Detective Nephron: A Case of Hypophosphatemia


Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. L.O. Henle, a budding nephrologist, presents a new case to the master consultant.

Nephron My apprentice, what do you have for me?
Henle No medical student or resident today. Not many are taking electives these days.
Nephron (smiling): Time will come, my dear apprentice, when nephrology will be sought after. Don’t give up your hopes. Keep doing what you love. After all, we want nephrologists who enjoy what they do!
Henle Glad to be on board. I am getting involved in the nephrology online journal club these days——and it’s been a fruitful experience.
Nephron (interrupting): Social media—forget that! Let’s get to the case!
Henle We have a case of hypophosphatemia.
Nephron Oh, come on! Is that real? Likely severe malnourishment…replete the patient intravenously and by mouth, and call it a day.
Henle (with a smile): She is a 55-year-old woman who had been doing well until 3 months ago, when she had abdominal distention and pain. She had been eating well until just 1 week ago, when she noticed fatigue and worsening distention and was admitted. She has ovarian cancer according to the primary team.
Nephron (angrily): Too much information. I am more concerned about what her urine looks like.
Henle Well, let’s make it simple. Hypophosphatemia usually happens in three ways—increased urinary excretion or decreased intestinal absorption or a cellular shift.
Nephron Ahh! That is a simplistic look. I like things simple and not too complex. I don’t want to confuse medical students these days! Nephrology can be made very simple if taught properly.
Henle Shifts are less likely here. I understand that refeeding is a possibility, but she was eating well until about a week ago, so that’s less likely in this case. Other causes could be insulin secretion, but her blood glucose levels have been normal and not low. Last, another cause of shifts could be hungry bone syndrome, which is not possible because she has not had any recent parathyroid surgery, and no such findings are on my history or physical examination. No acute respiratory alkalosis either; that could cause a shift.
Nephron (getting bored): Good work. So is this an intestinal problem or a kidney problem?
Henle Well, the urinary phosphorus is very high, and the fractional excretion of phosphate is 30 percent. I don’t think the kidney is doing the right thing here. In the setting of low serum phosphorus, the kidney should be retaining phosphorus and not wasting it. The fractional excretion of phosphate should be less than 5 percent. I think this is renal phosphate wasting.
Nephron (happy): Ahh! Now that is interesting! Are you sure that there is no vitamin D deficiency or diarrhea or intake of any binders that the patient might be taking, such as niacin, aluminum, antacids?
Henle Yes, we checked for all those, and she is not taking any such medications.
Nephron Good work, my apprentice. How do we want to investigate this phosphate wasting problem?
Henle The problem is related to the kidneys, so it’s either a hormonal problem or a direct tubular defect. Let me start with the tubular defects first. They could be defects leading to solitary hypophosphaturia from drugs, or a Fanconi syndrome from…hmmm, she is not using anything specifically that could cause that…she hasn’t received any chemotherapy yet, or any antibiotics that could cause that.
Nephron (chewing): Want some cashews or almonds?
Henle No, thanks.
Henle Well, there are no signs of a complete Fanconi syndrome—no glucosuria, uricosuria, hypokalemia, or any combination of those. In addition, her serum free light chains are normal, ruling out a paraprotein-mediated disease. I doubt she would have two malignancies at the same time.
Nephron Good work, my friend. Let’s move on to the hormones. What hormones are we planning to discuss here?
Henle Two that are commonly associated with this entity are parathyroid (PTH) hormone and vitamin D. If this was primary hyperparathyroidism, there would be hypercalcemia and an elevated PTH level as well. She did have slightly elevated calcium, but her PTH level was in the low to normal range. Could she have secondary hyperparathyroidism? That’s less likely because her renal function is normal, and her calcium is not low.
Nephron Good thus far.
Henle Yes, I know. In addition, she had a low 1,25-OH vitamin D3, moderately low to normal 25-OH vitamin D3, and normal PTHrP (parathyroid hormone-related protein) as well. But clearly, she doesn’t have a profound vitamin D deficiency.
Nephron What happens in the kidney with vitamin D?
Henle Well, if the kidney is working well, the 25-OH vitamin D3 should get converted to 1,25-OH vitamin D3, and the levels should be relatively good. Hmm, so why is her 1,25-OH vitamin D3 low? I thought hypophosphatemia results in stimulation of calcitriol levels, which would tend to raise the serum phosphate by increasing intestinal phosphate absorption and perhaps by bone resorption.
