Avoiding Pitfalls That Delay Diagnosis & Treatment of Primary Hyperparathyroid Disease is a series of blogs that we will posting in order to shed light on the most common issues patients face that delay diagnosis and surgical treatment.

#3 A doctor does not want to confirm the diagnosis or refer for surgery until the adenoma is visible on a scan. 

We often hear patients say that their physicians do not want to confirm the diagnosis until the adenoma is seen on a scan. However primary hyperparathyroidism is diagnosed biochemically through blood work.

A scan should not be necessary to confirm the diagnosis.

Learn more here:  The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism – October 2016

In other instances, patients report that the physician will confirm the diagnosis, but will not refer for surgery until a positive scan confirms the location of an adenoma.

Why is such an emphasis placed on a positive scan?

Surgeons who perform focused exploratory surgeries directed by preoperative localizing studies will want and need a scan to know exactly where they will find the adenoma(s), as the surgery is being directed by the localizing study.  GP’s and/or Endocrinologists understand this, so they may be reluctant to refer a patient for surgery until they are able to provide the surgeon with the information they believe is needed to move forward with surgery.

If a surgeon plans to perform a bilateral exploratory surgery, a scan may not be required. During a bilateral exploratory surgery, the surgeon plans to search for and assess all four glands. Every patient should be made aware that the amount of time spent exploring in the neck impacts how much scar tissue results. It requires an expert to locate these small glands, that are each the size of a grain of rice, without excessive exploring. 

Why is this important? Expert surgeons (those who perform a minimum of 50 parathyroidectomies a year) should have a high surgical success rate. Do not be shy about asking a surgeon the number of parathyroid surgeries they perform and their success rates. Unfortunately,  not all first surgeries are a success.  Should a second surgery becomes necessary, excessive scar tissue may prevent having a subsequent successful surgery. As a result of the scar tissue, a positive scan is almost always required for a re-operation if attempted. 

There are surgeons who are able to perform a 4-gland check without using the typical or traditional bilateral exploratory techniques. In our cases, a four-gland check was performed in approximately 20 minutes without the need to explore. A sestamibi scan was performed on the day of surgery only for the purpose of confirming that the adenoma(s) were not located in more unusual places, such as the chest or jaw. This generally confirms that the adenoma(s) and healthy glands, that will also be checked during the surgery, are located right behind the thyroid gland where they should be.

Parathyroid surgery is surgeon specific.  As always, it is important to advocate for yourself… ask questions to fully understand the surgical plan and the level of expertise of the surgeon.

Learn more about the various types of localizing studies on the American Association of Endocrine Surgeons Patient Education Site: http://endocrinediseases.org/parathyroid/diagnosis_localization.shtml

If you missed the previous blogs in the series Avoiding Pitfalls That Delay Diagnosis & Treatment of Primary Hyperparathyroid Disease here are the links to catch up…

#1. Your doctor reports your serum blood calcium is in “normal” range . What could be the problem? 

#2. Slightly elevated calcium values are ignored. 

Avoiding Pitfalls That Delay Diagnosis & Treatment is a series of blogs that we are posting to shed light on the most common issues patients face that delay diagnosis and surgical treatment of primary hyperparathyroid disease.

#2  The lab report your doctor is reviewing provides the correct range for your specific age, as normal ranges are dependent upon a person’s age. Your doctor casually mentions that your calcium values are just slightly elevated or at the upper limit of normal for your age but there is no need to be concerned. The doctor might even suggest that you cut back your consumption of calcium rich foods to see if that helps lower your calcium value. The doctor says they will make a note in your chart to keep an eye on it the next time you have lab work done.

Slightly elevated calcium should not be ignored. High serum blood calcium values are not caused by calcium rich foods! 

Based on reported patient experiences and our own, many doctors do not realize what mildly elevated calcium values mean and make light of it, if it is mentioned at all. In the meantime, it is often these elevated calcium values, that have been labeled as “mild” that are wreaking havoc on the patient’s health and causing some of the very symptoms the person is seeking help for.

Many of us have come to learn that we must advocate for ourselves. The first step is to become educated by always asking for a copy of our lab results. Any number above or below a range should be questioned. In the case of primary parathyroid disease, in order to advocate for ourselves we need to know what the upper limit of normal calcium is for our age. In our last blog post we discussed the primary reason why it is necessary to know the upper limit of serum calcium for our age. Knowing the upper limit for our blood calcium based on our age is so critical to making a proper diagnosis, that it merits repeating again.

