they recommend that these surgeries are best managed by experienced surgeons, precise preoperative localization, intraoperative PTH monitoring, and team approach.92 RLN monitoring is helpful in identifying and preserving the RLN; preoperative laryngoscopic exam should be performed in all reoperative patients, even when the voice is normal. Detailed recommendations on preoperative evaluation, surgical management, and alternative nonsurgical management of reoperative cases have been described in this joint AHNS and BAETS guidelines.119 Parathyromatosis Parathyromatosis is a condition in which there is multiple hyperfunctioning parathyroid tissue in the neck and can occur iatrogenically due to improper handling and rupture of the parathyroid glands during surgery. It is important to carefully remove parathyroid adenomas intact, not only to maintain the integrity, but also to prevent leaving any portion of the diseased gland behind. Leaving even a small portion can cause regrowth and recurrent HPT. This is difficult to cure surgically (Fig. 123.8). In all cases of reoperation, the diagnosis should be clear and operations limited to patients with significant symptoms. Reoperation can be difficult in a scarred field with oftentimes altered anatomy, so the benefits should outweigh the increased risk with these operations. Localization studies are invaluable, and 4D CT scan has proven to be helpful in these cases. The operative approach can be the traditional anterior approach or a lateral approach between the anterior border of the sternocleidomastoid and the strap muscles. NONSURGICAL MANAGEMENT Patients with HPT who do not meet surgical criteria are treated by maintaining adequate hydration and avoiding calcium supplements, food or drink with high-calcium content, and medications that increase the serum calcium level. Calcimimetics are approved for patients with secondary HPT, although they have been used with some success in patients with primary HPT who are not good surgical candidates. They can be expensive, and some patients cannot tolerate the gastrointestinal side effects. PERMANENT HYPOPARATHYROIDISM Hypoparathyroidism results from deficient PTH production. Hypoparathyroidism causes neuromuscular excitability, which can have variable symptoms ranging from paraesthesia and muscle cramps to tetany and seizures. Iatrogenic hypoparathyroidism can occur as a complication following head and neck surgery and procedures that can cause parathyroid gland injury. Noniatrogenic causes include autoimmunity to parathyroid cells and genetic deficiencies affecting either the parathyroid gland development or secretory function.120 Untreated hypoparathyroidism biochemically presents with hypocalcemia, low or absent PTH, and hyperphosphatemia. Hypocalcemia is usually treated with oral calcium and vitamin D supplements. Permanent hypoparathyroidism is a persistent hypocalcemia with low PTH level more than 6 months after surgery. Treatment is usually a combination of calcium and vitamin D supplementation. Recombinant human PTH (rhPTH[1–84]) is currently commercially available and is used to help decrease the requirement of calcium and vitamin D.121,122 Phase III REPLACE trial showed that rhPTH(1–84) 50 to 100 µg injected subcutaneously once daily reduced calcium and vitamin D oral medication requirements by half in 53% of adult hypoparathyroid patients. In addition, in 43% of the patients, it eliminated the need of vitamin D and reduced calcium requirement to less than 500 mg daily.123,124 rhPTH has a limitation, which is its potential to cause osteosarcoma in as demonstrated by studies performed on rats.122 It is intuitive that it is best to take meticulous and thoughtful measures to prevent parathyroid gland injury, to recognize the parathyroid gland injury immediately, and to take prompt action.121 Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. 1908 PART VI Head and Neck Surgery and Oncology SUMMARY The management of HPT has evolved over time. Diagnosis early in the disease process is currently common, and surgical treatment is safe and effective. The management of HPT requires a thorough, methodical approach to diagnosis, patient evaluation including careful considerations of syndromic HPT and genetic screening when applicable, and development of a comprehensive therapeutic strategy. Advances in surgery and preoperative localization have made curative resection less invasive and safer, with ability to predict cure intraoperatively with improvements in outcome and reductions in treatment time, morbidity, and cost. Although these changes have revolutionized the surgical approach to parathyroid gland diseases, they may not be universally applicable and should not be used as a substitute for a well-founded knowledge of surgical embryology, anatomy, and technique. Most patients with HPT who undergo surgical therapy will benefit metabolically and symptomatically. For a complete list of references, visit ExpertConsult.com. Downloaded for thanapa quannuy ([email protected]) at Prince of Songkla University from ClinicalKey.com by Elsevier on July 11, 2020. For personal use only. No other uses without permission. Copyright ©2020. Elsevier Inc. All rights reserved. CHAPTER 123 Management of Parathyroid Disorders1908.e1 REFERENCES 1. Owen RIII: On the anatomy of the Indian Rhinoceros (Rh. unicornis, L.), Trans Zool Soc London 4:31–58, 1852. 2. Seiple C, Johns B: On a new gland in man and several mammals (Glandulae parathyroideae), 1938. Press, SRC—BaiduScholar. 3. 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