Parathyroid Hyperplasia
Parathyroid hyperplasia is an enlargement of two or more parathyroid glands due to an increase in the number of parathyroid cells. It is a less common cause of primary hyperparathyroidism than a single parathyroid adenoma, but it is particularly important because it is more often associated with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN 1), MEN 2A, MEN 4, familial isolated hyperparathyroidism, and hyperparathyroidism–jaw tumor syndrome. Parathyroid hyperplasia can also occur as a response to conditions that stimulate the parathyroid glands, such as chronic kidney disease (secondary hyperparathyroidism) and long-standing secondary disease that becomes autonomous (tertiary hyperparathyroidism). Evaluation and treatment differ from those of a single adenoma and typically involve surgery on multiple glands when operative treatment is chosen.
What is it?
The parathyroid glands are four small glands, each usually about the size of a grain of rice, located behind the thyroid gland in the neck.
They produce parathyroid hormone (PTH), which plays a central role in regulating calcium in the body. PTH raises blood calcium by acting on the bones, kidneys, and, indirectly through vitamin D, the intestines. This tightly regulated system keeps calcium levels within a narrow range, which is essential for nerve function, muscle activity, bone health, and many other body processes.
Parathyroid hyperplasia is an enlargement of two or more parathyroid glands due to an increase in the number of parathyroid cells.
Unlike a single parathyroid adenoma, in which only one gland is typically responsible for excess PTH, hyperplasia usually involves multiple glands. Because more than one gland is involved, evaluation, surgical planning, and long-term follow-up differ in important ways.
Parathyroid hyperplasia can occur in several settings.
Primary hyperparathyroidism due to hyperplasia occurs when multiple parathyroid glands produce excess PTH autonomously, independently of normal feedback from calcium. This is less common than primary hyperparathyroidism due to a single adenoma.
Multi-gland disease is more likely in hereditary syndromes, particularly MEN 1, MEN 2A, MEN 4, familial isolated hyperparathyroidism, and hyperparathyroidism–jaw tumor syndrome. Hyperparathyroidism–jaw tumor syndrome is associated with CDC73 (HRPT2) mutations and an increased risk of parathyroid carcinoma. Sporadic (non-hereditary) primary parathyroid hyperplasia can also occur without a known hereditary cause.
Secondary hyperparathyroidism occurs when the parathyroid glands are stimulated to produce more PTH by chronic conditions. It is most commonly caused by chronic kidney disease, in which impaired activation of vitamin D, reduced calcium absorption, and elevated phosphorus drive persistent stimulation.
Long-standing untreated vitamin D deficiency and certain malabsorption disorders can also contribute. In secondary hyperparathyroidism, elevated PTH is typically a physiologic response, and calcium levels may be low, low-normal, or normal rather than elevated.
Tertiary hyperparathyroidism occurs when long-standing secondary hyperparathyroidism becomes autonomous, meaning that the parathyroid glands continue to produce excess PTH even after the original stimulating factor—such as kidney disease—has been corrected. This is commonly seen after successful kidney transplantation.
Calcium levels are typically elevated in tertiary hyperparathyroidism, and PTH remains inappropriately high for calcium.
Symptoms and clinical effects vary by type. Many patients with mild primary hyperparathyroidism due to hyperplasia have no symptoms and are identified through routine blood tests showing elevated calcium.
Others develop the same range of symptoms seen with a single parathyroid adenoma, including fatigue, weakness, cognitive changes, low mood, bone or joint pain, kidney stones, frequent urination, constipation, nausea, and, in more severe cases, confusion or heart-rhythm changes. Long-term effects can include reduced bone density and increased fracture risk, kidney stones, and reduced kidney function.
Distal-forearm bone density is often measured because primary hyperparathyroidism can affect cortical bone at that site earlier than at other locations. Cardiovascular effects have also been reported in some studies, but their clinical importance varies among patients.
In secondary hyperparathyroidism from chronic kidney disease, symptoms and complications may include bone pain, muscle weakness, itching, and calcium deposits in soft tissues, including blood vessels, which can contribute to cardiovascular disease. Altered bone remodeling (renal osteodystrophy) is also common.
