Basics
Description
Hypophosphatemia is defined by serum phosphorus values below the age-appropriate normal range.
Alert
- Normal phosphorus concentrations in infants and children are significantly higher than in adults.
- Hypophosphatemia can be missed if an adult normal range is used for pediatric patients.
Epidemiology
Acute hypophosphatemia is a common laboratory finding in the hospital, especially in the intensive care unit (ICU) setting.
Etiology
- Chronic hypophosphatemia is a common etiology of rickets. It can result from multiple causes, including:
- Vitamin D deficiency
- Most common form of rickets
- X-linked hypophosphatemic (XLH) rickets
- Most common inherited cause of rickets (prevalence ā1 in 20,000)
- Other genetic forms of rickets are less common.
- Isolated dietary phosphate deficiency is rare; dietary phosphate deficiency usually involves generalized malnutrition.
Genetics
Genetic forms are less common than acquired forms and occur due to mutations in:
- PHEX (XLH rickets)
- FGF23 (autosomal dominant hypophosphatemic rickets [ADHR])
- DMP1 (autosomal recessive hypophosphatemic rickets [ARHR])
- ENPP1 (ARHR, generalized arterial calcification of infancy [GACI])
- FAM20C (autosomal recessive hypophosphatemia, Raine syndrome)
- SCL34A3 (NPT2c, hereditary hypophosphatemic rickets with hypercalciuria [HHRH])
- CYP27B1 (1Ī±-hydroxylase deficiency)
- VDR (vitamin D receptor)
- GNAS (McCune-Albright syndrome, activating mutations of GsĪ±, sometimes associated with hypophosphatemia)
- Others
Risk Factors
- Nutritional
- Vitamin D deficiency
- Malnutrition/refeeding syndrome
- Chronic diarrhea
- Medications affecting phosphate absorption
- Antacids
- Sevelamer
- Lanthanum carbonate
- Excess calcium salts
- Genetics
- Primary renal phosphate wasting disorders (see "Differential Diagnosis")
- Vitamin D metabolism disorders
- Renal Fanconi syndrome
- Other:
- Medications affecting renal phosphate transport
- Treatment of diabetic ketoacidosis
- Acute respiratory alkalosis
- Post renal transplant
- Hungry bone syndrome after parathyroidectomy for hyperparathyroidism
Pathophysiology
- Decreased nutritional intake or malabsorption
- Redistribution of extracellular phosphate into the intracellular compartment
- Increased renal phosphate loss (due to medications, hormonal effects, or primary renal tubulopathy)
Diagnosis
History
- Family history of hypophosphatemia or rickets
- Medications
- Known disease affecting phosphate metabolism (see "Differential Diagnosis")
- Nutritional history
- Vitamin D intake, phosphate sources
- Anorexia or other malnutrition
- Parenteral or enteral nutrition formulation
- Duration of symptoms (acute vs. chronic)
- Dental abnormalities
- Abscessed teeth associated with XLH
- Gastrointestinal symptoms
- Cardiovascular, respiratory, or neurologic symptoms (may accompany acute hypophosphatemia, usually in hospital setting)
- Myalgia or weakness
- Bowed legs, short stature
- Bone pain or stress fractures/pseudofractures
- Precocious puberty, caf © au lait macules, fibrous dysplasia-due to McCune-Albright syndrome
Physical Exam
- Height, rate of growth
- Rachitic features
- Frontal bossing
- Delayed closure of fontanelle
- Rachitic rosary
- Harrison sulcus (groove corresponding to the rib insertion site of the diaphragm)
- Widened wrists or ankles
- Valgus, varus, or windswept deformity of the legs
- Dental abscess
- Muscle weakness
- Caf © au lait macules (McCune-Albright syndrome)
Diagnostic Tests & Interpretation
Lab
Confirm laboratory diagnosis before treating (unless unstable).
