Normocalcemic Hyperparathyroidism

What is Normocalcemic Hyperparathyroidism ?

Normocalcemic primary hyperparathyroidism (NHPT) is a recent categorization of primary hyperparathyroidism (PHPT). NHPT is a medical condition where there are high levels of parathyroid hormone (PTH) produced by one or more parathyroid glands. PTH is a hormone that regulates the amount of calcium in your blood and bones. However, despite the higher levels of PTH, the calcium levels in the blood remain normal when tested at least twice over a period of six months.

Before diagnosing NHPT, it’s necessary to rule out secondary hyperparathyroidism (SHPT). SHPT is a condition where the increase in PTH and growth of parathyroid glands is a response to low calcium levels in the blood – this could be due to various reasons such as low vitamin D levels or long-term kidney failure. In SHPT, elevated PTH levels will drop to normal when the cause of the low calcium is addressed. Oftentimes, people with long-term SHPT develop growth in all four parathyroid glands, which can progress to tertiary hyperparathyroidism. It’s important to properly identify SHPT through a detailed medical history, physical exam, and specific lab tests before concluding NHPT.

In terms of treatment, SHPT involves addressing the reasons for the low calcium levels that increase PTH. On the other hand, the treatment of NHPT is centered on correcting the issue in the abnormal parathyroid gland(s), which may involve removing the parathyroid gland surgically.

It’s also crucial to differentiate NHPT from PHPT, which is characterized by high calcium levels in the blood. Many patients diagnosed with NHPT eventually develop PHPT, which suggests that in some cases, NHPT might be an early form of PHPT. Predicting which patients will go on to develop the high calcium levels associated with PHPT is not possible. Consequently, doctors need to closely monitor blood calcium levels in these patients. The processes for diagnosing and treating NHPT and PHPT are very similar.

What Causes Normocalcemic Hyperparathyroidism ?

NHPT, a health condition that affects the parathyroid glands in your neck, can be caused by a single growth, multiple growths, or an overall increase in the size of these glands. It’s been noted that radiation to the neck can increase the chance of getting NHPT. In several studies, multiple growths in the parathyroid glands seem to increase the likelihood of NHPT.

SHPT, another health condition relating to these glands, can be caused by various factors including a lack of vitamin D, chronic kidney disease, conditions that prevent your gut from absorbing nutrients properly, surgeries for weight loss, long-term low calcium intake, and high levels of calcium in urine. In patients with chronic kidney disease, a lack of active vitamin D leads to a decrease in the amount of calcium absorbed in the gut. Consequently, the amount of calcium in blood reduces and triggers an increase in the secretion of parathyroid hormone. For individuals with this disease, treatment options can include vitamin D supplements to maintain a certain level of vitamin D in the blood, consumption of activated vitamin D, phosphate binders, and other types of medication to reduce the secretion of the parathyroid hormone. In severe cases, surgery to the parathyroid might be necessary.

There are additional causes of SHPT including older anti-seizure medications, celiac disease, and certain other medications like bisphosphonates, denosumab, diuretics, and lithium. If a medication is suspected to be causing high PTH levels, it can be verified by stopping the medication for a few months and then rechecking the PTH levels. If it was indeed the medication, then the levels should return to normal once it’s stopped. If not, there may be another cause.

In 1988, a theory suggested there are two stages to hyperparathyroidism: the first where PTH levels are high but calcium levels are normal and doesn’t usually cause symptoms, and the second where both calcium and PTH levels are high, which is known as classical PHPT.

Other potential causes of NHPT include partial resistance to parathyroid hormone, decreased production of a certain type of vitamin D in older individuals, and reduced responsiveness of parathyroid cells to calcium. PTH levels are not usually checked in patients with normal calcium levels, but recently, centers focusing on bone conditions have started assessing potential risk factors more proactively, helping identify people with NHPT.

A patient with developing PHPT might have an increase in their calcium and PTH levels but still fall within the normal reference range for the general population. Such an individual can be diagnosed with NHPT due to the high PTH level. Therefore, doctors should consider individual baseline values when assessing patients. This is important but can be challenging in practice. Moreover, about 2.5% of the population might show slightly high PTH levels without having any disease, as the normal range of PTH levels in a population follows a bell curve (a common type of distribution).

