Just as a matter of apparent coincidence, there were two case reports published recently on hyperparathyroidism (overly active parathyroid glands) in patients with chronic hypophosphatemia. Take together, they raise some interesting questions, which weren’t addressed by the case reports themselves.
The first is: “A case report of X-linked hypophosphatemia combined with primary hyperparathyroidism.”
I’ve mentioned before that I think most case reports related to XLH are a waste of everyone’s time, since they usually come across as someone seeing an XLH patient for the first time ever, finding it interesting, and then writing an article to justify the time spent reading up about the condition (although I don’t know if that’s in fact what happened). They seem to be on topics that the true experts wouldn’t even spend more than two seconds on, since they’ve seen it so often. And patients have either experienced it themselves or know other patients who have.
The linked article is about how XLH patients can have primary hyperparathyroidism (overactive parathyroid glands which are NOT triggered by the phosphorus supplements). Okay. So what? In this case, the primary hyperparathyroidism was caused by a tumor, so it’s a little like saying that a given patient can have two separate diseases. I suppose it’s useful to remind clinicians that some symptoms can have more than one cause, so never assume it’s caused by the first disease, even if it’s a known symptom of that disease.
It’s well known that some XLHers can have hyperparathyroidism even before they begin treatment for the XLH. I knew that before I knew that my condition was called XLH. When I was in my twenties, before I’d ever taken any phosphorus, before I knew I had XLH and not some mythological disorder called vitamin D resistant rickets, my orthopedist freaked over my PTH levels. I believe it was known as far back as the early 2000s (if not even earlier) that some XLHers had hyperparathyroidism even in the absence of phosphorus treatment. I remember reading it somewhere 15 or so years ago when I was active on the XLH Network’s listserv, but of course I can’t find it now.
So it would be natural for an XLH-expert clinician to assume that an untreated XLHer who developed hyperparathyroidism was simply one of those patients who can develop this symptom in the absence of treatment, and therefore miss the tumor. I suppose this is a good reminder not to make assumptions. The rest of the article just makes me a bit angry on behalf of the patient who had been misdiagnosed and mistreated for their entire life (focusing on calcium issues). Even though the authors finally get the patient the correct diagnosis, they still don’t do anything for the XLH. The authors seem to take at face value that the patient was entirely asymptomatic other than low phosphorus levels, despite treatment that did not include any phosphorus supplements (and this was before burosumab, so that wasn’t an option). I’m much more inclined to think that the patient had symptoms that were unrecognized by both patient and clinician, and therefore the patient’s phosphorus-related symptoms will continue to worsen until they can’t be denied,a t which point they will be irreversible. The patient’s parathyroid levels were normalized, but her XLH remains entirely untreated.
And that brings us to the second case report, which I think raises really good questions (that the authors seem to have missed). The patient has TIO, not XLH, and establishes that TIO patients can also get hyperparathyroidism after a period of hypophosphatemia caused by a tumor instead of genetic variant. Note that I think the title is misleading, for reasons I’ll get into below, so don’t panic. This second case report is “Hyperparathyroidism Secondary to Burosumab Treatment.” Basically, it reports on a TIO patient, whose FGF23-producing tumor could not be removed, then was treated with burosumab (never on phos supplements before that, so comparable to a young XLHer whose first ever treatment is burosumab), and his phosphorus levels normalized, but his parathyroid hormone levels rose above normal.
It’s the causal link implied by the title that I think is misleading. This is just me, a layperson, not a doctor, following the logic, but I don’t believe (or at least don’t see the evidence for the conclusion) that there’s something intrinsic to burosumab that caused the hyperparathryoidism. Instead, I think there’s some additional trigger (besides the PHEX mutation or the tumor) that some XLH and TIO patients share, which causes the parathyroid glands to think that normal phos levels are abnormally high. The title, I think, would be more accurate if it were “Hyperparathyroidism secondary to treatment that normalizes the serum phosphorus, including burosumab treatment.”
Why do I think that? Well, let’s start with the previous case report that alludes to something that has long been known, namely that some XLH patients (me included) have hyperparathyroidism even without ever being treated with phos supplements. That suggests that for some of us, the parathyroids sense normal phos levels as excessive.
Then look at the basic, escalating feedback loop that XLHers encounter with the old treatment, and that led to hyperparathyroidism (either temporary/secondary or permanent/tertiary). What happened was that the patient would take their phos supplement, the blood levels normalized for a few hours, but then the parathyroids freaked out because the phos levels were so much higher than they were used to and produced extra parathyroid hormone, which triggered phos wasting, until the blood levels dropped to XLH-normal levels (which are too low for bone mineralization), and then the patient took more phos, which normalized the blood level briefly and freaked out the parathyroids again. Rinse, repeat, multiple times a day. Eventually, the glands are just permanently freaked out (tertiary hyperparathyroidism).
Given what we know about that feedback loop and the XLHers who have hyperparathyroidism before ever going into that feedback loop, I have to wonder if a long period of low phosphorus levels (not the transient kind that occurs with surgery or dietary issues) somehow resets what the parathyroids consider to be “normal” phosphorus levels. In which case, it seems possible that a TIO patient experiencing chronic hypophosphatemia for months/years prior to diagnosis (we know it generally takes multiple years to get this ultra-rare diagnosis) might do the same thing to the parathyroids that the initial three years of life with low phosphorus experienced by a typical spontaneous XLHer (like me) before diagnosis, does to the patient, resetting what the parathyroid considers normal. So then, when the phosphorus levels are normalized, whether it’s with burosumab or supplements, the parathyroids are going to start freaking out inappropriately.
Anyway, I’m skeptical that it’s something intrinsic to burosumab causing the hyperparathyroidism in this case. It seems more likely to me (layperson, not doc) that anything that normalized the blood levels would result in overactive parathyroids for this patient, whether it was burosumab or the old phos supplements. The question for research is: Why do some patients, and not others, have easily freaked parathyroids that over-react to perfectly normal phos levels? Is it more common in spontaneous cases (longer delay between first experiencing low phos to diagnosis and effective treatment) than in familial cases (more likely to get early diagnosis/treatment)? How common is it that XLHers on burosumab experience hyperparathyroidism, and is it the same percentage as the patients whose parathyroids have been reset to think a lower phos level is normal? It would also be useful to know if the XLH kids who start on burosumab at age one or so, before their phos levels have been low for too long, develop hyperparathyroidism while on burosumab treatment.
If we can get answers to those questions, we might be able to develop a treatment that can reset what the parathyroids consider normal, and we can predict and treat the patients who are most in need of that resetting.
Bottom line: we need more research into parathyroid glands to better understand what it is that causes them to read normal phos levels as excessive. I suspect, just as a matter of logic, not as a doctor, that the answer lies in pursuing that issue, rather than focusing on the specific treatment that normalizes phos levels.
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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