How to differentiate the various sources of Alkaline Phosphatase (ALP)?

From the Guidelines

To differentiate the various sources of alkaline phosphatase (ALP) elevation, the most effective approach is to use a combination of isoenzyme fractionation, heat stability testing, and measurement of other liver enzymes like GGT, ALT, and AST, as recommended by the most recent study 1. This approach allows for the separation of ALP into its tissue-specific forms (liver, bone, intestinal, placental) and helps determine if the elevation is liver-related. Some key points to consider when differentiating the sources of ALP elevation include:

• Measuring GGT levels, as concomitantly elevated GGT can help confirm that an elevated ALP originates from the liver and indicates cholestasis 1
• Using bone-specific markers such as osteocalcin or N-telopeptide to confirm bone origin
• Considering the pattern of elevation, as very high ALP levels (>1000 U/L) typically suggest bone disease or biliary obstruction
• Taking into account the clinical context, such as pregnancy, which normally elevates placental ALP, and growing children, who have higher bone ALP
• Being aware of certain medications like phenytoin that can induce ALP production
• Noting the timing of elevations, as transient elevations may occur after fatty meals (intestinal source) while persistent elevations suggest ongoing pathology in liver or bone. Additionally, the latest study 1 suggests that fractionating alkaline phosphatase into its liver, bone, and intestinal isoenzyme fractions can also be very informative, and that glutamate dehydrogenase (GLDH) is a mitochondrial enzyme which is currently undergoing regulatory evaluation as a possible liver injury biomarker. However, the most recent and highest quality study 1 provides the most relevant guidance on differentiating the sources of ALP elevation.

From the Research

Differentiation of ALP Sources

To differentiate the various sources of Alkaline Phosphatase (ALP), it is essential to understand the different isozymes and their tissue-specific expression. The main sources of ALP include:

• Bone: Bone-specific ALP (BSAP) is involved in bone calcification and mineralization 2, 3
• Liver: Liver ALP is present in the canalicular membrane of hepatocytes and is involved in the transport of phosphate into the bile 2, 3
• Intestine: Intestinal ALP is thought to play a role in the transport of phosphate into epithelial cells of the intestine 2, 3
• Placenta: Placental ALP is involved in the regulation of phosphate metabolism during pregnancy 2
• Kidney: Kidney ALP is involved in the regulation of phosphate metabolism and mineralization 2, 3

Isoenzymes of ALP

There are four main isozymes of ALP, which can be differentiated based on their tissue-specific expression and physiochemical properties:

• Tissue-nonspecific ALP (L/B/K ALP): present in liver, bone, and kidney 2, 4
• Intestinal ALP: present in the ileal mucosa 2, 4
• Placental ALP: present in the placenta 2, 4
• Germ cell ALP: present in germ cells 2

Measurement and Detection

The measurement and detection of ALP isozymes can be used to differentiate the various sources of ALP. Methods such as electrophoresis, chromatography, and immunoassays can be used to separate and measure the different isozymes 5, 4, 3. Additionally, the combined detection of ALP isozymes with other biomarkers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and carbohydrate antigen 19-9 (CA 19-9) can be used for more accurate diagnosis of specific tumors 5.