57 HYPERPARATHYROIDISM
Robert C. McIntyre Jr., M.D.

1. What is the prevalence of hyperparathyroidism (HPT)?

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There are approximately 100,000 new cases of HPT annually in the United States. Primary HPT occurs in 1 in 500 women and in 1 in 2000 men older than 40 years. Approximately 10% of patients with primary HPT are referred for surgery.

2. What are the symptoms of hyperparathyroidism?

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“Painful bones, renal stones, abdominal groans, and psychic moans.” The three most common symptoms are fatigue, depression, and constipation. The classic symptoms and signs are:

* Bones: arthralgia, osteoporosis, pathologic fractures
* Stones: renal stones, renal insufficiency, polyuria, polydipsia
* Abdominal groans: pancreatitis, peptic ulcer disease, constipation
* Psychic moans: fatigue, weakness, depression

3. What are the leading causes of hypercalcemia?

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HPT is the most common cause of hypercalcemia among outpatients and the second most common cause in the hospital setting. The most common cause of hypercalcemia in hospitalized patients is malignancy. Primary HPT and malignancy account for 90% of cases of hypercalcemia.

4. What is the differential diagnosis of hypercalcemia?

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* EndocrineHPT
* Hyperthyroidism
* Addison’s disease

* MalignancyBone metastasis
* Paraneoplastic syndromes
* Solid tumors (squamous or small cell lung carcinoma)
* Hematologic malignancy (myeloma, leukemia, lymphoma)

* Increased intakeMilk alkali syndrome
* Vitamin D intoxication
* Granulomatous disease
* Sarcoidosis
* Tuberculosis

* MiscellaneousFamilial hypocalciuric hypercalcemia (FHH)
* Thiazide use
* Lithium use

5. What is the essential laboratory evaluation for HPT?

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Elevated serum calcium (> 10.3 mg/dL) should be assessed at least twice. Hypercalcemia must be associated with elevation of parathyroid hormone (intact). Serum phosphate levels are low in nearly 80% of patients. Serum chloride is increased in 40% of patients. A chloride-to-phosphate ratio greater than 33 suggests primary HPT. Increased alkaline phosphatase levels occur only in the setting of advanced bone disease. A 24-hour urine collection for calcium excretion excludes benign FHH. In patients with primary HPT, the 24-hour urine calcium is > 150 mg/day versus < 100 mg/day in those with FHH.

6. Describe the anatomy of the parathyroid glands.

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The upper parathyroid glands arise from the dorsal part of the fourth brachial pouch along with the lateral lobes of the thyroid. The lower parathyroid glands arise from the dorsal part of the third brachial pouch along with the thymus.
The average weight of a normal parathyroid gland is 35-50 mg. The upper parathyroid gland lies on the posterior portion of the upper half of the thyroid, cephalad to the inferior thyroid artery, and posterior to the recurrent laryngeal nerve. The normal lower parathyroid gland is found on the lateral or posterior surface of the lower pole of the thyroid gland.
Four glands are present in 89% of patients, five in 8%, six in 3%, and < four in 0%.
The upper parathyroid glands' location is more constant. The most common ectopic sites of the upper glands are posterior to the esophagus or in the tracheoesophageal groove down into the posterior superior mediastinum. The lower parathyroid glands are more commonly ectopic and may be in the thyrothymic ligament, thymus, mediastinum (but outside the thymus), or carotid sheath or within the thyroid.

7. What are the indications for parathyroidectomy?

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All patients with symptomatic HPT or with serum calcium 1 mg/dL above normal should benefit from a parathyroidectomy. Careful history indicates the majority of patients (> 90%) have symptoms. The treatment of asymptomatic patients with minimal elevation (10.3-11.0 mg/dL) of serum calcium is controversial. However, at least four factors favor operation:

1. Patients with untreated primary HPT have an increased death rate caused by cardiovascular disease.
2. Patients with HPT have abnormal quality-of-life scores, and these scores improve to normal after operative success.
3. The cost of parathyroidectomy is equivalent to medical follow-up at 5 years.
4. Experienced endocrine surgeons have a high success rate (≥ 95%) with very low morbidity and mortality rates.

