What is fractionated Alkaline Phosphatase (ALP)?

Fractionated Alkaline Phosphatase (ALP)

Fractionated alkaline phosphatase is a diagnostic test that separates and identifies the different isoenzymes or isoforms of ALP to determine their tissue of origin, which helps pinpoint the cause of elevated total ALP levels. 1

Understanding ALP Isoenzymes

Alkaline phosphatase exists as several isoenzymes originating from different tissues:

• Liver/biliary isoenzymes: Produced by liver cells and biliary epithelium
• Bone isoenzymes: Produced by osteoblasts
• Intestinal isoenzymes: Produced by intestinal mucosa
• Placental isoenzymes: Present during pregnancy
• Other sources: Kidneys and leukocytes (in smaller amounts)

Clinical Significance of Fractionation

When total ALP is elevated, fractionation helps determine the source:

• Liver/biliary origin: Suggests cholestatic liver disease, biliary obstruction, or infiltrative liver disease 1
• Bone origin: Indicates bone disorders like Paget's disease or metastatic bone disease 1
• Mixed origin: May suggest multiple pathologies (e.g., liver disease with bone metastases) 2

Diagnostic Approach

1. Initial evaluation of elevated ALP:

   • First, confirm hepatic origin by checking gamma-glutamyl transferase (GGT) 1
   • Elevated GGT + elevated ALP suggests cholestatic liver disease
   • Normal GGT + elevated ALP suggests bone origin

2. Fractionation techniques:

   • Isoelectric focusing can resolve up to 17 fractions with ALP activity 3
   • Single-molecule analysis platforms can distinguish enzyme isotypes 4

3. Interpretation of fractionated ALP:

   • Fractions 1a and 1b: Strong correlation with biliary diseases 3
   • Fractions 2,3, and 4: Consistent increases in primary disorders of hepatocytes 3
   • Fraction 10: Potential marker of activated T-lymphocytes 3

Clinical Applications

Fractionated ALP provides valuable diagnostic information in:

• Distinguishing liver vs. bone disease: Critical when total ALP is elevated but cause is unclear 1
• Chronic liver disorders: Helps differentiate primary biliary cirrhosis and primary sclerosing cholangitis from alcoholic cirrhosis 3
• Cancer diagnosis: Aids in detecting metastatic disease to liver or bone 2, 5
  • 57% of isolated elevated ALP cases are due to underlying malignancy 2
  • 29% are due to bone disease 2
  • 7% are due to unsuspected parenchymal liver disease 2

Important Pitfalls and Considerations

• Don't assume normal transaminases rule out liver disease: Cholestatic disorders can progress with minimal transaminase elevation 1
• Avoid pretreatment with phospholipase-C or sialidase: These alter isoelectric focusing patterns and cause loss of diagnostic information 3
• Don't overlook the prognostic value: An isolated elevated ALP of unclear etiology is associated with poor prognosis (47% mortality within an average of 58 months) 2
• Consider geographic variations: In some regions, cholangiocarcinoma and tropical diseases may cause marked ALP elevation 6

Emerging Applications

Recent research suggests fractionated ALP may have potential as:

• A tumor biomarker when combined with other tests (AST/ALT, BSAP, CA 19-9, LDH) 5
• A prognostic indicator in certain cancers, with both high and low levels potentially significant depending on cancer type 5