Normocalcemic Primary Hyperparathyroidism (nPHPT)
Normocalcemic hyperparathyroidism was first described in the late 1960’s & formally recognized as a disease entity in the Third International Workshop on Management of Asymptomatic PHPT in 2008. Since that time it has been the subject of much controversy and heartache. It describes a version of hyperparathyroidism where the calcium is in the normal range and the parathyroid hormone (PTH) is consistently elevated. As it is a version of hyperparathyroidism it can present with lots of symptoms, be accompanied by kidney stones & osteoporosis, or be without any symptoms (asymptomatic).
Other Causes of High PTH Levels
There are many other conditions that can mimic Normocalcemic PHPT’s biochemical presentation of normal calcium levels and elevated PTH levels. Table 1 shows these potential conditions or causes:
Table 1: Other Causes of High PTH Levels
Cause of Secondary HPT
Biochemical Marker
Treatment
Vitamin D Deficiency
25 (OH) Vit D3
Vitamin D3 Supplementation
Low Calcium Intake
Low Serum & 24 hour Urine Ca
Diet Modification Ca Supplementation
Low Magnesium
Serum Magnesium level
Magnesium Supplementation
Renal Ca Leak
(Renal Tubular Dysfunction)
Normal Serum Ca,
Hypercalciuria
Long History of Kidney Stones
HCTZ
Reduced Kidney Function
GFR<60
Treat Kidney Issues
Malabsorption
Tissue Transglutaminase Antibody Elevated
Target Therapy
Activated Vitamin D Issues
Possible Low 1,25(OH) Vitamin D
Rocalcitrol
Medications
- Lithium
- HCTZ
- Bisphosphonates
- Tamoxifen
- Denosumab
Stop or Change Meds
How Does Normocalcemic pHPT Differ from Hypercalcemic pHPT
1. How Do the Parathyroids Work?
Under normal circumstances healthy parathyroid glands are set to try to achieve a certain calcium level (that is genetically determined). This means our genes determine what the calcium number is and all our life our parathyroid glands will try to maintain our blood calcium level very close to this number (called the Calcium Set Point). So in Graph 1, the calcium set point is 9.0 and if the blood calcium level goes below that number, let’s say 9.4, then the parathyroid glands produce 30% more PTH to bring the calcium back up to 9.5 Graph 2. And if the blood calcium level goes up to 9.7 then significantly less PTH is released by the parathyroid glands to allow the calcium level to go back down to 9.5.
2. How Does A Parathyroid Adenoma Develop?
When a person gets pHPT caused by a parathyroid adenoma, it is as a consequence of getting a mutation in one single parathyroid cell in one gland that causes a change in the Calcium Set Point; as demonstrated in Graph 5, the Calcium Set Point for the one abnormal cell is 11.0. That cell will do its best to bring the calcium level up to 11.0. As it works harder and harder it will multiply more and more until it becomes millions of copies (clones) of abnormal cells clumped together called a parathyroid adenoma. As the parathyroid adenoma gets larger at some point it can produce enough PTH to elevate the calcium to the higher Calcium Set Point (11.0) and essentially hijack the parathyroid hormonal system.This tumor doesn’t realize it’s making a mistake and will work relentlessly to bring your calcium up and maintain it close to 11.0, the new set point.
3. How Does Normocalcemic pHPT Develop?
If the Calcium Set Point change happens to be outside the normal laboratory range (green area in the graphs 6-9) then that person will be seen to have high calcium levels (Graph 6). If on the other hand, the Calcium Set Point change is for a number in the normal range then the person will have normal calcium levels and yet will still have hyperparathyroidism (Graph 7). Are these the same disease? Are the people who follow Graph 6 have more symptomatic then those on Graph 7? There are no clear answers to these very crucial questions. Some research points to them being the same, others show them to have dissimilarities. But one thing that can be said is that the amount of change in the calcium level along with the elevation of PTH is very similar or the same. The work by Dr. Anna Bargren shows that the calcium level does not necessarily correlate with development of symptoms. So the chemical change in the body is similar, and the chance of developing symptoms is similar.
