Differentiating Primary Hyperparathyroidism from Familial Hypocalciuric Hypercalcemia

Our guest blogger, Dr. Kevin Parrack a surgeon from the Norman Parathyroid Center educates us about differentiating Primary Hyperparathyroidism (pHPT) from Familial Hypocalciuric Hypercalcemia (FHH) in a two-part series. Part 1 below discusses important differences between the two conditions. Part 2, scheduled to post later this month, focuses on the practical application of differentiating pHPT and FHH using a case study.

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When it comes to diagnosing primary hyperparathyroidism, there are a number of issues that have been debated over time. One of the tools that can be easily misunderstood is the urinary calcium test. This is a study that is broadly used but frequently misunderstood. It is used as an attempt to differentiate Primary Hyperparathyroidism (pHPT) from Familial Hypocalciuric Hypercalcemia (FHH, often referred to as FHH1).

WHY IS IT IMPORTANT TO DIFFERENTIATE? Patients with pHPT and FHH both typically have elevated blood calcium levels and parathyroid hormone levels (PTH) that are not normal for the corresponding calcium levels (either high or inappropriately at the higher end of normal). This is a problem because only a select few patients with FHH will benefit from having parathyroid surgery. Most will not have a change in their labs after surgery, nor will they have any clinical benefit. So it is important to differentiate the two in hopes of avoiding an unnecessary surgery on a patient with FHH.

WHY IS A URINARY CALCIUM TEST ORDERED? The idea behind the urinary calcium test is that most patients with primary hyperparathyroidism have a high urinary calcium level, and patients with FHH have a low urinary calcium level. So many doctors will order a 24-hour urinary calcium collection or calcium: creatinine clearance ratio as a standard test when they see blood labs consistent with primary hyperparathyroidism. The assumption is that if the urinary calcium level is below a certain threshold, then the patient likely has FHH and not pHPT. That can lead to a diagnosis of FHH and subsequently a recommendation for no surgery.

WHAT’S THE PROBLEM? As we will see, the problem with this pathway is that some patients with pHPT will be misdiagnosed with FHH, and this can lead to harm to these patients. There are a few factors regarding the urinary calcium collections that lead to this error in diagnosis.

  • Some patients with pHPT can have very low urinary calcium levels. This is due to problems in vitamin D metabolism in the parathyroid patients.
  • The error rate for the urinary calcium collections is higher than what would be considered acceptable in the blood labs, so erroneously low urinary calcium levels can be reported.
  • FHH is extremely rare, so even though the above two issues are not common, the very low incidence of FHH means that the false positive rate of the urinary testing is relatively high.

This is not a minor problem for a patient who has pHPT.

We know that pHPT decreases a person’s life expectancy and can lead to symptoms that interfere with their quality of life.

Therefore if a patient has a urinary calcium level that is consistent with FHH, is then labeled with this diagnosis despite the fact that they have pHPT and does not have surgery, they may have a shorter, less enjoyable life. This is a problem we should avoid.

WHAT IS FHH? In order to understand what to do about the problem, we first have to understand FHH. Understanding certain nuances allows us to develop a plan that helps ensure that FHH is not diagnosed in error. We must balance the desire to avoid an unnecessary surgery in a patient with FHH against the goal of offering an indicated surgery to appropriate patients with pHPT.

FHH is a rare disorder caused by mutations in a gene for the calcium-sensing receptor (CaSR). This receptor is found in both parathyroid and kidney tissue where it is integral to maintaining a balance in the blood and urinary calcium levels. It is also found in many other tissues, including the bone and brain, and responds to more than just calcium, but we will keep our focus narrow.

WHAT DOES THE CALCIUM-SENSING RECEPTOR DO? On the parathyroid gland the CaSR allows the parathyroid gland to sense a low calcium and increase parathyroid hormone (PTH) production, or sense a high calcium and decrease PTH production. In the kidney the CaSR allows the kidney to respond to high blood calcium by excreting more calcium into the urine, or to respond to a low blood calcium by excreting less calcium in the urine.