Here is a link to a Hypercalcemia Calculator to discover your upper limit based on your age.

Mildly elevated calcium do as much damage to our bodies as higher values.  According to surgeons at the Norman Parathyroid Center who have gathered the largest databank of information based on treating thousands of cases per year….

Hypercalcemia complications develop over time. Thus the severity of hypercalcemia is related to how long you have calcium levels that are high, not how high it has become. A calcium of 10.5 is just as dangerous as a calcium of 11.5. Even “mild” hypercalcemia will lead to many other health problems if left untreated. It is the duration of hypercalcemia that matters, not the height of the calcium!  

If calcium values are above the upper limit for your age, then it would be wise to consider requesting a parathyroid hormone (PTH) test. Primary hyperparathyroid disease is diagnosed biochemically, through blood work. It is the relationship between serum blood calcium, PTH and Vitamin D from the same blood draw that enables a proper diagnosis.

Dr. Deva Boone MD, FACS,FACE

Vitamin D in Parathyroid Disease – The topic that generates the most confusion for parathyroid patients and their doctors is Vitamin D. Some of the interactions and concepts with Vitamin D are complex, but in this blog I hope to highlight a few principles that will help you understand this vitamin and its place in parathyroid disease.

Example –  Let’s review a pretty common scenario. Laura is a 54 year old woman recently told by her primary care physician, Dr. Smith, that she has low Vitamin D levels. Dr. Smith knows the importance of Vitamin D, so he prescribes the logical treatment for Vitamin D deficiency: Vitamin D supplementation. If Dr. Smith routinely checks a lot of different labs, he may even notice that Laura’s parathyroid hormone (PTH) level is a little high. Dr. Smith vaguely remembers something from his training about low Vitamin D levels leading to high PTH levels, and concludes that giving large doses of Vitamin D will fix Laura’s PTH levels in addition to her Vitamin D levels.

Common Error – Dr. Smith has just made the most common physician error that I see in treating patients with parathyroid disease. Dr. Smith means well, and a true Vitamin D deficiency can be treated with Vitamin D supplementation. Chronic Vitamin D deficiency can lead to a rise in PTH in certain circumstances. So what was the error?

To understand this, I need to back up a bit, and explain a few things about Vitamin D.

 Forms of Vitamin D – There are many different forms of Vitamin D. For our purposes, there are two forms that we need to focus on.

1.   25-hydroxyvitamin D (25-OH Vit D). This form is also called calcifediol or calcidiol – I will generally avoid using these names because they sound so much like “calcium” that it can be confusing. For the rest of the article, this will be called 25-OH Vitamin D or inactive Vitamin D. When your doctor checks your Vitamin D, this is the form that he or she is usually checking (usually not any of the other forms). It can be thought of as the inactive Vitamin D in your body. This is the form that cannot actually do much until it is converted into the active form, which brings us to…

2. 1,25-dihydroxyvitamin D (1,25-diOH Vit D). This form is the active form, and is also known as calcitriol. For the rest of the article, I will refer to this one as 1,25 Vitamin D or the active Vitamin D. This is the form that produces the effects of Vitamin D. When we talk about the role of Vitamin D in the body, we are talking about what this form does.

 Conversion from Inactive to Active Vitamin D – In your body, you have both inactive and active forms of Vitamin D. As you might guess, the inactive 25-OH needs to be converted into the active 1,25 form. This occurs in the kidneys, by a specific enzyme (it’s called 25-hydroxyvitamin D₃1-alpha-hydroxylase). The activity level of this enzyme determines how much inactive Vitamin D is converted to active Vitamin D. If the enzyme is sluggish, then not much Vitamin D will be activated. If the enzyme is fired up, then a lot of the inactive form will be converted to the active form. If more active form is created, then you will see more activity of Vitamin D. I will explain that further in a moment.

What determines the activity level of the converting enzyme?  – Here is a question with extreme importance, though many doctors do not know or have forgotten the answer: What determines the activity level of that enzyme? Or, put another way, what determines how much active Vitamin D is made? This isn’t just a question for biochemists, because the answer has consequences for every patient with parathyroid disease.

The answer is parathyroid hormone (PTH). PTH essentially “turns on” the enzyme, telling it to speed up and activate more Vitamin D. PTH is made by the parathyroid glands. If your parathyroid glands make more PTH, then more Vitamin D will be activated.