So if someone who has normocalcemic pHPT waits long enough can they become hypercalcemic? Another important question that deserves a clear answer. It truly depends on where in the process of disease they are! If they have reached their ultimate Set Point & that number is in the normal range (Graph 7 & 9), then they will never become hypercalcemic. On the other hand, if their Set Point is above the normal range at 10.5 (Graph 8), but the tumor is still not large enough to be able to produce adequate amounts of PTH to reach the calcium level of 10.5, then this person may have a calcium of 10.0 (which is still in the normal range). However, given enough time, the tumor will continue to grow & until it can produce enough PTH for their calcium to rise and be above the normal range & at their Set Point of 10.5. In this scenario a “wait & see” approach may lead to the person ultimately becoming hypercalcemic (or have high blood calcium levels). However, does that change what the disease is? No, the person has hyperparathyroidism in either scenario. If the hyperparathyroidism is giving the person problems & symptoms then waiting for it to progress to higher numbers is inviting more problems. On the other hand, if the person has no symptoms, no kidney stones, & no bone loss then “waiting to see” what happens may be the prudent course. So basically must consider the whole person and the impact of this disease on their body, mind & quality of life.
4. How Does a Person Get Mild Normocalcemic pHPT?
Although in the textbooks and research projects Mild Hyperparathyroidism is described as not causing kidney stones, kidney malfunction, or osteoporosis; in practical terms mild hyperparathyroidism happens when the calcium level is only minimally higher then the normal calcium Set Point for an individual (Graph 9).
But it is hard to know what a person’s normal calcium Set Point is. The only way to find out is if the person has had multiple blood calcium tests in the distant past that show numbers in a certain narrow range. If the current calcium blood levels are consistently higher then the older numbers then it can be said that the person has minimal change or dramatic change in calcium levels. Unfortunately, blood calcium levels are not routinely tested, especially in the younger population to be available for later comparisons.
5. How Do You Diagnose Normocalcemic pHPT?
Figuring out if a person has normocalcemic hyperparathyroidism is like solving a mystery. You have to gather a lot of information and eliminate all other potential possibilities. I usually ask my patients for the following: 2 sets of labs (Calcium, PTH, & Vitamin D Levels) done fasting at 8 AM A comprehensive metabolic panel or CMP 24 hour urine calcium & creatinine collection Along with the labs to rule out other potential causes of high PTH levels shown on Table 1. I also ask my patients to search and see if they have old calcium blood tests to see if we can establish if the person had a much lower calcium set point in the past that now is consistently higher, indicating the set point alteration or hyperparathyroidism. This unfortunately is not always available, but can be very helpful.
Once these are done and you can determine if the person has normocalcemic pHPT or Secondary HPT due to the causes in Table 1., which are incidentally treatable without surgery. If it is determined that the person has primary normocalcemic hyperparathyroidism, then you have to have an extensive discussion about the path forward; do they have signs and symptoms the would make them a candidate for treatment or is it best to continue to monitor their health.
6. How Do You Treat Normocalcemic pHPT?
The treatment for Normocalcemic pHPT is exactly the same as for Hypercalcemic pHPT, parathyroidectomy. However, the challenge is to decide who is a good candidate for surgery. To come to this decision you and your physician need to gather a lot of data, as well as looking at the overall impact of this disease on your health & quality of life. If there has been an impact that you can clearly feel, then you have to rule out other potential causes, and then decide if considering the risks of surgery & potential benefits if it is worthwhile to have surgery. This is neither an easy decision, nor one to be taken lightly. That is when you need the support of family/friends & a physician you trust to help you put all the information in perspective & decide.
7. Case Example
This young man had been feeling of body aches and constipation for a long period of time. He had high blood pressure (hypertension – HTN) being controlled by medications. He suffered from depression & anxiety which had been progressive; he was taking anti-depressant medications without improvement. His routine blood tests were always normal.
