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Surgery_Schwartz. on this technique. Although port placements are variable, as is the case with endoscopic thy-roidectomy, they all involve creation of a working space in the neck using CO2 insufflation, with the reported advantages being superior cosmesis and excellent visualization. Although feasi-ble, these techniques also have been associated with increased operating times, more personnel, and greater expense, and have, in general, not been useful for patients with multiglandu-lar disease, a large thyroid mass, or previous neck surgery and irradiation. Their greatest use has been in patients with tumors at ectopic sites such as the mediastinum where thoracoscopic parathyroidectomy is an excellent alternative to sternotomy. Robotic approaches using a gasless, transaxillary technique are also being used for parathyroidectomy. Reported advantages include improved three-dimensional magnified visualization, refined ergonomic control, more freedom of motion with multi-articulated instruments, and


Surgery_Schwartz

Surgery_Schwartz. used for parathyroidectomy. Reported advantages include improved three-dimensional magnified visualization, refined ergonomic control, more freedom of motion with multi-articulated instruments, and improved cosmetic result as a result of incision placement in the axilla.Studies have shown that if both sestamibi scan and neck ultrasound studies independently identify the same, enlarged parathyroid gland, and no other gland, it is indeed the abnormal gland in approximately 95% of cases. These patients with spo-radic PHPT are candidates for a focused neck exploration, an approach that is most commonly referred to as minimally inva-sive parathyroidectomy. A standard bilateral neck exploration is planned if parathyroid localization studies or IOPTH are not available; if the localizing studies fail to identify any abnormal parathyroid gland or identify multiple abnormal glands in patients with a family history of PHPT, MEN1, or MEN2A; or if a concomitant thyroid disorder requires bilateral


Surgery_Schwartz

Surgery_Schwartz. fail to identify any abnormal parathyroid gland or identify multiple abnormal glands in patients with a family history of PHPT, MEN1, or MEN2A; or if a concomitant thyroid disorder requires bilateral exploration. In addition, finding a minimally abnormal parathy-roid gland on the side indicated by localization studies during focal exploration should prompt a bilateral exploration or at least the identification of a normal parathyroid gland on the same side. In patients with MEN1, HPT should be corrected before treatment of gastrinomas because gastrin levels decline after parathyroidectomy.Conduct of Parathyroidectomy (Standard Bilateral Explo-ration) An experienced parathyroid surgeon with a thor-ough knowledge of parathyroid anatomy and embryology and meticulous technique is crucial for the best surgical results. The procedure usually is performed under general anesthesia. The patient is positioned supine on the operating table with the neck extended. For a bilateral exploration, the


Surgery_Schwartz

Surgery_Schwartz. best surgical results. The procedure usually is performed under general anesthesia. The patient is positioned supine on the operating table with the neck extended. For a bilateral exploration, the neck is explored via a 3to 4-cm incision just caudal to the cricoid cartilage. The initial dissection and exposure is similar to that used for thy-roidectomy. After the strap muscles are separated in the midline, one side of the neck is chosen for exploration. In contrast to a thyroidectomy, the dissection during a parathyroidectomy is maintained lateral to the thyroid, making it easier to identify the parathyroid glands and not disturb their blood supply.Identification of Parathyroids. A bloodless field is important to allow identification of parathyroid glands. The middle thyroid veins are ligated and divided, thus enabling medial and anterior retraction of the thyroid lobe, with the aid of a peanut sponge or placement of 2-0 silk sutures into the thyroid. The space between the carotid


Surgery_Schwartz

Surgery_Schwartz. ligated and divided, thus enabling medial and anterior retraction of the thyroid lobe, with the aid of a peanut sponge or placement of 2-0 silk sutures into the thyroid. The space between the carotid sheath and thyroid is then opened by gentle sharp and blunt dissection, from the cricoid cartilage superiorly to the thy-mus inferiorly and the RLN is identified. Approximately 85% of the parathyroid glands are found within 1 cm of the junction of the inferior thyroid artery and RLNs. The upper parathyroid glands usually are superior to this junction and dorsal (posterior) to the nerve, whereas the lower glands are located inferior to the junction and ventral (anterior) to the recurrent nerve. Because parathyroid glands are partly surrounded by fat, any fat lobule at typical parathyroid locations should be explored because the normal or abnormal parathyroid gland may be concealed in the fatty tissue. The thin fascia overlying a “suspicious” fat lobule should be incised using a sharp


Surgery_Schwartz

Surgery_Schwartz. locations should be explored because the normal or abnormal parathyroid gland may be concealed in the fatty tissue. The thin fascia overlying a “suspicious” fat lobule should be incised using a sharp curved hemostat and scalpel. This maneuver often causes the parathyroid gland to “pop” out. Alternatively, gentle, blunt peanut sponge dissection between the carotid sheath and the thyroid gland often reveals a “float” sign, suggesting the site of the abnormal parathyroid gland. Normal parathyroids are light beige and only slightly darker or brown compared to adjacent fat.Parathyroid tissue needs to be distinguished from normal or brown fat tissue, thyroid nodules, lymph nodes, and ectopic thymus. Lymph nodes generally are light beige to whitish gray in color, glassy, and multiple in number, whereas thyroid nod-ules generally are more vascular, firm, dark or reddish brown in color, and have a more variegated appearance. Intraoperatively, 7Standard 24 hr irma


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Surgery_Schwartz. and multiple in number, whereas thyroid nod-ules generally are more vascular, firm, dark or reddish brown in color, and have a more variegated appearance. Intraoperatively, 7Standard 24 hr irma pg/ml2000160012008004000correlation r = 0.9161r2 = 0.8393p value <0.00010400800120016002000Figure 38-32. Correlation of the 10-minute incubation time quick parathyroid hormone assay with the 24-hour immunoradiometric (irma) parathyroid hormone assay from 138 paired intraoperative samples from 38 patients undergoing parathyroidectomy. (Repro-duced with permission from Irvin G, Dembrow VD, Prudhomme DL: Clinical usefulness of an intraoperative “quick parathyroid hormone” assay, Surgery. 1993 Dec;114(6):1019-1022.)Brunicardi_Ch38_p1625-p1704.indd 167401/03/19 11:21 AM 1675THYROID, PARATHYROID, AND ADRENALCHAPTER 38a suspicious nodule may be aspirated using a fine needle attached to a syringe containing 1 cc of saline. Very high PTH levels in the aspirate have been shown to be diagnostic


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Surgery_Schwartz. AND ADRENALCHAPTER 38a suspicious nodule may be aspirated using a fine needle attached to a syringe containing 1 cc of saline. Very high PTH levels in the aspirate have been shown to be diagnostic in the intraopera-tive identification of parathyroid glands. Several characteristics such as size (>7 mm), weight, and color are used to distinguish normal from hypercellular parathyroid glands. Hypercellular glands generally are darker, more firm, and more vascular than normocellular glands. No single method is 100% reliable, and therefore, the parathyroid surgeon must rely on experience and, at times, advice from a pathologist to help distinguish normal from hypercellular glands. Although several molecular studies have shown use in distinguishing parathyroid adenomas from hyperplasia, this determination also must be made by the sur-geon intraoperatively by documenting the presence of a normal parathyroid gland.Location of Parathyroid Glands. The majority of lower para-thyroid glands are


Surgery_Schwartz

Surgery_Schwartz. also must be made by the sur-geon intraoperatively by documenting the presence of a normal parathyroid gland.Location of Parathyroid Glands. The majority of lower para-thyroid glands are found in proximity to the lower thyroid pole (Fig. 38-33A). If not found at this location, the thyrothymic liga-ment and thymus should be mobilized. The upper end of the cervical thymus is gently grasped with a right-angle clamp, and the distal portion is bluntly dissected from perithymic fat with a peanut sponge. One can then “walk down” the thymus with suc-cessive right-angle clamps (Fig. 38-33B). Applying light tension along with a “twisting” motion helps to free the upper thymus. The carotid sheath also should be opened from the bifurcation to the base of the neck if the parathyroid tumor cannot be found. If these maneuvers are unsuccessful, an intrathyroidal gland should be sought by using intraoperative ultrasound, incising the thyroid capsule on its posterolateral surface, or by perform-ing an


Surgery_Schwartz

Surgery_Schwartz. If these maneuvers are unsuccessful, an intrathyroidal gland should be sought by using intraoperative ultrasound, incising the thyroid capsule on its posterolateral surface, or by perform-ing an ipsilateral thyroid lobectomy and “bread-loafing” the thy-roid lobe. Preoperative or intraoperative ultrasonography can be useful for identifying intrathyroidal parathyroid glands. Rarely, the third branchial pouch may maldescend and be found high in the neck (undescended parathymus), anterior to the carotid bulb, along with the missing parathyroid gland. Upper para-thyroid glands are more consistent in position and usually are found near the junction of the upper and middle thirds of the gland, at the level of the cricoid cartilage (Fig. 38-33C). Ectopic upper glands may be found in carotid sheath, tracheoesopha-geal groove, retroesophageal, or in the posterior mediastinum. The locations of ectopic upper and lower parathyroid glands are shown in Fig. 38-34. Every attempt must be made to


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Surgery_Schwartz. sheath, tracheoesopha-geal groove, retroesophageal, or in the posterior mediastinum. The locations of ectopic upper and lower parathyroid glands are shown in Fig. 38-34. Every attempt must be made to identify all four glands. Treatment depends on the number of abnormal glands.1. A single adenoma is presumed to be the cause of a patient’s PHPT if only one parathyroid tumor is identified and the other parathyroid glands are normal, a situation present in about 80% of patients with PHPT. Adenomas typically have an atrophic rim of normal parathyroid tissue, but this char-acteristic may be absent. The adenoma is dissected free of surrounding tissue, taking care to stay immediately adjacent to the tumor, without fracturing it. The vascular pedicle is clamped, divided, and ligated. Care should be taken to not rupture the parathyroid gland to decrease the risk of parathy-romatosis. If there is any question about the presumed nor-mal glands, one of them should be biopsied and examined by


Surgery_Schwartz

Surgery_Schwartz. be taken to not rupture the parathyroid gland to decrease the risk of parathy-romatosis. If there is any question about the presumed nor-mal glands, one of them should be biopsied and examined by frozen section.2. If two abnormal and two normal glands are identified, the patient has double adenomas. Triple adenomas are pres-ent if three glands are abnormal and one is normal. Mul-tiple adenomas are more common in older patients with an incidence of up to 10% in patients >60 years old. The abnormal glands should be excised, provided the re-maining glands are confirmed as such, thus excluding asymmetric hyperplasia after biopsy and frozen section.3. If all parathyroid glands are enlarged or hypercellular, pa-tients have parathyroid hyperplasia that has been shown to occur in about 15% of patients in various series. These glands are often lobulated, usually lack the rim of normal Upper parathyroid glandRecurrentlaryngeal n.Inf. thyroid a. ThymusLowerparathyroidglandThyroidABCFigure


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Surgery_Schwartz. of patients in various series. These glands are often lobulated, usually lack the rim of normal Upper parathyroid glandRecurrentlaryngeal n.Inf. thyroid a. ThymusLowerparathyroidglandThyroidABCFigure 38-33. Conduct of parathyroidectomy. A. Exposure of the lower parathyroid gland near the inferior pole of the thyroid gland and anterior to the recurrent laryngeal nerve. B. A thymectomy may be necessary if the lower parathyroid cannot be found in its usual location, or if the patient has familial primary hyperparathyroid-ism or secondary hyperparathyroidism. C. Exposure of the upper parathyroid gland near the insertion of the recurrent laryngeal nerve at the level of the cricothyroid muscle. a. = artery; Inf. = inferior; n. = nerve.Brunicardi_Ch38_p1625-p1704.indd 167501/03/19 11:21 AM 1676SPECIFIC CONSIDERATIONSPART IIparathyroid gland seen in adenomas, and may be variable in size. It often is difficult to distinguish multiple adenomas from hyperplasia with variable gland size.