Role of active 1,25 Vitamin D  – Now we need to know what active Vitamin D (1,25 Vitamin D) actually does. There are two very important actions of 1,25 Vitamin D:

1. Increase intestinal absorption of calcium

2. Prevent loss of calcium into urine, by increasing the amount of calcium reabsorbed in the kidneys

Both of these actions serve the same purpose, to increase the amount of calcium in the blood.

Recap – Let’s recap the process we have so far: You have a bunch of inactive Vitamin D in your body, but it cannot do anything until it is activated. It has to be activated in the kidneys by a certain enzyme. That enzyme is always working, but will be sluggish until it gets a kick in the pants from PTH. Once PTH stimulates that enzyme, it churns through the inactive Vitamin D to make active Vitamin D. Active Vitamin D then helps your body increase the blood calcium levels.

Function of Parathyroid Glands

Why is PTH in charge of this Vitamin D process? – PTH is in charge because the parathyroid glands are built to regulate calcium. In fact, that is all that the parathyroid glands do: control the calcium levels in the blood. Activating Vitamin D is one of the main ways in which PTH controls calcium levels. The parathyroid glands monitor the amount of calcium in the blood. When the blood calcium level is too low, the parathyroid glands make PTH in order to raise calcium levels. When the calcium level is too high, the parathyroid glands stop making PTH, so the calcium level will fall back down. This happens many times throughout the day, without you even realizing it, and it keeps your calcium in a very tight range – if your parathyroid glands are working normally.

How Parathyroid Tumor Affects The Process – If you have a parathyroid tumor, things are a little different. In this scenario, your overactive parathyroid gland with a tumor is no longer doing its job properly. It’s not carefully calibrating the amount of PTH production based on the current blood calcium level. Instead, it is just making PTH without any consideration to the calcium level. Even as the calcium level gets too high, it keeps making PTH. That PTH is going to continually activate the enzyme that produces active Vitamin D. Active Vitamin D is produced from inactive Vitamin D, so the more that enzyme works, the more active Vitamin D you have – and the less inactive Vitamin D you have.

You can now see why patients with parathyroid tumors have low levels of inactive Vitamin D. All of that form of Vitamin D is being converted to active Vitamin D! If you measure the levels of active Vitamin D in patients with parathyroid disease, you will find that they are usually high.

It’s worth repeating: For patients with parathyroid tumors, the level of active Vitamin D (1,25 Vitamin D) is often HIGH, because the inactive form is being converted into the active form. But this is not the form of Vitamin D that physicians generally measure. Instead, we check the inactive form.

Why is inactive Vitamin D routinely checked rather than the active form? There is a reason why we routinely check the inactive 25-OH form rather than the active 1,25 form.

Levels of the inactive form are more stable over a longer period of time. The active form tends to break down within a few hours, so you are getting a very brief snapshot of Vitamin D status. The inactive form gives a better sense of long-term Vitamin D status in most patients. For those who have normal parathyroid function, the inactive form is really all you need to measure to get a good sense of overall Vitamin D status. But for patients who have a parathyroid tumor, the inactive form is misleading.

Most patients with parathyroid disease have low levels of the inactive form, and are diagnosed with Vitamin D deficiency. If you measured the active form, you would find that most of these patients actually have high Vitamin D (but it is in the active form). It is possible to check the active form in a blood test; your doctor just needs to request the 1,25 dihydroxy Vitamin D specifically. When most doctors order Vitamin D, they will automatically get the 25-OH inactive Vitamin D.

 Back to Laura and Dr. Smith – When Dr. Smith found that Laura had a low Vitamin D, what he meant was that she had a low 25-OH Vitamin D, because that is generally what doctors are referring to when they do not specify the form. If Laura has normal parathyroid function, then her active form will also likely be low. If she has a parathyroid tumor, then it is not surprising that she has a low inactive form, because it has been converted to the active form.

Here is the mistake Dr. Smith made: he didn’t check a calcium level before prescribing Vitamin D. If he had, he would have seen that Laura’s calcium level was 10.5 mg/dl, which is high for her age. Combined with an elevated PTH level, we can be certain that Laura has primary hyperparathyroidism, usually caused by a parathyroid tumor. Her parathyroid tumor is acting inappropriately, putting out more PTH than it should be. This is causing the inactive Vitamin D to be converted to the active form. Her active form of Vitamin D is likely high, but no one has checked it.