Tertiary hyperparathyroidism produces symptoms similar to primary hyperparathyroidism, driven by persistent hypercalcemia and PTH excess.
Diagnosis and evaluation combine clinical assessment, blood tests, and imaging. Blood tests typically include total calcium and, when appropriate, ionized calcium, phosphorus, PTH, 25-hydroxyvitamin D, kidney function (creatinine, urea, and estimated glomerular filtration rate), and albumin.
A 24-hour urinary calcium measurement is often obtained in primary disease and helps distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcemia (FHH), a benign inherited condition that mimics primary hyperparathyroidism biochemically but generally does not benefit from surgery.
The calcium-to-creatinine clearance ratio can also help distinguish these conditions, and genetic testing may be considered in selected patients.
Vitamin D status is considered carefully because low 25-hydroxyvitamin D can raise PTH and complicate the interpretation of laboratory results.
Bone density testing (DEXA) evaluates bone health at the lumbar spine, hip, and distal one-third of the radius. Imaging of the kidneys may be used to evaluate for kidney stones.
Additional testing—including vitamin D metabolites, phosphate handling studies, and specific measurements relevant to chronic kidney disease-mineral and bone disorder—may be appropriate depending on the clinical setting.
When surgery is being considered for primary or tertiary hyperparathyroidism due to hyperplasia, imaging is used to try to localize the affected glands, although imaging is generally less useful for identifying multi-gland disease than for a single adenoma.
Ultrasound of the neck by an experienced operator can identify some enlarged parathyroid glands, but multi-gland disease is often incompletely characterized.
Sestamibi (Tc-99m sestamibi) scans, often with SPECT or SPECT/CT, use a radiotracer preferentially retained by hyperfunctioning parathyroid tissue. 4D CT (parathyroid CT) provides detailed anatomical and dynamic information and can be particularly useful when other imaging is inconclusive, in reoperative cases, or for locating ectopic parathyroid tissue.
MRI is used in selected patients, including those requiring radiation avoidance or those with anatomy that is difficult to characterize by other modalities.
The choice of imaging modality depends on local expertise and clinical circumstances.
Because multi-gland disease is often incompletely characterized by imaging, bilateral neck exploration is more commonly used at surgery than in patients with a suspected single adenoma. Even when imaging suggests multi-gland disease, direct surgical assessment of all four glands is often required to guide the extent of resection.
Genetic evaluation is important when a hereditary syndrome is suspected. It should be considered in patients with early age at diagnosis, multi-gland disease, ectopic parathyroid tumors, atypical parathyroid histology, features suggestive of a related syndrome, or a personal or family history of related tumors.
Identifying a hereditary cause has important implications for surgical strategy, long-term follow-up, and family screening.
Important to Know
Management of parathyroid hyperplasia depends on the underlying type—primary, secondary, or tertiary—as well as symptoms, complications, calcium and PTH levels, kidney function, and overall health.
Care is best coordinated by primary care clinicians, endocrinologists, nephrologists in patients with kidney disease, endocrine or head-and-neck surgeons, geneticists, radiologists, and nuclear medicine specialists, with input from other specialists as needed.
For primary hyperparathyroidism due to hyperplasia, surgery is often recommended in symptomatic patients or those meeting accepted surgical criteria, which may include significantly elevated calcium, reduced bone density, kidney complications, or younger age.
Surgical strategy differs from that used for a single adenoma because multiple glands are involved.
Two main approaches are commonly used. Subtotal parathyroidectomy removes approximately three and a half of the four glands, leaving a well-vascularized remnant of parathyroid tissue in place. Total parathyroidectomy with autotransplantation removes all four glands and transplants a small portion of parathyroid tissue into an easily accessible location, most commonly the forearm, which can be re-explored later if needed.
The choice between approaches is individualized in collaboration with an experienced parathyroid surgeon.
Intraoperative PTH monitoring—measuring PTH before and after removal of parathyroid tissue—may help confirm adequate reduction, although its performance is more complex in multi-gland disease than in a single adenoma.