In FHH the CaSR receptor is not working normally, which reduces the sensitivity of the receptor to calcium levels. Imagine being in a house where the thermostat registers the temperature lower than it really is. It would keep cranking up the heater even if the temperature in the house were normal or elevated. The results of a poorly functional CaSR is that a higher than normal calcium level is needed to stimulate the parathyroid glands to decrease PTH. So most patients with FHH will have a high calcium level and an inappropriately normal or elevated PTH level in their blood labs.

Similarly the kidneys are confused, they don’t realize the blood calcium is so high, so they keep trying to retain calcium in the blood, by preventing it from being excreted in the urine. The overall result is that the blood calcium goes up, the urine calcium goes down, and the PTH is higher than it should be. The PTH is normal, but not suppressed, in most FHH patients, high in others.

For most people with FHH it is a benign disease, causing no symptoms and no problems. With certain forms of FHH, kidney stones, bone problems, pancreatitis or other issues may be more likely than in the general population.

UNDERSTANDING FHH GENETIC MUTATIONS If the cause of this problem is a genetic mutation, understanding some of the details about these particular mutations can help us tell the difference between FHH and pHPT.

Most patients with FHH have one inactivating mutation in the gene that is responsible for CaSR. That means they have one normal CaSR gene, and one mutated CaSR gene that doesn’t work properly. Having just one non-working gene is enough to cause abnormal labs. Another way to say this is that people who are herozygous for CaSR non-functional mutations can develop FHH. This means that FHH is an autosomal dominant disorder.

In autosomal dominant disorders an affected person will have a parent who has the disorder and roughly 50% of the children of an affected individual will have the disorder. In other words in FHH families, about half the family will have FHH.

With all this information in mind we can now try and spot patients who might have FHH, and avoid suspecting it in patients who likely have pHPT, even if their urinary labs are consistent with FHH.

FHH PROFILE FHH patients are usually asymptomatic, with high calcium levels starting in childhood and persisting for life, have multiple hypercalcemic family members, usually with one or more family members who had parathyroid surgery that did not change their labs or symptoms.

Patients who have had blood labs consistent with primary hyperparathyroidism or FHH but do not have a story that matches the FHH profile, usually have pHPT. And avoiding an operation in these patients because urinary labs suggest FHH can hurt the patient.

WHAT ABOUT PEOPLE WHO DON’T KNOW THEIR FAMILY MEDICAL HISTORY? People who do not know their family history should be treated the same as people who know their family history does not include hyperpercalcemia. This is true because genetic disorders that cause hypercalcemia, including FHH, are so rare. Proper counseling is required, but refusing surgery based on urinary calcium testing alone in such patients can be an error. It is true that in this situation some FHH patients will wind up with a surgery that may not clinically benefit them, but if the surgery is done at a center with extremely low surgical risks, this is safer than not doing a surgery in a patient with pHPT that can lead to early demise or serious medical problems.

WHAT ABOUT PEOPLE WHO HAVE A STORY & FAMILY HISTORY THAT FIT FHH? What can be done to clarify the diagnosis in hopes of avoiding an unnecessary surgery? The first step is to get parathyroid blood panels and proper urinary studies on all family members with high calcium levels. The calcium : creatinine clearance ratio is better than the 24-hour total calcium level. While it is not perfect we see fewer mistakes with the ratio than the urinary calcium level test results. If all or nearly all hypercalcemic family members have blood and urine labs that are consistent with the biochemical FHH profile, then this is a reasonable diagnosis to consider. Genetic testing and counseling is appropriate, and if the diagnosis of FHH is confidently made, then surgery is unlikely to play a role. There is a subset of FHH patients who may benefit from surgery for whom expert selection and counseling is required before surgery is considered.

WHAT IF UNCERTAINTY PERSISTS? In some cases despite the best workup the diagnosis remains unclear. Doctors know there is an overlap in the urine studies between FHH and pHPT, and the genetic testing available is not infallible, nor are all related mutations characterized. For patients in whom the truth is not clear from the labs, careful counseling is required. If the odds that surgery will help is high enough some patients will choose surgery because they do not want to risk keeping a parathyroid tumor that could hurt them, and they want to know the truth. Others will choose not to have surgery because the risks and costs of surgery are not worth it to them. And for other patients the odds that surgery will help them is so low that surgery should not be offered.