- Serum phosphorus concentration-below age-appropriate normal range (ideally fasting)
- Normal ranges by age
- 0-1 month 4.8-8.2 mg/dL
- 1-4 month 4.8-8.1 mg/dL
- 4 months-1 year 4.8-6.8 mg/dL
- 1-5 years 3.6-6.5 mg/dL
- 5-10 years 3.4-5.5 mg/dL
- 10-20 years 2.6-5.2 mg/dL
- >20 years 2.5-4.9 mg/dL
- Serum calcium
- Normal in most primary renal phosphate wasting disorders
- Elevated in primary hyperparathyroidism
- Low or low normal in vitamin D deficiency rickets
- Parathyroid hormone concentration
- Can be elevated if chronic hypophosphatemia is due to vitamin D deficiency or to XLH (pre- or posttreatment). Elevations in parathyroid hormone (PTH) concurrent with hypercalcemia indicate primary hyperparathyroidism.
- Alkaline phosphatase
- Elevated in rickets and many patients with hyperparathyroidism
- Serum creatinine
- 25-hydroxyvitamin D
- Low in vitamin D deficiency rickets
- 1,25-dihydroxyvitamin D
- Low in 1Ī±-hydroxylase deficiency
- Elevated in vitamin D receptor mutations and nutritional phosphate deficiency
- Low or inappropriately normal in fibroblast growth factor 23 (FGF23)-mediated causes of hypophosphatemia
- Urine phosphorus and creatinine for assessment of tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR or TP/GFR)
- Should be obtained at same time as serum phosphorus and creatinine
- TP/GFR = serum phosphorus - (urine phosphorus serum creatinine/urine creatinine)
- Normal or high in vitamin D-mediated hypophosphatemia and nutritional deficiency
- Low in renal phosphate wasting disorders
- FGF23 (a phosphaturic hormone)-may be helpful in renal phosphate wasting disorders
- Elevated in many forms of inherited rickets (XLH, ADHR, ARHR)
- Elevated in most patients with tumor-induced osteomalacia (TIO) due to FGF23-secreting tumors
- Low in nutritional phosphate deficiency or malabsorption or Fanconi syndrome or HHRH
Imaging
- Radiographs to evaluate for signs of rickets
- Skeletal survey in patients suspected of fibrous dysplasia of bone
- Bone scan is also very sensitive in evaluating for fibrous dysplasia.
- Rare: other imaging to identify TIO-these rare tumors can be very difficult to localize
- PET/CT scan, MRI, CT, octreotide scan, whole body sestamibi scan
Diagnostic Procedures/Other
- Genetic studies, when appropriate
Differential Diagnosis
- Nutritional- or absorption-related
- Low phosphorus intake
- Premature infants
- Chronic diarrhea
- Short bowel syndrome
- Vitamin D deficiency
- Nutritional, lack of sun exposure
- 1Ī±-hydroxylase deficiency
- Vitamin D receptor mutation
- Medications
- Antacids
- Sevelamer
- Lanthanum carbonate
- Excess calcium salts
- Redistribution of phosphate into the intracellular compartment
- Insulin therapy for diabetic ketoacidosis
- Acute respiratory alkalosis
- Refeeding syndrome
- Hungry bone syndrome (after parathyroidectomy for primary hyperparathyroidism)
- Increased renal phosphate loss
- Medications (glucocorticoids, diuretics)
- Primary hyperparathyroidism
- FGF23-dependent (FGF23 excess)
- XLH rickets
- ADHR (may present after childhood with new-onset hypophosphatemia; consider ADHR if considering TIO)
- ARHR
- TIO (primarily diagnosed in adults, but cases reported in children)
- Fibrous dysplasia of bone
- Postrenal transplant phosphate wasting
- FGF23-independent
- Renal Fanconi syndrome
- Familial
- Medication-induced
- Associated with other disorders (cystinosis, multiple myeloma, and others)
- HHRH (rare-mutations impairing NPT2c)
Treatment
Medication
- Acute
- Oral phosphate supplementation preferred route
- Intravenous phosphate should be used with caution:
- High doses require central venous catheter.
- Can cause severe hypocalcemia: Monitor calcium.