Surgery_Schwartz

Surgery_Schwartz. AM 1676SPECIFIC CONSIDERATIONSPART IIparathyroid gland seen in adenomas, and may be variable in size. It often is difficult to distinguish multiple adenomas from hyperplasia with variable gland size. Hyperplasia may be of the chief cell (more common), mixed, or clear cell type. Patients with hyperplasia may be treated by subtotal para-thyroidectomy or by total parathyroidectomy and autotrans-plantation, with the choice of procedure being determined by rates of recurrence, postoperative hypocalcemia, and failure rates of autotransplanted tissue. Initial studies demonstrated equivalent cure rates and postoperative hypocalcemia for the two techniques, with the latter having the added advantage of avoiding recurrence in the neck. However, autotrans-planted tissue may fail to function in about 5% of cases.All four parathyroid glands are identified and carefully mobilized. For patients with hyperplasia, a titanium clip is placed across the most normal gland, leaving a 50-mg rem-nant and


Surgery_Schwartz

Surgery_Schwartz. 5% of cases.All four parathyroid glands are identified and carefully mobilized. For patients with hyperplasia, a titanium clip is placed across the most normal gland, leaving a 50-mg rem-nant and taking care to avoid disturbing the vascular pedicle and that the gland is resected with a sharp scalpel. If possible, it is preferable to subtotally resect an inferior gland, which is more easily accessible in case of recurrence due to its anterior location with respect to the RLN. The resected parathyroid tis-sue is confirmed by frozen section or PTH assay. If the rem-nant appears to be viable, the remaining glands are resected. If there is any question as to the viability of the initially subtotally resected gland, another gland is chosen for subtotal resection, and the initial remnant is removed. Whenever multiple para-thyroids are resected, it is preferable to cryopreserve tissue, so that it may be autotransplanted should the patient become hypo-parathyroid. Parathyroid tissue usually is


Surgery_Schwartz

Surgery_Schwartz. Whenever multiple para-thyroids are resected, it is preferable to cryopreserve tissue, so that it may be autotransplanted should the patient become hypo-parathyroid. Parathyroid tissue usually is transplanted into the nondominant forearm. A horizontal skin incision is made over-lying the brachioradialis muscle a few centimeters below the antecubital fossa. Pockets are made in the belly of the muscle, and one to two pieces of parathyroid tissue measuring 1 mm each are placed into each pocket. A total of 12 to 14 pieces are transplanted. Autotransplanted tissue also has been reported to function when transplanted into fat.Indications for Sternotomy A sternotomy is usually not rec-ommended at the initial operation, unless the calcium level is >13 mg/dL. Rather, it is preferred to biopsy the normal glands and subsequently close the patient’s neck and obtain localiz-ing studies, if they were not obtained previously. Intraoperative PTH assay during the operation from large veins may be


Surgery_Schwartz

Surgery_Schwartz. the normal glands and subsequently close the patient’s neck and obtain localiz-ing studies, if they were not obtained previously. Intraoperative PTH assay during the operation from large veins may be helpful. Using highly selective venous catheterization postoperatively also may be needed when noninvasive localization studies are negative, equivocal, or conflicting. Lower parathyroid glands tend to migrate into the anterior mediastinum in the thymus or perithymic fat and usually can be approached via a cervical inci-sion. A sternotomy is needed to deliver these tumors in approxi-mately 5% of cases. Generally, the gland can be approached by a partial sternotomy to the third intercostal space. The midline sternotomy can be extended to the left or right side as required. Upper glands tend to migrate to the posterior mediastinum in the tracheoesophageal groove. Mediastinal glands also may be found in the aortopulmonary window or pericardium, or attached to the ascending aorta, aortic


Surgery_Schwartz

Surgery_Schwartz. to migrate to the posterior mediastinum in the tracheoesophageal groove. Mediastinal glands also may be found in the aortopulmonary window or pericardium, or attached to the ascending aorta, aortic arch, or its branches.Special Situations Normocalcemic Hyperparathyroidism. This disorder is becoming increasingly recognized in clinical practice (preva-lence from 0.5% to 16%) and is defined by the presence of an elevated PTH level with repeatedly normal calcium (including ionized calcium) levels. In addition, other secondary causes of elevated PTH should be ruled out, namely, vitamin D deficiency, osteomalacia, hypercalciuria (renal leak), and renal insufficiency. Data regarding the natural history of this disorder are limited. In a series of 37 patients, Lowe and colleagues87 showed that 19% of patients became frankly hyper-calcemic within 3 years. In addition, 57% developed osteoporo-sis, 11% developed fragility fractures, and 14% developed nephrolithiasis. Although the study had some


Surgery_Schwartz

Surgery_Schwartz. of patients became frankly hyper-calcemic within 3 years. In addition, 57% developed osteoporo-sis, 11% developed fragility fractures, and 14% developed nephrolithiasis. Although the study had some limitations, it led the authors to suggest that normocalcemic HPT may represent a variant of “symptomatic” PHPT and may not be an early form of “asymptomatic” disease. Limited studies show that 800.811217440.222128040.20.8626Figure 38-34. Location of ectopic upper and lower parathyroid glands. (Reproduced with permission from Akerström G, Malmaeus J, Bergström R: Surgical anatomy of human parathyroid glands, Surgery. 1984 Jan;95(1):14-21.)Brunicardi_Ch38_p1625-p1704.indd 167601/03/19 11:22 AM 1677THYROID, PARATHYROID, AND ADRENALCHAPTER 38parathyroidectomy is more likely to be unsuccessful in these patients. In the absence of strong data, no guidelines are avail-able for this entity.88 As such, most clinicians follow a conserva-tive course unless patients progress to the classic


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Surgery_Schwartz. in these patients. In the absence of strong data, no guidelines are avail-able for this entity.88 As such, most clinicians follow a conserva-tive course unless patients progress to the classic hypercalcemic form or develop nephrolithiasis, reduced bone mineral density, or fragility fractures.Parathyroid Carcinoma. Parathyroid cancer accounts for approximately 1% of PHPT cases. It may be suspected preop-eratively by the presence of severe symptoms, serum calcium levels >14 mg/dL, significantly elevated PTH levels (five times normal), and a palpable parathyroid gland. Local invasion is quite common; approximately 15% of patients have lymph node metastases, and 33% have distant metastases at pre-sentation. Intraoperatively, parathyroid cancer is suggested by the presence of a large, gray-white to gray-brown parathyroid tumor that is adherent to or invasive into surrounding tissues like muscle, thyroid, RLN, trachea, or esophagus. Enlarged lymph nodes also may be present. Frozen sections


Surgery_Schwartz

Surgery_Schwartz. to gray-brown parathyroid tumor that is adherent to or invasive into surrounding tissues like muscle, thyroid, RLN, trachea, or esophagus. Enlarged lymph nodes also may be present. Frozen sections are generally unreliable. Accurate diagnosis necessitates histologic examina-tion. The major diagnostic criteria include vascular or capsular invasion, trabecular or fibrous stroma, and frequent mitoses. It is, however, important to emphasize that these classic findings are not as frequently noted as previously reported, and some may be found in benign adenomas as well.Treatment of parathyroid cancer consists of neck explora-tion, with en bloc excision of the tumor and the ipsilateral thy-roid lobe, in addition to the removal of contiguous lymph nodes (tracheoesophageal, paratracheal, and upper mediastinal). The recurrent nerve is not sacrificed unless it is directly involved with tumor. Adherent soft tissue structures (strap muscles or other soft tissues) should also be resected.89 Modified


Surgery_Schwartz

Surgery_Schwartz. The recurrent nerve is not sacrificed unless it is directly involved with tumor. Adherent soft tissue structures (strap muscles or other soft tissues) should also be resected.89 Modified radical neck dissection is recommended in the presence of lateral lymph node metastases. Prophylactic neck dissection is not advised. If the diagnosis is made postoperatively, a decision must be made regarding the adequacy of initial surgery based on a review of operative notes, pathology reports, localization studies, and cal-cium and PTH levels. If any question exists, histologic review by another experienced pathologist can be helpful. Additional procedures can include ipsilateral thyroid lobectomy with resec-tion of contiguous structures and lymph nodes if the features are typical or the patient remains hypercalcemic. Patients with equivocal pathologic findings and normocalcemia may be monitored closely. Reoperation is indicated for locally recur-rent or metastatic disease to control


Surgery_Schwartz

Surgery_Schwartz. patient remains hypercalcemic. Patients with equivocal pathologic findings and normocalcemia may be monitored closely. Reoperation is indicated for locally recur-rent or metastatic disease to control hypercalcemia. Adjuvant radiation therapy should be considered in patients at high risk of local recurrence such as those with close or positive margins, invasion of surrounding structures, or tumor rupture. Radiation may also be used as primary therapy in unresectable disease or for palliation of bone metastases. Chemotherapy is not very effective. Bisphosphonates have shown some effectiveness in treating hypercalcemia associated with parathyroid carcinoma. Cinacalcet hydrochloride, a calcimimetic, can reduce PTH lev-els by directly binding to the CASR cells on the parathyroid gland and has been shown to be useful in controlling hyper-calcemia in patients with refractory parathyroid carcinoma.90 Other promising approaches include antiparathyroid hormone immunotherapy, octreotide, and the


Surgery_Schwartz

Surgery_Schwartz. shown to be useful in controlling hyper-calcemia in patients with refractory parathyroid carcinoma.90 Other promising approaches include antiparathyroid hormone immunotherapy, octreotide, and the telomerase inhibitor azido-thymidine, but additional investigations are needed in this area.Familial Hyperparathyroidism. PHPT may occur as a com-ponent of various inherited syndromes such as MEN1 and MEN2A. Inherited PHPT also can occur as isolated familial HPT (non-MEN) or familial HPT with jaw tumors. The diag-nosis of familial HPT is known or suspected in approximately 85% of patients preoperatively. Furthermore, patients with hereditary HPT generally have a higher incidence of multiglan-dular disease, supernumerary glands, and recurrent or persistent disease. Therefore, these patients warrant a more aggressive approach and are not candidates for various focused surgical approaches.91 Although not absolutely necessary, preoperative sestamibi scan and ultrasound can be obtained in patients


Surgery_Schwartz

Surgery_Schwartz. a more aggressive approach and are not candidates for various focused surgical approaches.91 Although not absolutely necessary, preoperative sestamibi scan and ultrasound can be obtained in patients with inherited HPT to identify potential ectopic glands. A standard bilateral neck exploration is performed, along with a bilateral cervical thymectomy, regardless of the results of localization studies. Both subtotal parathyroidectomy and total parathyroid-ectomy with autotransplantation are appropriate, and parathy-roid tissue also should be cryopreserved. If an adenoma is found in patients with familial HPT, the adenoma and the ipsilateral normal parathyroid glands are resected. The normal-appearing glands on the contralateral side are biopsied and marked, so that only one side of the neck will need to be explored in the event of recurrence. Patients with MEN2A require total thyroidectomy and central neck dissection for prevention/treatment of MTC, a procedure that places the


