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Episode 73: Understanding Hypophosphatemia: Recognition, Diagnosis, and Treatment
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Welcome to ACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com podcasts. And now let's meet the endocrine experts who will be talking with us today.
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Welcome to another episode of the ACE podcast. I'm Dr. Steven Pitak. I'm a past president of ACE and ISCD, and I just retired as chief of endocrinology at Houston Methodist Hospital. I've also been an endocrine consultant to NASA at the Johnson Space center for about 18 years, and I specialize in rare bone disease. Today, we're discussing a commonly missed but clinically important topic, hypophosphatemia. Before we begin, I'd like to thank our sponsor, Kyua Kieran for supporting this important conversation. Joining me today are Dr. Layla Tabatabhai and Dr. Basma Abdulhadi. Thank you both for being here. Layla, let's start with you. Could you introduce yourself and share your background and area of expertise?
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Thank you, Steve. I'm so pleased to be here tonight with you and Basma. I'm Dr. Layla Tabatabhai. I'm an endocrinologist with a specialized focus in metabolic bone disease, including disorders of phosphate homeostasis, osteomalacia, and particularly advanced osteoporosis and fragility fractures. I'm associate professor of clinical medicine at Weill Cornell and I also practice at Houston Methodist. We still miss you there. So I split my time between clinical care, education and research.
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Wonderful. Great to have you. Basma, could you introduce yourself?
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Thank you, Steve. Yes, I'm very happy to be here. I'm Dr. Basma Abdulhadi. I'm an endocrinologist and an assistant professor of medicine at the of Alabama. My interests include metabolic bone disease and osteoporosis. I work closely with our radiology department at UAB as the head of bone density.
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Perfect. Well, let's dive in. First. We see a lot of confusion between osteoporosis and osteomalacia. Can you explain the difference to us?
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So I frame it this way. Osteoporosis is a quantitative problem, so that's related to the amount of bone mass that we see. So it's reduced bone mass with normal mineralization. Osteomalacia, on the other hand, is qualitative. It has to do with bone quality, and it means that there's impaired mineralization of the osteoid that most commonly comes from vitamin D deficiency or phosphate deficiency. And clinically, osteomalacia can bring bone pain, muscle weakness and what we call pseudo fractures, or what's known as looser zones. And so on the other hand, osteoporosis many times is silent until a fracture occurs.
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Lab work also helps in differentiating the two. In osteomalacia, alkaline phosphatase is typically elevated, and depending on the cause, you might see low phosphate levels and often low or inappropriately normal125 dihydroxy vitamin D. In primary osteoporosis, calcium phosphate and alkaline phosphatase levels are usually normal.
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That distinction becomes vital when a patient isn't improving on standard osteoporosis therapy, when the true problem is osteomalacia. So it's very important to make a diagnosis. So let's talk about symptoms. What should raise the suspicion in children with hypophosphatemia?
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So in children, we usually think of a hypophosphatemia causing rickets. So they have growth delays, lower extremity deformity, genoverum volume, widened wrists, delayed tooth eruptions. They can also have some dental abscesses, especially in X linked hypophosphatemia. Some may have hearing issues, fatigue, bone pain, which are very common but easy to overlook.
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In adults, it's important to look for diffuse bone pain, proximal muscle weakness. And the way you ask about that is, is it difficult to climb stairs, Is it difficult to get out of a chair? Adults can also fatigue and pseudo fractures. So they're commonly found in the lateral femur, in the ribs, in the pelvis. So many times they'll be complaining of that pain. They'll have imaging, and the imaging will show that pseudo fracture or looser zone, and then in acute or severe hypophosphatemia, such that the patient might be hospitalized, you can, you can see rhabdomyolysis, respiratory muscle weakness, paresthesias, and occasionally cardiac dysfunction.
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B
So cardiomyopathy, the clinical picture spans musculoskeletal, neuromuscular, and sometimes cardiopulmonary problems, which is important for our listeners to understand that this can be quite severe in some patients. So the key issue, of course, is the check phosphate message. The core message is we'll miss hypophosphatemia if we don't measure phosphate level.
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C
That's exactly right. Serum phosphate is not on the basic metabolic panel nor the comprehensive metabolic panel that we typically order. So if you're only ordering these types of metabolic panels which is what our primary care physicians do, what we typically do for every kind of visit, we're going to miss. Hypophosphatemia. Very, very important to order a fasting phosphate. Whenever you see a patient with bone pain, proximal muscle weakness, atypical fractures, pseudo fractures, rickets or osteomalacia, or risk factors such as malabsorption, chronic antacid use, Roux En Y gastric bypass, for example, as a cause of malabsorption or as we'll discuss a little bit later, recent IV iron infusion.