- Telemetry recommended due to possible arrhythmias
- Replete vitamin D if needed (this will not acutely increase serum phosphorus levels)
- Chronic
- If dietary deficiency or malabsorption: oral phosphate and vitamin D repletion
- If renal phosphate wasting due to an FGF23-mediated cause
- Phosphate 20-40 mg/kg/day divided in 3-5 doses
- Start therapy with low doses and then increase gradually to reduce risk of diarrhea.
- Calcitriol 20-30 ng/kg/day in 2 divided doses (may require higher doses)
- Non-FGF23-mediated renal phosphate wasting with elevated 1,25-dihydroxyvitamin D (HHRH)
- Phosphate 20-40 mg/kg/day divided in 3-5 doses
Additional Treatment
- Chronic hypophosphatemic disorders resulting in skeletal deformity (especially inherited causes) may require surgical intervention to correct valgus or varus deformities of the lower extremities.
- Adequate medical therapy should be initiated first, as it may reduce the need for surgical interventions.
- Routine dental care
- Dental abscess common in some genetic forms of hypophosphatemia
- For the rare cases of TIO, complete surgical removal of the offending tumor is curative.
General Measures
- Routine dental care at least twice per year (especially for patients with inherited rickets)
- Audiology evaluation in patient with inherited hypophosphatemic rickets
- Increased risk of hearing loss
Ongoing Care
Follow-up Recommendations
- For chronic hypophosphatemia
- Frequent laboratory monitoring is mandatory if long-term phosphate and calcitriol therapy is needed (every 3-4 months)
- Calcium
- Phosphorus
- Creatinine
- Alkaline phosphatase
- Parathyroid hormone
- Urine calcium, creatinine, and phosphorus
- The goal is NOT to normalize serum phosphate in chronic renal phosphate wasting disorders, as this may lead to secondary or tertiary hyperparathyroidism and/or nephrocalcinosis.
- Periodic radiographic studies
- Annual renal ultrasound to evaluate for nephrocalcinosis
- Periodic x-ray of knees/wrists to evaluate response to treatment
- Improvement in rachitic changes
- Improvement in varus/valgus deformities
Prognosis
- Hypophosphatemia due to nutritional deficiency
- Hypophosphatemia resolves with adequate replacement of nutritional deficiencies or discontinuation of phosphate-binding agents.
- Acute hypophosphatemia (typically seen in the hospital setting) can be life-threatening and requires careful monitoring and treatment.
- Hypophosphatemia resolves when the underlying condition is treated.
- Chronic renal phosphate wasting disorders have a variable response to treatment. Some have radiographic healing of rickets, correction of varus/valgus deformity, and normalization of alkaline phosphatase, whereas others have an incomplete response to therapy.
- Short stature is a common result of chronic hypophosphatemia.
- Hypophosphatemia resolves with removal of the offending tumor in patients with TIO, but long-term monitoring for recurrence is necessary, as hypophosphatemia may recur years later.
Additional Reading
- Carpenter TO, Imel EA, Holm IA, et al. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388. [View Abstract]
- Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin Endocrinol Metab. 2012;97(3):696-706. [View Abstract]
Codes
ICD09
- 275.3 Disorders of phosphorus metabolism
- 270.0 Disturbances of amino-acid transport
ICD10
- E83.39 Other disorders of phosphorus metabolism
- E72.09 Other disorders of amino-acid transport
- E83.31 Familial hypophosphatemia
SNOMED
- 4996001 Hypophosphatemia (disorder)
- 82236004 Familial x-linked hypophosphatemic vitamin D refractory rickets (disorder)
FAQ
- Q: What is the most important complication of intravenous phosphate administration?
- A: Severe life-threatening hypocalcemia. Infusions of phosphate should be slow and monitored with telemetry.
- Q: Should I measure FGF23 concentrations?
- A: Generally, a diagnosis can be made without FGF23 measurement. FGF23 measurement is only useful if the TP/GFR is low.
- Q: What are dietary phosphate sources?
- A: Phosphate sources are ubiquitous; examples include processed meats, dairy, legumes, nuts, whole grains, citrus, and colas. Phosphates are used as a preservative in processed foods.