Primary Hyperparathyroidism: High Calcium from Overactive Parathyroid Glands

What Is Primary Hyperparathyroidism (PHPT)?

Primary hyperparathyroidism (PHPT) is a condition where one or more parathyroid glands become overactive and produce excessive amounts of parathyroid hormone (PTH), causing abnormally high calcium levels in the blood. It is the most common cause of hypercalcemia (elevated blood calcium) in outpatients and the third most common endocrine disorder after diabetes and thyroid disease.

The parathyroid glands are four small glands, each about the size of a grain of rice, located behind the thyroid gland in your neck. Their primary function is to regulate calcium levels in the body through the production of parathyroid hormone. When these glands function normally, they maintain calcium within a tight range essential for proper nerve function, muscle contraction, bone health, and blood clotting.

In primary hyperparathyroidism, one or more of these glands becomes overactive—typically due to a benign tumor called an adenoma—and produces parathyroid hormone regardless of blood calcium levels. This autonomous hormone production leads to persistently elevated calcium levels, which can affect multiple organ systems throughout the body. The condition differs from secondary hyperparathyroidism, which occurs as a response to low calcium levels typically caused by kidney disease or vitamin D deficiency.

Understanding the distinction between primary and secondary forms is crucial for proper treatment. In PHPT, the parathyroid glands themselves are the problem, whereas in secondary hyperparathyroidism, the glands are responding appropriately to signals from elsewhere in the body. Primary hyperparathyroidism requires treatment directed at the parathyroid glands, while secondary forms require addressing the underlying cause.

The Role of Parathyroid Hormone in Your Body

Parathyroid hormone (PTH) serves as the master regulator of calcium metabolism in your body. When calcium levels drop, the parathyroid glands release PTH, which acts on three main targets: the bones, kidneys, and intestines. In the bones, PTH stimulates the release of calcium into the bloodstream by activating cells called osteoclasts that break down bone tissue. In the kidneys, PTH increases calcium reabsorption while decreasing phosphate reabsorption. It also stimulates the kidneys to produce active vitamin D, which enhances calcium absorption from the intestines.

Under normal circumstances, this system operates like a thermostat. When blood calcium rises to an appropriate level, PTH secretion is suppressed, and calcium levels stabilize. However, in primary hyperparathyroidism, this feedback mechanism fails because the abnormal parathyroid tissue continues to produce PTH regardless of calcium levels. The result is a persistent state of elevated calcium and the various symptoms and complications that can accompany it.

Who Gets Primary Hyperparathyroidism?

Primary hyperparathyroidism can affect anyone but occurs most frequently in certain populations. Women are two to three times more likely to develop the condition than men, with the highest incidence occurring in postmenopausal women between ages 50 and 60. The condition is rare in children but increases steadily with age, affecting approximately 2% of women over age 55.

Risk factors for developing PHPT include previous radiation exposure to the head and neck area, long-term lithium therapy for bipolar disorder, and family history of parathyroid disease. Certain inherited genetic conditions, including Multiple Endocrine Neoplasia (MEN) types 1 and 2A, significantly increase the risk of developing hyperparathyroidism at younger ages. However, the vast majority of cases occur sporadically without any identifiable cause or family history.

What Are the Symptoms of Primary Hyperparathyroidism?

The classic symptoms of primary hyperparathyroidism are remembered by the phrase "stones, bones, groans, and moans"—referring to kidney stones, bone pain, abdominal complaints (constipation, nausea), and psychiatric symptoms (depression, fatigue, memory problems). However, many patients today are asymptomatic and discovered through routine blood tests showing elevated calcium.

The presentation of primary hyperparathyroidism has changed dramatically over the past several decades. Before routine blood testing became widespread, patients typically presented with severe symptoms including kidney stones, significant bone disease, and profound weakness. Today, with the advent of automated blood chemistry panels that include calcium measurement, most cases are detected at an earlier, often asymptomatic stage. Studies suggest that up to 80% of newly diagnosed patients have no obvious symptoms at the time of diagnosis.