I hope that this has helped answer more questions than it raises. I have operated on multiple patients who were diagnosed with FHH based on urinary studies but turned out to have parathyroid tumors. These patients were relieved to have their symptoms resolved and labs normalized by surgery. Through their own persistence they got the help they needed to be correctly diagnosed and avoid a life with uncured parathyroid disease. I balance this against the very few patients who I operated on that turned out to have FHH.

Dr. Kevin Parrack M.D., FACS

Dr. Kevin Parrack is a surgeon at the Norman Parathyroid Center, a high volume parathyroid practice that treats around four thousand parathyroid patients per year. In this role Dr. Parrack focuses on teaching patients and physicians about parathyroid disease in hopes that more people will become familiar with this problem and therefore fewer people will suffer from it without appropriate treatment.

Dr. Parrack obtained his undergraduate degree at NYU before graduating from Stony Brook School of Medicine. He completed his residency program at Columbia Presbyterian in Manhattan and the endocrine surgery fellowship at the Cleveland Clinic. His focus on teaching began in college, where his first career was in test prep for the medical school entrance exam. Throughout his training Dr. Parrack worked on admissions and academic committees, designed curriculums and teaching aids, and that interest carried into his role as a surgeon. Before coming to the Norman Parathyroid Center Dr. Parrack was a faculty surgeon at Columbia where he was the director of the Thyroid Biopsy Center and managed outreach to the community to increase awareness regarding endocrine disease.

Ask The Expert – Dr. Courtney Balentine

Ask The Expert – Dr. Courtney Balentine

Ask the Expert 2

CREATE YOUR FREE ACCOUNT TO JOIN OUR PARATHYROID PEEPS COMMUNITY ON INSPIRE  

Learn more about Inspire here

Dr. Courtney Balentine is a fellowship-trained endocrine surgeon with a research program dedicated to improving outcomes for patients with endocrine disease, particularly primary hyperparathyroidism. He serves as a Medical Advisor to the Parathyroid Peeps on Inspire. We are pleased to announce that Dr. Balentine will be available from Monday, November 11 to Friday, November 15 to answer your questions about the diagnosis of primary hyperparathyroid disease. 

How to participate: 

  • Join our Parathyroid Peeps community on Inspire
  • Set and review your privacy settings for your new account.
  • Ask your questions in the comment section of the pinned post entitled “Ask the Expert” that will be up beginning Monday, November 11.   
  • Dr. Balentine will post answers to your questions daily. His answers will appear in the comment section as well. 
  • Note: Answers may not immediately follow the question within the thread due to the format.  You may find it helpful to refer to (click on) the “In Reply To: post number” at the top of Dr. Balentine’s replies to view the question being answered. 
  • Our topic for this month is Diagnosis of Primary Hyperparathyroid Disease. Please understand if Dr. Balentine is unable to get to your question due to time or topic constraints. 

More About Dr. Balentine’s Research…

Dr. Balentine’s work focuses on improving processes for diagnosing patients with hyperparathyroidism to facilitate early detection and treatment. His ultimate goal is to ensure that patients with hyperparathyroidism are diagnosed and treated as early as possible without experiencing unnecessary delays. Dr. Balentine is also interested in reducing disparities among older patients with hyperparathyroidism who are even more likely to experience delays in diagnosis and treatment than younger patients. Dr. Balentine works closely with patients and other stakeholders, including the PARAthyroid Peeps, to design and test interventions that address these gaps in care. His research program has been funded by NIH, the Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and numerous surgical societies. Dr. Balentine is proud to provide endocrine surgical care to our Veterans. His clinical practice is based at the North Texas VA Hospital. 

Watch our video interview with Dr. Balentine. 

 

Meet Our Medical Advisors on Inspire

Meet Our Medical Advisors on Inspire

With your continued interest and support our Parathyroid Peeps community is growing!  If you haven’t yet joined our parathyroid community on Inspire, we invite you to do so today.  As a member you can receive support and also help others by sharing your patient experience.

On September 30th through October 4th we will be hosting our first of many “Ask The Expert” events. Instructions will be prominently posted within the community a few days before the event begins explaining how to participate and where to post your questions.

LINKS TO:  

Learn more our support community on Inspire 

Become a member to participate in our “Ask The Expert” Events. 

