A case of severe hypophosphatemia with recent weight loss, muscle pain and weakness

65 year-old woman presented with a phosphorus level of 1.0 mg/dL. abdominal distention and  edema

General

Heent

Neck

Cardiovascular

Lungs

Abdomen

Extremities

Skin

Neurological Exam

REFERENCE LINK

https://www.hopkinsmedicine.org/johns_hopkins_bayview/_docs/education_training/grand_rounds_presentations/janlebeursm.pdf

https://pubmed.ncbi.nlm.nih.gov/30023010/#&gid=article-figures&pid=figure-1-uid-0

She has a low PTH level, making this non PTH-mediated process.  FePhos was 20%.Two hormones can do this—either HIGH PTH or fibroblast growth factor 23 (FGF-23). Next step is to obtain a  FGF-23 level.  In her case FGF-23 level  was 1232RU/mL (reference range <180 RU/mL).. So, this is an FGF-23–induced hypophosphatemia. Where is this coming from? Her (25[OH]D3) was  normal . Her liver biochemistries were slightly elevated, her alkaline phosphatase was disproportionately elevated. Another increased urinary excretion as the cause of the hypophosphatemia is  Fanconi syndrome.  However she is not any chemotherapy agents or tenofovir, no h/o multiple myeloma.   She has normal immunofixation, and no serum free light chain excess.She has normal magnesium, glucose, uric acid, and potassium levels. She has a urinalysis with no glucosuria, making this less likely to be Fanconi syndrome.  Her high level of FGF-23, elevated alkaline phosphatase, low 1,25(OH)2D3 level, low PTH, and elevated urinary fractional excretion of phosphorus gives her a diagnosis of oncogenic renal hypophosphatemia from tumor-induced osteomalacia(TIO).

Oncogenic renal phosphate wasting secondary to FGF-23 secretion is a rare paraneoplastic syndrome, causing TIO, also referred to as oncogenic osteomalacia. Most commonly seen in  benign mesenchymal tumors of soft tissue or bone, though they may rarely be seen in Malignant neoplasm such as small/squamous cell lung cancer, colon cancer, prostate cancer, ovarian cancer,
lymphoma, osteosarcoma, and multiple myeloma.FGF-23 is a phosphatonin made by osteocytes and plays a major role in the bone-kidney axis by regulating phosphate,1,25(OH)2D3, and bone mineralization.. Typically, with TIO ,serum phosphorus is low and serum 1,25(OH)2D3 levels are low or inappropriately normal. The 25(OH)D3 and calcium levels are usually normal. A markedly elevated FGF-23 level is usually the hallmark fi nding in TIO and provides strong support for a diagnosis of TIO. In response to high serum phosphorus and vitamin 1,25(OH)2D3 levels, FGF-23 is secreted. It then binds to the FGF receptor, Klotho complex, in renal tubular epithelial cells, decreasing proximal tubule expression of sodium phosphate cotransporters. Th is results in decreased phosphorus reabsorption, phosphaturia, and corresponding hypophosphatemia. In addition, FGF-23 inhibits 1α-hydroxylase activity in the proximal tubule by downregulation of CP27B1, thus decreasing 1,25(OH)2D3. levels. This, in turn, decreases phosphate absorption in the gut which potentiates the hypophosphatemia. FGF-23 is also thought to be an inhibitor for PTH secretion. In TIO, FGF-23 is secreted in an unregulated fashion, likely by tumor cells, causing marked hypophosphatemia and osteomalacia

Common causes of hypophosphatemia. 

Increased urinary phosphate
Medications: tenofovir, acetazolamide, bicarbonate, IV iron
Tumor-induced osteomalacia/mutations
Fanconi syndrome, -Increased urinary losses
Primary/secondary hyperparathyroidism

Spurious hypophosphatemia  can be caused by interference of paraproteins or medications with the phosphate assay

Decreased urinary phosphate

-Intracellular shift
Acute respiratory alkalosis
Tumor consumption: lymphoma, leukemia blast crisis
Sepsis, Increased insulin levels: diabetic ketoacidosis, insulin-dependent diabetes, refeeding syndrome
Hungry bone syndrome

–Decreased intestinal absorption

Malabsorption: bowel surgery, pancreatitis, Crohn’s, celiac disease, chronic diarrhea
Chronic kidney/liver disease, Phosphate absorption inhibitors: niacin, phosphate binders, antacids
Nutritional deficiency: anorexia, alcoholism, marasmus Vitamin D deficiency

Normal renal  response to hypophosphatemia is to increase phosphate reabsorption resulting in exceptionally low urine phosphate excretion. Filtrated phosphate  is predominantly absorbed in the the proximal tubule via the sodium-phosphate cotransporters NaPiIIa and NaPiIIc in the proximal tubule. Hypophosphatemia leads to increased synthesis of new transporters causing increased reabsorption of phosphate by the kidney. In patients with hypophosphatemia:●A 24-hour urine phosphate < 100 mg or a FEPO4 < 5 (  FEPO4  =  [UPO4  x  PCr  x  100]  ÷  [PPO4  x  UCr] -where U is urine and P is plasma)  indicates as expected drop in renal phosphate wasting. This can be seen in various forms of  redistribution clinical conditions(eg, refeeding , acute respiratory alkalosis) or low  intestinal absorption (eg, intestinal phosphate binding by calcium, magnesium, or aluminum to form insoluble salts in chronic antacid or increased intestinal transit and secretions as in  chronic diarrhea , decreased intestinal  phosphate transport from chronic niacin treatment. steatorrhea)●A 24-hour urine phosphate > 100 mg or a FEPO4 >5 percent  indicates high kidney phos excretion suggesting underlying primary or secondary hyperparathyroidism, or renal tubular defect both of which impair phosphate reabsorption by diminishing the activity of the sodium-phosphate cotransporters (NaPi-IIa and NaPi-IIc) in the proximal tubule. Primary Hyperparathyroidism presents with  hypercalcemia, hypophosphatemia, and urinary phosphate wasting, where as hypocalcemia is common in secondary hyperparathyroidism from vitamin D deficiency.  Persistent post transplant hypophosphatemia is due to persistent high secretion of PTH by hyperplastic parathyroid glands and to persistently elevated plasma levels of fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone which is high in kidney disease. Tubular defects comprise impairment in proximal phosphate transport (as seen in hypophosphatemic rickets or tumor-induced osteomalacia) or as a generalized defect in proximal function (called the Fanconi syndrome) The Fanconi syndrome occurs with cystinosis, Wilson’s disease, multiple myeloma (in which filtered light chains are toxic to the proximal tubule), heavy metal toxicity, and medications ( tenofovir, ifosamide). is typically accompanied by other evidence of low proximal tubular reabsorption, including glucosuria (at a normal plasma glucose concentration), hypouricemia, aminoaciduria, and a hyperchloremic metabolic acidosis due to urinary bicarbonate wasting. Hereditary forms of hypophosphatemic rickets and oncogenic osteomalacia, result from excess production of the phosphaturic hormone FGF23. Associated sympotms include history of nontraumatic fractures with skeletal deformities, bone pain associated with severe osteopenia and  progressive muscle weakness.