However, the absence of classic symptoms does not necessarily mean the disease is not affecting the body. Many patients experience subtle symptoms that they may not recognize as related to their condition until after successful treatment. These can include fatigue that seems disproportionate to activity levels, difficulty concentrating or "brain fog," mild depression or anxiety, and a general sense of not feeling well. Patients often report a dramatic improvement in energy and mental clarity following parathyroidectomy, suggesting that even "asymptomatic" disease can significantly impact quality of life.

Kidney and Urinary Symptoms

The kidneys are significantly affected by elevated calcium levels. Excessive calcium in the blood leads to increased calcium excretion in the urine, which can result in kidney stone formation. Approximately 15-20% of patients with PHPT develop kidney stones, compared to about 5% of the general population. These stones are typically composed of calcium oxalate or calcium phosphate and can cause severe pain (renal colic), blood in the urine, and urinary tract infections.

Beyond kidney stones, chronically elevated calcium can impair the kidneys' ability to concentrate urine, leading to excessive urination (polyuria) and subsequent increased thirst (polydipsia). Over time, untreated hypercalcemia can cause nephrocalcinosis—a condition where calcium deposits accumulate within the kidney tissue itself—potentially leading to chronic kidney disease. Studies have shown that up to 17% of patients with PHPT have some degree of kidney impairment at diagnosis.

Bone and Skeletal Symptoms

Parathyroid hormone's primary target in regulating calcium is bone tissue. In PHPT, chronically elevated PTH levels lead to increased bone resorption, where bone is broken down faster than it can be rebuilt. This results in decreased bone mineral density and increased risk of fractures. The condition preferentially affects cortical bone (the hard outer layer), particularly at the distal radius (wrist) and hip, though trabecular bone (the spongy interior) is also affected.

Patients may experience bone pain, particularly in the back, hips, and limbs. In severe or long-standing cases, patients can develop significant osteoporosis with an increased risk of fragility fractures—fractures that occur from minor trauma that would not normally break healthy bone. Historically, patients sometimes developed a condition called osteitis fibrosa cystica, characterized by bone cysts and "brown tumors," though this is now rare due to earlier diagnosis.

Neuropsychiatric and Cognitive Symptoms

Perhaps the most underappreciated symptoms of primary hyperparathyroidism are neuropsychiatric in nature. Patients commonly report fatigue that is out of proportion to their activity levels, difficulty concentrating, poor memory, and a general feeling of cognitive "sluggishness." Depression and anxiety are significantly more common in patients with PHPT compared to the general population, with some studies suggesting rates two to three times higher.

These symptoms can be subtle and develop gradually, making them easy to attribute to aging, stress, or other factors. Patients may not recognize the connection until after treatment, when they experience what many describe as a "lifting of the fog." Research has consistently shown improvements in quality of life, mood, and cognitive function following successful parathyroidectomy, even in patients who were considered asymptomatic before surgery.

Gastrointestinal Symptoms

Elevated calcium affects the smooth muscle of the gastrointestinal tract, leading to decreased motility and various digestive symptoms. Constipation is one of the most common complaints, affecting up to 30% of patients. Other gastrointestinal symptoms include nausea, loss of appetite, and vague abdominal discomfort. In the past, peptic ulcer disease was associated with hyperparathyroidism, though this connection is less clear with modern treatment of ulcers.

What Causes Primary Hyperparathyroidism?

Primary hyperparathyroidism is most commonly caused by a benign tumor (adenoma) affecting a single parathyroid gland (80-85% of cases). Other causes include hyperplasia of multiple glands (10-15%) and, rarely, parathyroid cancer (<1%). Risk factors include age over 50, female sex, radiation exposure, lithium use, and certain genetic syndromes.

Understanding the underlying cause of hyperparathyroidism is important because it affects treatment planning. The vast majority of cases—approximately 80-85%—are caused by a single parathyroid adenoma. An adenoma is a benign (non-cancerous) tumor that develops within one of the parathyroid glands, causing it to grow larger and produce excessive amounts of PTH autonomously, independent of the body's normal feedback mechanisms.

In approximately 10-15% of cases, the cause is hyperplasia, where all four parathyroid glands become enlarged and overactive. This pattern is more common in familial forms of the disease and in patients with secondary hyperparathyroidism that has evolved over time. Hyperplasia typically requires a different surgical approach than single adenoma disease, as the surgeon must address multiple glands.