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We are honored to introduce you to

Dr. Deva Boone and Dr. Courtney Balentine

who serve as Medical Advisors to our Parathyroid Peeps community on Inspire…

 

Screen Shot 2015-04-28 at 12.09.41 AMDr. Deva Boone is one of the busiest parathyroid surgeons in the U.S., performing over 600 parathyroid operations annually.  She is the Medical Director at the Norman Parathyroid Center. 

After obtaining her medical degree from Cornell University, she completed general surgery residency at St. Luke’s Roosevelt Hospital in New York City.  While there, she received several awards for research, and during her final year received the highest award for outstanding contributions to surgical education and research. After residency Dr. Boone received additional fellowship training in endocrine surgery (thyroid and parathyroid surgery) at NorthShore University in Chicago. She joined the Norman Parathyroid Center in 2014. She enjoys surgical missions and has provided surgical care to patients in Nigeria, Myanmar, and the Dominican Republic.

 

balentineUAB

Dr. Courtney Balentine is a fellowship-trained endocrine surgeon with a research program dedicated to improving outcomes for patients with endocrine disease, particularly primary hyperparathyroidism.

Dr. Balentine’s work focuses on improving processes for diagnosing patients with hyperparathyroidism to facilitate early detection and treatment. His ultimate goal is to ensure that patients with hyperparathyroidism are diagnosed and treated as early as possible without experiencing unnecessary delays. Dr. Balentine is also interested in reducing disparities among older patients with hyperparathyroidism who are even more likely to experience delays in diagnosis and treatment than younger patients. He works closely with patients and other stakeholders to design and test interventions that address these gaps in care. His research program has been funded by NIH, the Agency for Healthcare Research and Quality, the Department of Veterans Affairs, and numerous surgical societies. Dr. Balentine is proud to provide endocrine surgical care to our Veterans. His clinical practice is based at the North Texas VA Hospital. 

Educational – “Color Me”

 

profile-pixThe exceptionally talented Mark A. Hicks is sharing his “Color Me” cartoon about hyperparathyroidism with us. Using a medium that is most familiar to him Mark notes, “It’s a lighthearted take on a serious health problem”

The cartoon came about because, while discussing some artwork Mark was doing for a notable parathyroid doctor, the doctor mentioned the general lack of knowledge of parathyroid disease in the medical community. Mark thought that maybe somebody should draw a simple picture that patients could use to help better explain hyperparathyroid disease and its symptoms to doctors. So that’s just what Mark did.

 

Mark hopes the Color Me activity will help raise awareness of the disease and its symptoms among patients and the healthcare community. 

Permission to use and share Color Me image granted by Mark A Hicks 8-13-19 

Mark A. Hicks is an award-winning freelance artist and illustrator who has been creating artwork for children’s books, magazines, greeting cards, and other countless publications for the past 30+ years. Please visit his website at: www.MARKiX.net for a few samples of his artwork and more information about his many projects.

 

Classic symptoms are often treated by specialists who do not necessarily consider primary hyperparathyroid disease as a possible root cause – Avoid the Pitfalls That Delay Diagnosis & Treatment

Classic symptoms are often treated by specialists who do not necessarily consider primary hyperparathyroid disease as a possible root cause – Avoid the Pitfalls That Delay Diagnosis & Treatment

Avoid The Pitfalls That Delay Diagnosis & Treatment of Primary Hyperparathyroid Disease is a series of blogs that shed light on the most common issues patients face that delay diagnosis and surgical treatment.

#5.  Classic symptoms are often treated by specialists who do not necessarily consider primary hyperparathyroid disease as a possible root cause.

Some of the symptoms patients report are more generalized, and can be attributed to any number of health issues. However, there are several classic symptoms associated with primary hyperparathyroid disease.  Medical students are often taught a rhyme to recall the effects of excess blood calcium levels. It goes something like this…

“Moans, Stones, Groans and Bones”

Each word in the short rhyme references common ailments typically associated with primary hyperparathyroid disease…

Moans (gastrointestinal conditions):

  • Constipation
  • Nausea
  • Decreased appetite
  • Abdominal pain
  • Peptic ulcer disease

Stones (kidney-related conditions):

  • Kidney stones
  • Flank pain
  • Frequent urination

Groans (psychological conditions):

  • Confusion
  • Dementia
  • Memory loss
  • Depression

Bones (bone pain and bone-related conditions):

  • Bone aches and pain
  • Fracture
  • Curving of the spine and loss of height

As patients, we may present with some, but not necessarily all, of these symptoms over time. You are invited to read Barbara, Sophie and Joyce’s stories to learn more about the symptoms we suffered from. 

