The parathyroid glands participate in the regulation

41 HERNAN I. VARGAS STANLEY R. KLEIN The parathyroid glands participate in the regulation of calcium metabolism. Disorders of the parathyroid gland are most commonly a result of hyperfunction and rarely hypofunction. In the past, hyperparathyroidism was characterized by abdominal pain, kidney stones, and bone pain. Currently, most patients are diagnosed before the development of symptoms because of improved biochemical techniques for detection of hypercalcemia. Hypofunction of the parathyroid glands is primarily iatrogenic, as a complication of thyroid or parathyroid surgery, and only rarely of congenital origin. CASE 1 ASYMPTOMATIC A 42-year-old female patient was seen for elective cholecystectomy. A calcium level obtained the day of admission was elevated. She denied any history of malignancy, weight loss, bone pain, renal stones, ulcers, or pancreatitis. Her calcium level was 12.8 mg/dl and serum phosphorus level 2.8 mg/dl. A 24-hour urinary collection for calcium was 280 mg/24 hr. A serum PTH level was elevated at 600 pg/ml. The patient underwent a neck exploration and removal of a left superior parathyroid adenoma, with frozen section confirmation of a normal left inferior parathyroid gland. CASE 2 SYMPTOMATIC A 60-year-old female presented with a second episode of back pain, hematuria, and passage of a renal stone. She again became asymptomatic with a calcium level of 13.6 mg/dl. She had an episode of pancreatitis 5 years previous attributed to cholelithiasis. She also admitted a history of peptic ulcer, treated with H 2 blockers. In addition to the calcium elevation, her serum phosphorus was 3.1 mg/dl and a 24-hour urinary calcium excretion was 300 mg/24 hr. The PTH level was 550 pg/dl. A chest x-ray showed diffuse osteopenia. The patient underwent neck exploration with findings of four diffusely enlarged parathyroid glands. All four glands were removed and one gland was minced. Onehalf of the tissue was placed into the muscles of the forearm through a small incision, and the remaining tissue was preserved. 295

2 9 6 E N D O C R I N E S Y S T E M GENERAL CONSIDERATIONS Hyperparathyroidism is a metabolic disorder characterized by increased production of parathormone (PTH). It is the most common cause of hypercalcemia in nonhospitalized patients; however, patients with hyperparathyroidism may have low, normal, or high serum calcium levels, mostly depending on renal function. It occurs in 1 of 1,200 adults, more commonly in women. The most common cause is a parathyroid adenoma (Case 1) (Fig. 41.1). It accounts for approximately 85% of cases. It is a benign, encapsulated neoplasm involving only one parathyroid gland. The tumor is composed of closely packed cells, predominantly chief cells. The diagnosis is safely confirmed when normal or suppressed parathyroid tissue is seen in a second gland (Case 1) or in a remnant of normal tissue in the diseased gland. Primary parathyroid hyperplasia is the cause of hyperparathyroidism in approximately 12% of patients (Case 2). It consists of proliferation of parathyroid cells in the absence of a known stimulus for PTH hypersecretion. Typically, all parathyroid glands are enlarged; however, there may be a significant difference among the glands due to variation in the extent of enlargement. On light microscopy there is an increased parenchymal cell mass with predominance of chief cells or clear cells. Stromal fat cells are markedly decreased. Of particular interest is the association of chief cell hyperplasia and multiple endocrine neoplasia (MEN) syndromes. The different components of the MEN syndrome and subtypes are noted in Table 41.1. Rarely, a parathyroid carcinoma is responsible for hyperparathyroidism. Characteristically, patients have higher calcium levels than patients with adenoma or hyperplasia, and most patients have metabolic alterations. On physical examination a palpable nodule in the neck may be noted. The parathyroid gland is markedly enlarged, ill-defined, and densely adherent to the surrounding tissues. Microscopically, vascular and capsular invasion may be seen. In patients with chronic renal failure or malabsorption syndromes there is an increase in secretion of PTH as a consequence of chronically low serum calcium levels. This is called secondary hyperparathyroidism. Patients develop bone pain or pathologic fractures that are secondary to bone resorption, decalcification, cysts, and brown tumor formation. In renal failure patients this is complicated by hyperphosphatemia and the inability to hydroxylate vitamin D 2. B A FIGURE 41.1 (A) The normal parathyroid glands are in close proximity to the thyroid gland. (B) A parathyroid adenoma will lead to feedback inhibition and atrophy of the normal glands.