8. What localization studies are available, and when are they indicated?

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The single best localization study is the sestamibi scan. Other noninvasive localization studies include ultrasound, computed tomography, and magnetic resonance imaging. Invasive localization procedures include arteriography and venous sampling. The tests are most accurate with a single abnormal parathyroid gland. Localization procedures in cases of hyperplasia may be misleading.
Localization studies are not routinely indicated before an initial operation, but they are mandatory before all reoperative parathyroidectomies for persistent or recurrent HPT and in patients with previous thyroid surgery.
Preoperative sestamibi scintigraphy is used by some surgeons for the initial operation to allow a focused parathyroidectomy or minimally invasive radio-guided parathyroidectomy.

9. What is the pathology of primary HPT?

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Primary HPT is caused by a single adenoma in 87% of cases, hyperplasia in 9%, double adenoma in 3%, and carcinoma in < 1%. In familial HPT, multiple endocrine neoplasia syndromes (MEN I and MEN II), and HPT due to end-stage renal disease, hyperplasia is the rule.

10. Outline the standard surgical strategy of an initial exploration for primary HPT.

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A meticulously dry, blood-free operative field must be maintained. Tissue in the region of the recurrent laryngeal nerve should not be clamped or divided until the nerve is definitively identified. The standard operation is a bilateral neck exploration. If a solitary adenoma and three normal glands are found, the adenoma is removed and one of the normal glands biopsied. Frozen-section examination confirms that the tissue is parathyroid but is unreliable to differentiate adenoma versus hyperplasia. Four-gland enlargement (hyperplasia) indicates either subtotal parathyroidectomy (leaving approximately 50 mg of well-vascularized parathyroid tissue in the neck) or total parathyroidectomy with autotransplantation of 50 mg of parathyroid tissue. If a remnant is left in the neck, it should be marked with a nonabsorbable suture or staple. In the setting of hyperplasia, a thymectomy eliminates the possibility of thymic supernumerary glands. If more than one enlarged gland is found in association with normal-appearing glands (double adenoma), all abnormal glands should be removed.
KEY POINTS: HYPERPARATHYROIDISM

1. It is the most common cause of hypercalcemia among outpatients and the second most common cause in the hospital setting.
2. The three most common symptoms are fatigue, constipation, and depression.
3. The single best localization study is the sestamibi scan.

11. Are there any newer alternatives to the standard operative approach?

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Focused parathyroidectomy, minimally invasive radio-guided parathyroidectomy (MIRP), and endoscopic neck exploration are new techniques. A focused parathyroidectomy uses the preoperative localization to guide a parathyroidectomy, avoiding a bilateral exploration. This approach is combined with intraoperative “rapid” parathyroid hormone assay. The parathyroid hormone is measured by a modified assay before operation and 10 minutes after adequate resection. A postresection level < 50% of the preoperative level and within the normal range predicts success. The MIRP uses a sestamibi scan the morning of surgery and an intraoperative gamma probe to guide parathyroidectomy. The ratio of ex vivo radioactivity to background is measured to determine success and, thus, the end of the operation.

12. What should one do if an adenoma is not found in the usual locations?

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Each normal gland should be biopsied for confirmation and marked. Normal parathyroid glands should not be removed. If three normal glands are identified, the surgeon should assess whether the missing gland is an upper or lower one. A missing upper gland often lies in the tracheoesophageal groove, posterior to the esophagus or in the posterior superior mediastinum. The common mistake is that the upper thyroid is not satisfactorily mobilized and dissection is not carried posterior enough. The location of a missing lower gland is more varied. First, the thyrothymic ligament should be inspected. The thymus then can be resected through the neck incision. If the adenoma is still not found, the surgeon should search for an undescended parathyroid gland. Next, the carotid sheath should be opened. Finally, the thyroid lobe on the side of the missing parathyroid should be palpated or examined by intraoperative ultrasound for nodules. If a nodule is found, a lobectomy is done and the tissue examined by frozen section; it may be an intrathyroidal parathyroid gland. A blind thyroid lobectomy is rarely helpful.
A sternotomy should not be done as part of an initial exploration. If the above maneuvers are unsuccessful in revealing a parathyroid adenoma, the surgeon should stop. A diagram of the location of the identified glands should be made for future reference. Persistent hypercalcemia indicates the need for localization procedures.