Nephron Good question, Henle. Why?
Nephron Want to eat some tofu?
Henle (surprised): No, sir. What’s with the food today? No coffee...let’s get back to the case.
Nephron So, my dear apprentice, where do we stand now? You have hypophosphatemia, low 1,25 vitamin D level, low normal PTH level, and normal renal function. Is this still a urinary loss of phosphorus?
Henle Yes. I think so. I think we might have another hormone that might be involved here: fibroblast growth factor (FGF-23). It’s a phosphaturic hormone, and perhaps this patient has an elevated FGF-23 level.
Nephron Good work, Henle. Why don’t we get a serum FGF-23 level and rule it out? Meanwhile, make sure you are replenishing the phosphorus with aggressive measures to keep this patient from being symptomatic.
Henle exits, and Nephron decides to have a cola drink today instead of his usual coffee.
Nephron Nothing better than a nice jolt of phosphorus.
Three days later, Henle enters with a smile.
Nephron So, what do we have, sir?
Henle A strikingly elevated FGF-23 level was noted.
Nephron (shocked): Henle, how do you explain the low 1,25 vitamin D in this instance?
Henle FGF-23 is an important hormone that is synthesized by osteocytes and osteoblasts. I believe that FGF-23 has one major function—to get that phosphorus out of the body. Hence, it will do anything in its power to increase excretion and decrease absorption. It is still an enigma as to how FGF-23 downregulates renal phosphate reabsorption, but it likely happens in the proximal tubule. FGF-23 also indirectly decreases the intestinal absorption of phosphate. In addition, it also decreases intestinal sodium phosphate transporters. But it also inhibits calcitriol synthesis in the kidney and stimulates the catabolism of active vitamin D sterols, so it will lower the 1,25 vitamin D levels in this case.
Nephron Very likely explanation. So that could explain the phosphaturia. The low 1,25 vitamin D with normal renal function might have been the clue in her case that FGF-23 was the real culprit. Good work. But why does she have elevated FGF-23?
Henle There are many possible causes of an elevated FGF-23 level. Given that her renal function is normal, the excretion of FGF-23 is not affected. In chronic kidney diseases, FGF-23 concentrations increase as GFR declines. In addition, a high-phosphate diet can induce a high FGF-23 state, but clearly that is not happening here. So that leaves me with causes of elevations in FGF-23 that are due to increased production. An active primary production of this hormone seems to be happening in her body. Intravenous iron use can cause it, but she never received that. Other genetic causes such as hypophosphatemic rickets are less likely. I think this is a paraneoplastic FGF-23 production from the ovarian cancer.
Nephron That is a nice chain of thought, Henle. What you are referring to is tumor-induced osteomalacia, a rare paraneoplastic syndrome characterized by elevated phosphatonins (FGF-23), renal phosphate wasting, and abnormal vitamin D metabolism, usually seen in benign mesenchymal tumors and head and neck cancers. To me, perhaps any cancer can cause it. Interestingly, although serum FGF-23 concentrations are also elevated in patients with advanced-stage ovarian cancer, low serum phosphorus is not usually observed. But it looks as if this did occur in your case. Fascinating! Please treat her cancer because that might improve her electrolyte disorder.
Henle Yes, sir!
Three days later, Henle enters.
Nephron How did she respond to chemotherapy?
Henle Imaging confirmed metastatic ovarian malignancy, and the patient elected for hospice care. Despite repletion with high doses of intravenous and oral phosphate and vitamin D, normalizing her phosphate was challenging because her underlying malignancy was progressive and untreated: unfortunately, not an ending we were hoping for.
Nephron My dear apprentice, you did what you could. I understand her choices, and we must respect that. Henle, you have stumped me this time with a great case of an electrolyte abnormality that was a paraneoplastic syndrome associated with metastatic cancer. Again, nephrologists can always be amazing detectives. Let’s go have some New York–style pizza. I feel like having a high-phosphorus diet today.
Detective Nephron was developed by Kenar Jhaveri, MD, associate professor of medicine at Hofstra North Shore LIJ School of Medicine. Thanks to Dr. Rimda Wanchoo, assistant professor of medicine at Hofstra North Shore LIJ School of Medicine, for her editorial assistance.