Plan A: The NIH

By November 2014, I had gathered ample evidence to suspect the genetic mutation called multiple endocrine neoplasia, type 1 (MEN-1) could be behind my medical problems over the past two years, so I began to devise a plan to rule it in or out definitively.   You can get diagnosed with MEN-1 in one of two ways:  a positive genetic test for MEN-1 or confirmed tumors in two of the three “P’s” – pituitary gland, pancreas and parathyroid glands.  I already had pituitary tumors removed this year and had some evidence that I might have parathyroid tumors, but I didn’t have strong evidence so I knew this was going to be an uphill battle.  Just like with Cushing’s, I had “mild” elevations in my labs and my parathyroid and calcium levels were fluctuating, so it was going to take time and doctors that understood the subtleties of this disease to figure this out clinically.  I had already started to look into the genetic tests, but without a doctor referral it cost thousands of dollars to get the genetic test.  Furthermore, since the test only picks up known mutations, roughly 40 percent of patients with MEN-1 that don’t have a family history of the disease (like me) end up with a negative genetic test.   So, my initial plan was to keep testing my PTH and calcium as long as the Wizard was willing and to bite the bullet and make an appointment with a private lab to at least explore the option of getting the genetic test.

Then, a patient group alerted me to the possibility of killing both birds with one stone at the National Institute of Health (NIH).  The NIH had an open research study on Hyperparathyroidism and if I was able to get into this study, they would give me a work-up for MEN-1 at the same time, including the genetic test!  I couldn’t believe my eyes when I saw the study.  I immediately contacted the lead researcher and gave him a brief rundown of my situation.  After exchanging a few emails and information on my labs and operative and pathology reports from my pituitary surgery, he told me that because I had Cushing’s and “very borderline hypercalcemia” they would admit me to the study.  Over Thanksgiving weekend, I found out I was in and that I was scheduled to be an inpatient at the NIH for five days in January.  That same weekend I got engaged to the most wonderful, supportive man I have ever met.  I was over the moon.  It was the happiest I remember being in a long time.  I felt like I was going to get my life back and finally get to start a real life as a healthy woman with M too.

I decided I would keep testing my calcium and PTH up until I went to the NIH to keep bolstering my case.  For someone my age, serum calcium levels in the 10s are abnormal and together with PTH levels that are normal or elevated in the presence of high calcium are evidence of parathyroid tumors.  Just like with Cushing’s, demonstrating these hormones were both inappropriately high on numerous occasions was necessary to get diagnosed with hyperparathyroidism (HPTH) and to get cleared for surgery.   So, I continued to test in December.   The month of December and the early part of January seemed to drag on as I was feeling very sick throughout this time.   In addition to increasing pain in my lower back, my digestive issues were getting worse and worse.  It was pretty clear I was not digesting most of my food – much of what I ate was leaving my system looking the same as when it went in.  And I had constant pain in the rough location of my gallbladder.  On several occasions, the pain would get so bad that for stretches of 4-5 days I had to take shallow breaths and I just couldn’t get comfortable because of the pain.  My GP ordered an ultrasound at one point and besides some evidence of an inflamed common bile duct, we didn’t see anything.  But it was clear that whatever GI issues I was having, they were getting worse.  HPTH can cause gall stones and pancreatitis, so my best guess was it was all related.  But since I didn’t have a diagnosis in hand, it was only a guess.

And then right before I went into the NIH, likely as a result of the malabsorption problems that flared up during December, my calcium dropped back into the 9s.  And when I went to the NIH and had my calcium tested, it was in the 9s for the first test and dropped into the 8s for the second.   How could this happen to me now, after months of high test results?  And despite the fact that there were good reasons my calcium dropped and despite months of “borderline” high calcium levels preceding these tests, the doctors overseeing the study decided I did not have HPTH.  I was heartbroken.  I know this might sound perverse to a healthy person, who might be asking why anyone in their right mind would hope they had a tumor (or even worse, a genetic mutation that was going to cause you to get tumors over and over).  But I am not a healthy person. I am a person that has been sick going on three years now.  And I just want an answer, a name, a plan to deal with whatever was wrong.  I didn’t even care what “it” was anymore.

I knew enough from my experiences with Cushing’s last year to realize that the NIH might be wrong.  That two negative test results didn’t mean much given the trend of positive test results I already had.  That it made sense for my calcium to drop if none of the calcium I was eating was actually entering my bloodstream because I couldn’t absorb nutrients.  So I knew that I was going to have to try and figure out how to help my GI system heal a little and retest when I got home.   And thankfully, the NIH did go through with the rest of the MEN-1 testing, even though they believed the odds I had MEN-1 were very low at this point.  So, I had the genetic test – I was told it would take between 3 and 6 months to get the results back for that.  And I also had a battery of labs and imaging done – tests of pancreatic hormones, pituitary hormones, CT scans, MRIs and an Octreoscan.