He was playing ping pong with his daughter and felt a sharp pain in his wrist. The pain continued for the following week and x-ray revealed a fracture. Since there was no fall or heavy impact to cause the fracture a bone density study was done (DEXA scan) which revealed osteoporosis of the bones of the arm. Work up of premature osteoporosis includes checking Calcium & PTH which revealed the calcium to be normal but the PTH elevated. This was repeated multiple times and showed consistent elevation of PTH. All other causes of PTH elevation (Table 1.) were evaluated. None were present. Ultrasound showed a possible lesion on the right lower side & 4D parathyroid CT scan confirmed an enlarged parathyroid in the right lower location. He had a successful minimally invasive parathyroidectomy under local anesthesia with a small amount of sedation. During surgery the recurrent laryngeal nerve was identified. The enlarged parathyroid was found on the right. PTH levels were drawn before removal of the abnormal gland and afterwards. The PTH levels dropped appropriately indicating a successful surgery.
He went home shortly after surgery and began calcium, vitamin D & magnesium supplement. His aches immediately felt better, and the remaining symptoms continued to improve over time. He stopped taking the anti-depressants, and felt very little anxiety. His blood pressure was better but still elevated.
Why are endocrinologists unlikely to send these patients for treatment ?
Because these is great controversy surrounding this diagnosis and the need for treatment. So unless these patient have kindly stones or osteoporosis their advice is generally that they are not sure if the other symptoms will improve with surgery for normocalcemic hyperparathyroidism.
What are the long term consequences of not treating normocalcemic primary hyperparathyroidism ?
Based on the current data, the only clear answer to this question is that not treating any form of hyperparathyroidism leads to continued bone loss. More research needs to be done to be able to delineate which patients will need treatment and which ones are better serve by being monitored. It is likely that people who have mild normocalcemic hyperparathyroidism (as described in section 4. above) will not have so much in terms of symptoms or bone loss. While as the gap between the person’s abnormal calcium level and the original calcium setpoint increases the number of symptoms and their severity increases.
In contrast the work by Dr. Jens Bollerslev shows that the quality of life of people with minimal blood calcium elevation above normal laboratory values (not setpoint) is only minimally improved, if at all with treatment over a 2 year period. However this quality of life test was not specific for parathyroid symptoms, and the patients were not separated between those who
were complaining of symptoms & those who had no complaints at all.
In another study Dr. Bollerslev looked at the effect on bone density, and just monitoring patients with minimal calcium evaluation lead
to
continued bone loss.
So basically it is uncertain who gets better with surgery, but for sure the bone density improves for all that treat hyperparathyroidism. No treating it however can lead to continued bone loss.
Why do the UK NICE guidelines for treatment of Hyperparathyroidism avoid taking about Normocalcemic pHPT?
UK guidelines recommend that all patients with calcium elevation and diagnosis of pHPT be treated & have parathyroidectomy. They base it on the fact that progression of disease is seen to have an impact on bone density & quality of life. It is also more costly to follow these patients with serial labs, & scans in their lifetime; a lot less expensive to do surgery. So basically ultimately the decision is a financial & societal one for the people who high calcium level. However, since the normocalcemic pHPT patients may have minimal set point alteration, and it may not be clear how severe their disease is, the doctors involved in making the NICE guidelines avoided talking about them. The normocalcemic patients need to be considered on an individual basis by a doctor that understands & takes an interest in these somewhat unusual cases to help them decide if surgery is potentially helpful.
Once you’ve decided that you need surgery, how do you pick your surgeon ?
These is no easy answer to this question, expect you want the surgeon that has a lot of experience doing parathyroid surgery, and takes a keen interest in taking care of hyper parathyroid patients. They should be doing more then 50 parathyroid surgeries a year. You have to feel that they really care about talking care of parathyroid patients. And ask them what their experience has been taking care of normocalcemic parathyroid patients. And most importantly, you have to feel that you can trust your surgeon; this relationship is very important. The recovery from parathyroid surgery can be somewhat unpredictable, and trusting your surgeon becomes very important also in the recovery please (you may need some guidance during the year after surgery to navigate your recovery).
Q & A
- Is it always possible to figure out if someone has primary normocalcemic pHPT?
