A parathyroid adenoma is a non-cancerous tumor that develops on one or more of the small parathyroid glands located in the neck, near the thyroid gland. This growth causes the affected gland to become overactive, leading to an overproduction of parathyroid hormone (PTH). The resulting condition, primary hyperparathyroidism, disrupts the body’s delicate balance of calcium. Understanding the origins involves examining the most frequent occurrences, as well as external and hereditary influences.
What Is a Parathyroid Adenoma?
The body typically possesses four parathyroid glands, which regulate calcium levels in the bloodstream and bones. These glands function as a thermostat for calcium, releasing PTH when levels are low and reducing its release when they are high. A parathyroid adenoma is the most common cause of primary hyperparathyroidism, accounting for approximately 85% of cases.
The tumor disrupts normal function by continuously secreting high amounts of PTH, regardless of the body’s calcium needs. This excess PTH pulls calcium from the bones and increases its reabsorption in the kidneys, leading to persistently high calcium levels in the blood (hypercalcemia). This imbalance can lead to symptoms like kidney stones, bone weakening, and generalized fatigue.
Sporadic Development: The Most Common Cause
The vast majority of parathyroid adenomas (80% to 85%) are sporadic, occurring randomly without an inherited predisposition or external cause. The underlying mechanism involves a somatic mutation, a genetic change that occurs in a single parathyroid cell after conception. This mutation causes the affected cell to grow and multiply uncontrollably, forming the adenoma.
These somatic mutations frequently involve genes that control the cell cycle. One established molecular driver is the \(CCND1/PRAD1\) oncogene, which is overexpressed in 20% to 40% of sporadic adenomas. The overexpression of this gene stimulates excessive parathyroid cell proliferation.
Another common alteration involves the \(MEN1\) tumor suppressor gene, with somatic mutations found in 15% to 20% of these tumors. Tumor suppressor genes halt cell growth; when both copies of the \(MEN1\) gene are inactivated, the cell loses its ability to regulate its growth, driving the formation of the single-gland tumor.
Environmental and Medical Risk Factors
While most cases are sporadic, certain external factors can increase the probability of developing a parathyroid adenoma.
Ionizing Radiation Exposure
Exposure to ionizing radiation, particularly directed at the head and neck during childhood or young adulthood, is a known risk factor. Historically, this exposure occurred as a side effect of radiation treatments. The risk of adenoma development is considered dose-dependent.
Lithium Use
The long-term use of the medication lithium has also been associated with an increased occurrence of parathyroid adenomas. Lithium, commonly prescribed for bipolar disorder, can lead to parathyroid gland dysfunction. It is thought to alter the sensitivity of the calcium-sensing receptor, affecting PTH secretion.
Environmental Chemicals
Environmental endocrine-disrupting chemicals, such as polychlorinated biphenyls (PCBs) and derivatives of DDT, have been detected in parathyroid tumor tissue. Although the precise mechanism is still being investigated, their presence suggests a potential link between environmental exposure and the development of parathyroid growths.
Inherited Genetic Syndromes
A smaller percentage of cases (5% to 10%) are linked to inherited germline mutations that run in families. These mutations predispose an individual to developing parathyroid adenomas, often at a younger age or in multiple glands. The three main hereditary syndromes associated with this condition are Multiple Endocrine Neoplasia Type 1 (MEN1), Multiple Endocrine Neoplasia Type 2A (MEN2A), and Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT).
MEN1 is caused by a germline mutation in the \(MEN1\) tumor suppressor gene, increasing the likelihood of tumors in the parathyroid, pituitary, and pancreas. HPT-JT results from a mutation in the \(CDC73\) gene, notable for its association with parathyroid tumors and non-cancerous jaw tumors. MEN2A results from a mutation in the \(RET\) proto-oncogene, characterized by parathyroid overactivity along with tumors in the adrenal and thyroid glands.