What are the causes of elevated Alkaline Phosphatase (ALP) levels?

From the Guidelines

Elevated alkaline phosphatase (ALP) levels require immediate investigation to determine the underlying cause, which could be liver disease, bone disorders, pregnancy, or certain medications, and the most recent evidence suggests that a comprehensive medical history, physical examination, and additional blood tests such as gamma-glutamyl transferase (GGT), bilirubin, and liver transaminases should be performed to distinguish between liver and bone sources 1.

Key Considerations

• ALP is produced by several tissues, primarily liver and bone, and elevated levels indicate increased enzyme production due to cellular damage or increased metabolic activity in these tissues.
• If GGT is also elevated, liver disease is more likely, while normal GGT with elevated ALP suggests bone pathology.
• Imaging studies like ultrasound or CT scan may be necessary for liver issues, while bone scans might be needed for suspected bone disorders.
• Management depends on the underlying cause—treating the primary liver condition, addressing bone disease, or discontinuing offending medications.

Diagnostic Approach

• Initial evaluation should include a comprehensive medical history, physical examination, and additional blood tests such as GGT, bilirubin, and liver transaminases to distinguish between liver and bone sources.
• Fractionating alkaline phosphatase into its liver, bone, and intestinal isoenzyme fractions can also be very informative, as suggested by a recent review article 1.
• Glutamate dehydrogenase (GLDH) is a mitochondrial enzyme which is currently undergoing regulatory evaluation as a possible liver injury biomarker, and elevated levels of GLDH can also provide further supporting evidence that aminotransferase elevations are of hepatic origin.

Management and Monitoring

• Mild, isolated ALP elevations (less than 2-3 times normal) without symptoms may warrant monitoring rather than extensive workup.
• Liver tests should be obtained following treatment cessation and for a duration of at least five half-lives of the parent drug and major metabolites, or for a longer time period if the potential for delayed liver injury exists, such as with immune checkpoint inhibitors 1.
• The European Association for the Study of the Liver (EASL) clinical practice guidelines on sclerosing cholangitis recommend that a diagnosis of large duct PSC should be made in the presence of typical findings of sclerosing cholangitis on high-quality cholangiography and after exclusion of secondary causes, and that magnetic resonance cholangiopancreaticography (MRCP) is the preferred diagnostic test 1.

From the Research

Alk Phos Elevation

• Alkaline phosphatase (ALP) elevation can be an indicator of liver or bone disease 2, 3, 4.
• In patients with primary biliary cholangitis (PBC), ALP elevation is a common finding, but some patients may have normal ALP levels despite having PBC 2.
• The diagnosis of PBC is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum ALP levels 2.
• Other enzymes such as gamma-glutamyl transpeptidase (GGT) and 5'-nucleotidase (5'-NU) can also be elevated in cholestatic liver disease 3, 5, 6.
• GGT is generally increased to a greater extent than ALP and 5'-NU in diseases that affect the biliary tract, making it a sensitive indicator of biliary-tract disease 6.
• However, certain drugs such as phenytoin and barbiturates can also elevate serum GGT activity without any other evidence of liver disease, highlighting the need for caution in interpreting test results 6.

Causes of Alk Phos Elevation

• Liver disease, such as primary biliary cholangitis (PBC) 2
• Bone disease 4
• Cholestasis, which can be intrahepatic or extrahepatic 3
• Biliary-tract disease 6
• Certain drugs, such as phenytoin and barbiturates 6

Diagnostic Value of Alk Phos and Other Enzymes

• ALP, GGT, and 5'-NU can be used to diagnose cholestasis and distinguish between intrahepatic and extrahepatic causes 3
• GGT is the most sensitive indicator of biliary-tract disease 6
• 5'-NU has the greatest diagnostic value for detecting liver metastases 5
• Combining multiple enzyme tests can improve diagnostic accuracy 5