Workup for Elevated Alkaline Phosphatase and White Blood Cell Count
The appropriate workup for a patient with elevated alkaline phosphatase (ALP) and elevated white blood cell count (WBC) should focus on identifying infectious, inflammatory, malignant, and bone disorders, as these abnormalities together most commonly indicate underlying malignancy, infection, or bone disease.
Initial Diagnostic Approach
Laboratory Tests
- Complete blood count with differential to characterize the leukocytosis
- Comprehensive metabolic panel including:
- Liver function tests (AST, ALT, bilirubin, GGT)
- Kidney function tests (BUN, creatinine)
- Electrolytes
- Glucose
- ALP isoenzymes to differentiate bone vs. liver source 1
- Gamma-glutamyl transferase (GGT) to distinguish between liver and bone sources of ALP elevation 1
- Inflammatory markers:
- C-reactive protein (CRP)
- Erythrocyte sedimentation rate (ESR)
- Blood cultures if infection is suspected
- Calcium and phosphate levels
- 25-hydroxy vitamin D level
- Parathyroid hormone level if bone disease is suspected
Imaging Studies
- Plain X-rays of any symptomatic bone areas 2
- Abdominal ultrasound as first-line imaging for suspected biliary obstruction or liver abnormalities 1
- Consider chest X-ray to evaluate for pulmonary infection or malignancy
- Additional imaging based on initial findings:
Focused Evaluation Based on Clinical Presentation
Malignancy Workup
Malignancy is a leading cause of isolated elevated ALP (57% in recent studies) 3:
- Evaluate for:
- Infiltrative intrahepatic malignancy
- Bony metastasis
- Combined hepatic and bone metastasis
- Consider bone marrow examination if hematologic malignancy is suspected 2
- Whole skeletal imaging (bone scan or whole-body MRI) if bone metastases are suspected 2
Infection/Inflammation Workup
- Identify source of infection through appropriate cultures
- Evaluate for sepsis, which can cause extremely high ALP levels (>1000 U/L) even with normal bilirubin 4
- Consider HIV testing, as AIDS-related opportunistic infections can cause marked ALP elevation 4
Bone Disease Workup
- Bone-specific ALP isoenzyme testing 1
- Consider DXA scan if osteoporosis is suspected 1
- Evaluate for Paget's disease, especially in older patients with focal bone pain
Liver/Biliary Disease Workup
- Ultrasound to evaluate for biliary obstruction, liver parenchymal abnormalities, and focal liver lesions 1
- Consider transient elastography (FibroScan) if liver fibrosis is suspected 1
Special Considerations
Age-Specific Considerations
- In patients under 40 years with suspected primary bone malignancy, urgent referral to a bone sarcoma center is recommended 2
- In patients over 40 years, metastatic carcinoma in bone is more likely 2
- In young children, consider benign transient hyperphosphatasemia 5
Timing of Follow-up
- If no clear etiology is found, repeat ALP and other relevant tests in 1-3 months 6
- Approximately half of isolated ALP elevations normalize within 1-3 months 6
- Persistent elevation beyond 3 months warrants continued investigation
Clinical Implications and Prognosis
- An isolated elevated ALP of unclear etiology is associated with significant mortality (47% mortality within an average of 58 months) 3
- Higher initial ALP levels (>1.5 times normal) are more likely to persist and may indicate more serious underlying pathology 6
Common Pitfalls to Avoid
- Do not attribute elevated ALP solely to liver disease without ruling out bone sources
- Do not overlook sepsis as a cause of extremely high ALP, even with normal bilirubin 4
- Avoid unnecessary invasive procedures in cases of likely benign or transient elevations
- Blood tests such as CRP, ESR, WBC, and ALP have limited diagnostic accuracy for certain conditions like Charcot neuro-osteoarthropathy 2
By following this systematic approach, clinicians can efficiently identify the underlying cause of elevated ALP and WBC, leading to appropriate treatment and improved patient outcomes.