Surgery_Schwartz

Surgery_Schwartz. the neck will need to be explored in the event of recurrence. Patients with MEN2A require total thyroidectomy and central neck dissection for prevention/treatment of MTC, a procedure that places the parathyroids at risk. Moreover, HPT is less aggressive in these patients. Hence, only abnormal para-thyroid glands need to be resected at neck exploration. The other normal parathyroid glands should be marked with a clip.Neonatal Hyperparathyroidism. Infants with neonatal HPT present with severe hypercalcemia, lethargy, hypotonia, and mental retardation. This disorder is associated with homozygous mutations in the CASR gene. As indicated earlier, urgent total parathyroidectomy (with autotransplantation and cryopreserva-tion) and thymectomy are indicated. Subtotal resection is associ-ated with high recurrence rates.Parathyromatosis. Parathyromatosis is a rare condition char-acterized by the finding of multiple nodules of hyperfunctioning parathyroid tissue throughout the neck and


Surgery_Schwartz

Surgery_Schwartz. with high recurrence rates.Parathyromatosis. Parathyromatosis is a rare condition char-acterized by the finding of multiple nodules of hyperfunctioning parathyroid tissue throughout the neck and mediastinum, usu-ally following a previous parathyroidectomy. The true etiology of parathyromatosis is not known. It is postulated to arise either from overgrowth of congenital parathyroid rests (ontogenous parathyromatosis) or seeding at surgery from rupture of parathy-roid tumors or subtotal resection of hyperplastic glands. Para-thyromatosis represents a rare cause of persistent or recurrent HPT92 and can be identified intraoperatively. Aggressive local resection of these deposits can result in normocalcemia but is rarely curative. Some studies suggest that these patients have low-grade carcinoma because of invasion into muscle and other structures distant from the resected parathyroid tumor.Postoperative Care and Follow-Up Patients who have under-gone parathyroidectomy are advised to


Surgery_Schwartz

Surgery_Schwartz. because of invasion into muscle and other structures distant from the resected parathyroid tumor.Postoperative Care and Follow-Up Patients who have under-gone parathyroidectomy are advised to undergo calcium level checks 2 weeks postoperatively, at 6 months, and then annu-ally. Recurrences are rare (<1%), except in patients with famil-ial HPT. Recurrence rates of 15% at 2 years and 67% at 8 years have been reported for MEN1 patients.Persistent and Recurrent Hyperparathyroidism. Per-sistence is defined as hypercalcemia that fails to resolve after parathyroidectomy and is more common than recurrence, which refers to HPT occurring after an intervening period of at least 6 months of biochemically documented normocalcemia.93 Recurrent disease is far less common than persistent HPT; however, both occur more frequently in the setting of familial HPT and MEN1, in particular. The most common causes for both these states include ectopic parathyroids, unrecognized


Surgery_Schwartz

Surgery_Schwartz. persistent HPT; however, both occur more frequently in the setting of familial HPT and MEN1, in particular. The most common causes for both these states include ectopic parathyroids, unrecognized 9Brunicardi_Ch38_p1625-p1704.indd 167701/03/19 11:22 AM 1678SPECIFIC CONSIDERATIONSPART IIhyperplasia, or supernumerary glands. More rare causes include parathyroid carcinoma, missed adenoma in a normal position, incomplete resection of an abnormal gland, parathyromatosis, or an inexperienced surgeon. The most common sites of ecto-pic parathyroid glands in patients with persistent or recurrent HPT are paraesophageal (28%), mediastinal (26%), intrathymic (24%), intrathyroidal (11%), carotid sheath (9%), and high cer-vical or undescended (2%) (Fig. 38-35).Once the diagnosis of persistent or recurrent HPT is sus-pected, it should be confirmed by the necessary biochemical tests. Other causes of an elevated serum PTH such as renal insufficiency, renal calcium leak, and GI tract abnormalities


Surgery_Schwartz

Surgery_Schwartz. HPT is sus-pected, it should be confirmed by the necessary biochemical tests. Other causes of an elevated serum PTH such as renal insufficiency, renal calcium leak, and GI tract abnormalities should be considered. A detailed family history should be per-formed to screen for familial disease, as this will influence the operative approach. In particular, a 24-hour urine collec-tion should be performed to rule out FHH. In redo-parathyroid surgery, the glands are more likely to be in ectopic locations, and postoperative scarring tends to make the procedure more technically demanding. Cure rates are generally lower (80–90% compared with 95–99% for initial operation), and risk of injury to RLNs and permanent hypocalcemia are higher. Therefore, an evaluation of severity of HPT and the patient’s anesthetic risk (using the American Society of Anesthesiology classifica-tion of physical status or the Goldman cardiac index) is impor-tant. There are no published guidelines directly applicable to


Surgery_Schwartz

Surgery_Schwartz. anesthetic risk (using the American Society of Anesthesiology classifica-tion of physical status or the Goldman cardiac index) is impor-tant. There are no published guidelines directly applicable to this group of patients. In general, patients with significant and ongoing problems such as recurrent kidney stones, a markedly elevated calcium level, or ongoing bone loss will need reex-ploration. Patients in whom the diagnosis remains in question or those with equivocal or minimal symptoms may be considered for conservative management. Preoperative localization studies are routinely performed. Noninvasive studies such as a sesta-mibi scan and ultrasound are obtained, supplemented by 4D-CT scans. If these studies are negative, discordant, or equivocal, obtaining an ultrasound-guided aspirate of a suspicious cervi-cal lesion or a highly selective venous catheterization for PTH levels (by an experienced angiographer) is recommended. Previ-ous operative notes and pathology reports should be


Surgery_Schwartz

Surgery_Schwartz. of a suspicious cervi-cal lesion or a highly selective venous catheterization for PTH levels (by an experienced angiographer) is recommended. Previ-ous operative notes and pathology reports should be carefully reviewed and reconciled with the information obtained from localization studies before any neck reexploration. An algorithm for the treatment of patients with recurrent and persistent HPT is shown in Fig. 38-36.Generally, these patients are approached with a focused exploration. The lateral approach is frequently used and can be achieved via the previous incision. The plane between the ster-nocleidomastoid and strap muscle is opened and allows for early identification of the RLN. Parathyroid tissue is cryopreserved routinely. Use of adjuncts, such as measuring intraoperative PTH levels, is critical to ensure adequate resection and avoid potentially harmful additional explorations. In case of difficult reexplorations, additional techniques such as bilateral internal jugular vein


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Surgery_Schwartz. is critical to ensure adequate resection and avoid potentially harmful additional explorations. In case of difficult reexplorations, additional techniques such as bilateral internal jugular vein sampling for PTH, thyroid lobectomy on the side of the missing gland, cervical thymectomy, and ligation of the ipsi-lateral inferior thyroid artery (after lobectomy, to cause infarc-tion of the missing gland) may be needed. Blind mediastinal exploration is not recommended. In patients who are denied, refuse, or fail exploration, medical options such as cinacalcet may be considered.Figure 38-35. Anatomic location of ectopic parathyroid glands. Numbers represent number of glands found in each location, with a total of 54. (Reproduced with permission from Shen W, Düren M, Morita E, et al: Reoperation for persistent or recurrent primary hyperparathyroidism, Arch Surg. 1996 Aug;131(8):861-867.)High


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Surgery_Schwartz. with a total of 54. (Reproduced with permission from Shen W, Düren M, Morita E, et al: Reoperation for persistent or recurrent primary hyperparathyroidism, Arch Surg. 1996 Aug;131(8):861-867.)High cervicalpositionCarotidsheathIntrathymicIntrathyroidalAnteriormediastinum(nonthymic)AortopulmonarywindowPosteriormediastinumParaesophageal5169213315C3C4C5C6C7T1T2T3T4Brunicardi_Ch38_p1625-p1704.indd 167801/03/19 11:22 AM 1679THYROID, PARATHYROID, AND ADRENALCHAPTER 38Recurrent or persistent HPT1) Confirm diagnosis2) Rule out FHH3) Review operative notes and pathologyParathyroidectomyPositiveNegativeNoninvasivelocalization studiesNegativePositiveSelective venous catheterization for PTHIs tumorlocalized?Follow-upif mildhypercalcemia ParathyroidectomyMedical therapyNoYesFigure 38-36. Management of recurrent and persistent hyperpara-thyroidism (HPT). FHH = familial hypocalciuric hypercalcemia; PTH = parathyroid hormone.Hypercalcemic Crisis. Patients with PHPT may occasionally present


Surgery_Schwartz

Surgery_Schwartz. of recurrent and persistent hyperpara-thyroidism (HPT). FHH = familial hypocalciuric hypercalcemia; PTH = parathyroid hormone.Hypercalcemic Crisis. Patients with PHPT may occasionally present acutely with nausea, vomiting, fatigue, muscle weak-ness, confusion, and a decreased level of consciousness—a complex referred to as hypercalcemic crisis. These symptoms result from severe hypercalcemia from uncontrolled PTH secre-tion, worsened by polyuria, dehydration, and reduced kidney function and may occur with other conditions causing hyper-calcemia. Calcium levels are markedly elevated and may be as high as 16 to 20 mg/dL. Parathyroid tumors tend to be large or multiple and may be palpable. Patients with parathyroid cancer or familial HPT are more likely to present with hypercalcemic crisis.Treatment consists of therapies to lower serum calcium levels followed by surgery to correct HPT. The mainstay of therapy involves rehydration with a 0.9% saline solution to keep urine output >100


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Surgery_Schwartz. consists of therapies to lower serum calcium levels followed by surgery to correct HPT. The mainstay of therapy involves rehydration with a 0.9% saline solution to keep urine output >100 cc/h. Once urine output is established, diure-sis with furosemide (which increases renal calcium clearance) is begun. If these methods are unsuccessful, other drugs may be used to lower serum calcium levels as outlined in Table 38-13. Occasionally, in life-threatening cases, hemodialysis may be of benefit.Secondary Hyperparathyroidism. Secondary HPT com-monly occurs in patients with chronic renal failure but also may occur in those with hypocalcemia secondary to inadequate cal-cium or vitamin D intake or malabsorption. The pathophysiol-ogy of HPT in chronic renal failure is complex and appears to be related to hyperphosphatemia (and resultant hypocalcemia), deficiency of 1,25-dihydroxy vitamin D due to loss of renal tissue, low calcium intake, decreased calcium absorption, and abnormal parathyroid


Surgery_Schwartz

Surgery_Schwartz. to hyperphosphatemia (and resultant hypocalcemia), deficiency of 1,25-dihydroxy vitamin D due to loss of renal tissue, low calcium intake, decreased calcium absorption, and abnormal parathyroid cell response to extracellular calcium or vitamin D in vitro and in vivo. Patients generally are hypocalce-mic or normocalcemic. Aluminum hydroxide, which often was used as a phosphate binder, has been shown to contribute to the osteomalacia observed in this disease. These patients gen-erally are treated medically with a low-phosphate diet, phos-phate binders, adequate intake of calcium and 1, 25-dihydroxy vitamin D, and a high-calcium, low-aluminum dialysis bath. Calcimimetics have been shown to control parathyroid hyper-plasia and osteitis fibrosa cystica associated with secondary HPT in animal studies and to decrease plasma PTH and total and ionized calcium levels in humans.As the indications for parathyroidectomy were not well established, surgical treatment was traditionally recommended


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Surgery_Schwartz. studies and to decrease plasma PTH and total and ionized calcium levels in humans.As the indications for parathyroidectomy were not well established, surgical treatment was traditionally recommended for patients with bone pain, pruritus, and (a) a calciumphosphate product ≥70, (b) calcium >11 mg/dL with markedly elevated PTH, (c) calciphylaxis, (d) progressive renal osteodys-trophy, and (e) soft tissue calcification and tumoral calcinosis, despite maximal medical therapy. Following the introduction of calcimimetics, there appears to have been a reduction in para-thyroidectomy rates. Parathyroidectomy has been reported to maintain biochemical targets for up to 5 years and improve bone density, fracture risk, calcinosis, hemoglobin levels, and even long-term survival. Studies also report that in a large series of patients on hemodialysis, calcimimetics increased the likelihood of achieving goal PTH (≤300 pg/mL), calcium, phosphate, and Ca × PO4 product, in addition to reducing the risk


