Primary Hyperparathyroidism (PHPT) occurs when one or more of the four parathyroid glands produce excess parathyroid hormone (PTH), leading to elevated calcium levels in the blood. Parathyroidectomy, the surgical removal of the overactive tissue, is the definitive treatment expected to normalize serum calcium levels. If a patient’s calcium remains high shortly after the operation, or returns to high levels months later, concern arises about the surgery’s success. This persistence of hypercalcemia requires examining three possibilities: incomplete removal of hyperfunctioning tissue, temporary physiological changes, or an unrelated underlying medical cause.
Incomplete Removal of Hyperfunctioning Tissue
The most common reason for persistent hypercalcemia immediately following parathyroid surgery is the failure to remove all tissue producing excess PTH. The surgeon may have removed only one hyperactive gland, missing a second, smaller, or “dormant” adenoma (a double adenoma). This second gland, previously suppressed by the dominant one, can become active after the main adenoma is removed, leading to recurrent high calcium.
Sometimes, the surgeon cannot locate the abnormal gland because it is in an unusual anatomical location. Parathyroid glands can migrate during embryonic development, leading to ectopic locations outside the typical area. Common ectopic sites include the thymus gland, deep in the chest, or behind the esophagus. If initial imaging failed to pinpoint this location, the surgeon may have missed it during the initial neck exploration.
Multi-gland disease, or hyperplasia, is another possibility where all four parathyroid glands are overactive, but only one or two were removed. The residual hyperfunctioning tissue keeps calcium levels elevated, meaning the partial removal was not curative. This typically requires a more extensive operation. Persistent hypercalcemia caused by missed tissue is often diagnosed through specialized post-operative imaging, such as a Sestamibi or 4D-CT scan, to pinpoint the remaining active tissue. Once localized, a second, targeted surgery can be performed to achieve a cure.
Delayed Drop Due to Post-Surgical Physiology
In some cases, surgery is technically successful, but the calcium level does not drop immediately due to temporary metabolic changes. One significant post-operative phenomenon is “hungry bone syndrome.” Years of excess PTH activity cause calcium to be pulled out of the skeleton, leading to demineralized bone.
When the source of excess PTH is suddenly removed, osteoclast activity (which breaks down bone) stops abruptly. Osteoblasts (which build new bone) rapidly pull calcium and other minerals from the bloodstream to remineralize the skeleton. This aggressive uptake can cause a temporary drop in serum calcium, often requiring significant supplementation, or it can delay the expected drop for weeks or months.
The remaining healthy parathyroid glands may also take time to resume normal function. These glands were suppressed by the overactive adenoma and need time to “wake up” and begin regulating calcium production appropriately. The combination of intense skeletal demand for calcium and the sluggish response of the remaining glands means calcium levels may only slowly drift into the normal range over the first few weeks post-operation. This is generally a transient issue that resolves as the body adjusts to the sudden withdrawal of excess hormone.
Hypercalcemia from Non-Parathyroid Causes
A third possibility is that the patient’s hypercalcemia was never solely caused by PHPT, or that a new, unrelated condition has developed. This must be investigated if PTH levels are low after surgery, indicating the procedure was successful. A genetic disorder called Familial Hypocalciuric Hypercalcemia (FHH) is often mistaken for PHPT because both cause high calcium and inappropriately normal or elevated PTH levels.
FHH is caused by a mutation in the calcium-sensing receptor gene, which causes the kidneys and parathyroid glands to misread the calcium level, leading to calcium retention. Surgery is ineffective for FHH and should be avoided, making correct diagnosis essential. A blood test measuring the calcium-to-creatinine clearance ratio in the urine helps differentiate FHH from PHPT.
Certain medications can also cause elevated calcium levels. Medications like lithium, often prescribed for mood disorders, or high-dose vitamin D supplements interfere with calcium metabolism, leading to hypercalcemia that persists despite successful parathyroid tissue removal. Hypercalcemia may also be an early sign of an underlying malignancy. Some cancers produce proteins that mimic PTH effects, leading to humoral hypercalcemia of malignancy. This requires comprehensive evaluation to ensure the persistent high calcium is not a sign of a new, serious disease.