Sadly, specialists who are treating some of the classic symptoms of primary hyperparathyroid disease are not necessarily well-versed in primary hyperparathyroid disease.

One might expect the specialist to have a thorough understanding of a related disease that is known to be a possible root cause of a condition they treat on a daily basis. However, for many of us, this has not been our experience.

No correlations were considered and therefore no attempts were made to discover the root cause – only symptoms were treated. 

Gastroenterologists are the medical professionals who treat the “moans”. They may very easily overlook high calcium as a root cause of certain gastrointestinal issues.  The story of a fellow advocate, and blogger Lora Park’s comes to mind. In her story she highlights the challenging gastrointestinal issues she faced and laments that she suffered for years without a diagnosis …

Did it start in 1980 when i started getting ‘fainty’ if i didn’t eat every 3 hours? Was it in 1987 when i kept going in to the Dr. complaining that everything was making me ill and having them look at me and say i was young and ‘perfect’ and it COULD be just nervous stomach, anxiety… or was it one of the numerous mysterious trips to ER with vomiting and cramping and being told my appendix needed to come out “STAT” only to find out a few minutes later that everything was ‘fine’.

Eventually, it was an astute RN who alerted Lora to the fact that she had an elevated calcium value.

Urologists are the ones to treat patients who are suffering from kidney stones.  Though there are a variety of reasons people get stones, primary hyperparathyroid disease is one root cause.  While we are asked to catch our stones to determine the type, it may end there. It would seem prudent to rule out whether the person has primary hyperparathyroid disease by doing a thorough diagnostic workup.

Psychologists will likely see patients who present with the “groans”.  Patients report having episodes of severe anxiety, depression and/or brain fog. While many of these professionals are now well-versed in understanding the psychological symptoms often associated with thyroid conditions, more education is needed to raise awareness among mental healthcare professionals so they are able to do the same for those potentially suffering from primary hyperparathyroid disease.

General Practitioners, Internists, Rheumatologists, Endocrinologists  treat diseases of the bone. Many PHPT sufferers report being diagnosed with osteoporosis and have shared with us that they were put on bone drugs for osteoporosis without having gone through a thorough diagnostic process. Or if they did, the physician did not necessarily understand the various biochemical presentations of primary hyperparathyroid disease and the diagnosis was overlooked. Sandi, a fellow patient advocate who suffered from osteoporosis for years shares her story  in this 28 minute video and expert parathyroid surgeon Dr. Boone, an expert in parathyroid disease, summarizes some of the hurdles in this 6.5 minute video. 

Others have reported that they were encouraged to take bone drugs after diagnosis as part of a “wait and see” model of care. This happened in Sophie’s case and it made no sense to her to take a medication that would not address the root cause. After doing her own research, she declined and self-referred to a parathyroid surgical center. Bone drugs will not help improve the bone health of a person if there is an underlying condition of primary hyperparathyroid disease.

Dentists may also see rapid changes/deterioration in dental health in patients who have  primary hyperparathyroid . Patients would benefit from dentists being familiar with the various symptoms (deterioration of bones and teeth specifically) and biochemical presentations.  Dentists could then suggest that these patients follow-up with their personal physician to determine if primary hyperparathyroid disease is possibly the underlying cause.

A glaring group of conditions treated by Cardiologists that is not addressed in the memorable rhyme, are those that effect the heart and blood vessels,  including high blood pressure (hypertension), hardening of the arteries (atherosclerosis), coronary artery disease, an enlarging heart (left ventricular hypertrophy), and abnormalities in the normal electrical activity of the heart. Learn more here. 