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Surgery_Schwartz. in a large series of patients on hemodialysis, calcimimetics increased the likelihood of achieving goal PTH (≤300 pg/mL), calcium, phosphate, and Ca × PO4 product, in addition to reducing the risk of fractures and cardiovascular complications.In the absence of randomized trials comparing medical ther-apy with parathyroidectomy, current recommendations from the National Kidney Foundation’s Kidney Disease Quality Outcomes Initiative (KDOQI) advise parathyroidectomy for patients on maximal medical therapy with (a) severe HPT (defined as PTH >800 pg/mL, (b) hypercalcemia, (c) osteoporosis or pathologic bone fracture, (d) Symptoms and signs such as pruritis, bone pain, severe vascular calcifications, myopathy, and (e) calci-phylaxis.94 Calciphylaxis is a rare, limband life-threatening complication of secondary HPT characterized by painful (some-times throbbing), violaceous, and mottled lesions usually on the extremities, which often become necrotic and progress to non-healing ulcers,


Surgery_Schwartz

Surgery_Schwartz. of secondary HPT characterized by painful (some-times throbbing), violaceous, and mottled lesions usually on the extremities, which often become necrotic and progress to non-healing ulcers, gangrene, sepsis, and death. Skin biopsy can be helpful to make the diagnosis. These are critically ill, high-risk patients, but successful parathyroidectomy sometimes relieves symptoms. Not all patients with calciphylaxis will have high PTH levels, and parathyroidectomy should not be undertaken in the absence of documented hyperparathyroidism. Assessment of parathyroid mass is thought to be an important factor for pre-dicting the response to medical management. Therefore, some groups recommend parathyroidectomy if the glands are >1 cm (or >500 mm3) on ultrasound. These glands are more likely to have developed nodular hyperplasia and hence might be refrac-tory to medical management.Patients should undergo routine dialysis the day before surgery to correct electrolyte abnormalities. Localization


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Surgery_Schwartz. developed nodular hyperplasia and hence might be refrac-tory to medical management.Patients should undergo routine dialysis the day before surgery to correct electrolyte abnormalities. Localization stud-ies are not necessary but can identify ectopic parathyroid glands. A bilateral neck exploration is indicated. The parathyroid glands in secondary HPT are characterized by asymmetric enlargement and nodular hyperplasia. These patients may be treated by sub-total resection, leaving about 50 mg of the most normal parathy-roid gland or total parathyroidectomy and autotransplantation Brunicardi_Ch38_p1625-p1704.indd 167901/03/19 11:22 AM 1680SPECIFIC CONSIDERATIONSPART IIof parathyroid tissue into the brachioradialis muscle of the non-dominant forearm, with parathyroid cryopreservation. Upper thymectomy usually is performed because 15% to 20% of patients have one or more parathyroid glands situated in the thy-mus or perithymic fat. Some groups recommend total parathy-roidectomy without


Surgery_Schwartz

Surgery_Schwartz. thymectomy usually is performed because 15% to 20% of patients have one or more parathyroid glands situated in the thy-mus or perithymic fat. Some groups recommend total parathy-roidectomy without autotransplantation because it is associated with a lower rate of recurrence.95 While it may be preferable in patients with calciphylaxis, this procedure is contraindicated in patients eligible for renal transplant. Since the evidence needed to determine the superiority of one approach over another is lacking, the choice of procedure is influenced by surgeon pref-erence and experience and various patient factors, as indicated earlier.Tertiary Hyperparathyroidism. Generally, renal transplan-tation is an excellent method of treating secondary HPT, but some patients develop autonomous parathyroid gland function and tertiary HPT. Tertiary HPT can cause problems similar to PHPT, such as pathologic fractures, bone pain and worsened bone disease, renal stones, peptic ulcer disease, pancreatitis,


Surgery_Schwartz

Surgery_Schwartz. gland function and tertiary HPT. Tertiary HPT can cause problems similar to PHPT, such as pathologic fractures, bone pain and worsened bone disease, renal stones, peptic ulcer disease, pancreatitis, and mental status changes. The transplanted kidney is also at risk from tubulointerstitial calcification and volume depletion. Similar to patients with secondary HPT, many patients with ter-tiary HPT are being treated with cinacalcet. Although the drug is effective and well-tolerated in these patients, the long-term effects on kidney allograft function are not known, and many of these patients have persistence of their hypercalcemic symp-toms. On the other hand, parathyroidectomy has been shown to lead to a more immediate and dramatic reduction in hypercal-cemic symptoms. As such, operative intervention is indicated if autonomous PTH secretion persists for >1 year after a successful transplant in patients with hypophosphatemia, low BMD/severe osteopenia, symptoms, and signs such as


Surgery_Schwartz

Surgery_Schwartz. intervention is indicated if autonomous PTH secretion persists for >1 year after a successful transplant in patients with hypophosphatemia, low BMD/severe osteopenia, symptoms, and signs such as fatigue, pruritis, bone pain, peptic ulcer disease or nephrocalcinosis, provided they are deemed operative candidates.96 All parathyroid glands should be identified. The traditional surgical management of these patients consisted of subtotal or total parathyroid-ectomy with autotransplantation and an upper thymectomy. Some authors suggest that these patients derive similar benefit from excision of only obviously enlarged glands, while avoid-ing the higher risks of hypocalcemia associated with the for-mer approach. Others recommend that all parathyroid glands be identified and subtotal parathyroidectomy be performed as long-term follow-up studies show that limited excisions in these patients are associated with an up to fivefold increased risk of recurrent or persistent disease. Further


Surgery_Schwartz

Surgery_Schwartz. be performed as long-term follow-up studies show that limited excisions in these patients are associated with an up to fivefold increased risk of recurrent or persistent disease. Further studies are needed to define the best operative approach for these patients.Complications of Parathyroid Surgery. Parathyroidectomy can be accomplished successfully in >95% of patients with minimal mortality and morbidity, provided the procedure is performed by a surgeon experienced in parathyroid surgery. Table 38-13Medications commonly used to treat hypercalcemiaMEDICATIONDOSAGE AND ADMINISTRATIONMECHANISM, ONSET OF ACTION, AND DURATIONSIDE EFFECTSBisphosphonates (pamidronate, zolendronic acid preferred in patients with malignancy due to rapid action)60–90 mg IV over 4–24 hInhibits osteoclastic bone resorption; rapid onset, 2–3 dMay cause local pain and swelling, low-grade fever, lymphopenia, electrolyte abnormalities, osteonecrosis of the jaw in some patients (iv use)Calcitonin4 IU/kg


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Surgery_Schwartz. bone resorption; rapid onset, 2–3 dMay cause local pain and swelling, low-grade fever, lymphopenia, electrolyte abnormalities, osteonecrosis of the jaw in some patients (iv use)Calcitonin4 IU/kg SC/IMInhibits osteoclast function, augments renal calcium excretion; onset of action in hours; but short lived, therefore not useful as sole therapyTransient nausea and vomiting, abdominal cramps, flushing, and local skin reactionMithramycin (plicamycin)25 μg/kg/d IV for 3–4 dInhibits osteoclasts RNA secretion; rapid onset of action (12 h); peaks at 48–72 h and lasts days to several weeksMay cause renal, hepatic, and hematologic complications, nausea and vomitingGallium nitrate200 mg/m2 BSA/d IV for 5 dReduces urinary calcium excretion; onset of action delayed (5–7 d)Nephrotoxicity, nausea, vomiting, hypotension, anemia, hypophosphatemiaGlucocorticoidsHydrocortisone 100 mg IV q8hDelayed onset of action (7–10 d); useful for hematologic malignancies, sarcoidosis, vitamin D intoxication,


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Surgery_Schwartz. vomiting, hypotension, anemia, hypophosphatemiaGlucocorticoidsHydrocortisone 100 mg IV q8hDelayed onset of action (7–10 d); useful for hematologic malignancies, sarcoidosis, vitamin D intoxication, hyperthyroidismHypertension, hyperglycemiaCalcimimetics (cinacalcet)Up to 90 mg 3 o 4 times per dayUseful in patients with parathyroid carcinoma and patients with chronic renal failureGastrointestinal complaints, hypotension, hypocalcemiaBSA = body surface area; IM = intramuscular; IV = intravenous; SC = subcutaneous.Brunicardi_Ch38_p1625-p1704.indd 168001/03/19 11:22 AM 1681THYROID, PARATHYROID, AND ADRENALCHAPTER 38Table 38-14Conditions causing hypocalcemiaHypoparathyroidism • Surgical • Neonatal • Familial • Heavy metal deposition • Magnesium depletionResistance to the action of parathyroid hormone • Pseudohypoparathyroidism • Renal failure • Medications—calcitonin, bisphosphonates, mithramycinFailure of normal 1,25-dihydroxy vitamin D productionResistance to the action of


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Surgery_Schwartz. parathyroid hormone • Pseudohypoparathyroidism • Renal failure • Medications—calcitonin, bisphosphonates, mithramycinFailure of normal 1,25-dihydroxy vitamin D productionResistance to the action of 1,25-dihydroxy vitamin DAcute complex formation or deposition of calcium • Acute hyperphosphatemia • Acute pancreatitis • Massive blood transfusion (citrate overload) • “Hungry bones”Specific complications include transient and permanent vocal cord palsy and hypoparathyroidism. The latter is more likely to occur in patients who undergo four-gland exploration with biopsies, subtotal resection with an inadequate remnant, or total parathyroidectomy with a failure of autotransplanted tissue. Furthermore, hypocalcemia is more likely to occur in patients with high-turnover bone disease as evidenced by elevated pre-operative alkaline phosphatase levels. Vocal cord paralysis and hypoparathyroidism are considered permanent if they persist for >6 months. Fortunately, these complications are rare,


Surgery_Schwartz

Surgery_Schwartz. by elevated pre-operative alkaline phosphatase levels. Vocal cord paralysis and hypoparathyroidism are considered permanent if they persist for >6 months. Fortunately, these complications are rare, occurring in approximately 1% of patients undergoing surgery by experi-enced parathyroid surgeons.Patients with symptomatic hypocalcemia or those with calcium levels <8 mg/dL are treated with oral calcium supple-mentation (up to 1–2 g every 4 hours). 1,25-Dihydroxy vitamin D (calcitriol [Rocaltrol] 0.25–0.5 μg twice a day) may also be required, particularly in patients with severe hypercalcemia and elevated serum alkaline phosphatase levels, preoperatively and with osteitis fibrosa cystica. Intravenous calcium supplementa-tion rarely is needed, except in cases of severe, symptomatic hypocalcemia.HypoparathyroidismHypocalcemia can be the result of a multitude of conditions, which are listed in Table 38-14. The parathyroid glands may be congenitally absent in DiGeorge syndrome, which also is


Surgery_Schwartz

Surgery_Schwartz. can be the result of a multitude of conditions, which are listed in Table 38-14. The parathyroid glands may be congenitally absent in DiGeorge syndrome, which also is characterized by lack of thymic development and, therefore, a thymus-dependent lymphoid system. By far, the most common cause of hypoparathyroidism is thyroid surgery, particularly total thyroidectomy with a concomitant central neck dissection. Patients often develop transient hypocalcemia due to ischemia of the parathyroid glands; permanent hypoparathyroidism is rare. Hypoparathyroidism also may occur after parathyroid surgery, which is more likely if patients undergo a subtotal resection or total parathyroidectomy with parathyroid autotransplantation.Acute hypocalcemia results in decreased ionized calcium and increased neuromuscular excitability. Patients initially develop circumoral and fingertip numbness and tingling. Mental symptoms include anxiety, confusion, and depression. Physical examination reveals positive


