Alkaline Phosphatase: Measurement and Clinical Significance
Alkaline phosphatase (ALP) is an enzyme that primarily measures hepatobiliary and bone disorders, with elevated levels indicating cholestatic liver disease when accompanied by elevated GGT or bone disorders when GGT is normal. 1
What ALP Measures
Alkaline phosphatase is an enzyme found in several tissues throughout the body, with the highest concentrations in:
- Liver (hepatobiliary system): Particularly in the bile canaliculi
- Bone: Produced by osteoblasts during bone formation
- Placenta: During pregnancy
- Intestine: Intestinal mucosa
- Kidney: Proximal convoluted tubules
ALP exists as several isoenzymes that are the products of a single gene but differ by post-translational glycosylation, making them difficult to distinguish in routine testing 2.
Clinical Significance of Elevated ALP
Pattern Recognition in Liver Disease
ALP is a key component in evaluating liver function and distinguishing patterns of liver injury:
- Cholestatic pattern: When ALP is ≥2 times the upper limit of normal (ULN), particularly with elevated gamma-glutamyl transpeptidase (GGT) 3
- Mixed pattern: When the ratio of ALT/ALP is >2 and <5 3
- Hepatocellular pattern: When the ratio of ALT/ALP is ≥5 3
Hepatobiliary Causes of Elevated ALP
- Biliary obstruction (intrahepatic or extrahepatic)
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- Drug-induced liver injury
- Infiltrative liver diseases 1
Bone-Related Causes of Elevated ALP
- Paget's disease
- Bone metastases
- Osteomalacia
- Rickets
- Healing fractures
- X-linked hypophosphatemia 1
Other Causes
- Pregnancy (placental production)
- Growth in children (bone growth)
- Certain malignancies 1
Diagnostic Approach to Elevated ALP
When ALP is elevated, a systematic approach should be followed:
Confirm hepatobiliary origin: Measure GGT (also elevated in hepatobiliary disease but not in bone disorders) 1
Basic laboratory workup:
- Complete blood count with differential
- Comprehensive liver panel (AST, ALT, bilirubin, albumin)
- Calcium and phosphate levels (to evaluate bone disorders) 1
Imaging:
- Abdominal ultrasound as first-line imaging
- MRCP for detailed biliary tract evaluation (sensitivity 86%, specificity 94%)
- CT or MRI for detailed liver assessment 1
Special Considerations
In Chronic Kidney Disease
Bone-specific alkaline phosphatase can help diagnose mineral and bone disorders in CKD patients 3, 1.
In Children
ALP is naturally elevated due to bone growth; GGT measurement helps identify potential biliary disease 1.
In Pregnancy
Consider placental production as a cause of elevated ALP 1.
In Cancer Patients
Elevated ALP may indicate bone metastases or biliary obstruction from malignancy 1.
Common Pitfalls in ALP Interpretation
- Failing to distinguish bone from liver source: Always check GGT when ALP is elevated
- Isolated interpretation: ALP should be interpreted alongside other clinical and laboratory findings
- Overlooking normal elevations: ALP is naturally higher in children, adolescents, and pregnant women
- Missing rare causes: Conditions like hypophosphatasia can cause abnormally low ALP levels
Clinical Application
The measurement of ALP has become one of the most frequently assayed enzymes in medicine 4, with applications in:
- Screening for liver and bone diseases
- Monitoring disease progression
- Evaluating treatment response
- Diagnosing specific conditions like hypophosphatasia (abnormally low ALP)
Recent advances include single-molecule analysis techniques that can distinguish between different ALP isozymes, potentially improving diagnostic specificity 5.