H Y P E R P A R A T H Y R O I D I S M 2 9 7 TABLE 41.1 Multiple endocrine neoplasia (MEN) syndromes MEN I (Werner) Pituitary adenoma Pancreatic islet cell tumors MEN IIA Medullary thyroid carcinoma Pheochromocytoma MEN IIB Medullary thyroid carcinoma Pheochromocytoma Ganglioneuromatosis Marfanoid habitus In some patients with secondary hyperparathyroidism the parathyroid glands function autonomously and patients develop hypercalcemia, paralleling rising levels of PTH. This is called tertiary hyperparathyroidism. Some patients with secondary hyperparathyroidism develop tertiary hyperparathyroidism; parathyroid glands function autonomously and patients develop hypercalcemia, paralleling rising PTH levels DIAGNOSIS The classic description of a patient with painful bones, renal stones, abdominal groans, and psychic moans is infrequently seen nowadays. Clinical manifestations related to hypercalcemia are listed in Table 41.2, and include peptic ulcer disease, kidney stones, and pancreatitis (Case 2). Demineralization of the skeleton, pathologic fractures, bone cysts, and brown tumors are a direct consequence of elevated PTH. TABLE 41.2 Symptoms and complications of hypercalcemia Peptic ulcer, pancreatitis, anorexia Muscle weakness Inability to concentrate, depression, delirium, coma Polyuria, polydipsia Renal stones, nephrocalcinosis With the advent of the blood biochemical analyzers, the measurement of calcium levels has become part of routine evaluation and over 50% of patients are identified by an elevated calcium level while they are asymptomatic (Case 1). The triad of hypercalcemia, hypercalciuria, and hypophosphatemia is suggestive of primary hyperparathyroidism. If these findings are coupled with an elevated PTH level, the biochemical diagnosis of primary hyperparathyroidism is very accurate, particularly since the introduction of the immunochemiluminiscence methodology for measurement of the intact hormone (Case 1). Triad of hypercalcemia, hypercalciuria, and hypophosphatemia is suggestive of primary hyperparathyroidism DIFFERENTIAL DIAGNOSIS Causes of hypercalcemia are noted in Table 41.3. A careful history may reveal vitamin D or thiazide diuretic intake. A thorough physical examination may disclose a breast, abdominal, or prostatic mass responsible for hypercalcemia as a consequence of a paraneoplastic syndrome (usually due to ectopic production of PTH). Evaluation should include a chest x-ray as a survey for lung cancer or pulmonary metastases with the added benefit of an assessment of bone density (Case 2). A mammogram or a bone scan may be necessary if malignancy is strongly suspected, often on the basis of a depressed PTH level or associated hyperphosphatemia. TABLE 41.3 Differential diagnosis of hypercalcemia Primary hyperparathyroidism Humoral hypercalcemia of malignancy Multiple myeloma Metastatic bone disease Sarcoidosis Thyrotoxicosis Thiazide diuretics Vitamin D toxicity Familial hypocalciuric hypercalcemia Prolonged immobilization Careful history may reveal vitamin D or thiazide diuretic intake Thorough physical examination may disclose breast, abdominal, or prostatic mass responsible for hypercalcemia as conse-