Parathyroid carcinoma, or cancer of the parathyroid gland, accounts for less than 1% of cases of primary hyperparathyroidism. It tends to cause more severe hypercalcemia and higher PTH levels than benign disease. Parathyroid cancer can be challenging to diagnose preoperatively and is sometimes only confirmed after surgery when pathology reveals invasion into surrounding tissues. Fortunately, it is extremely rare, and the vast majority of patients with PHPT have benign disease that is highly treatable.

Risk Factors and Genetic Conditions

Several factors increase the risk of developing primary hyperparathyroidism. Age is a significant factor, with the condition becoming more common with advancing years. Female sex confers a two to three-fold increased risk, likely related to hormonal changes associated with menopause. Previous radiation exposure to the head and neck region, whether for medical treatment or from environmental sources, increases the risk of developing parathyroid tumors decades later.

Long-term use of lithium, a medication commonly prescribed for bipolar disorder, is associated with an increased risk of hyperparathyroidism. Lithium affects the calcium-sensing receptors on parathyroid cells, leading to altered PTH secretion. Patients on long-term lithium therapy should have their calcium levels monitored regularly.

Inherited genetic conditions account for approximately 5-10% of cases and should be suspected in patients who develop PHPT at a young age, have multiple gland disease, or have a family history of hyperparathyroidism. Multiple Endocrine Neoplasia type 1 (MEN1) is the most common hereditary cause, also associated with tumors of the pituitary gland and pancreas. MEN2A, though primarily associated with thyroid cancer, also includes hyperparathyroidism in affected families. Other genetic syndromes include familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumor syndrome.

How Is Primary Hyperparathyroidism Diagnosed?

Primary hyperparathyroidism is diagnosed by blood tests showing elevated calcium levels together with elevated or inappropriately normal PTH levels. The diagnosis is biochemical—you do not need imaging to confirm PHPT. Additional tests include vitamin D levels, kidney function, 24-hour urine calcium, and bone density scans. Imaging (sestamibi scan, ultrasound) is used only to locate the abnormal gland before surgery, not to make the diagnosis.

The diagnosis of primary hyperparathyroidism is fundamentally a laboratory diagnosis based on characteristic blood test findings. The hallmark is elevated serum calcium in combination with an elevated or inappropriately normal parathyroid hormone level. Under normal physiologic conditions, high calcium levels would suppress PTH secretion. When calcium is elevated but PTH is not suppressed (remains high or even "normal"), this indicates that the parathyroid glands are functioning autonomously—the defining feature of primary hyperparathyroidism.

It's important to understand that a "normal" PTH level in the presence of elevated calcium is actually abnormal. If your calcium is high, your PTH should be suppressed below the normal range. A PTH that is in the normal range when calcium is elevated indicates inappropriate parathyroid gland function and supports the diagnosis of PHPT. This concept of "inappropriately normal" PTH is sometimes missed, leading to delayed diagnosis.

Initial Blood Tests

When hyperparathyroidism is suspected, several blood tests are typically ordered. Serum calcium, preferably measured multiple times to confirm persistent elevation, is the starting point. Total calcium levels can be affected by albumin levels (the protein that carries calcium in the blood), so many laboratories also calculate "corrected calcium" or measure ionized (free) calcium for accuracy.

Parathyroid hormone (PTH) measurement is essential and should be performed using the intact PTH assay, which measures the complete, biologically active hormone molecule. Other tests that help complete the evaluation include vitamin D levels (both 25-hydroxyvitamin D and sometimes 1,25-dihydroxyvitamin D), phosphorus (typically low in PHPT), kidney function tests (creatinine, estimated GFR), and sometimes a 24-hour urine collection for calcium and creatinine to calculate the calcium-creatinine clearance ratio.

Additional Evaluation

Once the diagnosis of primary hyperparathyroidism is established biochemically, additional tests help assess the impact on target organs and guide treatment decisions. A bone density scan (DEXA or DXA) measures bone mineral density at the spine, hip, and forearm to evaluate for osteoporosis. The forearm measurement is particularly important in PHPT because cortical bone (which predominates in the forearm) is preferentially affected.