Some of the lab results were unusual.  The first is a pituitary hormone called TSH.  TSH stimulates the thyroid gland to make T4 which is converted to T3 and stimulates the metabolism.   TSH, T3 and T4 work in a feedback loop much like Ca and PTH do (or cortisol and ACTH).  If T3 and T4 are low, the pituitary gland pumps out TSH.  If T3 and T4 are high, TSH production is decreased.  Interestingly, my TSH levels were almost undetectable, despite the fact that my T3 and T4 were not high.  The NIH got very excited about this, going so far as to say I had “endocrinologist-induced hyperthyroidism” but this didn’t make any sense to me.  This should only be true if my T3 and T4 were too high and they were on the low side of normal – which meant my TSH should have been high, not low.  Looking back over my old thyroid labs, it was clear my TSH had been suppressed for over a year.  So this was odd, but it didn’t seem consistent with hyperthryoidism (too much T3 and T4) at all.

The other odd finding that everyone dismissed was a really low gastrin reading.  Gastrin is a hormone that stimulates the release of gastric acid, which helps break down food in the stomach.  The reference range for Gastrin is <100.  My reading was <10.  And this test result fit my symptoms – I was not digesting my food!  I asked repeatedly about whether this result was normal, especially given my symptoms and I kept getting the same answer:  we only care if gastrin is too high, not too low.  There are other neuroendocrine tumors called gastrinomas, which produce too much gastrin and cause stomach ulcers, hence this answer.  But given my symptoms, I was sure this was a clue and I was disappointed no one but me wanted to investigate further.

During my googling in the months preceding my trip to the NIH, I encountered several times a discussion of another neuroendocrine tumor called a somatostatinoma.  As the name suggests, the tumor produces excess amounts of the hormone somatostatin.  Somatostatin serves as a master hormonal brake of sorts:  it’s job is to inhibit several other hormones, including gastrin.  One of the main signs of a somatostatinoma is abdominal pain and undigested food/malabsorption.  In fact, it was the only neuroendocrine tumor that caused patients to have signs of undigested food – and this is because too much somatostatin suppresses lots of pancreatic hormones including gastrin, glucagon, insulin and others.  It also inhibits several pituitary hormones, including growth hormone…and TSH.  So, when I saw the low gastrin, I asked – three times at the NIH – if the low gastrin could be caused by excess somatostatin.  All three times, I could see a little light go off in the heads of the fellows I was talking to (I only saw the attending once after my initial admission).  But no one ever agreed to actually test my somatostatin.  In their defense, somatostatinomas are VERY rare.  Roughly 1 in 40 million people a year are diagnosed with somatostatinomas.  But it did seem to fit.  I just filed this thought for later.

The other unusual finding that popped up while I was at the NIH came from the Octreoscan.  Octreoscans are special scans designed to find neuroendocrine tumors (NETs).  Many NETs have somatostatin receptors on their surfaces and the Octreoscan exploits this fact to find the tumors.  Patients are injected with Octreotide (which is very similar to somatostatin) which is bound to radioactive material.  The Octreotide subsequently binds to the receptors on the tumors and the radioactive material can then be spotted on a special scanner.

No one was more surprised than the doctors at the NIH that the Octreoscan indicated there was something suspicious for a neuroendocrine tumor in my mediastinum (chest), as up until this point they couldn’t find anything wrong with me.   Unfortunately, a clear tumor was not picked up on the CT and MRIs – there was some debate over whether an odd looking thing in my chest that did show up was residual thymus or if it could be a tumor, but there was no smoking gun.  So, even though we found something, there was still a chance it could be incidental (despite my symptoms, etc. etc.).  As part of MEN-1, patients can get NETs called thymic carcinoids, which was a possibility.  Carcinoids can also produce hormones and can sometimes cause digestive problems, wheezing and “flushing”  (getting a hot, red face and chest) and sometimes show up in labs.  But thymic carcinoids, of course, are less likely to be symptomatic and less likely to be diagnosed by lab work.  I did have flushing and some mild breathing trouble too and the NIH did conduct a round of labs to test for carcinoids, but the tests all came back negative.  At the end of the day, they determined I should get another CT scan in 2-3 months to see whether anything in the region of my thymus changed.  So more watching and waiting – but at least a clue that this might be the source of at least some of my problems.

So, I came home from the NIH in mid-January with no answers but quite a few more questions and at least a few clues that I would try and chase down at home as part of Plan B.

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