From the Guidelines
Elevated alkaline phosphatase (ALP) levels require a thorough clinical evaluation to determine the underlying cause, starting with confirmation of the elevation and fractionation of ALP to determine its source, followed by additional liver function tests and imaging studies as needed. The next steps should include ordering a fractionation of ALP to determine if the source is liver, bone, intestine, or placenta 1. Additional liver function tests including AST, ALT, GGT, bilirubin, and albumin should be ordered to assess for liver disease. If liver pathology is suspected, ultrasound of the liver and biliary system is recommended to evaluate for obstruction, masses, or structural abnormalities 1. For suspected bone disease, consider calcium, phosphate, vitamin D levels, and bone imaging. A detailed medical history and physical examination are essential, focusing on symptoms of liver disease (jaundice, abdominal pain), bone disorders (bone pain, fractures), or medication use that could affect ALP. The degree of elevation can provide clues—mild elevations (1-2 times normal) may be seen in various conditions including pregnancy, while significant elevations (>4 times normal) often indicate cholestatic liver disease or bone disorders like Paget's disease. Some key considerations include:
- Concomitantly elevated GGT can help confirm that an elevated ALP originates from the liver and indicates cholestasis 1
- Choledocholithiasis is the most common cause of extrahepatic biliary obstruction and elevated ALP of liver origin 1
- Isolated elevated ALP of hepatic origin (without other elevated liver function tests) that persists over time suggests a chronic cholestatic process, such as partial bile duct obstruction, primary biliary cholangitis, primary sclerosing cholangitis, or drug-induced cholestasis 1
- Treatment will depend on the identified cause, ranging from addressing underlying liver disease to managing bone disorders or discontinuing offending medications. Some studies suggest that abdominal US has a low sensitivity for detection of choledocholithiasis, but it has high specificity 1, and that liver biopsy may be considered in patients with chronic HCV viremia and either normal or abnormal serum ALT levels 1. However, the most recent and highest quality study 1 provides the most relevant guidance for the next steps in evaluating elevated ALP levels.
From the Research
Next Steps for Elevated Alkaline Phosphatase (ALP) Levels
The next steps for elevated ALP levels involve identifying the underlying cause of the elevation. According to 2, extremely high levels of ALP are most frequently seen in patients with sepsis, malignant obstruction, and AIDS.
- Possible causes of elevated ALP levels include:
- Bone involvement from malignancy or Paget's disease
- Sepsis
- Biliary obstruction
- AIDS
- Diffuse liver metastases
- Benign intrahepatic disease
- Diagnostic approaches:
- Measurement of gamma-glutamyl transpeptidase to differentiate between bone and liver origin of elevated ALP 3
- Serum alkaline phosphatase isozyme pattern by electrophoresis to differentiate various pathological states 3
- Correlation with bone metabolic markers or hepatic function markers to identify the cause of increased ALP 4
- Clinical significance:
- Isolated elevated ALP of unclear etiology is associated with several specific and important disorders, including metastatic intrahepatic malignancy 5
- Elevated ALP in postmenopausal women is mainly caused by high bone turnover 4
- Persistent AP elevations are often associated with clinically obvious life-threatening diagnoses 6
Laboratory Tests
Additional laboratory tests may be necessary to determine the cause of elevated ALP levels, including:
- Gamma-glutamyl transpeptidase
- Bone metabolic markers
- Hepatic function markers
- Serum alkaline phosphatase isozyme pattern by electrophoresis
Clinical Evaluation
A careful history, physical exam, and routine lab studies are necessary to detect obvious diagnoses and determine the next steps for elevated ALP levels 6. Repeat enzyme determination at 1-3 months may be necessary to monitor the progression of the disease.