Kidney imaging, usually with ultrasound or CT scan, may be performed to check for kidney stones, which may be present even without symptoms. Some guidelines recommend routine imaging of the kidneys in all patients with PHPT to identify asymptomatic nephrolithiasis or nephrocalcinosis. Kidney function tests assess whether there has been any impairment of renal function from chronic hypercalcemia.

Localization Studies Before Surgery

An important concept to understand is that imaging studies (sestamibi scan, ultrasound, CT, or MRI) are used for localization before surgery, not for diagnosis. You do not need a positive imaging study to diagnose primary hyperparathyroidism—the diagnosis is made by blood tests. However, if surgery is planned, these imaging studies help the surgeon locate the abnormal parathyroid gland(s) and plan a minimally invasive approach.

The sestamibi scan (also called parathyroid scintigraphy) involves injection of a mildly radioactive tracer that is preferentially taken up by overactive parathyroid tissue. The scan can identify the location of a parathyroid adenoma and help distinguish single-gland from multi-gland disease. Ultrasound of the neck is a non-invasive option that can identify enlarged parathyroid glands adjacent to the thyroid. Often, both sestamibi scan and ultrasound are performed, as concordant positive results increase confidence in the adenoma location.

How Is Primary Hyperparathyroidism Treated?

Surgery (parathyroidectomy) is the only definitive cure for primary hyperparathyroidism, with cure rates exceeding 95%. However, not all patients need immediate surgery. Treatment options include: (1) Surgical removal of the overactive gland(s), (2) Active surveillance with regular monitoring for mild asymptomatic cases, or (3) Medical management with medications to lower calcium or protect bones when surgery is not possible.

The management of primary hyperparathyroidism depends on whether the patient has symptoms, the severity of biochemical abnormalities, and the presence of target organ damage. The treatment approach has been refined over decades based on accumulated evidence, leading to clear guidelines on who should undergo surgery and who can safely be observed. The fundamental decision is between surgical cure and conservative management.

For patients with symptomatic disease—including kidney stones, osteoporosis with fractures, neurocognitive symptoms significantly affecting quality of life, or severely elevated calcium—surgery is strongly recommended. For patients without obvious symptoms, guidelines have established specific criteria for recommending surgery based on age, calcium level, kidney function, and bone density. Even patients who don't meet surgical criteria can choose surgery if they prefer definitive treatment over ongoing monitoring.

Parathyroid Surgery (Parathyroidectomy)

Surgical removal of the abnormal parathyroid tissue—parathyroidectomy—is the only treatment that cures primary hyperparathyroidism. When performed by an experienced surgeon, the procedure has an excellent success rate exceeding 95%, a low complication rate, and typically results in rapid normalization of calcium and PTH levels. Most patients experience improvement in symptoms within days to weeks after surgery, with continued improvement in bone density over the following years.

The traditional approach to parathyroid surgery involves bilateral neck exploration, where the surgeon examines all four parathyroid glands and removes the abnormal one(s). However, advances in preoperative imaging and intraoperative PTH monitoring have enabled minimally invasive approaches for suitable candidates. Minimally invasive parathyroidectomy (MIP), also called focused or targeted parathyroidectomy, involves a smaller incision and direct approach to the abnormal gland identified on preoperative imaging. This approach is appropriate when imaging clearly identifies a single adenoma.

The choice of surgical approach depends on several factors including localization study results, likelihood of multi-gland disease, surgeon experience, and patient preference. Regardless of approach, the key to successful surgery is an experienced parathyroid surgeon. Studies consistently show that surgeons who perform high volumes of parathyroid operations have better outcomes with fewer complications.

When Is Surgery Recommended?

International guidelines have established criteria for recommending surgery in patients with asymptomatic primary hyperparathyroidism. Surgery is recommended if any of the following are present:

• Serum calcium more than 1 mg/dL above normal (e.g., calcium >11.5 mg/dL when upper normal is 10.5)
• Bone density T-score ≤-2.5 at any site (spine, hip, or forearm) or vertebral fracture on imaging
• Kidney stones or nephrocalcinosis documented on imaging
• Reduced kidney function with estimated GFR <60 mL/min
• 24-hour urine calcium >400 mg/day with increased stone risk
• Age under 50 years (younger patients benefit most from early surgery)

Importantly, patients who do not meet these criteria but prefer surgery over ongoing monitoring are also appropriate candidates. Quality of life considerations, patient preference, and the safety of modern parathyroid surgery all factor into the decision. Many experts increasingly recommend surgery for all patients fit for surgery, given the excellent cure rate and the potential for subtle symptoms to improve.

