In the latest Clinical Problem-Solving article, a 40-year-old woman presented to the emergency department with pain, weakness, and poor oral intake. In the 3 months preceding presentation, she noted the gradual onset of bilateral diffuse flank pain that progressed to affect her lower back, abdomen, and both arms and legs.
On skeletal imaging, osteomalacia can present with pseudofractures, insufficiency fractures, and “hot spots” on bone scintigraphy that mimic metastatic cancer.
• What are the clinical manifestations of hypophosphatemia and at what phosphate level do they occur?
Clinical manifestations of hypophosphatemia are rarely apparent until levels are below 1 mg/dl. Common symptoms and signs include fatigue, proximal myopathy, dysphagia, ileus, and impaired cardiac contractility. There may be central nervous system involvement, with irritability, delirium, or coma. Hemolysis and impaired granulocyte function have also been described. Finally, chronically low serum phosphate levels lead to a reduction in bone-mineral deposition, presenting as rickets in childhood and osteomalacia in adulthood. Rickets is associated with stunted linear growth and bone deformities. In adulthood, bone deformities are rare, but widespread bone pain may occur.
• What is the most common cause of hypophosphatemia?
Hypophosphatemia can rarely be caused by low dietary intake of phosphate, as in patients with alcohol abuse or prolonged starvation, especially in association with diarrhea, malabsorptive states, or high antacid intake, which inhibits phosphate absorption. A second mechanism for hypophosphatemia is redistribution of phosphate from the vascular compartment, either into cells (such as in acute leukemia, during treatment of diabetic ketoacidosis, or in refeeding after prolonged starvation) or into bone. Phosphate redistribution into bone occurs with “hungry bone” syndrome, in which case the decrease in parathyroid hormone levels following parathyroidectomy for primary hyperparathyroidism leads to rapid deposition of calcium and phosphate as hydroxyapatite into undermineralized bone within an expanded remodeling space. The most common cause of hypophosphatemia is urinary loss of phosphate. Urinary losses are most commonly caused by elevated levels of parathyroid hormone or fibroblast growth factor 23 (FGF-23), which reduce phosphate reabsorption, or proximal renal tubular dysfunction (Fanconi’s syndrome).
Morning Report Questions
Q: What is Fanconi’s syndrome?
A: Disorders of the proximal renal tubules lead to impaired phosphate reabsorption and hypophosphatemia, but typically also affect the other functions of the kidney tubules (renal Fanconi’s syndrome). Increased urinary losses of bicarbonate result in a non-anion gap metabolic acidosis (proximal renal tubular acidosis) and losses of potassium result in hypokalemia; there is also increased urinary loss of amino acids. Hypouricemia, glycosuria, proteinuria, and mild renal dysfunction are also consistent with this disorder. This syndrome may be genetic; occur as a complication of myeloma, amyloidosis, or Sjogren’s syndrome; or occur secondary to medications (e.g., acetazolamide, topiramate, ifosfamide, tenofovir) or heavy metal poisoning.
Q: How often is renal tubular dysfunction observed in patients taking tenofovir?
A: The full Fanconi’s syndrome is rare, reported in less than 0.1% of patients, but partial renal tubular dysfunction (defined by the presence of at least two of the following: glycosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria, or beta2-microglobulinuria) was noted in a fifth of patients taking tenofovir when assessed prospectively. Risk factors for renal dysfunction with tenofovir include increased age, low body weight, prior renal impairment, and concomitant use of other nephrotoxic drugs. In case reports and case series, Fanconi’s syndrome most often occurs in the first year of therapy and in patients with HIV infection, possibly due to higher levels from coadministration with ritonavir. Guidelines recommend that patients receiving tenofovir should undergo screening with calculation of estimated glomerular filtration rate, measurement of serum phosphate, and assessment for proteinuria and glycosuria every 6 months.