What is the workup for a patient with severe vitamin D deficiency (less than 6 ng/mL)?

Workup for Severe Vitamin D Deficiency (Level <6 ng/mL)

For a patient with severe vitamin D deficiency (<6 ng/mL), immediately initiate treatment with ergocalciferol 50,000 IU weekly for 8-12 weeks while simultaneously evaluating for underlying causes of deficiency and assessing for complications. 1, 2

Immediate Laboratory Assessment

Obtain the following labs before or concurrent with treatment initiation:

• Serum calcium - to rule out hypocalcemia and establish baseline before supplementation 3
• Serum phosphate - may be low in severe deficiency with secondary hyperparathyroidism 4
• Parathyroid hormone (PTH) - expect secondary hyperparathyroidism with levels this low; levels below 15 ng/mL are associated with greater severity of secondary hyperparathyroidism 4
• Alkaline phosphatase - may be elevated if osteomalacia is present 5
• Serum creatinine/eGFR - to assess kidney function, as chronic kidney disease is a major risk factor for deficiency and affects treatment approach 1
• C-reactive protein (CRP) - if >40 mg/L, inflammation can significantly reduce plasma vitamin D levels and complicate interpretation 1

Clinical Assessment for Complications

Evaluate for symptoms and signs of severe deficiency:

• Musculoskeletal symptoms: symmetric low back pain, proximal muscle weakness, muscle aches, throbbing bone pain with pressure over sternum or tibia 5
• Fracture risk assessment: history of falls, previous fractures, bone density if indicated 6
• Osteomalacia signs: bone tenderness, waddling gait, difficulty rising from chair 5

Identify Underlying Causes

Systematically evaluate for conditions causing or contributing to severe deficiency:

Malabsorption Syndromes

• Post-bariatric surgery (especially Roux-en-Y gastric bypass) - these patients require intramuscular vitamin D if available, as oral supplementation results in higher rates of persistent deficiency 1
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) 1
• Celiac disease - consider testing if not previously diagnosed 1
• Pancreatic insufficiency 1
• Short-bowel syndrome 1

Reduced Synthesis or Intake

• Limited sun exposure: institutionalized patients, homebound elderly, cultural practices (veiling), occupational factors 1, 7
• Dark skin pigmentation: African Americans have 2-9 times higher prevalence of low vitamin D but paradoxically lower fracture rates 3
• Chronic kidney disease: reduced 1α-hydroxylase activity, dietary restrictions, increased urinary losses 1, 4
• Chronic liver disease: impaired 25-hydroxylation 2
• Medications: anticonvulsants, glucocorticoids, antiretrovirals may accelerate vitamin D catabolism 8

Increased Requirements

• Obesity: vitamin D sequestration in adipose tissue (though may still be bioavailable) 3, 8
• Pregnancy and lactation: increased demands 3

Treatment Protocol

Loading Phase (Weeks 1-12)

Standard regimen: Ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) 50,000 IU once weekly for 8-12 weeks 1, 2, 5

• Cholecalciferol (D3) is strongly preferred over ergocalciferol (D2) because it maintains serum levels longer and has superior bioavailability, particularly important with intermittent dosing 1, 4
• Total cumulative dose over 12 weeks: 600,000 IU 1
• Take with food to enhance absorption 9

Critical Pitfall to Avoid

Never use single ultra-high loading doses (>300,000-540,000 IU at once) - these have been shown to be inefficient or potentially harmful, particularly for fall and fracture prevention 3, 1, 8

Special Populations Requiring Modified Approach

For patients with malabsorption syndromes:

• Intramuscular cholecalciferol 50,000 IU is preferred when available, as it results in significantly higher 25(OH)D levels and lower rates of persistent deficiency compared to oral supplementation 1
• If IM unavailable or contraindicated (anticoagulation, infection risk): use oral calcifediol [25(OH)D] if available (higher intestinal absorption) OR substantially higher oral doses (4,000-5,000 IU daily for 2 months) 3, 1

For chronic kidney disease (GFR 20-60 mL/min/1.73m²):

• Use standard nutritional vitamin D (ergocalciferol or cholecalciferol) - do NOT use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) for nutritional deficiency 1, 4

Essential Co-Interventions

Ensure adequate calcium intake: 1,000-1,500 mg daily from diet plus supplements 1, 2

• Calcium supplements should be taken in divided doses of no more than 600 mg at once for optimal absorption 1
• Adequate calcium is necessary for clinical response to vitamin D therapy 2

Monitoring Protocol

Follow-up at 3 Months

Recheck 25(OH)D level after completing 8-12 week loading phase (at 3 months from treatment initiation) 1, 2

• Target level: ≥30 ng/mL for anti-fracture efficacy (≥24 ng/mL for anti-fall efficacy) 1, 4, 6
• If using intermittent dosing (weekly), measure just prior to next scheduled dose 1

If Level Remains <30 ng/mL Despite Treatment

• Assess adherence to regimen 8
• Re-evaluate for malabsorption syndromes 1
• Consider genetic variations in vitamin D metabolism (individual response is highly variable) 1
• Increase maintenance dose or administer additional loading doses 2

Maintenance Phase (After Achieving Target)

Transition to maintenance therapy: 1,000-2,000 IU cholecalciferol (D3) daily 1, 2, 5

• Alternative: 50,000 IU monthly (equivalent to approximately 1,600 IU daily) 1, 4
• For elderly patients (≥65 years): minimum 800 IU daily, though 700-1,000 IU daily is more effective for fall and fracture prevention 1, 4

Safety Considerations

Upper safety limit: 100 ng/mL - avoid exceeding this level 1, 4

Daily doses up to 4,000 IU are generally safe for adults, with some evidence supporting up to 10,000 IU daily for several months without adverse effects 3, 1, 8

Toxicity symptoms (rare): hypercalcemia, hyperphosphatemia, suppressed PTH, hypercalciuria, dizziness, renal failure 3

• Toxicity typically only occurs with prolonged daily doses >10,000 IU or single doses of millions of IU 3

Expected Response

Using the rule of thumb: 1,000 IU vitamin D daily increases serum 25(OH)D by approximately 10 ng/mL (though individual responses vary significantly) 1, 4

With 50,000 IU weekly for 12 weeks (600,000 IU total), expect an increase of approximately 40-70 ng/mL from baseline, bringing a level of 6 ng/mL to 46-76 ng/mL 1, 10

The exact increase depends on body weight, baseline level, and individual metabolism: Δ25(OH)D = 0.025 × (dose per kg body weight) 10