Risk Factors and Frequency for Normocalcemic Hyperparathyroidism

Normohyperparathyroidism (NHPT) is a medical condition that affects about 15.4% of all patients who also have primary hyperparathyroidism (PHPT). This mainly includes more women than men. Generally, around 0.4% to 0.6% of people suffer from NHPT. However, it can be difficult to measure exactly how many people have this condition because:

• Doctors don’t usually test for NHPT in patients with normal calcium levels in the blood. It’s more likely to be detected in patients with kidney stones or osteoporosis, which can cause a bias in detection.
• Different studies have used different measurement standards for evaluating NHPT. Therefore, accuracy can differ.
• Some research only looks at the total level of calcium in the body, without checking if the form of calcium that can easily interact with the body (ionized calcium) is too high.

There aren’t enough people with NHPT to properly investigate how it develops over time. Some people with normal calcium levels might show high levels of calcium when tested on a different day, which would change their diagnosis.

It’s also uncertain which patients with NHPT will develop classic PHPT and which ones won’t. We do know that the chances of this happening increase over time, especially for older patients who originally had higher levels of calcium in their blood and urine.

A few patients who don’t have high calcium levels but are undergoing surgery for thyroid issues may unexpectedly have issues with their parathyroid glands (parathyroid incidentalomas). They tend to be younger and have smaller parathyroid glands compared to those receiving surgery for confirmed classic PHPT. These incidentaloma patients also generally secrete less parathyroid hormone (PTH) than typical patients with NHPT.

No significant difference was found in terms of gender, type of cells involved, or prevalence in multiple glands between normocalcemic incidentaloma patients and those with classic PHPT. This suggests that NHPT could be an early stage or precursor to classic PHPT.

Signs and Symptoms of Normocalcemic Hyperparathyroidism

NHPT, or non-parathyroid hypercalcemia, often doesn’t show any symptoms. However, some people might experience fractures or kidney stones. Despite not showing symptoms, some individuals might still show abnormalities in their DEXA scan (a kind of bone density test) or renal (kidney) ultrasound. Some people with NHPT may also have high blood pressure or mental health symptoms, but it’s not clear if these are directly related to NHPT.

Clinical history should focus on potential causes of SHPT, or secondary hyperparathyroidism. Doctors should ask if there any symptoms that are indicative of celiac disease, previous stomach surgery, or other conditions that interfere with nutrient absorption. Information about estimated calcium intake, the risk of vitamin D deficiency, and a detailed history of medicines used should also be taken. In addition, if family members have had kidney stones or a history of early-onset osteoporosis, a search for family causes of PHPT (primary hyperparathyroidism) might be needed. It is also important to note that there have been infrequent cases of NHPT presenting as sudden parathyroid gland infarction (death of tissue due to lack of blood) or parathyroid cancer.

Testing for Normocalcemic Hyperparathyroidism

If you have osteoporosis or kidney stones, your doctor might suspect you have a condition called normocalcemic primary hyperparathyroidism (NHPT). To confirm this, they’ll examine your blood and urine for signs of the disease. These tests include checks for calcium, phosphate, kidney function, vitamin D levels, and calcium in your urine. If these tests suggest NHPT, your doctor will repeat them in six months to make sure the results are consistent. They might also use a calculation called the parathyroid function index to tell if you have NHPT or a similar condition called secondary hyperparathyroidism (SHPT). Once you’re diagnosed with NHPT, the doctor will guide your treatment based on guidelines for people with a related condition, hypercalcemic primary hyperparathyroidism.

Doctors also have to rule out other causes of your symptoms. For example, a lack of calcium can make it look like you have NHPT, when in fact you have SHPT. An oral calcium supplement can help to clarify your diagnosis. In some cases, you might need more testing. These could include challenging your body with a particular type of water pill called a thiazide, or using a calcium loading test.

NHPT is diagnosed using blood and urine tests, so you should not need imaging tests like ultrasounds or scans. However, if you need surgery or have other complications, imaging tests can help your doctor plan your treatment. The common tests in these cases are neck ultrasound and parathyroid nuclear medicine scans, which show how well the parathyroids are working. Unfortunately, these tests are not always reliable, especially for multiple gland disease or for NHPT. Imaging is best used as a guide for surgery.

Some reports suggest higher success with a test called four-dimensional computed tomography (4D-CT) and novel PET tracers. However, these tests can have their problems, such as limited availability, higher radiation exposure, and questionable accuracy. A magnetic resonance imaging (MRI) scan might be considered if the parathyroid scan and ultrasound are negative or disagree.

