Understanding Primary Hyperparathyroidism: A Patient's Guide to Diagnosis and Treatment

Table of Contents

• The Clinical Problem
• Symptoms and Presentation
• Potential Complications
• Diagnosis and Evaluation
• Surgical Treatment Options
• Medical Management Approaches
• Clinical Recommendations
• Important Limitations
• Source Information

The Clinical Problem

Primary hyperparathyroidism occurs when one or more of your four parathyroid glands become overactive, producing too much parathyroid hormone (PTH). This leads to elevated calcium levels in your blood. In healthcare systems where routine blood testing is common, most patients are diagnosed with mild-to-moderate hypercalcemia (high blood calcium) along with inappropriately normal or high PTH levels.

The condition affects women more frequently than men, with an estimated incidence of 66 cases per 100,000 person-years in women compared to 25 per 100,000 in men. Approximately 50% of patients with mild-to-moderate hypercalcemia undergo surgical treatment, and studies show that 30-40% of remaining patients eventually require surgery within 15 years of follow-up.

About 80% of patients have a single parathyroid adenoma (benign tumor), while 10-11% have multiple adenomas. Less than 10% have hyperplasia of all four glands, and parathyroid carcinoma causes fewer than 1% of cases. The presentation varies significantly based on healthcare resources available, with patients in resource-limited settings typically presenting with more advanced disease.

Symptoms and Presentation

In well-resourced healthcare systems, fewer than 20% of patients present with obvious symptoms. When symptoms do occur, they can include:

• Fatigue and general weakness
• Depression and anxiety
• Memory problems and difficulty concentrating
• Constipation (especially with moderate-to-severe hypercalcemia)
• Bone pain or fractures
• Kidney stones and renal colic (pain from stones moving through urinary tract)

Severe symptoms like obtundation (reduced alertness) or significant neuromuscular weakness are very uncommon and usually associated with large adenomas or parathyroid cancer. Patients may also experience increased thirst and frequent urination due to the effects of high calcium levels.

It's important to note that while many patients report neuropsychiatric symptoms, a direct causal link between these symptoms and parathyroid disease remains uncertain. Dehydration or immobilization can worsen hypercalcemia, so maintaining good hydration is particularly important for patients with this condition.

Potential Complications

Primary hyperparathyroidism can lead to several serious complications if left untreated. The most significant concerns involve your bones and kidneys.

Bone Loss and Fracture Risk

Your skeletal health is significantly affected by hyperparathyroidism. Research shows that 23% of patients have bone density values in the femur that are less than 80% of normal, while 58% show reduced bone density in the radius compared to age-matched healthy individuals. Another study found that 15% of patients had osteopenia in the lumbar spine.

A more recent study of 4,016 patients undergoing bone density measurements found that 451 had significantly low bone mineral density, and among these, 52 patients (12%) had primary hyperparathyroidism. This suggests the condition is more common among people with low bone density than previously recognized.

Bone mass typically declines slowly in hyperparathyroidism patients. During a 15-year observational study, spinal bone mineral density was preserved while bone density in the femoral neck and radius gradually declined. Importantly, studies have shown increased risk of fractures in the spine, wrist, rib, and pelvis. The risk of hip fracture may also be increased, though the evidence is less conclusive.

Kidney Stones and Renal Complications

Symptomatic kidney stone disease occurs less frequently than in the past in well-resourced healthcare systems, but remains a significant concern. A U.S. study found that 3% of 1,190 adults evaluated for kidney stones had hyperparathyroidism. The estimated prevalence of radiographically identified kidney stones among hyperparathyroidism patients ranges from 7-20%.

Patients with hyperparathyroidism and kidney stones tend to have higher 24-hour urinary calcium levels and higher serum 1,25-dihydroxyvitamin D levels compared to the general population with stones. Other risk factors include hypocitraturia (low citrate in urine) and hyperoxaluria (high oxalate in urine). The type of stones also matters—patients with mixed calcium oxalate-apatite stones or pure apatite stones are more likely to have hyperparathyroidism.

Cardiovascular and Neuropsychiatric Concerns

Patients with primary hyperparathyroidism may experience higher rates of hypertension, changes in left ventricular mass and function, and other adverse cardiac changes. Observational studies have reported increased risks of death from any cause and specifically from cardiovascular causes.

Depression, anxiety, and cognitive difficulties are frequently reported, though the exact relationship between these symptoms and parathyroid disease remains uncertain. Some studies suggest these symptoms may improve after successful treatment, but the evidence is not consistent.

Diagnosis and Evaluation

The diagnosis of primary hyperparathyroidism is based on finding elevated blood calcium levels with inappropriately normal or high parathyroid hormone levels. Your doctor will typically order several tests to confirm the diagnosis and assess complications.

