Why does alkaline phosphatase (ALP) elevate with bile stasis (bilary obstruction)?

From the Guidelines

Alkaline phosphatase (ALP) elevates with biliary stasis because this enzyme is primarily produced by the cells lining the bile ducts and is normally excreted into bile. When bile flow is obstructed or slowed (biliary stasis), ALP accumulates in the liver and leaks into the bloodstream, causing elevated serum levels. This process occurs because biliary stasis triggers increased production of ALP by bile duct cells through a compensatory mechanism, as the body attempts to improve bile flow. Additionally, the retained bile acids in biliary stasis can stimulate hepatocytes to synthesize more ALP. The elevation of ALP typically precedes or accompanies rises in bilirubin levels in conditions causing biliary obstruction, such as gallstones, primary biliary cholangitis, primary sclerosing cholangitis, or malignancies affecting the biliary tree. This relationship between ALP and biliary stasis makes ALP a valuable marker for distinguishing between hepatocellular and cholestatic patterns of liver injury in clinical practice, as noted in the EASL clinical practice guidelines on sclerosing cholangitis 1. Some key points to consider in the evaluation of ALP elevation in the context of biliary stasis include:

• The most common pattern of liver biochemistry abnormality in primary sclerosing cholangitis (PSC) is a cholestatic picture with raised alkaline phosphatase (ALP) and γ-glutamyl transpeptidase, as reported in the British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis 1.
• ALP is the most commonly utilized surrogate biomarker for measuring PSC disease progression, and a reduction of ALP has been utilized as an indicator of treatment response, as discussed in the consensus guidelines for the detection, assessment, and management of suspected acute drug-induced liver injury occurring during clinical trials in adults with chronic cholestatic liver disease 1.
• In the context of pregnancy, mild elevations in alkaline phosphatase levels are common during the second and third trimester, but intrahepatic cholestasis of pregnancy is diagnosed based on a serum bile acid level >10 mmol/L in the setting of pruritus, as recommended in the AGA clinical practice update on pregnancy-related gastrointestinal and liver disease 1. Overall, the elevation of ALP in biliary stasis is a complex process involving increased production and leakage of the enzyme into the bloodstream, and its measurement is a valuable tool in the diagnosis and management of various liver diseases.

From the Research

Alkaline Phosphatase Elevation in Biliary Stasis

• Alkaline phosphatase (AP) is not only a signpost of cholestasis but also a surrogate marker of the severity of primary biliary cirrhosis and primary sclerosing cholangitis 2.
• The elevation of serum alkaline phosphatase activity in biliary obstruction is due to the regurgitation of bile alkaline phosphatase into the circulation, as well as the induction of hepatic alkaline phosphatase by bile acids 3, 4.
• Bile acids, such as taurocholate, taurochenodeoxycholate, and tauroursodeoxycholate, can induce the synthesis of alkaline phosphatase by cultured hepatocytes and increase its activity in the liver and serum 3.
• The composition of the intrahepatic bile acid pool influences the hepatic response to acute cholestasis, and various bile acids have different effects on alkaline phosphatase activity and bile secretion pressure 3.

Mechanism of Alkaline Phosphatase Elevation

• The elevation of serum alkaline phosphatase activity in biliary obstruction is not due to simple overspill of the enzyme from the liver into the circulation, but rather to the regurgitation of bile alkaline phosphatase and the induction of hepatic alkaline phosphatase by bile acids 4.
• A high molecular weight form of alkaline phosphatase is present in the serum and bile of rats with biliary obstruction, and this form is a useful diagnostic marker of biliary obstruction 4.

Clinical Significance of Alkaline Phosphatase Elevation

• Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis, and persistent normalization is associated with even fewer adverse endpoints and longer survival 5.
• The level of alkaline phosphatase is a predictor of primary endpoint-free survival in patients with primary sclerosing cholangitis, and its normalization is associated with a decreased risk of requiring liver transplantation 5.