If your doctor finds that you have osteoporosis, they might give you a DEXA scan. This scan measures bone mineral density. You might also need renal imaging to look for calcium deposits in the kidneys. This can be done with an ultrasound, x-rays, or a CT scan.

Treatment Options for Normocalcemic Hyperparathyroidism

For patients who cannot or do not want to undergo surgery, a combination of different medications can be used to manage symptoms. These include bisphosphonates and calcimimetic drugs. Bisphosphonates, such as alendronate, have been found to increase bone mass density, which can be helpful for patients with bone loss. Calcimimetic drugs, like cinacalcet, work by lowering the levels of parathyroid hormone that high-risk patients have. These treatments are often beneficial, but more studies are needed to fully understand their effectiveness.

It’s important to note that while these medications can manage some symptoms of primary hyperparathyroidism, they do not fully replace the benefits offered by surgery. If symptoms continue to worsen, surgery is usually recommended. Doctors use different tools to monitor patients’ conditions, which can include measuring calcium and parathyroid hormone levels in blood, checking for kidney stones, and evaluating bone health.

Patients are also advised to have a healthy diet that meets the nutritional guidelines for calcium and vitamin D. Supplementing vitamin D, in particular, can be helpful, as studies have shown that it can reduce parathyroid hormone levels and improve bone health. However, all supplements should be taken under the direction of a healthcare professional.

Surgery is the most effective treatment for primary hyperparathyroidism. Minimally invasive techniques have been developed which can improve a patient’s bone density. However, the benefits of surgery go beyond just bone health – it can also decrease the risk of kidney stones. Experienced surgeons tend to achieve better outcomes, with patients experiencing fewer complications and shorter hospital stays.

While surgery can be very effective, it is important to know that it does not completely eliminate some problems associated with the condition, such as kidney stones and mental health issues. Nonetheless, it can dramatically decrease the frequency of these issues. It is also common for patients to have parathyroid hormone levels monitored during the surgery, using a rapid test which helps ensure all problematic tissue has been removed.

What else can Normocalcemic Hyperparathyroidism be?

Secondary Hyperparathyroidism (SHPT) is a condition that can give similar results to Non-classical Hyperparathyroidism (NHPT) in medical tests. This can make diagnosis difficult, and it is important to carefully consider and exclude SHPT before concluding that the cause of a patient’s symptoms is NHPT. Some of the possible reasons a person might develop SHPT include:

• A lack of calcium in the body
• Chronic kidney disease
• Hypercalciuria (high calcium in urine)
• Hypophosphatemia (low phosphorus in blood)
• Disorders that prevent proper absorption of nutrients
• Bariatric surgery
• Celiac disease
• Inflammatory bowel disease
• Specific medications like anticonvulsants (phenytoin, phenobarbital), bisphosphonates, denosumab, diuretics, and lithium
• Obesity
• Paget disease of bone
• Deficiency in vitamin D

Conditions causing hypercalciuria due to lack of calcium from too much sodium intake, drinking excess tea or coffee, or using loop diuretics (like furosemide) can lead to SHPT. Genetic testing can detect the rare genetic defects that cause hypercalciuria. Vitamin D deficiency can be due to not getting enough sunlight, a diet low in Vitamin D, not eating fortified foods, conditions causing poor absorption (including after bariatric surgery), and certain medications. Older adults, malnourished children, pregnant and lactating women, and patients with chronic kidney disease, especially in the early stages, are at a higher risk of vitamin D deficiency.

Lithium can affect the parathyroid glands’ response to calcium, leading to an increase in PTH release. This could result in classical PHPT. Certain medications, like cinacalcet, have been shown to effectively manage this condition.

NHPT can be very similar to SHPT in patients with chronic kidney disease, complicating the process of distinguishing between the two. NHPT requires the rule-out of all other possible causes of hyperparathyroidism. It can be challenging, if not impossible, to distinguish between NHPT and SHPT in chronic kidney disease patients when their GFR (a measure of kidney function) is less than 60 mL/min.