13. What is the outcome of surgery for primary HPT?

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The expected cure rate should be ≥ 95% for patients undergoing an initial exploration for primary HPT. Symptomatic improvement exceeds 95%. Quality-of-life scores return to normal at 6 months. After parathyroidectomy, 80% of symptomatic patients have improvement in bone density and renal function. Even in asymptomatic patients, urinary calcium and deoxypyridinoline levels decrease. Patients have fewer episodes of nephrolithiasis, gout, and peptic ulcer disease. Parathyroidectomy also appears to improve longevity in patients with primary HPT.

14. What are the complications of parathyroidectomy?

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Permanent recurrent laryngeal nerve injury occurs in < 1% of patients; however, a temporary nerve paresis occurs in 3%. Temporary hypocalcemia occurs in 10% of patients, but permanent HPT occurs in only 2% of cases. An elevated preoperative alkaline phosphatase level and abnormal renal function may predict which patients are likely to have "hungry bone" syndrome.

15. What are the physical signs of hypocalcemia after surgery?

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Chvostek’s sign is spasm of the facial muscles caused by tapping the facial nerve trunk. Trousseau’s sign is carpal spasm elicited by occlusion of the brachial artery for 3 minutes with a blood pressure cuff.

16. How should patients with hypocalcemia be treated?

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Patients with tetany caused by hypoparathyroidism require emergency treatment with intravenous calcium to prevent laryngeal stridor and convulsions. One ampule of 10% calcium gluconate (90 mg elemental calcium per 10 mL) should be given in 100-mL saline over 20 minutes followed by an infusion of calcium (5 ampules of calcium gluconate in 500 cc of saline) at 50 mL/h. Maintaining calcium levels of 7.5-9.0 mg/dL is adequate. Oral calcium should be started as soon as possible in the form of calcium carbonate (Tums or Oscal) at 2-3 g/day in divided doses (3-4 times/day). Calcium citrate is preferred for patients with renal lithiasis because the citrate may be prophylactic against renal lithiasis. In most patients, vitamin D preparations increase intestinal absorption and can be given as calcitriol (Rocaltrol), 0.25-0.75 mg per day.

17. Define persistent and recurrent HPT.

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Operative success is defined by long-term normocalcemia. Persistent HPT is defined as hypercalcemia within 6 months of surgery; recurrent HPT is defined as hypercalcemia after 6 months.

18. What is the strategy for managing patients with persistent or recurrent HPT?

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First, the patient should be reevaluated to ensure that the hypercalcemia is caused by primary HPT and not some other cause. Patients should be evaluated for familial hypocalciuric hypercalcemia, which does not warrant reoperation. The severity of disease is evaluated to ensure that repeat operation is justified. Previous operative notes and pathology reports should be reviewed to assist in planning repeat therapy. Localization studies should be used extensively. Before reexploration, vocal cord function should be assessed in all patients.
Repeat cervical exploration is done through the previous incision. Because the strap muscles are usually adherent to the thyroid, a lateral approach through the plane between the sternocleidomastoid and strap muscles may be used instead of the usual medial approach. With positive localization studies or retrospective determination of the side of the missing adenoma, the dissection may be limited if an adenoma is found.
An alternative to repeat exploration is angiographic ablation of parathyroid tissue, which is especially useful for mediastinal adenomas because it avoids a median sternotomy. It is performed by delivering ionic contrast through an arterial catheter wedged into the feeding vessel.

19. Who performed the first parathyroidectomy?

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In 1925, Felix Mendl performed the first successful parathyroidectomy at the Hochenegg Clinic in Vienna. His patient was Albert, a 34-year-old tram car conductor who could not work because of severe osteitis fibrosa cystica.

20. Who was Captain Martell?

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An officer in the U.S. Merchant Marine, Captain Martell was the first patient in the United States to undergo surgery for primary HPT. Captain Martell had progressive HPT that reduced his height from 6 feet to a kyphotic 5 feet, 6 inches. After seven operations, the adenoma was finally removed from the mediastinum; however, the captain died in chronic renal failure.

References
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