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Surgery_Schwartz. excitability. Patients initially develop circumoral and fingertip numbness and tingling. Mental symptoms include anxiety, confusion, and depression. Physical examination reveals positive Chvostek’s sign (contraction of facial muscles elicited by tapping on the facial nerve anterior to the ear) and Trousseau’s sign (carpopedal spasm that is elic-ited by occluding blood flow to the forearm with a blood pres-sure cuff for 2–3 minutes). Tetany, which is characterized by tonic-clonic seizures, carpopedal spasm, and laryngeal stridor, may prove fatal and should be avoided. Most patients with post-operative hypocalcemia can be treated with oral calcium and vitamin D supplements; IV calcium infusion is rarely required except in patients with preoperative osteitis fibrosa cystica.ADRENALHistorical BackgroundEustachius provided the first accurate anatomic account of the adrenals in 1563. The anatomic division of the adrenals into the cortex and medulla was described much later, by Cuvier in


Surgery_Schwartz

Surgery_Schwartz. BackgroundEustachius provided the first accurate anatomic account of the adrenals in 1563. The anatomic division of the adrenals into the cortex and medulla was described much later, by Cuvier in 1805. Subsequently, Thomas Addison in 1855 described the features of adrenal insufficiency, which still bear his name. DeCreccio provided the first description of congenital adrenal hyperplasia (CAH) occurring in a female pseudohermaphrodite in 1865. Pheochromocytomas were first identified by Frankel in 1885, but were not named as such until 1912 by Pick, who noted the characteristic chromaffin reaction of the tumor cells. Adren-aline was identified as an agent from the adrenal medulla that elevated blood pressure in dogs and was subsequently named epinephrine in 1897. The first successful adrenalectomies for pheochromocytoma were performed by Roux in Switzerland and Charles Mayo in the United States.In 1932, Harvey Cushing described 11 patients who had moon facies, truncal obesity,


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Surgery_Schwartz. adrenalectomies for pheochromocytoma were performed by Roux in Switzerland and Charles Mayo in the United States.In 1932, Harvey Cushing described 11 patients who had moon facies, truncal obesity, hypertension, and other features of the syndrome that now bears his name. Although several individuals prepared adrenocortical extracts to treat adrenalec-tomized animals, cortisone was first synthesized by Kendall. Aldosterone was identified in 1952, and the syndrome result-ing from excessive secretion of this mineralocorticoid was first described in 1955 by Conn.EmbryologyThe adrenal or suprarenal glands are two endocrine organs in one; an outer cortex and an inner medulla, each with distinct embryologic, anatomic, histologic, and secretory features. The cortex originates around the fifth week of gestation from mesodermal tissue near the gonads on the adrenogenital ridge (Fig. 38-37). Therefore, ectopic adrenocortical tissue may be found in the ovaries, spermatic cord, and testes. The


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Surgery_Schwartz. of gestation from mesodermal tissue near the gonads on the adrenogenital ridge (Fig. 38-37). Therefore, ectopic adrenocortical tissue may be found in the ovaries, spermatic cord, and testes. The cortex dif-ferentiates further into a thin, definitive cortex and a thicker, inner fetal cortex. The latter is functional and produces fetal adrenal steroids by the eighth week of gestation, but undergoes involution after birth, resulting in a decrease in adrenal weight during the first three postpartum months. The definitive cor-tex persists after birth to form the adult cortex over the first 3 years of life. In contrast, the adrenal medulla is ectodermal in origin and arises from the neural crest. At around the same time as cortical development, neural crest cells migrate to the para-aortic and paravertebral areas and toward the medial aspect of the developing cortex to form the medulla. Most extra-adrenal neural tissue regresses but may persist at several sites. The larg-est of these is


Surgery_Schwartz

Surgery_Schwartz. paravertebral areas and toward the medial aspect of the developing cortex to form the medulla. Most extra-adrenal neural tissue regresses but may persist at several sites. The larg-est of these is located to the left of the aortic bifurcation near the inferior mesenteric artery origin and is designated as the organ of Zuckerkandl. Adrenal medullary tissue also may be found in neck, urinary bladder, and para-aortic regions. Several Brunicardi_Ch38_p1625-p1704.indd 168101/03/19 11:22 AM 1682SPECIFIC CONSIDERATIONSPART IIfactors are involved in adrenal development and include insulin-like growth factor 2; gastric inhibitory peptide; and the dosagesensitive, sex-reversal adrenal hypoplasia (DAX1) gene.AnatomyThe adrenal glands are paired, retroperitoneal organs located superior and medial to the kidneys at the level of the elev-enth ribs. The normal adrenal gland measures 5 × 3 × 1 cm and weighs 4 to 5 g. The right gland is pyramidal shaped and lies in close proximity to the right


Surgery_Schwartz

Surgery_Schwartz. to the kidneys at the level of the elev-enth ribs. The normal adrenal gland measures 5 × 3 × 1 cm and weighs 4 to 5 g. The right gland is pyramidal shaped and lies in close proximity to the right hemidiaphragm, liver, and inferior vena cava (IVC). The left adrenal is closely associated with the aorta, spleen, and tail of the pancreas. Each gland is supplied by three groups of vessels—the superior adrenal arter-ies derived from the inferior phrenic artery, the middle adrenal arteries derived from the aorta, and the inferior adrenal arteries derived from the renal artery. Other vessels originating from the intercostal and gonadal vessels may also supply the adrenals. These arteries branch into about 50 arterioles to form a rich plexus beneath the glandular capsule and require careful dissec-tion, ligation, and division during adrenalectomy. In contrast to the arterial supply, each adrenal usually is drained by a single, major adrenal vein. The right adrenal vein is usually short and


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Surgery_Schwartz. ligation, and division during adrenalectomy. In contrast to the arterial supply, each adrenal usually is drained by a single, major adrenal vein. The right adrenal vein is usually short and drains into the IVC, whereas the left adrenal vein is longer and empties into the left renal vein after joining the inferior phrenic vein. Accessory veins occur in 5% to 10% of patients—on the right, these vessels may drain into the right hepatic vein or the right renal vein; on the left, accessory veins may drain directly into the left renal vein. The anatomic relationships of the adre-nals and surrounding structures are depicted in Fig. 38-38.The adrenal cortex appears yellow due to its high lipid content and accounts for about 80% to 90% of the gland’s vol-ume. Histologically, the cortex is divided into three zones—the zona glomerulosa, zona fasciculata, and zona reticularis. The outer area of the zona glomerulosa consists of small cells and is the site of production of the mineralocorticoid


Surgery_Schwartz

Surgery_Schwartz. into three zones—the zona glomerulosa, zona fasciculata, and zona reticularis. The outer area of the zona glomerulosa consists of small cells and is the site of production of the mineralocorticoid hormone, aldo-sterone. The zona fasciculata is made up of larger cells, which often appear foamy due to multiple lipid inclusions, whereas the zona reticularis cells are smaller. These latter zones are the site of production of glucocorticoids and adrenal androgens. The adrenal medulla constitutes up to 10% to 20% of the gland’s volume and is reddish-brown in color. It produces the catechol-amine hormones epinephrine and norepinephrine. The cells of the adrenal medulla are arranged in cords and are polyhedral in shape. They often are referred to as chromaffin cells because they stain specifically with chromium salts.Adrenal PhysiologyCholesterol, derived from the plasma or synthesized in the adre-nal, is the common precursor of all steroid hormones derived from the adrenal cortex.


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Surgery_Schwartz. with chromium salts.Adrenal PhysiologyCholesterol, derived from the plasma or synthesized in the adre-nal, is the common precursor of all steroid hormones derived from the adrenal cortex. Cholesterol initially is cleaved within mitochondria to 5-δ-pregnolone, which in turn is transported to the smooth endoplasmic reticulum where it forms the substrate for various biosynthetic pathways leading to steroidogenesis (Fig. 38-39).Mineralocorticoids. The major adrenal mineralocorticoid hormones are aldosterone, 11-deoxycorticosterone (DOC), and cortisol. Cortisol has minimal effects on the kidney due to hor-mone degradation. Aldosterone secretion is regulated primarily by the renin-angiotensin system. Decreased renal blood flow, decreased plasma sodium, and increased sympathetic tone all stimulate the release of renin from juxtaglomerular cells. Renin, in turn, leads to the production of angiotensin I from its pre-cursor angiotensinogen. Angiotensin I is cleaved by pulmo-nary


Surgery_Schwartz

Surgery_Schwartz. all stimulate the release of renin from juxtaglomerular cells. Renin, in turn, leads to the production of angiotensin I from its pre-cursor angiotensinogen. Angiotensin I is cleaved by pulmo-nary angiotensin-converting enzyme (ACE) to angiotensin II; the latter is not only a potent vasoconstrictor, but it also leads to increased aldosterone synthesis and release. Hyperkalemia is another potent stimulator of aldosterone synthesis, whereas ACTH, pituitary pro-opiomelanocortin, and antidiuretic hor-mone are weak stimulators.Aldosterone is secreted at a rate of 50 to 250 μg/d (depend-ing on sodium intake) and circulates in plasma chiefly as a complex with albumin. Small amounts of the hormone bind to corticosteroid-binding globulin, and approximately 30% to 50% of secreted aldosterone circulates in a free form. The hormone has a half-life of only 15 to 20 minutes and is rapidly cleared via the liver and kidney. A small quantity of free aldosterone also is excreted in the urine.


Surgery_Schwartz

Surgery_Schwartz. circulates in a free form. The hormone has a half-life of only 15 to 20 minutes and is rapidly cleared via the liver and kidney. A small quantity of free aldosterone also is excreted in the urine. Mineralocorticoids cross the cell membrane and bind to cytosolic receptors. The receptor-ligand complex subsequently is transported into the nucleus where it induces the transcription and translation of specific genes. Aldo-sterone functions mainly to increase sodium reabsorption and potassium and hydrogen ion excretion at the level of the renal distal convoluted tubule. Less commonly, aldosterone increases sodium absorption in salivary glands and GI mucosal surfaces.9123678CA45BFigure 38-37. Cross-section of the embryo depicting adrenal development: (1) neural tube, (2) chorda, (3) aorta, (4) base of the mesentery, (5) digestive tube, (6) adrenal cortex, (7) undifferenti-ated gonad, (8) mesonephros, and (9) neural crest. Cells migrate from the neural crest to form the ganglia of the


Surgery_Schwartz

Surgery_Schwartz. (4) base of the mesentery, (5) digestive tube, (6) adrenal cortex, (7) undifferenti-ated gonad, (8) mesonephros, and (9) neural crest. Cells migrate from the neural crest to form the ganglia of the sympathetic trunk (A), sympathetic plexi (B), and the adrenal medulla and paraganglia (C). (Reproduced with permission from Avisse C, Marcus C, Patey M, et al: Surgical anatomy and embryology of the adrenal glands, Surg Clin North Am. 2000 Feb;80(1):403-415.)Brunicardi_Ch38_p1625-p1704.indd 168201/03/19 11:22 AM 1683THYROID, PARATHYROID, AND ADRENALCHAPTER 38AbdominalaortaInferiorvena cavaLeft inferiorphrenica. and v.Right phrenic a.Celiac trunkSuperiormesenteric a.Left adrenal gland Right adrenal gland Left superior adrenal aa.Right superior adrenal aa.Inferior adrenal a.Renal a. and v.Left adrenal v.Inferior adrenal a.Rightadrenalv.Middleadrenala.Figure 38-38. Anatomy of the adrenals and surrounding structures. a. = artery; v. =


