Normohormonal Primary Hyperparathyroidism (NHpHPT)
Normohormonal hyperparathyroidism (HPT) describes a version of hyperparathyroidism where the calcium is elevated and the parathyroid hormone (PTH) is mostly or always in the normal range. As it is a form of hyperparathyroidism it can present with lots of symptoms, be accompanied with kidney stones & osteoporosis, or be without any symptoms (asymptomatic).
Other Causes of High Calcium Levels
There are many other conditions that can mimic Normohormonal Hyperparathyroidism’s biochemical presentation of high calcium levels and normal PTH levels. Table 1. shows these potential conditions or causes:
Table 1
Causes of Hypercalcemia
HyperThyroidism
Adrenal Insufficiency
Pheochromocytoma
Bone Metastasis
Multiple Myeloma
Lithium
Theophylline
Medications
Omeprazole
Vitamin A
Calcium Carbonate (TUMS)
PTH Analogues (Forteo)
Foscarnet
Growth Hormone
Aromatase Inhibitors
Immobilization
TPN (Total Nutrition Intravenously)
How Does Normohormonal 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 Normohormonal pHPT Develop?
There are many different theories about how Normohormonal pHPT develops including 1) PTH hormones that is shaped differently or is just a fragment of PTH (so the blood test doesn’t detect it) but functions the same, 2) PTHrp, 3) antibodies that interfere with the blood test, 4) pulsatilla release of PTH & 5) increased sensitivity to PTH. Most of these theories have been disproven, and the most plausible possibility is that these patients are much more sensitive to PTH hormone and don’t require as much PTH to cause calcium level to rise. In hypercalcemic HPT (classic or textbook HPT) when the set point changes and a parathyroid adenoma develops the calcium/parathyroid curve shifts into the high calcium range (Graph 6). If you look at the calcium/PTH curve from a different perspective, by graphing calcium agains the amount of calcium produced by the tumor (Graph 7) rather then percentage of maximum PTH produced (Graph 6) then it becomes more clear how much more active a parathyroid adenoma is. It has much taller graph because it produces so much more PTH.
In normohormonal HPT when the set point changes and a parathyroid adenoma develops the calcium/parathyroid curve shifts into the high calcium range (Graph 9). This curve is no different the curve seen in hypercalcemic HPT (Graph 8) except in hypercalcemic HPT the PTH levels are you usually high & above normal levels going in this case up to 200 pg/ml, while in the normohormonal HPT case (Graph 9) the PTH is usually in the normal range and can
occasionally go up to 75. In other words when you look at the curve for the normal parathyroids on both these graphs ( Graph 8 & 9) the range of normal for PTH is very different for normohormonal HPT & hypercalcemic HPT; in the normohormonal HPT in Graph 9 the normal range of PTH hormone is 2-25, while in the hypercalcemic HPT Graph 8 the range is 15-65. Essentially the higher sensitivity for PTH hormone makes the range of normal for normohormonal hyperparathyroidism people is lower then others.
So if someone who has normohormonal HPT waits long enough can they develop high PTH? This is a very good question; if the person who has NHpHPT follows the curve ( ) in Graph 9 has a high part that is above normal (75 pg/ml) then at times the PTH will be high, while most of the time it’ll be in the normal range. On the other hand if the person has NHpHPT & follows the curve ( ) in Graph 10 has a high part (45 pg/ml) that is less the upper limit of normal (65 pg/ml), then the PTH will never be high. So a “wait & see” approach may lead to higher PTH numbers in the first scenario but never in the second scenario; it should only be used in a person who doesn’t have symptoms, kidney stones or osteoporosis.
4. How Do You Diagnose Normohormonal HPT?
Figuring out if a person has normohormonal 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 calcium levels shown on Table
1. This includes PTHrp, ACE levels, SPEP among others
Once these are done and you can determine if the person has normohormonal HPT or hypercalcemia due to one of the causes in Table 1. 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.
5. Case Example
This young woman had been having fatigue for a long time, and issues with focus and memory. She has been feeling body aches and & anxiety which had been progressive; she was taking anti-anxiety medications with little improvement. She felt unmotivated. She has had 2 episodes of kidney stones that were very painful and had passed in her urine without surgery. One occurred over 15 years ago, and one more recently.