A patient may report having a fluttering, racing heart and /or it is discovered that they have high blood pressure. When the doctor cannot find anything else particularly wrong with the patient, they may put the patient on blood pressure medications. Yet elevated calcium values may not be considered and/or ignored if mildly elevated.  Once diagnosed, patients have realized that their blood calcium were elevated during that time and found that their heart stopped fluttering/racing and blood pressure returned to normal following surgical removal of the diseased parathyroid gland(s).

imageConclusion: We understand it is not at all unusual for patients suffering from primary hyperparathyroid disease to go undiagnosed for many years. Parathyroid experts believe the average patients goes undiagnosed at least 8 years, if not longer.  Remember that it is the length of time that calcium values are elevated outside of normal range which wreaks havoc in our bodies, rather than the degree to which calcium is elevated. Thus, the condition should not be referred to as “mild” if serum  blood calcium is slightly elevated.  A “wait and see” approach is actually very harmful to our health. Of course, we cannot attribute the delays in diagnosis entirely to the specialists treating our symptoms. Remember that in our first blog in this series, we discussed that labs often do not report calcium values based on a persons age.  However, an excellent understanding of primary hyperparathyroid disease by healthcare professionals across all specializations who treat related symptoms and conditions, would help drastically reduce the delays in diagnosis we experience as patients. 

RESOURCES FOR YOU: 

Hypercalcemica Calculator: Here is a link to the Norman Parathyroid Center’s hypercalcemia calculator to find the upper limit of blood calcium for your age. Note that when you enter your age in the calculator that your upper limit will appear in the paragraph below in both mg/dl (USA) or mmil/L in most other countries. See the example image below for someone who is 50 years of age. Screen Shot 2019-05-21 at 4.02.43 PM.png

A new way to help us remember the symptoms of Primary Hyperparathyroid Disease : See our High Calcium Is Bad  symptom list.

Help Advocate – Raise Awareness – Provide & Receive Support: Learn more about our Parathyroid Peeps Community on Inspire through this link.  PLEASE JOIN US ON  INSPIRE

If you missed the previous blogs in the series, Avoid The Pitfalls That Delay Diagnosis & Treatment of Primary Hyperparathyroid Disease, here are 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. 

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

#4. A patient may be incorrectly diagnosed as having secondary hyperparathyroidism when they instead have primary hyperparathyroid disease that requires surgical treatment

Please remember that we are not medical professionals. Read our Terms of Use/Disclaimer. 

A patient may be incorrectly diagnosed as having secondary hyperparathyroidism when they instead have primary hyperparathyroid disease that requires surgical treatment – Avoid The Pitfalls That Delay Diagnosis & Treatment

A patient may be incorrectly diagnosed as having secondary hyperparathyroidism when they instead have primary hyperparathyroid disease that requires surgical treatment – Avoid The Pitfalls That Delay Diagnosis & Treatment

Avoid The Pitfalls That Delay Diagnosis & Treatment of Primary Hyperparathyroid Disease is a series of blogs that shed light on the most common issues patients face that delay diagnosis and surgical treatment.

#4  A patient may be incorrectly diagnosed as having secondary hyperparathyroidism when they instead have primary hyperparathyroid disease that requires surgical treatment.

Primary hyperparathyroid disease means the hyperactivity of one or more parathyroid glands is caused by the gland(s) becoming a non-cancerous adenoma. Secondary hyperparathyroidism means that a disease or issue outside of the parathyroid glands is causing the glands to become enlarged and hyperactive.

Here are some of the reasons why a person might experience secondary hyperparathyroidism:

Kidney failure requiring dialysis (GFR less than 25) 

According to American Association of Endocrine Surgeons Patient Education Site:

It is usually caused by kidney failure, a problem where the kidney is unable to clean the blood of phosphorus produced by the body and unable to make enough vitamin D (specifically calcitriol, the active form of vitamin D). The build-up of phosphorous leads to low levels of calcium in the blood, which in turn stimulates the parathyroid glands to increase parathyroid hormone (PTH) production, which in turn causes them to grow. As the disease progresses, the parathyroid glands no longer respond normally to calcium and Vitamin D.

