The parathyroid gland is a key regulator of calcium homeostasis. While hyperparathyroidism is now most often diagnosed in asymptomatic patients, untreated it can have devastating effects on multiple organ systems. Primary hyperparathyroidism, the most common cause of hypercalcemia in nonhospitalized patients, is treated surgically in most cases.

During the fifth week of gestation, the parathyroid glands form from the third and fourth branchial pouches. The glands derived from the third pouches descend caudally in the neck along with the thymus gland (formed from the third branchial arch), while the glands from the fourth pouches remain stationary. Knowledge of this embryologic migration, which results in the glands arising from the fourth pouches to be superiorly located and those from the third pouches to be inferior, is critical when searching for ectopically located glands.

The superior parathyroid glands are typically closely associated with the posterolateral aspect of the superior poles of the thyroid gland. The inferior glands, which are more variable in positioning, are most commonly found near the inferior poles of the thyroid gland. These are sometimes embedded within the superior aspect of the thymus gland or within the thyrothymic ligament.

Deviation from the standard migratory pattern during embryogenesis can lead to aberrantly located glands in approximately 15 to 20% of patients, although this has been reported to be higher in individuals with renal hyperparathyroidism. Aberrant glands can occur in any location along their migration course and have been identified from the carotid bifurcation to the level of the aortic arch.

While the majority of people have four parathyroid glands, approximately 2 to 5% have five or more glands. A similar percentage has fewer than four glands.

The blood supply to parathyroid glands is fairly constant. Both the superior and inferior glands are fed from branches of the inferior thyroid artery. Occasionally, superior glands are supplied by an anastomotic branch from the inferior to the superior thyroid artery or are fed by both arteries. These arteries enter the glands at their hila, an anatomic characteristic which distinguishes them from surrounding fat. The arterial branches supplying the glands can be variably positioned relative to the recurrent laryngeal nerve.

Normal parathyroid glands, often bean shaped, appear a distinct yellowish brown, often described as caramel in color. Manipulation of the glands and their blood supply during surgery will change the color to a darker mocha brown. Healthy glands weigh 30 to 40 mg on average.

Physiology

Parathyroid hormone (PTH) impacts calcium homeostasis by targeting the kidneys, skeletal system, and gastrointestinal tract. The parathyroid chief cells are responsible for the production and storage of PTH. Hormone release by parathyroid glands is directly controlled by feedback inhibition of the glands by serum calcium.

PTH acts to raise calcium levels by several mechanisms. It influences the kidneys to increase calcium reabsorption, promotes resorption and calcium release by the bones and enhances absorption of calcium in the intestines by increasing renal activation of vitamin D.

Hyperparathyroidism is the most common disorder of parathyroid function. Hyperparathyroidism is categorized as primary, secondary or tertiary depending on the etiology. Primary and tertiary hyperparathyroidism are treated surgically while secondary hyperparathyroidism is usually managed medically.

Primary Hyperparathyroidism

Essentials of Diagnosis

• Elevated serum calcium level
  
• Elevated serum PTH level
  
• Must differentiate between primary, secondary and tertiary hyperparathyroidism.

Primary hyperparathyroidism is due to a primary defect in the parathyroid glands, such that elevated serum calcium fails to inhibit additional PTH release. Approximately 0.3 to 1% of the general population develops primary hyperparathyroidism. Rare prior to puberty, its incidence peaks in women in their fourth to seventh decades.

Pathogenesis

In a majority of primary hyperparathyroidism patients, dysfunctional calcium sensing receptors on the surface of chief cells is the cause. Single adenomas are present in 80 to 85% of cases, double adenomas in 2 to 3%, and multigland hyperplasia in 12 to 15%. Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.

Clinical Findings

The introduction over 30 years ago of accurate and mechanized laboratory tests for serum calcium levels has allowed for earlier and more frequent detection of primary hyperparathyroidism. Historically, patients presented with the classic constellation of “groans, bones, stones, and psychiatric overtones”. Currently, the vast majority of patients are diagnosed on routine lab testing and are asymptomatic. Long-standing, untreated primary hyperparathyroidism can lead to early death, often from cardiac dysfunction.

In addition to generalized fatigue and weakness, multiple systems can be impacted:

• Gastrointestinal: Abdominal pain, constipation, nausea, vomiting, peptic ulcer, and pancreatitis.
  
• Rheumatologic: Bone pain, osteoporosis, arthralgia, myalgia, and gout.
  
• Renal: Nephrolithiasis, polyuria, polydipsia, and renal failure.
  
• Psychiatric: Depression, dementia, and confusion.
  
• Cardiovascular: Hypertension and cardiac arrhythmias.

Diagnosis

Laboratory

While there are numerous physiological derangements that can occur in primary hyperparathyroidism, elevated calcium and PTH levels are fundamental to the diagnosis. Several additional laboratory tests can contribute to making an accurate diagnosis.

• Hypercalcemia: An elevated calcium level is a hallmark of the diagnosis. While an elevated serum calcium level is almost always present and adequate for diagnosis, in some situations, only the physiologically active ionized calcium is elevated. In the blood, approximately 50% of calcium is bound to protein, typically albumin, 5% is complexed with phosphate or citrate and the remainder is ionized. In the setting of hypoalbuminemia, serum calcium levels can be normal while the ionized fraction is elevated.
  
• Hyperparathyroidism: The introduction of new assays has allowed accurate assessments of intact PTH levels. In primary hyperparathyroidism, PTH levels can range from the high end of normal to markedly elevated level. In the setting of hypercalcemia, a PTH level at the high end of normal should be considered inappropriate and needs further diagnostic workup.
  
• Hypophosphatemia: Increased PTH levels promote renal excretion of phosphate. Approximately 50% of patients with primary hyperparathyroidism have below normal serum phosphate levels.
  
• Normal to elevated urine calcium: A 24 h total urine calcium level and calcium clearance can help in differentiating familial hypocalciuric hypercalcemia (FHH) from primary hyperparathyroidism, in which normal to elevated urine calcium levels are present. Inappropriately low urine calcium excretion suggests FHH.

Radiologic