Should Laura take Vitamin D supplements? Does she need more Vitamin D? No. Recall one of the main roles of Vitamin D: helping to raise the blood calcium levels. Her calcium is already high; she doesn’t need to make it higher. Taking Vitamin D (either D2 or D3, which are both inactive forms) will lead to even higher levels of active Vitamin D (which is already high!) and higher levels of calcium. Meanwhile, the inactive Vitamin D levels will likely remain on the low end – because as soon as it gets in, it is being converted to the active form. Laura needs her parathyroid tumor removed; she does not need Vitamin D.

In Laura’s case, her inactive Vitamin D is low because her PTH is high. The PTH is causing the Vitamin D to be low. But I mentioned earlier that a low Vitamin D could cause the PTH to be high. How do we know that Laura’s low Vitamin D is not causing her PTH elevation?

The answer is the calcium level. If someone has a true Vitamin D deficiency over a long period of time, they will have problems with absorbing calcium in the intestines, since Vitamin D is essential for that. Calcium levels will then run in the low range (usually mid 8s to low 9s in mg/dl). Because the parathyroid glands are sensitive to calcium levels, they will start making more hormone (PTH) when they sense the low calcium. In this scenario, low Vitamin D leads to low calcium, which leads to high PTH levels. If the calcium is high, then low Vitamin D cannot lead to high PTH, and we can assume that the high PTH is the cause of the low Vitamin D, not the other way around.

Another common mistake – Laura’s friend Peter sees Dr. Jones. Peter was also recently told that he had a low Vitamin D level. His physician, Dr. Jones, knew to check a calcium level, and found that it was high. She also found a high PTH. So far she is on the right track. She vaguely remembered a connection between calcium, Vitamin D, and PTH. But she incorrectly concludes that a low Vitamin D level can lead to a rise in PTH, which then raises the calcium level. This is another very common mistake I see. Dr. Jones is now under the impression that she can “treat” the high calcium with Vitamin D supplements. This logic is incorrect, because low Vitamin D causes low calcium, which then causes high PTH levels. If the calcium is high, it will suppress the parathyroid glands and cause them to stop making more PTH, regardless of what the Vitamin D level is. If the calcium is high, and the PTH is also high, then there is a problem with the parathyroid glands. Treating this with Vitamin D is not going to help, and may actually harm the patient, since Vitamin D can raise blood calcium levels that are already high.

A note on Vitamin D supplements – I will not go into whether there is a health benefit to taking Vitamin D supplements, or how much benefit there is. This issue is complicated. Many people do not need these supplements, though many also do. If you are taking Vitamin D supplements, you need to know about the risk of taking high doses. Recall that Vitamin D helps the intestines absorb calcium. High-dose Vitamin D can thus lead to elevated calcium levels. Sometimes I will review the records of a patient with high calcium levels and I will notice that the person is taking 5000 units or more of Vitamin D daily. Some can take this dose safely and have no side effects! But others will get high calcium levels. This confuses the picture and makes it hard to tell whether the high calcium is due to a parathyroid tumor or Vitamin D oversupplementation. If the PTH level is high, then the answer is clear: it is a parathyroid tumor. Patients with Vitamin D oversupplementation and high calcium will have PTH levels that are low or low normal (usually in the 10 to 35 pg/ml range). If you have high calcium and are on high-dose Vitamin D, you should stop now, for two reasons:

1. Vitamin D can raise your calcium further, which can make you feel worse.

2. Vitamin D may be the cause of the high calcium, and stopping it will correct your calcium levels. Note that it may take a few months for your Vitamin D levels to drop sufficiently to see a drop in the calcium. Also remember that if the PTH is high or high-normal, then the problem is not Vitamin D. You should stop taking Vitamin D – and then see a surgeon about getting your parathyroid tumor removed.

Take-home message – Vitamin D exists in multiple forms, and the one that we commonly measure is the inactive 25-OH form. This is frequently low in patients with parathyroid disease, because PTH drives the conversion of the inactive form into the active form. If you are diagnosed with a Vitamin D deficiency, the first thing to do is check your calcium. If your calcium is HIGH, with a low Vitamin D, then you likely have a parathyroid tumor. You do not need to take Vitamin D – you need to check a PTH level and may need a parathyroid operation. If your calcium is LOW, with a low Vitamin D, then you should take Vitamin D supplements. When taking supplements, be wary of taking high doses without a clear indication, and if your calcium is high, stop taking the supplement.

Learn more about Dr. Deva Boone….