Malabsorption Syndromes when the intestines do not absorb vitamins and minerals properly or as a result of malnutrition. This can occur as a result of:

  • Gastric Stapling
  • Gastric (stomach) bypass
  • Intestinal bypass
  • Roux-n-Y Bypass
  • Celiac Disease
  • Crohn’s Disease

Severe Vitamin D deficiency is another reason 

It is often presumed that a patient’s low Vitamin D is the reason their calcium values are high. The patient is then given the diagnosis of having secondary hyperparathyroidism and given a protocol for Vitamin D supplementation. Patients report this as a common hurdle faced when trying to get a correct diagnosis. Supplementing with Vitamin D only made their symptoms worse and further delayed surgical treatment.

While severe Vitamin D deficiency can indeed be a secondary cause, we have learned that there is a flaw in many people’s understanding of the relationship of blood calcium values to inactive Vitamin D  (Vitamin D 25-OH ) which is most commonly being measured.

A patient will actually have low inactive Vitamin D BECAUSE the calcium is high when presenting with primary hyperparathyroid disease. In a recent blog hosted on our website, Dr. Deva Boone, an expert in parathyroid disease, discussed the role of Vitamin D in relation to primary hyperparathyroid disease in great detail.

Click here to read the informative article to learn more about the conversion process of Vitamin D 25-OH inactive to Vitamin D 1,25-OH2 active, and why inactive Vitamin D is so often low when a person is suffering from primary hyperparathyroid disease.

Resource link: Norman Parathyroid Center – secondary hyperparathyroidism.

Sadly, this misunderstanding often causes delays in diagnosis even when a patient has a classic biochemical presentation –  high blood calcium, high parathyroid hormone levels and low inactive Vitamin D – which should make it exceptionally easy to make a proper diagnosis.  

Were you told that you had secondary hyperparathyroidism when in fact it was primary? Please join us in our community on Inspire to share your story.  

If you missed the previous blogs in the series Avoid The 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. 

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

Please remember that we are not medical professionals. Read our Terms of Use/Disclaimer. 

A doctor does not want to confirm a  diagnosis of primary hyperparathyroid disease or refer for surgery until the adenoma is visible on a scan – Avoid The Pitfalls That Delay Diagnosis & Treatment

A doctor does not want to confirm a diagnosis of primary hyperparathyroid disease or refer for surgery until the adenoma is visible on a scan – Avoid The Pitfalls That Delay Diagnosis & Treatment

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. 

Slightly elevated calcium values are ignored… Avoid The Pitfalls of Delayed Diagnosis & Treatment of Primary Hyperparathyroid Disease

Slightly elevated calcium values are ignored… Avoid The Pitfalls of Delayed Diagnosis & Treatment of Primary Hyperparathyroid Disease

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.

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Your doctor reports your serum blood calcium is in “normal” range . What could be the problem? … Avoiding Pitfalls That Delay Diagnosis & Treatment

Avoiding Pitfalls That Delay Diagnosis & Treatment 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 treatment of primary hyperparathyroid disease.

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 # 1 – Your doctor reports your serum blood calcium is in the normal range. When you review a copy of the report, it is indeed. What could be the problem?  A BIG PROBLEM:  Normal ranges reported vary from lab to lab. Laboratories do not always correct blood calcium values for a person’s age. This is important as normal ranges for serum calcium are age-dependent. Yet labs will often give a normal range for the general population and that normal range may go up to 10.5 mg/dl or higher.

This results in mature adults with serum calcium values over 10.1 being reported as “normal” which often delays diagnosis. According to experts, those whose calcium values fluctuate and/or exceed the upper limit for their age should be evaluated for primary hyperparathyroid disease.

Therefore, it is very important to know what the upper limit of serum calcium is for your age. Here is a link to a hypercalcemia calculator hosted by the Norman Parathyroid Center on  parathyroid.com to help you determine the high limit based on your age. 

Hypercalcemia Calculator : Calculate the upper limit of serum blood calcium for your age

Please join us on Inspire to share your experiences in relation to this topic. Were your calcium values reported as “normal” but you actually were suffering from primary hyperparathyroid disease? You can help others by sharing your journey and/or receive support from those who have been surgically cured.

 

 

Confused About Vitamin D supplementation in relation to parathyroid disease? Expert parathyroid surgeon Dr. Boone explains…

Confused About Vitamin D supplementation in relation to parathyroid disease? Expert parathyroid surgeon Dr. Boone explains…

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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.

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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.

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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.

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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.