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Surgery_Schwartz. adrenal aa.Inferior adrenal a.Renal a. and v.Left adrenal v.Inferior adrenal a.Rightadrenalv.Middleadrenala.Figure 38-38. Anatomy of the adrenals and surrounding structures. a. = artery; v. = vein.Pregnenolone17˜-hydroxypregnenoloneAndrostenedioneDHEADHEASCortisolAldosteroneCholesterol12217˜-hydroxyprogesterone311-deoxycortisol42Progesterone311-deoxy-corticosterone4.5Corticosterone518-hydroxy-corticosterone567678Figure 38-39. Synthesis of adrenal steroids. The enzymes involved are (1) p450scc (cholesterol side chain cleavage), (2) 3β-hydroxysteroid dehydrogenase, (3) p450c21 (21β-hydroxylase), (4) p450c11 (11β-hydroxylase), (5) p450c11AS (aldosterone synthase), (6) p450c17 (17α-hydroxylase activity), (7) p450c17 (17,20-lyase/desmolase activity), and (8) sulfokinase. DHEAS = dehydroepiandrosterone sulfate.Glucocorticoids. The secretion of cortisol, the major adrenal glucocorticoid, is regulated by ACTH secreted by the anterior pituitary, which, in turn, is under the control of


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Surgery_Schwartz. sulfate.Glucocorticoids. The secretion of cortisol, the major adrenal glucocorticoid, is regulated by ACTH secreted by the anterior pituitary, which, in turn, is under the control of corticotrophin-releasing hormone (CRH) secreted by the hypothalamus. ACTH is a 39-amino-acid protein, which is derived by cleavage from a larger precursor, pro-opiomelanocortin. ACTH is further cleaved into α-melanocyte-stimulating hormone and corticotrophin-like intermediate peptide. ACTH not only stimulates the secretion of glucocorticoids, mineralocorticoids, and adrenal androgens, but is also trophic for the adrenal glands. ACTH secretion may be Brunicardi_Ch38_p1625-p1704.indd 168301/03/19 11:22 AM 1684SPECIFIC CONSIDERATIONSPART IIstimulated by pain, stress, hypoxia, hypothermia, trauma, and hypoglycemia. ACTH secretion fluctuates, peaking in the morn-ing and reaching nadir levels in the late afternoon. Thus, there is a diurnal variation in the secretion of cortisol, with peak cortisol excretion


Surgery_Schwartz

Surgery_Schwartz. ACTH secretion fluctuates, peaking in the morn-ing and reaching nadir levels in the late afternoon. Thus, there is a diurnal variation in the secretion of cortisol, with peak cortisol excretion also occurring in the early morning and declining dur-ing the day to its lowest levels in the evening (Fig. 38-40). Corti-sol controls the secretion of both CRH and ACTH via a negative feedback loop. A similar mechanism leads to the inhibition of CRH secretion by ACTH.Cortisol is transported in plasma bound primarily to corti-costeroid-binding globulin (75%) and albumin (15%). Approxi-mately 10% of circulating cortisol is free and is the biologically active component. The plasma half-life of cortisol is 60 to 90 minutes and is determined by the extent of binding and rate of inactivation. Cortisol is converted to diand tetrahydrocor-tisol and cortisone metabolites in the liver and the kidney. The majority (95%) of cortisol and cortisone metabolites are con-jugated with glucuronic acid in the


Surgery_Schwartz

Surgery_Schwartz. is converted to diand tetrahydrocor-tisol and cortisone metabolites in the liver and the kidney. The majority (95%) of cortisol and cortisone metabolites are con-jugated with glucuronic acid in the liver, thus facilitating their renal excretion. A small amount of unmetabolized cortisol is excreted unchanged in the urine.Glucocorticoid hormones enter the cell and bind cytosolic steroid receptors. The activated receptor-ligand complex is then transported to the nucleus where it stimulates the transcription of specific target genes via a “zinc finger” DNA binding ele-ment. Cortisol also binds the mineralocorticoid receptor with an affinity similar to aldosterone. However, the specificity of mineralocorticoid action is maintained by the production of 11β-hydroxysteroid dehydrogenase, an enzyme that inactivates cortisol to cortisone in the kidney. Glucocorticoids have impor-tant functions in intermediary metabolism but also affect con-nective tissue, bone, immune, cardiovascular, renal,


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Surgery_Schwartz. that inactivates cortisol to cortisone in the kidney. Glucocorticoids have impor-tant functions in intermediary metabolism but also affect con-nective tissue, bone, immune, cardiovascular, renal, and central nervous systems, as outlined in Table 38-15.Sex Steroids. Adrenal androgens are produced in the zona fasciculata and reticularis from 17-hydroxypregnenolone in response to ACTH stimulation. They include dehydroepiandros-terone (DHEA) and its sulfated counterpart (DHEAS), andro-stenedione, and small amounts of testosterone and estrogen. Adrenal androgens are weakly bound to plasma albumin. They exert their major effects by peripheral conversion to the more potent testosterone and dihydrotestosterone but also have weak intrinsic androgen activity. Androgen metabolites are conju-gated as glucuronides or sulfates and excreted in the urine. Dur-ing fetal development, adrenal androgens promote the formation of male genitalia. In normal adult males, the contribution of adrenal androgens


Surgery_Schwartz

Surgery_Schwartz. glucuronides or sulfates and excreted in the urine. Dur-ing fetal development, adrenal androgens promote the formation of male genitalia. In normal adult males, the contribution of adrenal androgens is minimal; however, they are responsible for the development of secondary sexual characteristics at puberty. Adrenal androgen excess leads to precocious puberty in boys and virilization, acne, and hirsutism in girls and women.Catecholamines. Catecholamine hormones (epinephrine, norepinephrine, and dopamine) are produced not only in the central and sympathetic nervous system but also the adrenal medulla. The substrate, tyrosine, is converted to catechol-amines via a series of steps shown in Fig. 38-41A. Phenyletha-nolamine N-methyltransferase, which converts norepinephrine to epinephrine, is only present in the adrenal medulla and the organ of Zuckerkandl. Therefore, the primary catecholamine produced may be used to distinguish adrenal medullary tumors from those situated at extra-adrenal


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Surgery_Schwartz. present in the adrenal medulla and the organ of Zuckerkandl. Therefore, the primary catecholamine produced may be used to distinguish adrenal medullary tumors from those situated at extra-adrenal sites. Catecholamines are stored in granules in combination with other neuropeptides, ATP, calcium, magnesium, and water-soluble proteins called chromogranins. Hormonal secretion is stimulated by various stress stimuli and mediated by the release of acetylcholine at the preganglionic nerve terminals. In the circulation, these pro-teins are bound to albumin and other proteins. Catecholamines are cleared by several mechanisms including reuptake by sym-pathetic nerve endings, peripheral inactivation by catechol O-methyltransferase and monoamine oxidase, and direct excre-tion by the kidneys. Metabolism of catecholamines takes place 2520151050Noon4 PM8 PMMidnight4 AM8 AMNoonLunchSnackSnackDinnerSleepB’fast200180160140120100806040200Plasma ACTH (pg/mL)Plasma 11-ohcs (µg/dL) Figure 38-40. Diurnal


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Surgery_Schwartz. of catecholamines takes place 2520151050Noon4 PM8 PMMidnight4 AM8 AMNoonLunchSnackSnackDinnerSleepB’fast200180160140120100806040200Plasma ACTH (pg/mL)Plasma 11-ohcs (µg/dL) Figure 38-40. Diurnal variation in cortisol levels as determined by half-hourly sampling in a 16-year-old girl. (Reproduced with permission from Krieger DT, Allen W, Rizzo F, et al: Characterization of the normal temporal pattern of plasma corticosteroid levels, J Clin Endocrinol Metab. 1971 Feb;32(2):266-284.)Brunicardi_Ch38_p1625-p1704.indd 168401/03/19 11:22 AM 1685THYROID, PARATHYROID, AND ADRENALCHAPTER 38Table 38-15Functions of glucocorticoid hormonesFUNCTION/SYSTEMEFFECTSGlucose metabolismIncreased hepatic glycogen deposition, gluconeogenesis, decreased muscle glucose uptake and metabolismProtein metabolismDecreased muscle protein synthesis, increased catabolismFat metabolismIncreased lipolysis in adipose tissueConnective tissueInhibition of fibroblasts, loss of collagen, thinning of skin, striae


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Surgery_Schwartz. muscle protein synthesis, increased catabolismFat metabolismIncreased lipolysis in adipose tissueConnective tissueInhibition of fibroblasts, loss of collagen, thinning of skin, striae formationSkeletal systemInhibition of bone formation, increased osteoclast activity, potentiate the action of PTHImmune systemIncreases circulation of polymorphonuclear cells; decreases numbers of lymphocytes, monocytes, and eosinophils; reduces migration of inflammatory cells to sites of injuryCardiovascular systemIncreases cardiac output and peripheral vascular toneRenal systemSodium retention, hypokalemia, hypertension via mineralocorticoid effect, increased glomerular filtration via glucocorticoid effectsEndocrine systemInhibits TSH synthesis and release, decreased TBG levels, decreased conversion of T4 to T3PTH = parathyroid hormone; T3 = 3,5’,3-triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone.primarily in the liver and kidneys and leads to the


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Surgery_Schwartz. to T3PTH = parathyroid hormone; T3 = 3,5’,3-triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone.primarily in the liver and kidneys and leads to the formation of metabolites such as metanephrines, normetanephrines, and VMA, which may undergo further glucuronidation or sulfation before being excreted in the urine (Fig. 38-41B).Adrenergic receptors are transmembrane-spanning mol-ecules that are coupled to G proteins. They may be subdivided into α and β subtypes, which are localized in different tissues, have varying affinity to various catecholamines, and mediate distinct biologic effects (Table 38-16). The receptor affinities for α receptors are—epinephrine > norepinephrine >> isopro-terenol; β1 receptors—isoproterenol > epinephrine = norepi-nephrine; and β2 receptors—isoproterenol > epinephrine >> norepinephrine.Disorders of the Adrenal CortexHyperaldosteronism. Hyperaldosteronism may be secondary to stimulation of the renin-angiotensin


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Surgery_Schwartz. and β2 receptors—isoproterenol > epinephrine >> norepinephrine.Disorders of the Adrenal CortexHyperaldosteronism. Hyperaldosteronism may be secondary to stimulation of the renin-angiotensin system from renal artery stenosis and to low-flow states such as congestive heart failure and cirrhosis. Hyperaldosteronism resulting from these condi-tions is reversible by treatment of the underlying cause. Primary hyperaldosteronism results from autonomous aldosterone secre-tion, which, in turn, leads to suppression of renin secretion. Pri-mary aldosteronism usually occurs in individuals between the ages of 30 to 50 years old and accounts for 1% of hypertension cases. It is associated with hypokalemia; however, more patients with Conn’s syndrome are being diagnosed with normal potas-sium levels. Most cases result from a solitary functioning adre-nal adenoma (∼70%) and idiopathic bilateral hyperplasia (30%). Adrenocortical carcinoma and glucocorticoid-suppressible hyperaldosteronism are rare,