2 9 8 E N D O C R I N E S Y S T E M quence of paraneoplastic syndrome (usually due to ectopic production of PTH) Evaluation should include chest x-ray as survey for lung cancer or pulmonary metastases with added benefit of assessment of bone density Mammogram or bone scan may be necessary if malignancy is strongly suspected, often on basis of depressed PTH level or associated hyperphosphatemia TREATMENT Classically, hyperparathyroidism has been treated by excision of the adenoma. The goal is to remove the hyperfunctioning parathyroid gland or glands with preservation of sufficient parathyroid tissue to maintain normal calcium homeostasis. The decision to operate is more difficult in asymptomatic patients (Case 1). Approximately 30 50% of asymptomatic patients will progress to develop a metabolic complication. Neck exploration is recommended for those who develop increasing hypercalcemia, evidence of loss of bone mass, or for those patients with impairment of renal function. At operation, the parathyroid glands are carefully examined and frozen sections are obtained as needed for confirmation of the clinical diagnosis (Case 1). A diagnosis of parathyroid adenoma is made if only one parathyroid gland is enlarged and the rest of the glands are normal or small. All parathyroid glands are enlarged in hyperplasia. On occasion, a minimally enlarged gland may be confused on gross examination with a normal gland. Hyperplasia is confirmed by hypercellularity in more than one gland on frozen section. Three and one-half glands are removed, leaving the equivalent of one normal gland as a functioning organ. Due to the chance of recurrent hyperparathyroidism from the remnant gland, some advocate total parathyroidectomy with autologous transplantation into the forearm in cases of parathyroid hyperplasia (Case 2). If recurrent hyperparathyroidism develops, re-excision of the extra parathyroid tissue is carried out under local anesthesia, avoiding the hazards of re-exploration of the neck. When the diagnosis of parathyroid carcinoma is made, wide excision with clear margins including the ipsilateral thyroid lobe and frequently the ipsilateral recurrent laryngeal nerve is necessary. The tumor must not be violated or recurrence in the soft tissues of the neck is likely. Many modalities are available for preoperative localization of the enlarged parathyroid glands; none are uniformly successful. These are listed in Table 41.4. When primary exploration of the neck is being performed by an experienced surgeon, these localizing techniques are not necessary. Radiologic studies are valuable and cost-effective in the patient with recurrent hyperparathyroidism or TABLE 41.4 Accuracy of localization studies in a patient in whom the diseased parathyroid gland was not identified on the first neck exploration. A parathyroid gland may be localized in the mediastinum and it may be the cause of failure of the neck exploration. Ectopic parathyroid glands may also be located in the carotid sheath or retropharyngeal space, or may even be intrathyroidal. Ectopic location is the result of embryologic migration. Autopsy studies have revealed four parathyroid glands in only 80% of patients. Thirteen percent of patients have five glands and 3% of patients have only three glands. This may cause difficulty at the time of surgery for obvious reasons. Postoperatively, bleeding and hematoma formation can be hazardous due to compression of the airway; meticulous attention to hemostasis is critical. Damage to the recurrent laryngeal nerve occurs in approximately 1 2% of cases. Hypoparathyroidism can occur but is usually transient unless all four parathyroid glands have been removed or devascularized. It is chronically treated with oral calcium and vitamin D 3. Classically, hyperparathyroidism has been treated by excision of adenoma; goal is to remove hyperfunctioning parathyroid gland or glands with preservation of sufficient parathyroid tissue to maintain normal calcium homeostasis FOLLOW-UP SENSITIVITY (%) FALSE-POSITIVE RATE (%) Noninvasive techniques Barium swallow Historical interest Ultrasound 75 20 Differential thallium technitium scan 74 25 Computed tomography 70 30 Magnetic resonance imaging 80 20 Invasive techniques Aspiration biopsy 80 0 Arteriography 85 5 Venous sampling 80 0 Intraoperative ultrasound 80 2 Patients with parathyroid adenoma have the best prognosis. Postoperatively, the calcium level decreases and normalizes over the course of hours or days. Transient (hours to days) hypocalcemia is common as the remaining glands have

H Y P E R P A R A T H Y R O I D I S M 2 9 9 been chronically suppressed. Patients with parathyroid hyperplasia are more likely to experience recurrent hypercalcemia and long-term follow-up is therefore recommended. If hypercalcemia persists or recurs postoperatively, a thorough assessment should question the previous diagnosis of primary hyperparathyroidism. Review of the operative report and pathology specimen may help clarify an erroneous diagnosis of hyperplasia versus adenoma. Persistent hypercalcemia is defined as an elevated calcium level within 6 months of surgery. It is most commonly due to a missed adenoma. A localization study is indicated to help direct the reoperation to the most likely location of the gland. If recurrent hypercalcemia develops 6 months after surgery, it is called recurrent hypercalcemia and usually indicates hyperplasia. SUGGESTED READINGS Clark OH: Surgical treatment of primary hyperparathyroidism. Adv Endocrinol Metab 6:1, 1995 A nice review of surgical management. Kaye TB: Hypercalcemia. How to pinpoint the cause and customize treatment. Postgrad Med 97:153, 1995 A straightforward approach to diagnosis. Kaplan EL, Yashiro T, Salti G: Primary hyperparathyroidism in the 1990s. Ann Surg 215:300, 1992 Current views on the diagnosis and management of hyperparathdroidism. Cope O: The story of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 274:1174, 1966 Historical perspective on parathyroid disease, including the natural history of untreated hyperparathyroidism. QUESTIONS 1. The following are complications of hypercalcemia, except for? A. Renal stones. B. Gallstones. C. Pancreatitis. D. Inability to concentrate, depression, delirium, coma. 2. The following are causes of hypercalcemia, except for? A. Hyperparathyroidism. B. Cancer metastatic to bone. C. Use of thiazide diuretics or vitamin D toxicity. D. Prolonged immobilization. E. Renal failure. 3. Which of the following laboratory examinations is characteristic of primary hyperparathyroidism? A. Elevated serum calcium. B. Low serum phosphate. C. Elevated PTH. D. Chloride/phosphate ratio greater than 33. E. All of the above. 4. Which of the following statements is false regarding hyperparathyroidism? A. The most common cause is a parathyroid adenoma. B. is seen in patients with renal failure or MEN syndrome. C. Parathyroid carcinoma is a common cause of hyperparathyroidism. D. Removal of the abnormal parathyroid tissue is the treatment of choice. (See p. 604 for anspwers.)