Some notable differences between NHPT and SHPT include:

• Patients with PHPT are more likely to have higher than normal calcium levels compared to those with SHPT.
• In NHPT, vitamin D levels are usually normal or high, but in SHPT due to chronic kidney disease, they are typically low.
• In NHPT, phosphate levels in the blood are usually low; in contrast, they tend to be high in SHPT due to chronic kidney disease.
• On a sestamibi scan, NHPT is more likely to show a hypersecreting parathyroid adenoma, while SHPT due to chronic kidney disease often shows parathyroid hyperplasia.

What to expect with Normocalcemic Hyperparathyroidism

Patients who undergo surgery for NHPT (Non-classical Hyperparathyroidism) generally experience good outcomes; they can avoid potential complications and increase the density of their bones. Recently developed, minimally invasive surgical techniques for parathyroids are less intrusive and typically have shorter operating times and fewer potential complications. Having the serum PTH (parathyroid hormone) levels closely monitored during the surgery has been linked to better patient outcomes.

However, even when the surgery is conducted by experienced surgeons, there can sometimes be operation failures or early recurrences of the issue. This can happen due to the challenge of locating smaller adenomas (a kind of benign tumor) and due to a higher possibility of having multiple parathyroid adenomas in NHPT. As an indicator of a successful surgery, the PTH level usually drops by more than 50% from the baseline level.

Having high-normal serum calcium levels, high urinary calcium levels, and an advanced age have been shown to progressively lead to hypercalcemic PHPT, a condition of too much calcium in the blood. Current guidelines for monitoring patients who have hyperparathyroidism include yearly measurements of serum calcium, 25-hydroxyvitamin D (a form of Vitamin D that is measured in the blood to check Vitamin D levels), and creatinine clearance (a test to see how well the kidneys filter waste) with DXA scans (a type of x-ray that measures bone mineral density) repeated every 1-2 years. Depending on the individual patient’s needs, abdominal imaging and 24-hour urine for calcium tests might also be necessary.

Possible Complications When Diagnosed with Normocalcemic Hyperparathyroidism

People with NHPT, a form of hyperparathyroidism, often have a more severe condition that affects multiple glands. This typically requires a more extensive surgical procedure, known as bilateral neck exploration. While surgery can lead to complications such as injury to a particular nerve in the throat, bleeding in the wound, and a decrease in calcium levels after the operation, these side effects are rare when the surgery is performed by an experienced parathyroid surgeon.

However, NHPT patients who undergo surgery generally have a higher chance of needing an additional operation – over twice as likely than those with hypercalcemic PHPT, another type of hyperparathyroidism. After surgery, they are also more likely to suffer from permanently low calcium levels, with around 11.4% affected compared to 1.4% of hypercalcemic PHPT patients. Roughly 25% of people with NHPT may experience kidney stones or kidney calcification.

Unlike patients who are suitable for surgery, those who are not may see an increase in calcium levels and bear a higher risk for kidney calcification and loss in bone mineral density. Hence, it’s important these individuals continue to be checked for these possible developments.

Possible Side Effects:

• Injury to the recurrent laryngeal nerve
• Bleeding at the site of the wound
• Decreased calcium levels after surgery
• Increased likelihood of needing another surgery
• Persistent lower calcium levels post-surgery
• Kidney stones
• Kidney calcification
• Increase in calcium levels for those not suitable for surgery
• Risk of kidney calcification in non-operative cases
• Loss in bone mineral density in non-operative cases

Preventing Normocalcemic Hyperparathyroidism

For patients with NHPT (a condition where the parathyroid glands are not working properly), it’s very important to understand how the parathyroid glands function independently and what it means if they’re producing too much PTH (parathyroid hormone). When a surgery is proposed as treatment, doctors should provide a detailed conversation about everything involved. This should include using visual aids like models and videos of the operation, clear discussions about any potential complications that might happen after surgery, how long the recovery period could be, and a straightforward but thorough explanation of the technology used in the surgery.

When patients with NHPT are selected for regular check-ups as opposed to surgery, it’s critical for them to learn about the importance of these frequent check-ups, the risks of having too much calcium in the blood (hypercalcemia), the possible problems that can arise from having too much parathyroid hormone, and the ways to ensure they’re getting enough calcium and vitamin D. Patients taking medicines to prevent bone loss (antiresorptive medications) must be guided properly about how much to take, how and when to take it, possible side effects, how long they’ll need to take it, how often they need to come back for check-ups, and what tests will be needed during these appointments. The doctor or medical staff should adapt their teaching method based on the patient’s ability to understand health information and services.