Surgery_Schwartz

Surgery_Schwartz. cases result from a solitary functioning adre-nal adenoma (∼70%) and idiopathic bilateral hyperplasia (30%). Adrenocortical carcinoma and glucocorticoid-suppressible hyperaldosteronism are rare, each accounting for <1% of cases. Glucocorticoid-suppressible hyperaldosteronism is an auto-somal dominant form of hypertension in which aldosterone secretion is abnormally regulated by ACTH. This condition is caused by recombinations between linked genes encoding closely related isozymes, 11b-hydroxylase (CYP11B1), and aldosterone synthase (CYP11B2) generating a dysregulated chimeric gene with aldosterone synthase activity. This entity is now designated familial hyperaldosteronism type I (FH-I). Initially, FH-III referred to patients with massive adrenal hyper-plasia refractory to glucocorticoid administration. However, the term is now more commonly used to describe patients with pri-mary hyperaldosteronism due to germline KCNJ5 mutations. This gene encodes an inward rectifier potassium


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Surgery_Schwartz. administration. However, the term is now more commonly used to describe patients with pri-mary hyperaldosteronism due to germline KCNJ5 mutations. This gene encodes an inward rectifier potassium channel, and the mutations affected amino acids in or close to the chan-nel’s selectivity filter. Somatic gain of function mutations are found in up to 40% of aldosterone-producing adenomas (APA). Familial hyperaldosteronism type II refers to families in which two first-degree relatives have been diagnosed with primary hyperaldosteronism (adenoma or hyperplasia) and in whom types I and III have been excluded. Other genes mutated in (APA) include CACNA1D (encodes a voltage-gated L-type calcium channel), ATP1A1 (encodes part of the Na+-K+-ATPase), ATP2B3 (encodes the plasma membrane Ca2+ ATPase), CACNA1H (encodes the α1 subunit of the T-type voltage calcium channel), and CTNNB1 (β-catenin).97Symptoms and Signs Patients typically present with hyperten-sion, which is long-standing, moderate to


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Surgery_Schwartz. CACNA1H (encodes the α1 subunit of the T-type voltage calcium channel), and CTNNB1 (β-catenin).97Symptoms and Signs Patients typically present with hyperten-sion, which is long-standing, moderate to severe, and may be difficult to control despite multiple-drug therapy. Other symp-toms include muscle weakness, polydipsia, polyuria, nocturia, headaches, and fatigue. Weakness and fatigue are related to the presence of hypokalemia.Diagnostic Studies Laboratory Studies. Hypokalemia is a common finding, and hyperaldosteronism must be suspected in any hypertensive patient who presents with coexisting spontaneous hypokale-mia (K <3.2 mmol/L) or hypokalemia (<3 mmol/L) while on diuretic therapy, despite potassium replacements. However, it is important to note that up to 40% of patients with a confirmed aldosteronoma were normokalemic preoperatively. Once the diagnosis is suspected, further tests are necessary to confirm the diagnosis. Before testing, patients must receive adequate sodium and


Surgery_Schwartz

Surgery_Schwartz. aldosteronoma were normokalemic preoperatively. Once the diagnosis is suspected, further tests are necessary to confirm the diagnosis. Before testing, patients must receive adequate sodium and potassium. Antihypertensive medications should be held, if possible, and spironolactone, β-blockers, ACE inhibitors, and angiotensin II receptor blockers should be avoided. Patients with primary hyperaldosteronism have an ele-vated plasma aldosterone concentration level with a suppressed plasma renin activity; a plasma aldosterone concentrationto-plasma renin activity ratio of 1:25 to 30 is strongly sugges-tive of the diagnosis.98 False-positive results can occur, particularly in patients with chronic renal failure. Patients with primary hyperaldosteronism also fail to suppress aldosterone levels with sodium loading. This test can be performed by performing a 24-hour urine collection for cortisol, sodium, and aldosterone after 5 days of a high-sodium diet or alternatively giving the


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Surgery_Schwartz. levels with sodium loading. This test can be performed by performing a 24-hour urine collection for cortisol, sodium, and aldosterone after 5 days of a high-sodium diet or alternatively giving the Brunicardi_Ch38_p1625-p1704.indd 168501/03/19 11:22 AM 1686SPECIFIC CONSIDERATIONSPART IIFigure 38-41. A. Synthesis of catecholamines. B. Metabolism of catecholamine hormones.Tyrosine hydroxylaseL-amino acid decarboxylase Dopamine-beta-hydroxylasePhenylethanolamine-N-methyltransferaseATyrosineDopa(L-dihydroxyphenylalanine)DopamineNorepinephrineEpinephrineMAOMAOMAOMAODihydroxymandelicacid3-methoxy-4-hydroxymandelic acidCOMTCOMTCOMTEpinephrineNorepinephrineMetanephrineNormetanephrineMAO Monoamine oxidase COMT Catechol O-methyltransferaseBBrunicardi_Ch38_p1625-p1704.indd 168601/03/19 11:22 AM 1687THYROID, PARATHYROID, AND ADRENALCHAPTER 38Table 38-16Catecholamine hormone receptors and effects they mediateRECEPTORTISSUEFUNCTIONα1Blood vesselsContraction GutDecreased motility, increased


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Surgery_Schwartz. AM 1687THYROID, PARATHYROID, AND ADRENALCHAPTER 38Table 38-16Catecholamine hormone receptors and effects they mediateRECEPTORTISSUEFUNCTIONα1Blood vesselsContraction GutDecreased motility, increased sphincter tone PancreasDecreased insulin and glucagon release LiverGlycogenolysis, gluconeogenesis EyesPupil dilation UterusContraction SkinSweatingα2Synapse (sympathetic)Inhibits norepinephrine release PlateletAggregationβ1HeartChronotropic, inotropic Adipose tissueLipolysis GutDecreased motility, increased sphincter tone PancreasIncreased insulin and glucagon releaseβ2Blood vesselsVasodilation BronchiolesDilation UterusRelaxationpatient 2 L of saline while in the supine position, 2 to 3 days after being on a low-sodium diet. Plasma aldosterone level <5 ng/dL or a 24-hour urine aldosterone <14 μg after saline loading essentially rules out primary hyperaldosteronism. Once the biochemical diagnosis is confirmed, further evaluation should be directed at determining which patients have a


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Surgery_Schwartz. <14 μg after saline loading essentially rules out primary hyperaldosteronism. Once the biochemical diagnosis is confirmed, further evaluation should be directed at determining which patients have a unilat-eral aldosteronoma vs. bilateral hyperplasia because surgery is almost always curative for the former, but usually not the latter. No biochemical studies can make this distinction with 100% sensitivity; thus, imaging studies are necessary.Radiologic Studies. CT scans with 0.5-cm cuts in the adrenal area can localize aldosteronomas with a sensitivity of 90%. A unilateral 0.5to 2-cm adrenal tumor with a normal-appearing contralateral gland confirms an aldosteronoma in the presence of appropriate biochemical parameters. MRI scans are less sen-sitive but more specific, particularly if opposed phase chemi-cal shift images are obtained. MRI scans also have increased use in pregnant patients or those unable to tolerate intravenous contrast. If adrenal hyperplasia is suspected, the algorithm


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Surgery_Schwartz. phase chemi-cal shift images are obtained. MRI scans also have increased use in pregnant patients or those unable to tolerate intravenous contrast. If adrenal hyperplasia is suspected, the algorithm depicted in Fig. 38-42 is useful. Selective venous catheteriza-tion and adrenal vein sampling (AVS) for aldosterone have been demonstrated to be 95% sensitive and 90% specific in localiz-ing the aldosteronoma. In this procedure, the adrenal veins are cannulated, and blood samples for aldosterone and cortisol are obtained from both adrenal veins and the vena cava after ACTH administration.99 Measurement of cortisol levels is necessary to confirm proper placement of the catheters in the adrenal veins. A greater than fourfold difference in the aldosterone-to-cortisol ratios between the adrenal veins indicates the presence of a uni-lateral tumor. Some investigators use this study routinely, but it is invasive, requires an experienced interventional radiolo-gist, and can lead to adrenal vein


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Surgery_Schwartz. veins indicates the presence of a uni-lateral tumor. Some investigators use this study routinely, but it is invasive, requires an experienced interventional radiolo-gist, and can lead to adrenal vein rupture in approximately 1% of cases. Therefore, most groups advocate use of this modal-ity selectively in ambiguous cases, when the tumor cannot be localized and in patients with bilateral adrenal enlargement to determine whether there is unilateral or bilateral increased secretion of aldosterone.100 Additional indications for forgoing AVS include patients who are suspected of having adrenocor-tical carcinoma, those with comorbid conditions precluding surgery and those with proven familial hyperaldosteronism type I or III. Scintigraphy with 131I-6β-iodomethyl noriodocho-lesterol (NP-59) also may be used for the same purpose. Like cholesterol, this compound is taken up by the adrenal cortex, but unlike cholesterol, it remains in the gland without undergo-ing further metabolism. Adrenal


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Surgery_Schwartz. may be used for the same purpose. Like cholesterol, this compound is taken up by the adrenal cortex, but unlike cholesterol, it remains in the gland without undergo-ing further metabolism. Adrenal adenomas appear as “hot” nod-ules with suppressed contralateral uptake, whereas hyperplastic glands show bilaterally increased uptake. This test, however, is not widely available. Newer isotopes such as 11C-metomidate in conjunction with PET-CT have also shown promise in the localization of aldosteronomas.101AdrenalectomyBilateral hyperfunctionor failure to localizeMedical managementAdrenalectomyUnilateralincreased aldosteroneCT scan or MRIUnilateral adrenal tumorusually 0.5 2 cmin diameterBilaterallyabnormal or normaladrenals1) Selective venous catheterization for aldosterone and cortisol or2) NP-59 scanFigure 38-42. Management of an adrenal aldosteronoma. CT = computed tomography; MRI = magnetic resonance imaging.Brunicardi_Ch38_p1625-p1704.indd 168701/03/19 11:22 AM


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Surgery_Schwartz. cortisol or2) NP-59 scanFigure 38-42. Management of an adrenal aldosteronoma. CT = computed tomography; MRI = magnetic resonance imaging.Brunicardi_Ch38_p1625-p1704.indd 168701/03/19 11:22 AM 1688SPECIFIC CONSIDERATIONSPART IIFigure 38-43. Some characteristic features of Cushing’s syndrome—moon facies, hirsutism, and acne.Table 38-17Etiology of Cushing’s syndromeACTH-dependent (70%) • Pituitary adenoma or Cushing’s disease (∼70%) • Ectopic ACTH productiona (∼10%) • Ectopic CRH production (<1%)ACTH-independent (20–30%) • Adrenal adenoma (10–15%) • Adrenal carcinoma (5–10%) • Adrenal hyperplasia—pigmented micronodular cortical hyperplasia or gastric inhibitory peptide-sensitive macronodular hyperplasia (5%)Other • Pseudo-Cushing’s syndrome • Iatrogenic—exogenous administration of steroidsaFrom small cell lung tumors, pancreatic islet cell tumors, medullary thyroid cancers, pheochromocytomas, and carcinoid tumors of the lung, thymus, gut, pancreas, and ovary.ACTH =


Surgery_Schwartz

Surgery_Schwartz. of steroidsaFrom small cell lung tumors, pancreatic islet cell tumors, medullary thyroid cancers, pheochromocytomas, and carcinoid tumors of the lung, thymus, gut, pancreas, and ovary.ACTH = adrenocorticotropic hormone; CRH = corticotrophin-releasing hormone.Treatment Preoperatively, control of hypertension and ade-quate potassium supplementation (to keep K >3.5 mmol/L) are important. Patients generally are treated with spironolactone (an aldosterone antagonist), amiloride (a potassium-sparing diuretic that blocks sodium channels in the distal nephron), nifedipine (a calcium channel blocker), or captopril (an ACE inhibitor). Unilateral tumors producing aldosterone are best managed by adrenalectomy, either by a laparoscopic approach (preferred) or via a posterior open approach. If a carcinoma is suspected because of the large size of the adrenal lesion or mixed hormone secretion, an anterior transabdominal approach is preferred to permit adequate determination of local invasion and