We need to gather a lot information to be able to make this diagnosis with confidence. The more information that we have, and the more experienced your doctor the better are the chances of them being able to clearly come to a diagnosis.
- Who is qualified to help a person with Normocalcemic Primary Hyperparathyroidism come to the correct diagnosis?
All physicians, including primary or family doctors, endocrinologists & parathyroid surgeons are qualified. However, they really need to understand this condition and the many ways it can present itself! Coming to this diagnosis requires a comprehensive work up. If the work up seems to indicate that there is another potential cause for PTH elevation, then it needs to be treated & corrected. Once that is done if the PTH comes down into the normal range or the person’s symptoms resolve then there is no need anything further. However, if the treatment is successful in correcting the problem (such as magnesium deficiency – corrected by taking magnesium supplements) but the PTH doesn’t come down then the diagnosis of normocalcemic pHPT still exists for the person and needs to be treated.
This can be a long journey and it requires that the patient & doctor have a good trusting relationship. The doctor must convey to the patient what is involved from the beginning, and that it may take a while before they have a clear answer. This is essential for the peace of mind of the person who is suffering, so that they can prepare themselves.
- Why are endocrinologists unlikely to send these patients for treatment?
Because there is great controversy surrounding this diagnosis and the need for treatment. So unless these patients have kidney stones or osteoporosis their advice is generally that they are not sure if the other symptoms will improve with surgery for normocalcemic hyperparathyroidism.
- What are the long term consequences of not treating normocalcemic primary hyperparathyroidism?
Based on the current data, the only clear answer to this question is that not treating any form of hyperparathyroidism leads to continued bone loss. More research needs to be done to be able to delineate which patients will need treatment and which ones are better serve by being monitored.
It is Likely that people who have mild normocalcemic hyperparathyroidism (as described in section 4. above) will not have so much in terms of symptoms or bone loss. While as the gap between the person’s abnormal calcium level and the original calcium setpoint increases the number of symptoms and their severity increases.
In contrast the work by Dr. Jens Bollerslev shows that the quality of life of people with minimal blood calcium elevation above normal laboratory values (not setpoint) is only minimally improved, if at all with treatment over a 2 year period. However this quality of life test was not specific for parathyroid symptoms, and the patients were not separated between those who were complaining of symptoms & those who had no complaints at all.
In another study Dr. Bollerslev looked at the effect on bone density and found surgery lead to improvement of bone density, and just monitoring patients with minimal calcium elevation lead to continued bone loss. So basically it is uncertain who gets better with surgery, but for sure the bone density improves for all that treat hyperparathyroidism. Not treating it however can lead to continued bone loss.
- Why do the UK NICE guidelines for treatment of Hyperparathyroidism avoid talking about Normocalcemic pHPT?
UK guidelines recommend that all patients with calcium elevation and diagnosis of pHPT be treated & have parathyroidectomy. They base it on the fact that progression of disease is seen to have an impact on bone density & quality of life. It is also more costly to follow these patients with serial labs, & scans in their lifetime; a lot less expensive to do surgery. So basically ultimately the decision is a financial & societal one for the people who high calcium levels.
However, since the normocalcemic pHPT patients may have minimal set point alteration, and it may not be clear how severe their disease is, the doctors involved in making the NICE guidelines avoided talking about them. The normocalcemic patients need to be considered on an individual basis by a doctor that understands & takes an interest in these somewhat unusual cases to help them decide if surgery is potentially helpful.
- Once you’ve decided that you need surgery, how do you pick your surgeon?
There is no easy answer to this question, except you want the surgeon that has a lot of experience doing parathyroid surgery, and takes a keen interest in taking care of hyperparathyroid patients. They should be doing more then 50 parathyroid surgeries a year. You have to feel that they really care about taking care of parathyroid patients. And ask them what their experience has been taking care of normocalcemic parathyroid patients.
And most importantly, you have to feel that you can trust your surgeon; this relationship is very important. The recovery from parathyroid surgery can be somewhat unpredictable, and trusting your surgeon becomes very important also in the recovery phase (you may need some guidance during the year after surgery to navigate your recovery).