Hyperparathyroidism

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How common is hyperparathyroidism (HPT)?

The prevalence of hyperparathyroidism is 1:1000. There are approximately 100,000 new cases of HPT annually in the United States. Seventy-four percent of all cases are in women, and the risk increases with age. Primary HPT occurs in 1 in 500 women and in 1 in 2000 men older than age 40.

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What are the symptoms of HPT?

Painful bones, renal stones, abdominal groans, psychic moans, and fatigue overtones. HPT is most commonly asymptomatic, but the classic symptoms and signs are that of hypercalcemia:

• Bones: Arthralgia, osteoporosis, and pathologic fractures

• Stones: Renal stones, renal insufficiency, polyuria, and polydipsia

• Abdominal groans: Pancreatitis, peptic ulcer disease, and constipation

• Psychiatric overtones: Fatigue, weakness, depression, memory loss, and irritability

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What is the most common cause of hypercalcemia in an outpatient versus an inpatient?

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.

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What is the differential diagnosis of hypercalcemia?

• Endocrine: HPT, hyperthyroidism, Addison’s disease

• Malignancy: Bone metastasis, paraneoplastic syndromes, solid tumors (squamous or small cell lung carcinoma), hematologic malignancy (multiple myeloma, leukemia, lymphoma)

• Increased intake: Milk-alkali syndrome, vitamin D intoxication

• Granulomatous disease: Sarcoidosis, tuberculosis

• Miscellaneous: Familial hypocalciuric hypercalcemia (FHH), thiazide diuretics, lithium

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How do you obtain a laboratory diagnosis of primary HPT?

The diagnosis of primary HPT is confirmed with an elevated serum calcium level, elevated parathyroid hormone (PTH), and the absence of low 24-hour urine calcium. An elevated serum calcium should be assessed at least twice and must be associated with elevation of intact PTH. A 24-hour urine collection for calcium >100 mg/day excludes benign FHH. Prior to the use of intact PTH levels, a chloride/phosphate ratio of >33 associated with hypercalcemia suggested primary HPT because serum phosphate levels are low in nearly 80% of patients, and serum chloride is increased in 40% of patients. Patients with elevated alkaline phosphatase associated with increased blood urea nitrogen and creatinine are at increased risk of hungry bone syndrome after parathyroidectomy.

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Can a patient have primary HPT and a normal PTH level?

Yes. A normal parathyroid response to elevated serum calcium is decreased PTH secretion. When serum calcium is high, the PTH level should be at the low end of normal. A PTH level at the high end of normal in the setting of hypercalcemia is inappropriately elevated and consistent with primary HPT. One should rule out FHH by testing 24-hour urine calcium.

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What is normocalcemic primary hyperparathyroidism (NPHPT)?

Occasionally, patients will be identified with an elevated PTH level and a normal serum calcium. This entity exists on the diagnostic spectrum of PHPT, and calcium is typically at the upper limits of the normal range. The majority of these patients will have an elevated ionized calcium. Adequate surveillance is important, as patients with NPHPT may develop hypercalcemia.

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What are the indications for parathyroidectomy in primary HPT?

Symptomatic PHPT is an indication for surgery, and careful history indicates that over 90% of patients have symptoms. The indications in asymptomatic patients have broadened in the past 15 years because of the sequelae of long-term disease, low morbidity in the hands of experienced endocrine surgeons, and cure rates of over 95%. Patients with untreated primary HPT have increased death rates caused by hypercalcemia-related cardiovascular disease. Patients also have improvements in abnormal quality-of-life scores after operative success, and the costs of surgery are equivalent to that of medical follow-up at 5 years.

The 2014 Endocrine Society Fourth International Workshop for Asymptomatic Primary HPT lists the following indications for parathyroidectomy:

• Serum calcium >1.0 mg/dL above upper limit of normal

• Bones: bone mineral density (BMD) and dual-energy x-ray absorptiometry (DEXA): T-score <−2.5 at lumbar spine, total hip, femoral neck, or distal one-third radius OR vertebral fracture by x-ray, computed tomography (CT), magnetic resonance imaging (MRI), or vertebral fracture assessment (VFA)

• Renal: Creatinine clearance 60 cc/min; 24-hour urine for calcium 400 mg/day (10 mmol/day) and increased stone risk by biochemical stone risk analysis; presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound (US), or CT

• Age <50 years

• Patients for whom medical surveillance is neither desired nor possible and in patients opting for surgery, in the absence of meeting any guidelines as long as there are no medical contraindications

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What are the embryologic origins and locations of the superior and inferior parathyroid glands?

The superior parathyroid glands arise from the dorsal part of the fourth brachial pouch. In the normal position, they lie on the posterior portion of the upper half of the thyroid, cephalad to the inferior thyroid artery, and posterior to the recurrent laryngeal nerve (RLN). The superior 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 inferior parathyroid glands arise from the dorsal part of the third brachial pouch along with the thymus. The most common location of the inferior parathyroids are on the lateral or posterior surface of the lower pole of the thyroid gland, caudal and anterior to the point where the inferior thyroid artery crosses the RLN. The inferior parathyroid glands are more commonly ectopic and may be in the thyrothymic ligament, thymus, mediastinum outside the thymus, carotid sheath, or within the thyroid (3%).

Four glands are present in 89% of patients, five in 8%, six in 3%, and less than four in 0%. The presence of as many as eight glands has been reported.

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