Active Surveillance (Watchful Waiting)

For patients with mild, asymptomatic primary hyperparathyroidism who do not meet surgical criteria and prefer not to have surgery, active surveillance is a reasonable option. This approach involves regular monitoring rather than immediate treatment, with the understanding that surgery may become necessary if the condition progresses or complications develop.

Active surveillance typically includes annual measurement of serum calcium and PTH, annual kidney function assessment (creatinine, estimated GFR), bone density scanning every 1-2 years, and periodic kidney imaging to check for stones. If monitoring reveals progression—worsening calcium levels, declining bone density, new kidney stones, or declining kidney function—surgery should be reconsidered.

Long-term studies of patients managed with surveillance show that approximately one-quarter to one-third will eventually develop indications for surgery over 10-15 years of follow-up. Most patients who don't progress can continue to be monitored safely, though they should understand that the condition will not resolve on its own without surgery.

Medical Management

Medications do not cure primary hyperparathyroidism but can help manage the condition in patients who cannot or choose not to have surgery. Cinacalcet (Sensipar) is a calcimimetic drug that acts on calcium-sensing receptors to reduce PTH secretion and lower calcium levels. It is approved for use in PHPT when surgery is not an option. While effective at controlling calcium levels, cinacalcet does not improve bone density and may cause gastrointestinal side effects.

Bisphosphonates (such as alendronate) and denosumab are anti-resorptive medications that can help preserve bone density in patients with hyperparathyroidism-related osteoporosis who cannot have surgery. These medications do not address the underlying parathyroid disease but can reduce fracture risk. Adequate vitamin D and calcium intake should be maintained, with guidance from a healthcare provider regarding appropriate levels.

When Should You See a Doctor?

See a doctor if routine blood tests show elevated calcium, or if you experience unexplained fatigue, frequent urination, excessive thirst, kidney stones, bone pain, or depression. Seek immediate medical attention for severe symptoms including confusion, extreme weakness, irregular heartbeat, or severe dehydration—these may indicate dangerously high calcium requiring urgent treatment.

Most people with primary hyperparathyroidism are identified through abnormal routine blood work rather than presenting with obvious symptoms. If your blood tests show an elevated calcium level, follow-up testing including PTH measurement should be performed to determine the cause. Even mildly elevated calcium warrants evaluation, as early diagnosis allows for appropriate monitoring or treatment before complications develop.

You should contact your healthcare provider if you experience symptoms that could be related to high calcium, including persistent fatigue, increased thirst and urination, constipation, bone or joint pain, depression or mood changes, difficulty concentrating, nausea, and muscle weakness. While these symptoms have many possible causes, they warrant evaluation—particularly if multiple symptoms occur together.

If you have been diagnosed with primary hyperparathyroidism and are being monitored, contact your healthcare provider if symptoms develop or worsen, as this may indicate disease progression requiring treatment. Keep your scheduled monitoring appointments, as changes in calcium, kidney function, or bone density may occur without obvious symptoms.

What Are the Complications of Untreated Hyperparathyroidism?

Untreated primary hyperparathyroidism can lead to serious complications including osteoporosis and fractures, kidney stones and chronic kidney disease, cardiovascular problems, and cognitive decline. Early treatment—particularly surgery—can prevent or reverse many of these complications, which is why timely diagnosis and management are important.

While many patients with primary hyperparathyroidism have mild disease that may not progress significantly, the condition does carry risks if left untreated over the long term. The chronically elevated calcium and PTH levels can affect multiple organ systems, sometimes causing irreversible damage. Understanding these potential complications helps inform treatment decisions.

Skeletal complications are among the most significant. Persistent elevation of PTH causes ongoing bone resorption, leading to reduced bone mineral density and osteoporosis. This increases the risk of fragility fractures, particularly of the spine, hip, and wrist. Fractures in the elderly can have serious consequences, including prolonged disability, loss of independence, and increased mortality. The good news is that bone density typically improves significantly following successful parathyroidectomy, and fracture risk decreases.