This young woman had been having fatigue for a long time, and issues with focus and memory. She has been feeling body aches and & anxiety which had been progressive; she was taking anti-anxiety medications with little improvement. She felt unmotivated. She has had 2 episodes of kidney stones that were very painful and had passed in her urine without surgery. One occurred over 15 years ago, and one more recently. She had been having gradual increase in the calcium levels over many year, as noted on her yearly routine blood tests. She was told “let’s keep an eye on it” but nothing was ever done. After many years she became concerned about the high calcium levels and especially because she had passed a kidney stones recently, and was having progressive bone loss (osteoporosis). She discussed it with her urologist that was seeing her for the kidney stone. The urologist ordered calcium, PTH & Vitamin D blood test that showed her PTH is in the normal range (52 pg/ml). Because the PTH was normal the urologist surmised that the parathyroid glands are not involved. Although the first blood test indicated the PTH was normal, she knew & felt that something was not functioning well in her body. She continued to pursue it, seeing multiple physicians & specialists including rheumatologist, endocrinologist & a functional medicine physician. None were able to find a clear answer. She studied about parathyroids and finally came to us. We repeated the calcium, PTH & vitamin D blood tests twice more fasting and at 8 AM, to get more consistency.
As well as doing a comprehensive blood & urine test to rule out other potential causes of high blood calcium levels; none of the other conditions that could cause hypercalcemia were present. Both times she had high calcium levels, and PTH levels that were in the normal range. Very importantly the PTH although normal was never in the low normal range even though the calcium was high, this was a clue that the PTH is not being suppressed by the high calcium levels. Interestingly the activated 1,25 (OH) Vitamin D was high.As you recall, inactive vitamin D or 25 (OH) Vitamin D is transformed into the active 1,25 (OH) Vitamin D by PTH in the kidney.
So having high 1,25 (OH) Vitamin D points towards the PTH level being high in this person’s body, even though it isn’t high based on the laboratory normal range. Once we had determined that no other cause for high calcium exists, and that calcium was consistently elevated without other external influences we began our search to f ind the abnormal parathyroid. Ultrasound did not reveal an enlarged parathyroid. The 4D parathyroid CT scan showed an enlarged parathyroid in the left upper location next to the esophagus. She 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 left. PTH levels were drawn before removal of the abnormal gland and afterwards. The PTH levels dropped appropriately indicating a successful surgery.
She went home shortly after surgery and began calcium, vitamin D & magnesium supplements. Her body aches felt better shortly after surgery, and the remaining symptoms continued to improve over time. The more active she was the more she could sense the improvements. Her bone density showed a 12% improvement two years after surgery. And her blood test showed that her PTH had settled in a much lower number in the normal range.
FAQ (Frequently Asked Questions)
Is it always possible to figure out if someone has primary
normohormonal HPT?
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. It’s necessary to get multiple blood tests at different dates to see how the calcium, PTH, and Vitmain D respond to each other. The pattern becomes very important. However, there are infrequent cases when the person has a NHpHPT but their PTH levels are very low and becomes more difficult to diagnose.
Who is qualified to help a person with Normohormonal 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 calcium 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 medication induced high calcium- corrected by changing medications) but the PTH doesn’t come down then the diagnosis of normohormonal 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 really high calcium levels, kidney stones or osteoporosis their advice is generally that they are not sure if the other symptoms will improve with surgery for normohormonal hyperparathyroidism.
What are the long term consequences of not treating normohormonal 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. Having said that, a great majority of people suffering from NHpHPT have calcium levels that are not tremendously elevated, and may seem based on calcium numbers to have mild hyperparathyroidism. However, mild hyperparathyroidism should be a designation only to be held for people who have no symptoms or mild symptoms that don’t effect their quality of life. So if you are having symptoms that are related to HPT then you should pursue getting a corrected diagnosis, and discuss treatment with an expert.
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.
Do people with normohormonal hyperparathyroidism have a higher chance of having multi gland disease or hyperplasia?
In general, the chance of parathyroid hyperplasia increases when PTH levels are lower then 100 pg/ml. So the chance hyperplasia can be higher in normohormonal hyperparathyroid cases. However, despite the increased chance of hyperplasia the majority of people still have an adenoma. So a thorough investigation and accurate localization studies are very important.
Can the PTH level be below normal levels in a person suffering from normohormonal hyperparathyroidism?
Yes, it can. Remember this condition is most likely arising because your particular body is very sensitive to PTH, so it doesn’t need to be exposed to a lot of PTH to have the high PTH effect. In other words their particular range of normal instead of being like the rest of the population (15-65 pg/ml) is much smaller; as an example the range for an NHpHPT person could be 10-25 pg/ml. In people who are extremely sensitive their range could be even lower 3-10 pg/ml which is why the study of Cleveland Clinic showed a patient with a PTH of 5 having surgery and having a single adenoma.
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 normohormonal 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 normohormonal 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). I firmly believe it’s also crucial that your surgeon perform rapid intraoperative PTH testing, as the incidence of multi gland disease is higher and the size of parathyroid adenomas in people with NHpHPT is smaller. It adds a measure of security that the surgery was successful.