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Also, we have to remember that there's a diurnal variation in phosphate levels. The phosphate tends to be higher later in the day. So context matters. If the lab results don't fit the clinical fixture, it's important to consider an assay interference or sample and handling issues.
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What about assay interference? What kind of things would be looking for?
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So we sometimes see pseudohypophosphatemia. Paraproteins and monoclonal gammopathies can interfere with the phosphate assays, causing phosphate to falsely appear low. If the number doesn't make sense, you always have to ask the lab for dilution studies, deprotonization or an alternative method of checking the phosphate levels. You would also need to correlate with clinical findings and other lab tests like alkaline phosphatase or tubular reabsorption of phosphate.
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C
And that's really critical. I want to emphasize we don't want to get fixated on a single lab value that contradicts the clinical picture. And back to what you said earlier, Steve, I think the take home message really is check a phosphate in these types of patients who are presenting with musculoskeletal complaints. I always tell my fellows, my trainees, if you're checking a vitamin D and you're checking a pth, you must check a phosphate. Those labs, those metabolic bone labs, they go together and it's really not a complete eval unless the phosphate is there.
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So briefly, what about a differential diagnosis of hypophosphatemia?
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So there's three sort of buckets when it comes to hypophosphatemia. So we need to think about first of all, redistribution. So that's when phosphate shifts inside of the cell. And that can happen in a few clinical scenarios, most commonly respiratory alkalosis. So hyperventilation. It can also happen in insulin treated patients as well as those who have refeeding syndrome. So a lot of times those hospitalized patients will present with hypophosphatemia and then hungry bone is a very common scenario as well. So patients with hyperparathyroidism who undergo parathyroidectomy, they will oftentimes have a post surgical hypophosphatemia sort of presentation. And the next sort of bucket to consider is decreased absorption. So again, going back to the malabsorptive patients, this would be celiac disease, inflammatory bowel disease, post bariatric surgery. And then we also have syndromes of vitamin D resistance as well as vitamin D deficiency. Sometimes those patients will have hypophosphatemia as well. And then phosphate binders. So remember your renal patients, end stage renal disease or advanced chronic kidney disease who are on binders such as sivellumr, calcium acetate, et cetera, and then excessive antacid use and then chronic alcoholism can also lead to decreased absorption. And then the final thing to consider where most of our sort of hereditary syndromes fall is the bucket for increased urinary losses. So this is phosphaturia, hyperphosphaturia, and that would be sort of a renal phosphate wasting syndrome. So of course, we do have to consider our renal colleagues. Our nephrology colleagues will be looking for Fanconi syndrome and also proximal tubulopathies that can be caused by tenofovir, fosphamide, cisplatin or heavy metals. Post transplant, we can see tubular dysfunction. And then of course, hyperparathyroidism can cause increased renal phosphate loss and then all of the FGF23 mediated syndrome. So we'll touch upon that a little bit later in this podcast. X linked hypophosphatemia, TIO or tumor induced osteomalacia, and then the ADHRA ARHR subtypes. So we'll be getting into those a little bit later as well.
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So the structure quickly narrows. The differential diagnosis, if urinary phosphate excretion is high in the setting of low serum phosphate, then you're looking at renal wasting and FGF 23 mediated causes rise to the top of the differential.
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So what kind of an evaluation do you recommend for teaching our fellows and other physicians who are interested in this disorder who may encounter it?
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That's a fantastic question, Steve. I think it's really important also to recognize many endocrinologists, though they may be very familiar with osteoporosis, with hyperparathyroidism, hypophosphatemia is not something that we commonly see. So I think it's great for everybody to be kind of aware of this. And so we obviously start with a fasting serum phosphate level. We also want to check a calcium, typically a full cmp. So that's going to include your calcium, your creatinine and estimated GFR, your alkaline phosphatase level, bicarbonate, and then of course a 25 hydroxy vitamin D level as well as a 125 dihydroxy vitamin D and then the parathyroid hormone level, PTH, and then the renal handling. So the kidney handling of phosphate and assessing for hyperphosphaturia, we would want to check some additional urinary studies. So a 24 hour urine phosphate collection can be done. Or in most cases we'll want to get a spot urine to check for fractional excretion of phosphate or the tubular maximum reabsorption of phosphate. And so that TMP GFR calculation is an important one to do. It's certainly not something I've memorized. I mean I look this one up every time. But you would want to calculate that using the spot urine results as well as your serum labs. And then a low TMP GFR in the presence of hypophosphatemia would be consistent with renal phosphate wasting. So that definitely helps narrow your differential.
