What is the appropriate workup for a patient presenting with fatigue and hypophosphatemia?

Workup for Fatigue with Hypophosphatemia

The workup for fatigue with hypophosphatemia should begin with measuring fractional excretion of phosphate (FEPhos) to distinguish renal phosphate wasting from other causes, followed by serum calcium and PTH levels to categorize the underlying etiology, while simultaneously evaluating for common contributing factors including medication history (particularly recent IV iron infusions), vitamin D status, and symptoms suggesting chronic phosphate depletion. 1

Initial Diagnostic Algorithm

Step 1: Confirm Hypophosphatemia and Calculate Fractional Excretion

• Measure serum phosphate level (hypophosphatemia defined as <2.5 mg/dL or 0.8 mmol/L) 1
• Calculate fractional excretion of phosphate (FEPhos): if >15% in the presence of hypophosphatemia, this confirms renal phosphate wasting 1
• Obtain simultaneous urine phosphate, serum phosphate, urine creatinine, and serum creatinine for this calculation 1

Step 2: Essential Laboratory Panel

• Serum calcium to categorize the type of phosphate wasting 1
• Parathyroid hormone (PTH) 2, 3
• 25-hydroxyvitamin D 2, 3
• Alkaline phosphatase (ALP) - elevated in rickets/osteomalacia 2
• Serum creatinine and BUN 2
• Serum magnesium (hypomagnesemia can contribute to hypophosphatemia) 2
• Complete blood count 2

Step 3: Medication and Exposure History

• Recent IV iron infusion history - particularly ferric carboxymaltose, which causes hypophosphatemia in 47-75% of patients 4
  • Hypophosphatemia typically develops within the first 2 weeks after IV iron administration 4
  • Symptoms include paradoxical worsening of fatigue, proximal muscle weakness, bone pain, and myalgias despite anemia correction 4
• Review medications that can cause phosphate wasting: diuretics, antacids, bisphosphonates, denosumab 5
• Assess alcohol use and nutritional status 2

Classification Based on Serum Calcium

Once FEPhos confirms renal phosphate wasting (>15%), categorize by calcium level 1:

High Serum Calcium

• Primary hyperparathyroidism - measure PTH (will be elevated or inappropriately normal) 1
• Consider parathyroid imaging if PTH elevated

Low Serum Calcium

• Secondary hyperparathyroidism - PTH elevated, 25-OH vitamin D typically low 1
• Evaluate for vitamin D deficiency, malabsorption, chronic kidney disease 1

Normal Serum Calcium

• Primary renal phosphate wasting syndromes 1:
  • X-linked hypophosphatemia (XLH) - most common genetic cause 2
  • Tumor-induced osteomalacia (oncogenic osteomalacia) - measure FGF23 if suspected 1
  • Fanconi syndrome - check for glucosuria, aminoaciduria, metabolic acidosis 1
  • Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Symptom-Specific Evaluation

Assess Severity and Chronicity of Symptoms

• Acute severe symptoms (serum phosphate <2.0 mg/dL): altered mental status, respiratory failure, cardiac dysfunction, rhabdomyolysis require urgent intervention 6, 1
• Chronic symptoms suggesting osteomalacia: persistent bone pain, fractures, proximal muscle weakness, difficulty with ambulation 4, 6, 7
• Fatigue pattern: worsening fatigue despite treatment of underlying condition (e.g., anemia) suggests treatment-emergent hypophosphatemia 4

Physical Examination Findings

• Proximal muscle weakness - assess ability to rise from chair, climb stairs 4, 7
• Bone tenderness on palpation 6
• In children: assess for rickets (bowed legs, rachitic rosary, growth impairment) 2
• Gait abnormalities 2
• Dental abnormalities (abscesses, early tooth loss) in chronic cases 2

Additional Testing Based on Clinical Context

If X-Linked Hypophosphatemia Suspected

• Genetic testing for PHEX gene mutations 2
• Radiographs of lower extremities to assess for rickets or osteomalacia 2
• Measure FGF23 levels (elevated in XLH) 2
• Assess for complications: renal ultrasound for nephrocalcinosis, cranial MRI if craniosynostosis suspected 2

If Drug-Induced (IV Iron) Hypophosphatemia

• Do not give phosphate supplementation - this can worsen the condition 6, 3
• Provide vitamin D supplementation to mitigate secondary hyperparathyroidism 6, 3
• Switch to alternative iron formulation if ongoing therapy needed (ferric derisomaltose, iron sucrose, or ferumoxytol have <10% incidence of hypophosphatemia) 4

If Tumor-Induced Osteomalacia Suspected

• Measure serum FGF23 (markedly elevated) 1
• Imaging to locate phosphaturic mesenchymal tumor: whole-body MRI, PET scan with somatostatin analogs 1

Critical Pitfalls to Avoid

• Do not dismiss persistent fatigue as residual anemia - this may indicate treatment-emergent hypophosphatemia requiring immediate evaluation 4
• Do not give phosphate supplementation for ferric carboxymaltose-induced hypophosphatemia - it is contraindicated and can worsen the condition 6, 3
• Do not overlook chronic manifestations - severe prolonged hypophosphatemia can cause osteomalacia lasting 6+ months with fracture risk 4, 6
• Do not assume asymptomatic = not clinically significant - asymptomatic hypophosphatemia is common, particularly with mild cases, but absence of symptoms does not exclude the diagnosis in at-risk patients 4
• Do not forget to check urinary calcium when evaluating for genetic causes - hereditary hypophosphatemic rickets with hypercalciuria (HHRH) presents with hypercalciuria unlike other forms 1

Monitoring During Workup

• Recheck serum phosphate levels at least weekly during initial evaluation 3
• Monitor serum calcium to detect hypercalcemia or hypocalcemia 3
• If initiating phosphate supplementation, monitor urinary calcium excretion to prevent nephrocalcinosis 3
• Reassess PTH if secondary hyperparathyroidism develops 3