Kidney complications include kidney stones, which can cause severe pain, urinary tract infections, and potentially kidney damage. More concerning is the risk of nephrocalcinosis and chronic kidney disease from prolonged hypercalcemia. Kidney function may be partially recoverable if treated early but can become permanent if the condition goes untreated for many years.

Cardiovascular effects of hyperparathyroidism are an area of active research. Elevated PTH and calcium have been associated with increased cardiovascular mortality, hypertension, and cardiac structural changes including left ventricular hypertrophy. Some studies suggest improvements in cardiovascular parameters after parathyroidectomy, though this remains an area of ongoing investigation.

Living with Primary Hyperparathyroidism

If you have been diagnosed with primary hyperparathyroidism, stay well hydrated (2-3 liters daily), avoid vitamin D supplements unless prescribed, do not take calcium supplements unless advised, keep scheduled monitoring appointments, and discuss any new or worsening symptoms with your doctor. Exercise regularly to help maintain bone health.

Whether you are awaiting surgery, being monitored with active surveillance, or managing the condition medically, certain lifestyle measures can help minimize risks and maintain your health. These recommendations apply to most patients with hyperparathyroidism, though individual advice may vary based on your specific situation.

Adequate hydration is particularly important because elevated calcium can impair the kidneys' ability to concentrate urine, leading to fluid loss. Aim to drink at least 2-3 liters (8-12 glasses) of water daily unless you have a medical condition requiring fluid restriction. Good hydration also helps reduce the risk of kidney stone formation by diluting the calcium in your urine.

Dietary calcium does not need to be severely restricted. While it might seem logical to avoid calcium when your blood calcium is high, extreme calcium restriction can actually stimulate PTH production further and deprive your bones of needed nutrients. Moderate dietary calcium intake (about 1000 mg daily from food sources) is generally recommended. However, calcium supplements should typically be avoided unless specifically recommended by your healthcare provider.

Vitamin D supplementation is a nuanced topic in hyperparathyroidism. While many patients with PHPT are vitamin D deficient and may benefit from supplementation to normalize vitamin D levels, high-dose vitamin D can raise calcium further. Work with your healthcare provider to determine if vitamin D supplementation is appropriate for you and at what dose.

Regular weight-bearing exercise helps maintain bone health and is recommended unless contraindicated for other reasons. Walking, jogging, dancing, tennis, and other activities that put stress on the bones can help maintain bone density. Discuss appropriate activities with your healthcare provider, especially if you already have significant osteoporosis.

Pregnancy and Primary Hyperparathyroidism

Primary hyperparathyroidism during pregnancy requires careful management due to risks to both mother and baby. Talk to your doctor before becoming pregnant if you have PHPT. Surgery may be recommended before pregnancy or during the second trimester. Mild cases may be managed conservatively with close monitoring and adequate hydration.

Primary hyperparathyroidism complicates approximately 1 in 1000 pregnancies and requires special consideration due to potential risks to both mother and fetus. Untreated hyperparathyroidism during pregnancy has been associated with maternal complications (hypercalcemic crisis, kidney stones, pancreatitis) and fetal/neonatal complications (low birth weight, preterm birth, and neonatal hypocalcemia due to suppression of the baby's parathyroid glands).

If you have primary hyperparathyroidism and are planning pregnancy, discuss this with your healthcare provider. Surgery before pregnancy may be recommended to eliminate the risk during pregnancy. If surgery is needed during pregnancy, the second trimester is generally considered the safest time to operate, when the risks of anesthesia and surgery are lowest for both mother and fetus.

For women with mild hyperparathyroidism during pregnancy, conservative management with close monitoring may be appropriate. This includes regular calcium level checks, adequate hydration, and avoidance of thiazide diuretics (which raise calcium). Calcium levels often improve somewhat during pregnancy due to increased blood volume and calcium transfer to the fetus, but careful monitoring remains essential.

After delivery, if you have untreated hyperparathyroidism, your baby should be monitored for neonatal hypocalcemia. The baby's parathyroid glands may have been suppressed by exposure to high calcium levels in utero and may take several days to begin functioning normally. Most cases are mild and resolve spontaneously, but monitoring ensures any problems are identified and treated promptly.