What does alkaline phosphatase (ALP) measure?

What Alkaline Phosphatase Measures

Alkaline phosphatase (ALP) is a membrane-bound enzyme that serves as a biochemical marker of cholestatic liver disease and bone turnover, not actual liver function. 1

Primary Clinical Significance

Hepatobiliary System

• ALP elevation indicates cholestasis or impaired bile flow, which can result from biliary obstruction or impaired bilirubin uptake 1
• When ALP is elevated in isolation (without other liver enzyme abnormalities), cholestatic disease should be suspected as the primary etiology 1
• ALP ≥2× upper limit of normal (ULN), particularly with concomitant elevated gamma-glutamyl transpeptidase (GGT) in the absence of bone disease, defines liver injury 1
• The enzyme does NOT measure hepatocellular synthetic function—albumin and prothrombin time are the actual markers of liver function 1

Bone Metabolism

• ALP reflects osteoblastic activity and bone formation, making it a marker of bone turnover 1
• Bone-specific alkaline phosphatase (B-ALP) is elevated in high-turnover bone disease, including Paget's disease, osteomalacia, and bone metastases 1
• In chronic kidney disease, ALP helps predict fracture risk when combined with parathyroid hormone (PTH) levels, though it has limited standalone diagnostic value 1
• High B-ALP levels can diagnose osteomalacia in the setting of vitamin D deficiency, hypocalcemia, or hypophosphatemia 1

Tissue Sources and Isoenzymes

• ALP is found in multiple tissues: liver, bone, intestines, placenta, and kidneys 1, 2
• Different isoenzymes exist, with liver and bone being the predominant sources in serum 2, 3
• To differentiate hepatic from bone sources, measure GGT—it elevates with liver disease but remains normal with isolated bone-source ALP elevation 1, 4

Physiologic Elevations (Not Pathologic)

Pregnancy

• ALP increases beginning in the second trimester and continues rising through the third trimester, reaching up to 2× ULN due to placental production 4
• This elevation with normal GGT, bilirubin, and aminotransferases represents normal pregnancy physiology and requires no intervention 4
• Any elevation in aminotransferases, bilirubin, or bile acids remains abnormal even in pregnancy and requires investigation 4

Growth and Age

• ALP is physiologically higher in childhood due to bone growth 4, 2
• Postmenopausal women have significantly higher B-ALP levels (39% increase) compared to premenopausal women due to increased bone turnover 5

Other Physiologic States

• Lactation and high-fat diets can increase ALP activity 2

Drug-Induced Elevations

• Glucocorticoids and anticonvulsants can induce ALP activity through enzyme induction mechanisms 2
• This represents induction rather than cellular damage 1

Clinical Interpretation Algorithm

Step 1: Confirm the elevation is real

• Verify ALP is ≥2× ULN for suspected liver injury 1
• Consider physiologic causes (pregnancy, growth, postmenopausal state) 4, 2

Step 2: Determine the source

• Measure GGT: elevated GGT suggests hepatic source; normal GGT suggests bone or placental source 1, 4
• In pregnancy with elevated ALP and normal GGT, this is physiologic 4

Step 3: Assess pattern of liver injury (if hepatic)

• Calculate R value: (ALT/ULN)/(ALP/ULN) 1
• Cholestatic pattern: R ≤2 1
• Mixed pattern: R >2 and <5 1
• Hepatocellular pattern: R ≥5 1

Step 4: Evaluate for bone disease (if bone source)

• Assess for Paget's disease, bone metastases, osteomalacia, or metabolic bone disease 1
• Consider measuring bone-specific ALP for greater specificity 1, 5
• In chronic kidney disease, combine with PTH levels for fracture risk assessment 1

Critical Pitfalls to Avoid

• Do not interpret ALP as a measure of liver "function"—it indicates cholestasis or bone turnover, not synthetic capacity 1
• Do not assume elevated ALP in pregnancy is pathologic—up to 2× ULN is normal if GGT, aminotransferases, and bilirubin are normal 4
• Do not use ALP alone to diagnose Charcot neuro-osteoarthropathy—it has insufficient accuracy and was normal in multiple studies of active disease 1
• Do not rely solely on ALP for bone disease diagnosis in chronic kidney disease—it should be combined with PTH and clinical context 1
• Isolated GGT elevation indicates enzyme induction, not cellular damage, and should not be confused with ALP-indicated cholestasis 1