Dr. Deva Boone is the Medical Director of the Norman Parathyroid Center at Tampa General in Tampa, Fl.  and is one of seven expert parathyroid surgeons at the high volume center that performs 4000+ parathyroidectomies per year.  

After growing up in New Jersey, she attended Cornell University for both her undergraduate degree and medical degree. She then trained in general surgery at St. Luke’s Roosevelt Hospital Center in New York City. While there, she received several awards for research and academic performance, including the highest award for outstanding contributions to surgical education and research. Dr. Boone received additional fellowship training in endocrine surgery at NorthShore University in Chicago. Dr. Boone joined the Norman Parathyroid Center in 2014. Dr. Boone oversees clinical research efforts at NPC and published their largest series of parathyroidectomy patients (over 20,000 from our database). She enjoys surgical missions and has provided surgical care to patients in Nigeria, Myanmar, and the Dominican Republic. 

We have some very exciting news about an advocacy project that we want to share with you….

Parathyroid Peeps has been invited to become a community partner on Inspire!  

We want to invite you to join us at ..

ParathyroidPeeps.inspire.com

We are joining other foundations and communities on Inspire including the National Osteoporosis Foundation, American Lung Association & Lupus Foundation of America, among many others.

Who is Inspire?  Inspire, with more than 100 national patient organization partnerships and over 1.5 million members, has created one of the largest platforms for patient engagement. Inspire is a community where patients are able to receive and provide support, share experiences and information. At the same time, Inspire provides the life science industry access to the true, authentic patient voice with the goal of accelerating medical progress.

As the mission of Parathyroid Peeps is to raise awareness and advocate for improvement in diagnosis and standards for surgical treatment, we believe Inspire provides a unique opportunity for our authentic patient voices to be heard!   Learn more here.

Here is one example of how patients’ voices accelerated research in another community:

Inspire and the Hereditary Neuropathy Foundation(HNF) collaborated to grow the Charcot-Marie Tooth (CMT) community and accelerate medical research. HNF member discussions helped researchers understand pain as a major CMT symptom as well as the type of pain and how to develop related questions and answers that would be most relevant to the CMT community. Today, pain is recognized as a very important endpoint in CMT treatment and outcome measures in clinical trials.

PARATHYROID PEEPS COMMUNITY MEMBERS ON INSPIRE WILL VALUE…

• Patient-centric content on interesting topics related to primary hyperparathyroid disease.
• 24/7 professional monitoring by Inspire’s Moderators to help ensure a safe and pleasant experience in the on-line community.
• Content organized by categories so members can easily find threads that pertain to topics of interest.
• Scheduled special event Q & A’s with medical professionals and researchers.
• Opportunities to participate in surveys,interviews and small group engagements.
• Ability to join other communities within Inspires 100 national patient organization partnerships and communities. This is beneficial to those who suffer from more than one condition.
• Receiving and providing support to others going through similar experiences.
• Anonymity, if desired, to help alleviate fears about publicly sharing details of ones health journey online.

Privacy:  Inspire encourages members to create user names that are unrelated to the patient’s actual name, and we do too. In any case, members maintain full control of how content is shared. We encourage you to carefully review Inspire’s privacy statement prior to joining to understand the differences in choosing how you will post:  Public (web), Member(Inspire platform) or Inspire friends.  Learn more here.

How is the public information that is shared in some Inspire communities potentially used?

1) Insights:Life science executives face mandates to include real world evidence and expand the role of patients in modernizing clinical trial design, determining new indications, creating outcomes measures that patients’ value and assessing treatment risks.  Learn more here.

2) Research / Clinical Trial Recruitment: Nationwide, some three-quarters of clinical trials do not meet their enrollment timelines. Inspire helps link them to patients who are looking for opportunities to participate.  Learn more here.

3) Engagement: Members may at times be invited to participate in surveys, interviews and small group engagements. Learn more here. 

4) Promotions: Companies and organizations may market directly to a target audience. You may opt out of receiving any condition-specific promotions that may be presented to you based on your profile information and/or the communities you join. Learn more here

Read more about  Inspire in the News  AND discover the Experts by Experience Series – a collaborative effort of the Mayo Clinic and Inspire.

We are looking forward to connecting with you in our community where patients will support one another on their journeys. At the same time, if we patients allow a candid view into our health journeys to those who are working to improve patient experiences and outcomes, free from primary research or institutional bias, we may be able to contribute to moving conversations forward that matter to us. The possibility is exciting…

Together we are better on Inspire…join us!   ParathyroidPeeps.inspire.com