From the Guidelines
Elevated alkaline phosphatase (ALP) should be further investigated to determine its cause, with a focus on differentiating between hepatic and non-hepatic origins, as suggested by the most recent guidelines 1. The first step in evaluating elevated ALP is to confirm the elevation with repeat testing and check for other liver enzymes (AST, ALT, GGT, bilirubin) and a complete blood count.
- Common causes of elevated ALP include:
- Liver disorders (hepatitis, cirrhosis, bile duct obstruction)
- Bone diseases (Paget's disease, osteomalacia, bone metastases)
- Pregnancy
- Certain medications
- Some cancers
- If the elevation is significant (more than twice the upper limit of normal), prompt evaluation by a healthcare provider is necessary, as indicated by the American College of Radiology guidelines 1. Diagnostic workup typically includes:
- A thorough medical history
- Physical examination
- Possibly imaging studies such as ultrasound, CT scan, or MRI of the liver and biliary system
- Bone-specific ALP can be measured if bone disease is suspected Treatment depends entirely on the underlying cause, such as stopping hepatotoxic medications, treating underlying infections, or managing bile duct obstructions, as outlined in the acr appropriateness criteria® abnormal liver function tests 1. ALP is produced by several tissues including liver, bone, intestine, and placenta, which explains why various conditions can cause its elevation.
- Isolated ALP elevation without other abnormal liver tests often suggests bone disorders or biliary obstruction rather than hepatocellular injury, highlighting the importance of a comprehensive diagnostic approach 1.
From the FDA Drug Label
In clinical studies of up to two years' duration, alendronate sodium 5 and 10 mg/day reduced cross-linked N-telopeptides of type I collagen (a marker of bone resorption) by approximately 60% and reduced bone-specific alkaline phosphatase and total serum alkaline phosphatase (markers of bone formation) by approximately 15 to 30% and 8 to 18%, respectively Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation In clinical trials, alendronate sodium 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase as well as in urinary markers of bone collagen degradation.
Elevated alkaline phosphatase can be decreased by alendronate sodium. The reduction in serum alkaline phosphatase may reflect the decrease in bone turnover due to alendronate sodium.
- Alendronate sodium 5 and 10 mg/day reduced total serum alkaline phosphatase by approximately 8 to 18% in clinical studies of up to two years' duration 2.
- Alendronate sodium 40 mg once daily for six months produced significant decreases in serum alkaline phosphatase in clinical trials 2 and 2.
From the Research
Causes of Elevated Alkaline Phosphatase
- The most common cause of elevated alkaline phosphatase (ALP) is underlying malignancy, accounting for 57% of cases, with 61 patients having infiltrative intrahepatic malignancy, 52 patients having bony metastasis, and 34 patients having both hepatic and bone metastasis 3.
- Bone disease is another common cause, accounting for 29% of cases 3.
- Unsuspected parenchymal liver disease, non-malignant infiltrative liver disease, and other disorders also account for a significant proportion of cases 3.
Diagnostic Approach
- Serum bilirubin and alkaline phosphatase seem to be the most potential tests in distinguishing benign and malignant causes of jaundice and/or cholestasis, with high levels being suggestive of malignant disease 4.
- The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency 5.
- For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken 5.
Clinical Significance
- An isolated, elevated ALP of unclear etiology is associated with several very specific and important disorders, in particular metastatic intrahepatic malignancy, and is uncommonly associated with primary parenchymal liver disease 3.
- Defective enzyme elimination could play a major role in the pathogenesis of serum alkaline phosphatase elevations 6.
- Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions, and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings 5.