The evaluation should include:

• Serum calcium levels (usually elevated)
• Intact parathyroid hormone levels (inappropriately normal or high)
• 25-hydroxyvitamin D levels (usually normal or low-normal)
• Glomerular filtration rate (kidney function)
• 24-hour urine calcium excretion
• Bone density measurement (including the distal third of the radius)
• Renal ultrasound to detect stones if there's clinical concern

It's important to distinguish primary hyperparathyroidism from other conditions that can cause high PTH levels, including:

• Secondary hyperparathyroidism (response to low calcium from vitamin D deficiency or kidney disease)
• Familial hypocalciuric hypercalcemia (a genetic condition usually not requiring treatment)
• Genetic syndromes like multiple endocrine neoplasia types 1 and 2
• Medication effects (long-term lithium therapy can cause similar findings)

Surgical Treatment Options

Surgery remains the only definitive treatment for primary hyperparathyroidism. Current guidelines recommend surgery for:

• Patients younger than 50 years
• Those with serum calcium more than 1.0 mg/dL above the upper normal limit
• Postmenopausal women and men over 50 with bone density T-scores of -2.5 or lower at central sites or the distal radius
• Patients who have had a recent fragility fracture
• Those with glomerular filtration rate below 60 mL/minute
• Patients with kidney stones
• Those with 24-hour urine calcium over 400 mg/day

Several imaging methods help surgeons locate abnormal parathyroid tissue before surgery:

During surgery, surgeons often use intraoperative PTH measurements to confirm they've removed all abnormal tissue. The PTH level should drop by at least 50% and into the normal range after removing the affected gland(s). In expert centers, cure rates exceed 95%.

Possible complications include recurrent laryngeal nerve injury (affecting voice, occurring in less than 1% of cases), wound infection, bleeding, and temporary hypocalcemia (low calcium) occurring in 15-30% of cases. Temporary hypocalcemia can usually be managed with calcitriol and calcium supplements.

Medical Management Approaches

For patients who cannot or choose not to undergo surgery, several medical approaches can help manage the condition. Monitoring recommendations include annual serum calcium measurements and bone density measurements every 1-2 years.

Medical therapies focus on three main areas:

Addressing Hypercalcemia

Cinacalcet is a medication that can lower serum calcium levels by increasing the sensitivity of calcium-sensing receptors. However, it doesn't prevent bone loss or reduce fracture risk. It's primarily used for patients with significant hypercalcemia who aren't surgical candidates.

Managing Bone Disease

Bisphosphonates can improve bone density in patients with hyperparathyroidism, but whether they actually reduce fracture risk remains unknown. These medications are typically used cautiously since bone density often improves significantly after successful surgery alone.

Studies show that surgical cure typically results in 2-4% increases in bone mass during the first postoperative year. Therefore, except in severe cases, doctors usually wait to see how much bone mass improves naturally after surgery before starting antiosteoporotic medications.

Nutritional Support

Addressing vitamin D and calcium deficiencies is crucial since these deficiencies can worsen hyperparathyroidism. However, supplementation must be carefully managed under medical supervision to avoid exacerbating hypercalcemia or hypercalciuria (excess calcium in urine).

Patients should maintain adequate but not excessive calcium intake (usually 1000-1200 mg/day from all sources) and ensure sufficient vitamin D levels (target 25-hydroxyvitamin D above 20 ng/mL).

Clinical Recommendations

Based on the current evidence, here are the key recommendations for patients with primary hyperparathyroidism:

1. Complete comprehensive evaluation including calcium, PTH, vitamin D levels, kidney function tests, 24-hour urine calcium, bone density measurement (including forearm), and renal ultrasound if stone symptoms are present
2. Consider surgical consultation if you meet any of these criteria:
   • Age under 50 years
   • Calcium level >1.0 mg/dL above normal range
   • Bone density T-score ≤ -2.5 at spine, hip, or forearm
   • History of fragility fracture
   • Kidney stones
   • 24-hour urine calcium >400 mg/day
   • Reduced kidney function (GFR <60 mL/minute)
3. For non-surgical candidates, medical management should include:
   • Regular monitoring of calcium and bone density
   • Addressing vitamin D and calcium deficiencies
   • Consideration of cinacalcet for significant hypercalcemia
   • Possible bisphosphonate therapy for osteoporosis
4. Lifestyle modifications including:
   • Maintaining good hydration
   • Moderate calcium intake (1000-1200 mg/day)
   • Adequate vitamin D supplementation to maintain levels >20 ng/mL
   • Regular weight-bearing exercise to support bone health

Important Limitations

While we have good evidence for many aspects of hyperparathyroidism management, several important questions remain unanswered:

The relationship between hyperparathyroidism and neuropsychiatric symptoms remains uncertain. Randomized controlled trials haven't consistently shown improvement in cognitive and emotional symptoms after surgical cure, though some patients report subjective improvement.

Similarly, whether surgery reduces cardiovascular risks associated with hyperparathyroidism remains unclear. Observational studies and follow-up data from randomized trials have shown no significant improvement in blood pressure or metabolic markers after surgery, with only modest changes in heart function measures at most.

The long-term benefits of medical management versus surgical treatment continue to be studied, particularly for patients with mild disease. The decision between surgery and monitoring should be made through detailed discussion with your healthcare team, considering your individual risk factors, preferences, and overall health status.

Source Information

Original Article Title: Primary Hyperparathyroidism

Authors: Karl L. Insogna, MD

Publication: The New England Journal of Medicine, September 13, 2018

DOI: 10.1056/NEJMcp1714213

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It maintains the full content and scientific accuracy of the original publication while making the information accessible to patients and their families.