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Next you would Wanna measure an FGF20 level in the face of a low phosphate fade, FGF23 should be suppressed. So if it's normal or elevated, then that's inappropriately high and points to an FGF 23 mediated disease.
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So lab set the context. Then you use your urine studies and then FGF23 to define the mechanism. So FGF23, what exactly does it do?
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So FGF23 decreases renal phosphate reabsorption by downregulating the sodium phosphate cotransporter in the proximal tubule. It also suppresses 1 alpha hydroxylate, so lowers 125 vitamin D. With less active vitamin D, you also reduce intestinal phosphate absorption.
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And what about FGF23 mediated disorders then? As far as what the classic picture is for Osteomalacia, Dr. Tabatabhai.
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So the really classic picture for osteomalacia clinically would be a low serum phosphate, a low or inappropriately normal125 dihydroxyvitamin D level, high alkaline phosphatase and a low TMP gfr. So that's the classic sort of osteomalacia picture. And again clinically you're going to see those symptoms of bone pain, possibly proximal muscle weakness, lots of pseudo fractures or abnormalities on X ray. So that complete picture starts to come together.
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The Practical pitfall that most physicians are not aware of, although hematologists are now beginning to become aware of it more. Are the problems with certain iron infusions, particularly ferric carboxymaltose, causing hypophosphatemia?
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Yes, absolutely. This is definitely something that, you know, made it onto those rare clinical cases, case report type of thing. But now there's definitely a lot more awareness. It's still under recognized. So in this case, what's happening is ferric carboxymaltose or FCM can cause marked hypophosphatemia. And what it does is it's rapidly increasing intact FGF23. So intact FGF23 is what we measure and what the FCM is doing, the iron is inducing reduced cleavage of FGF23. So there's higher intact FGF23 levels with ferric carboxyltose infusion. So the risk of hypophosphatemia is going to increase with repeated iron infusions as well as low body weight, having a low phosphate at baseline and vitamin D deficiency. So if you have a patient who is undergoing regular iron infusions, particularly with ferric carboxymaltose, very important to monitor their phosphate before dosing and one to two weeks after, especially if patients are reporting a lot of bone pain or weakness.
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Doctor, what about XLH in particular?
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So XLH is due to fex mutations. It's an X linked dominant disease entity with variable expressivity. Clues include lifelong short stature, dental abscesses, family history of rickets or leg deformities. Labs typically will show a low phosphate level, low tubular, maximum reabsorption, normal calcium, high normal FGF 23 and low or inappropriately normal active vitamin D. Genetic testing confirms the diagnosis and helps with family counseling.
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In terms of therapy, conventionally we used to treat these patients with XLH with high doses of oral phosphate along with activated vitamin D, So calcitriol or alpha calcitol. The problem is those treatments had a very high pill burden, so rickets would improve, but it came at a cost. There was also the risk of secondary hyperparathyroidism and hypercalceuria and eventually nephrocalcinosis. So long term usage of oral phos and activated vitamin D requires really careful monitoring and really, I think, especially because there's an alternative that's extremely effective, now available, the usage of oral phosphate and activated vitamin D, it is decreasing. I think it's, as I mentioned, very, very high pill burden for patients and that can be especially problematic for children, active adolescents, and adults. So now fortunately we have burosumab. So burosumab is an anti FGF23 monoclonal antibody. And what this does is it directly reduces FGF 23 levels in the body and thereby essentially reverses and provides a biochemical cure, if you will, for the XLH process. So burosumab is a first line treatment for children over the age of 6 months who have XLH. And it's also indicated for adults with symptomatic osteomalacia, pseudo fractures or significant pain and functional limitation. So definitely an indication for usage of burosumab across the age spectrum. Really important to recognize that we we don't stop treating XLH when growth plates are closed. Very, very important to keep treating XLH across the lifespan. So in adolescents and in adults as well. And burosumab will raise the serum phosphate and normalize the levels in the vast majority of patients. It will improve the healing of rickets in children and promotes fracture and pseudo fracture healing in adults and it reduces pain. So it's had really excellent outcomes that have been seen in the clinical trials. Now it's very important to recognize that burosumab should not be combined with conventional phosphate or calcitriol therapy. And of course there are serious side effects to monitor for and it should be used under the care of a specialist.
