The first article that I could find was written by Lotz in 1964 Trans Assoc Am Physicians titled “osteomalacia and debility resulting from phosphorus depletion”. I was unable to generate this article.
One of the first papers to address this issue in clinical patients was authored by a young Jay Stein and his professors in Oklahoma City in 1966 American Journal of Medical Sciences where he described 54% of patients admitted with acute alcoholism had phosphorus levels less than 3.0 mg/dL. To be fair the authors were aware from the Annino and Relman 1959 American Journal of Clinical Pathology article that glucose loading resulted in phosphate lowering. I haven’t included that article in this review. They even looked at patients without glucose loading and still found that 40% of patients with acute alcoholism had significant hypophosphatemia.
The first description of the wide spectrum of abnormalities was published by Lotz (yep same guy as above) with his mentor Fred Bartter (yep same guy) in 1968 NEJM article “evidence for a phosphorus-depletion syndrome in man”. They took 3 normal patients and 3 patients with documented hypoparathyroid states and exposed them to phosphorus binding antacids. A syndrome of phosphorus depletion was described including hypophosphatemia (levels about 1 mg/dL), hypophosphaturia, increased GI calcium absorption, hypercalciuria, increased skeletal reabsorption, bone pain, debility, anorexia, weakness, malaise, anorexia and tremor.
My introduction to the topic occurred when reading Hibbard Williams review in 1975 Western Journal of Medicine. I will repeat what I said last week at a Baylor nephrology conference, you really should look at old WJM reviews, under the direction of Lloyd Smith. Many are spectacular. In this review, a wide group of states lead to hypophosphatemia, including antacid use, starvation, dialysis vs zero phosphate dialysate, alcoholism, glicose refeeding including TPN, hyperparathyroidism, hyperventilation, diabetic ketoacidosis, proximal renal tubular defects, hereditary forms, and osteomalacia. In addition the wide spectrum of clinical presentations were described including all forms of neuromuscular findings, hematologic abnormalities of red cell, white cells and platelets, presumably related to deficient ATP-DPG, and loss of membrane stability, hepatic abnormalities, and skeletal abnormalities related to bone resorption. Specifically missing in the discussion was the description of muscle abnormalities (cardiomyopathy, respiratory muscle dysfunction, rhabdomyolysis). Treatment was recommended in patients with the above symptoms, or when phosphorus levels declined to levels less than 1.0 mg/dL. This article remains one of my 10 most favorite articles of all time.
The quintessential review of the topic was authored by Jim Knochel in a 1977 Archives of Internal Medicine article. The list of conditions leading to severe hypophosphatemia (phosphorus levels < 1 mg/dL) included: alcoholic withdrawal, diabetes mellitus, pharmacologic phosphate binding, recovery-diuretic phase after severe burns, hyperalimentation, nutritional recovery syndrome, severe respiratory alkalosis. Burns was really the only new condition. Definitive complications of hypophosphatemia included: red cell dysfunction, leukocyte dysfunction, platelet dysfunction, CNS dysfunction, rhabdomyolysis (the new kid on the block). This just in … that Knochel kid knew about rhabdomyolysis! Proximal tubular dysfunction with multiple electrolyte wasting related to hypophosphatemia was discussed. Therapy with NaPhos – KPhos and milk was described with a goal of 1 gm (33 mmole)/day.
The most recent review was authored by Felsenfeld in a 2012 AJKD article. Not much different is reported from previous papers.
I will briefly talk about the new kid on the block hypophosphatemia associated with CRRT. If you look at the above WJM article, Hibbard Williams did mention dialysis vs 0 potassium dialysate as a cause of severe hypophosphatemia. It certainly doesn’t happen much in conventional outpatient HD, but it has always struck me as interesting the high frequency of hypophosphatemia with CRRT (especially with the newer versions). Maybe it’s the CRRT membrane. Certainly, oral replacement is possible, but a make your own dialysate can be done. Assuming a 5 L (50 dL) dialysate bag, addition of 2 mL of KPhos will generate a solution of potassium 8.8/5.0 = 1.8 mM, and phosphate 200(OK 186 for purists) /50 = 4.0 mg/dL. A nice review of the topic was authored by Santiago in a 2009 KI article.
I’ll finish with a memorable case from my intern year. It was February 1977. I was on the nephrology service with the best resident in the program (Bob Crawford, subsequent cardiologist in Peoria IL), and the chief of medicine (Dick Rieselbach, author of the chapter on uric acid in the original Brenner-Rector textbook). We had an old emaciated lady (she looked 100) with established CKD (cr ~2.0+ mg/dL), who presented with vague nonspecific symptoms. Admission lab revealed phosphate level < 2.0 mg/dL. Dr Rieselbach (always up on current literature – note the publication date of the Knochel paper) told us that this lady needed treatment for this. OK…… we gave her Fleets PhosphoSoda (129 mg/mL) 5mL every 4 hours for several days. The poor lady developed unrelenting diarrhea. She was a little demented, but kept screaming ” you guys are KILLING me”! Yep… we were. Routine lab done on the last day of the rotation was a bit altered with phosphate level 21 mg/dL, and calcium level 3.0 mg/dL (QT interval was measured in days rather than msec). I asked Dr. Crawford if he wanted to call the chief and tell him what happened. His answer was ” nope… that’s intern’s work”! No …. we didn’t write this one up. She did get better with saline expansion alone. Be careful with phosphate replacement in patients with underlying CKD.
Reference: [1] [2] [3] [4] [5]
Nephrology Fellowship 