Success and complication rates depend heavily on surgeon experience, and referral to a high-volume parathyroid surgeon is generally recommended, particularly for hereditary or reoperative cases.
Long-term follow-up after surgery is important. Patients with hyperplasia, especially in hereditary syndromes, have a higher risk of recurrence than patients with a single adenoma.
Postoperative care includes monitoring calcium and PTH levels, watching for transient or persistent hypoparathyroidism—which can cause low calcium and symptoms such as tingling, muscle cramping, or spasms—and providing calcium and vitamin D as needed.
“Hungry bone syndrome,” in which calcium is rapidly deposited into bones after surgery, can produce prolonged low calcium and low phosphorus. It may require several days or occasionally weeks of intensive calcium and active-vitamin-D therapy, particularly when significant bone disease has been long-standing.
Medical monitoring is appropriate for some patients with mild primary disease who do not meet surgical criteria and for those who are not surgical candidates.
Monitoring typically includes periodic assessment of calcium, PTH, kidney function, urinary calcium, and bone density, along with correction of vitamin D deficiency and management of hydration and general health.
For secondary hyperparathyroidism from chronic kidney disease, treatment focuses on managing the underlying disease and its mineral disturbances.
Key elements include control of phosphorus through dietary phosphorus restriction and, when necessary, phosphate binders; correction of vitamin D deficiency; and, in selected patients, use of active vitamin D analogs. Careful management of calcium is important, and calcimimetics such as cinacalcet, an oral medication, or etelcalcetide, an intravenous medication used in dialysis patients, are used to lower PTH.
Nephrology involvement is essential. In patients with severe or refractory secondary hyperparathyroidism that does not respond to medical therapy, subtotal parathyroidectomy or total parathyroidectomy with autotransplantation may be considered.
For tertiary hyperparathyroidism, treatment often involves parathyroidectomy after kidney transplantation or when calcium remains elevated despite optimization of kidney and mineral care.
Surgical strategy is similar to that used in primary hyperplasia, and coordination with transplant and nephrology teams is important.
For patients with hereditary syndromes such as MEN 1, MEN 2A, and MEN 4, care includes surgical planning that anticipates likely multi-gland involvement, coordinated management of other endocrine tumors associated with the syndrome, and long-term surveillance.
Genetic counseling is essential, and family screening allows earlier detection and improved outcomes in at-risk relatives.
Prophylactic thyroidectomy in children with certain RET mutations (MEN 2A) is an important preventive step but is separate from parathyroid management.
Severe or symptomatic hypercalcemia requires urgent medical treatment.
Initial treatment typically includes intravenous saline hydration and, when appropriate, medications to lower calcium, which may include intravenous bisphosphonates such as zoledronic acid, calcitonin for rapid short-term lowering, and, in selected cases, cinacalcet or denosumab.
The choice of therapy depends on the severity of hypercalcemia, kidney function, cardiovascular status, prior treatments, and other clinical factors.
Care is typically coordinated by primary care clinicians, endocrinologists, nephrologists, and endocrine or head-and-neck surgeons, with input from other specialists as needed.
Imaging and laboratory findings should always be interpreted alongside the patient’s symptoms, examination, family history, medications, and broader clinical context, rather than in isolation.
Patient education is an important part of care. Understanding the specific type of hyperparathyroidism, the reasons for recommended monitoring or surgery, medication adherence, the meaning of laboratory and imaging results, and warning signs of complications can support better outcomes.
Because recurrence is more common with hyperplasia than with a single adenoma, ongoing follow-up is particularly important.
Red-flag symptoms include severe muscle weakness, marked confusion or drowsiness, unresponsiveness, extreme thirst and frequent urination, severe abdominal pain, severe nausea and vomiting, severe constipation, irregular heartbeat with dizziness or fainting, marked dehydration, severe muscle cramps or spasms after neck surgery (which may indicate significantly low calcium), fever with a painful or red neck (which may suggest infection), rapid clinical deterioration, or any sudden severe symptoms.
These symptoms warrant prompt or urgent medical evaluation, as they may indicate severe hypercalcemia, hypercalcemic crisis, postoperative hypocalcemia, infection, or another serious complication.