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Surgery_Schwartz. is suspected because of the large size of the adrenal lesion or mixed hormone secretion, an anterior transabdominal approach is preferred to permit adequate determination of local invasion and distal metastases. Only 20% to 30% of patients with hyperaldosteron-ism secondary to bilateral adrenal hyperplasia benefit from sur-gery, and as described, selective venous catheterization is useful to predict which patients will respond. For the other patients, medical therapy with spironolactone, amiloride, or triamterene is the mainstay of management. Glucocorticoid-suppressible hyperaldosteronism is treated by administering exogenous dexa-methasone at doses of 0.5 to 1 mg daily. Treatment with spirono-lactone may help decrease glucocorticoid requirements in this condition and avoid symptoms of Cushing’s syndrome. Postop-eratively, some patients experience transient hypoaldosteronism requiring mineralocorticoids for up to 3 months. Recent studies suggest that postresection hyperkalemia may be


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Surgery_Schwartz. syndrome. Postop-eratively, some patients experience transient hypoaldosteronism requiring mineralocorticoids for up to 3 months. Recent studies suggest that postresection hyperkalemia may be more common and last longer than previously appreciated; therefore, it should be screened for in patients who are older and who have had a longer duration of hypertension, impaired kidney function, and higher preoperative aldosterone levels, making them a high-risk group.102 Rarely, acute Addison’s disease may occur 2 to 3 days after adrenalectomy. Adrenalectomy is >90% successful in improving hypokalemia and about 70% successful in cor-recting hypertension. Patients who respond to spironolactone therapy and those with a shorter duration of hypertension with minimal renal damage are more likely to achieve improvement in hypertension, whereas male patients, those >50 years old, and those with multiple adrenal nodules, are least likely to benefit from adrenalectomy.Cushing’s Syndrome. Cushing


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Surgery_Schwartz. to achieve improvement in hypertension, whereas male patients, those >50 years old, and those with multiple adrenal nodules, are least likely to benefit from adrenalectomy.Cushing’s Syndrome. Cushing described patients with a pecu-liar fat deposition, amenorrhea, impotence (in men), hirsutism, purple striae, hypertension, diabetes, and other features that con-stitute the syndrome (Fig. 38-43). He also recognized that sev-eral of these patients had basophilic tumors of the pituitary gland and concluded that these tumors produced hormones that caused adrenocortical hyperplasia, thus resulting in the manifestations of the syndrome. Today, the term Cushing’s syndrome refers to a complex of symptoms and signs resulting from hypersecretion of cortisol regardless of etiology. In contrast, Cushing’s disease refers to a pituitary tumor, usually an adenoma, which leads to bilateral adrenal hyperplasia and hypercortisolism. Cushing’s syndrome (endogenous) is a rare disease, affecting 10 in 1


Surgery_Schwartz

Surgery_Schwartz. disease refers to a pituitary tumor, usually an adenoma, which leads to bilateral adrenal hyperplasia and hypercortisolism. Cushing’s syndrome (endogenous) is a rare disease, affecting 10 in 1 mil-lion individuals. It is more common in adults but may occur in children. Women are more commonly affected (male-to-female ratio is 1:8). Although most individuals have sporadic disease, Cushing’s syndrome may be found in MEN1 families and can result from ACTH-secreting pituitary tumors, primary adre-nal neoplasms, or an ectopic ACTH-secreting carcinoid tumor (more common in men) or bronchial adenoma (more common in women).Cushing’s syndrome may be classified as ACTH-dependent or ACTH-independent (Table 38-17). The most common cause of hypercortisolism is exogenous administration of steroids. However, approximately 70% of cases of endogenous Cush-ing’s syndrome are caused by an ACTH-producing pituitary tumor. Primary adrenal sources (adenoma, hyperplasia, and Brunicardi_Ch38_p1625-p1704.indd


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Surgery_Schwartz. approximately 70% of cases of endogenous Cush-ing’s syndrome are caused by an ACTH-producing pituitary tumor. Primary adrenal sources (adenoma, hyperplasia, and Brunicardi_Ch38_p1625-p1704.indd 168801/03/19 11:22 AM 1689THYROID, PARATHYROID, AND ADRENALCHAPTER 38Table 38-18Features of Cushing’s syndromeSYSTEMMANIFESTATIONGeneralWeight gain—central obesity, buffalo hump, supraclavicular fat padsIntegumentaryHirsutism, plethora, purple striae, acne, ecchymosisCardiovascularHypertensionMusculoskeletalGeneralized weakness, osteopeniaNeuropsychiatricEmotional lability, psychosis, depressionMetabolicDiabetes or glucose intolerance, hyperlipidemiaRenalPolyuria, renal stonesGonadalImpotence, decreased libido, menstrual irregularitiescarcinoma) account for about 20% of cases, and ectopic ACTH-secreting tumors account for <10% of cases. CRH also may be secreted ectopically in bronchial carcinoid tumors, pheochro-mocytomas, and other tumors. These patients are difficult to distinguish from


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Surgery_Schwartz. tumors account for <10% of cases. CRH also may be secreted ectopically in bronchial carcinoid tumors, pheochro-mocytomas, and other tumors. These patients are difficult to distinguish from those with ectopic ACTH production, but can be diagnosed by determining CRH levels. Patients with major depression, alcoholism, pregnancy, chronic renal failure, or stress also may have elevated cortisol levels and symptoms of hypercortisolism. However, these manifestations resolve with treatment of the underlying disorder, and these patients are deemed to have pseudo-Cushing’s syndrome.Primary adrenal hyperplasia may be micronodular, mac-ronodular, or massively macronodular. Adrenal hyperplasia resulting from ACTH stimulation usually is macronodular (3-cm nodules). Primary pigmented nodular adrenocortical disease is a rare cause of ACTH-independent Cushing’s syndrome, which is characterized by the presence of small (<5 mm), black adrenal nodules. Primary pigmented nodular adrenocortical disease may


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Surgery_Schwartz. disease is a rare cause of ACTH-independent Cushing’s syndrome, which is characterized by the presence of small (<5 mm), black adrenal nodules. Primary pigmented nodular adrenocortical disease may be associated with Carney complex (atrial myxomas, schwanno-mas, and pigmented nevi) and is thought to be immune related.Symptoms and Signs The classical features of Cushing’s syn-drome are listed in Table 38-18. Early diagnosis of this disease requires a thorough knowledge of these manifestations, coupled with a high clinical suspicion. In some patients, symptoms are less pronounced and may be more difficult to recognize, par-ticularly given their diversity and the absence of a single defin-ing symptom or sign. Progressive truncal obesity is the most common symptom, occurring in up to 95% of patients. This pattern results from the lipogenic action of excessive corti-costeroids centrally and catabolic effects peripherally, along with peripheral muscle wasting. Fat deposition also occurs in


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Surgery_Schwartz. This pattern results from the lipogenic action of excessive corti-costeroids centrally and catabolic effects peripherally, along with peripheral muscle wasting. Fat deposition also occurs in unusual sites, such as the supraclavicular space and posterior neck region, leading to the so-called buffalo hump. Purple striae are often visible on the protuberant abdomen. Rounding of the face leads to moon facies, and thinning of subcutaneous tis-sues leads to plethora. There is an increase in fine hair growth on the face, upper back, and arms, although true virilization is more commonly seen with adrenocortical cancers. Endocrine abnormalities include glucose intolerance, amenorrhea, and decreased libido or impotence. In children, Cushing’s syndrome is characterized by obesity and stunted growth. Patients with Cushing’s disease also may present with headaches, visual field defects, and panhypopituitarism. Hyperpigmentation of the skin, if present, suggests an ectopic ACTH-producing tumor with


Surgery_Schwartz

Surgery_Schwartz. Patients with Cushing’s disease also may present with headaches, visual field defects, and panhypopituitarism. Hyperpigmentation of the skin, if present, suggests an ectopic ACTH-producing tumor with high levels of circulating ACTH.Diagnostic Tests The aims of diagnostic tests in the evalua-tion of patients suspected of having Cushing’s syndrome are twofold: to confirm the presence of Cushing’s syndrome and to determine its etiology (Fig. 38-44).Laboratory Studies. Cushing’s syndrome is characterized by elevated glucocorticoid levels that are not suppressible by exog-enous hormone administration and loss of diurnal variation. This phenomenon is used to screen patients using the overnight low-dose dexamethasone suppression test. In this test, 1 mg of a synthetic glucocorticoid (dexamethasone) is given at 11 p.m. and plasma cortisol levels are measured at 8 a.m. the following morning. Physiologically normal adults suppress cortisol levels to <3 μg/dL, whereas most patients with


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Surgery_Schwartz. is given at 11 p.m. and plasma cortisol levels are measured at 8 a.m. the following morning. Physiologically normal adults suppress cortisol levels to <3 μg/dL, whereas most patients with Cushing’s syndrome do not. False-negative results may be obtained in patients with mild disease; therefore, some authors consider the test positive only if cortisol levels are suppressed to <1.8 μg/dL. False-positive results can occur in up to 3% of patients with chronic renal fail-ure, depression, or those taking medications such as phenytoin, which enhance dexamethasone metabolism. In patients with a negative test but a high clinical suspicion, the classic low-dose dexamethasone (0.5 mg every 6 hours for eight doses, or 2 mg over 48 hours) suppression test or urinary cortisol measurement should be performed. Measurement of elevated 24-hour urinary cortisol levels is a very sensitive (95–100%) and specific (98%) modality of diagnosing Cushing’s syndrome and is particularly useful for identifying


Surgery_Schwartz

Surgery_Schwartz. Measurement of elevated 24-hour urinary cortisol levels is a very sensitive (95–100%) and specific (98%) modality of diagnosing Cushing’s syndrome and is particularly useful for identifying patients with pseudo-Cushing’s syn-drome. A urinary cortisol-free excretion of less than 100 μg/dL (in most laboratories) rules out hypercortisolism. Recently, salivary cortisol measurements using commercially available kits also have demonstrated superior sensitivity in diagnosing Cushing’s syndrome and are being increasingly used. Overall, 24-hour urinary tests for free cortisol and the overnight dexa-methasone suppression test at the 5 μg/dL cutoff have the high-est specificity for the diagnosis of Cushing’s syndrome.103Once a diagnosis of hypercortisolism is established, further testing is aimed at determining whether it is ACTH-dependent or ACTH-independent Cushing’s syndrome. This is best accom-plished by measurement of plasma ACTH levels (normal 10–100 pg/mL). Elevated ACTH levels are found


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Surgery_Schwartz. determining whether it is ACTH-dependent or ACTH-independent Cushing’s syndrome. This is best accom-plished by measurement of plasma ACTH levels (normal 10–100 pg/mL). Elevated ACTH levels are found in patients with adrenal hyperplasia due to Cushing’s disease (15–500 pg/mL) and those with CRH-secreting tumors, but the highest levels are found in patients with ectopic sources of ACTH (>1000 pg/mL). In con-trast, ACTH levels are characteristically suppressed (<5 pg/mL) in patients with primary cortisol-secreting adrenal tumors. The high-dose dexamethasone suppression test is used to distinguish between the causes of ACTH-dependent Cushing’s syndrome (pituitary vs. ectopic). The standard test (2 mg dexamethasone every 6 hours for 2 days) or the overnight test (8 mg) may be used, with 24-hour urine collections for cortisol and 17-hydroxy steroids performed over the second day. Failure to suppress urinary cortisol by 50% confirms the diagnosis of an ectopic ACTH-producing tumor. Patients