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And we don't want to forget dental and orthopedic co management. This is a multidisciplinary disorder and we want to coordinate this care. So next, what about the differential among FGF 23 mediated causes? There's some very rare disorders that we probably will not encounter typically, but we should at least know about them.
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Yes, that is correct, Steve. So we have autosomal dominant hypophosphotomic crickets and we have autosomal recessive types. So an autosomal dominant dominant hypophosphotimic rickets. We have FGF 23 mutations that are resistant to cleavage. It typically can present in childhood or in adulthood and it often worsens with iron deficiency. With the autosomal recessive hypophosphotin brickets, it could be due to DMP1 variants or ENPP1 variants where we also have elevated FGF23 levels. Clinical patterns can hint at the subtype, but this is where genetic testing will clarify the diagnosis.
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And then of course, we want to make sure we focus also on the differential that includes tumor induced osteomalacia. How do you evaluate and localize these types of rare tumors?
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So with Tumor induced osteomalacia. We have to start with the biochemical pattern. So typically we'll have low phosphate, low tubular, maximum reabsorption of phosphate, inappropriately high, normal FGF 23, low or normal 125 dihydroxyvitamin D and elevated alkaline phosphatase. If the labs fit, that's when we move to imaging. The first imaging modality we can use is a cross sectional imaging. So MRI or CT scan, we typically will scan extremities, head and neck and the pelvis. We can also use functional imaging. So adotitate PET science scan is highly sensitive for these mesenchymal tumors. An FDG pad can also be helpful but is less specific. Now if the imaging is negative, we can consider repeat scanning. We can scan the patient from head to toe using an MRI or we can use select the venous sampling for.
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And when possible. The cure for TIO is always going to be surgical resection. So that's why identifying that that tumor, as BASMA said, is so critical and it's a really curative surgery. So phosphate will normalize within days of surgical resection and symptoms will improve as osteomalacia heals.
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Some of these tumors are unredectable or occult. So in that case we would we can use borisimab, which is approved in many regions for tumor induced osteomalacia. We can also use conventional phosphate. Phosphate plus Calci trial octreotide can also be used if the tumor is somatostatin receptor positive. Radiation or ablation can also be considered in some cases.
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The key takeaway of course is don't stop at the low phosphate. You need to identify the mechanism so you can treat the cause. What about a checklist for clinicians as to how to proceed with this in summary?
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Yeah, absolutely. So, you know, hopefully first and foremost we're going to order a phosphate. So very, very important to remember it's not on your typical panels unless there's some specialized lab testing by a nephrologist, for example, there may be a phosphate included there. But otherwise for the rest of us, we need to order a phosphate anytime. We're evaluating patients who might be presenting with proximal muscle weakness, atypical fractures, rickets, and also remember, after ferric carboxymaltose or IV iron infusions, we definitely want to order that phosphate level and then if it's low, go ahead and proceed with a basic workup. So the alkaline phosphatase level 25 and125 dihydroxy vitamin D levels, PTH, calcium and creatinine and then it's important to calculate a TMP GFR or do a fractional excretion of phosphate from a 24 hour urine and to determine whether there's renal wasting of phosphate occurring and then if that wasting is present, absolutely, you'd want to measure an FGF23 level. So intact FGF23 is available now on commercial lab assays and that will help determine whether it's an FGF23 mediated hypophosphatemia and in the case that it is suspected FGF mediated process. Hopefully the family history and age at presentation will help guide you as to whether it could be xlh. Many cases are spontaneous and actually are not detected or found, you know via family history. But also if it appears that it could be a very recent onset or something suggestive of a rapid process, we should suspect and evaluate for tumor induced osteomalacia. And in that case, as BASMA mentioned, we would want to proceed with functional imaging including a gallium dotatate PET scan when available because that that type of test is highly sensitive for isolating these.
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Tumors in an XLH FGF23 mediated disease. Consider using Borisamab when indicated. If you're using conventional therapy then monitor for PTH elevation, hypercalcemuria and nephrocalcinosis.
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Well, this has been terrific. Hypoposphatemia is often under recognized, but the downstream consequences such as osteomalacia fractures and functional decline can be substantial. To our listeners. The single most important actionable message today is to check a phosphate. It's not on the typical chem panel so you have to order it when the story fits. Leila and Bazma, thank you so much for sharing your expertise and a special thanks to Kaio Akirin for supporting this discussion. If you found this helpful, please follow the ACE Podcast and share this with your colleagues. Until next time, thanks for listening to another great ACE podcast. Join us for another episode@aace.com podcasts and help us in our mission to elevate clinical endocrinology. Together we are ACE.