What are the causes of elevated alkaline phosphatase (ALP) levels?

Causes of Elevated Alkaline Phosphatase Levels

Elevated alkaline phosphatase (ALP) levels can be attributed to various hepatic and non-hepatic conditions, with cholestatic liver disease, bone disorders, and malignancies being the most common causes requiring clinical attention.

Origin of Alkaline Phosphatase

ALP is primarily produced in:

• Liver: Present in the canalicular membrane of hepatocytes (biliary epithelium)
• Bone: Significant source, especially during growth
• Other tissues: Intestines, kidneys, placenta, and white blood cells in smaller amounts 1

Differentiating Hepatic vs. Non-Hepatic Sources

Diagnostic Approach:

1. Measure Gamma-Glutamyl Transferase (GGT)

   • GGT is found in liver, kidneys, intestine, prostate, and pancreas
   • GGT is NOT found in bone
   • Concomitantly elevated GGT confirms hepatic origin of elevated ALP 1

2. Consider physiologic causes:

   • Childhood (associated with bone growth)
   • Pregnancy (due to placental production) 1
   • Benign familial hyperphosphatasemia (genetic condition) 2

Hepatic Causes of Elevated ALP

Cholestatic Conditions:

• Extrahepatic biliary obstruction:

  • Choledocholithiasis (most common cause) 1
  • Malignant obstruction
  • Biliary strictures
  • Infections (AIDS cholangiopathy, liver flukes)

• Intrahepatic cholestasis:

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Drug-induced cholestasis
  • Infiltrative liver diseases (sarcoidosis, amyloidosis, hepatic metastases) 1

Other Liver Conditions:

• Cirrhosis
• Chronic hepatitis
• Viral hepatitis
• Congestive heart failure (hepatic congestion)
• Ischemic cholangiopathy
• Sepsis (can cause extremely high ALP even with normal bilirubin) 3

Non-Hepatic Causes of Elevated ALP

Bone Disorders:

• Paget's disease
• Bony metastases
• Fractures 1
• Primary bone tumors

Malignancies:

• Infiltrative intrahepatic malignancy
• Bony metastasis (29% of cases with isolated elevated ALP) 4
• Hematologic malignancies

Other Causes:

• Infections (particularly in immunocompromised patients)
• Mycobacterium avium intracellulare (MAI) infection
• Cytomegalovirus infection
• Drug-induced elevations (including Dilantin toxicity) 3
• Lead toxicity

Clinical Significance of Extremely High ALP

In patients with ALP levels >1,000 IU/L, the most common causes are:

• Sepsis (can occur with normal bilirubin)
• Malignant biliary obstruction
• AIDS-related conditions 3
• Metastatic disease (both hepatic and bony)

Prognostic Implications

An isolated elevated ALP of unclear etiology warrants thorough investigation as:

• 57% of cases are associated with underlying malignancy
• 47% of patients with isolated elevated ALP died within an average of 58 months 4

Pitfalls and Caveats

• ALP is commonly elevated in patients with malignancy, so it should not be used alone to determine eligibility for clinical trials 1
• Isolated ALP elevation that persists over time suggests chronic cholestatic processes 1
• Consider fractionating ALP into liver, bone, and intestinal isoenzyme fractions when the source is unclear 1
• In patients with sepsis, extremely high ALP can occur even with normal bilirubin levels 3

Recommended Diagnostic Approach

1. Confirm elevation with repeat testing
2. Check GGT to determine if source is hepatic
3. Review medication history for potential drug-induced causes
4. Consider imaging of the biliary tree if hepatic source is suspected
5. Evaluate for bone disease if GGT is normal
6. Screen for underlying malignancy, especially with persistent unexplained elevation

Remember that an isolated elevated ALP without obvious etiology should prompt thorough investigation, as it is frequently associated with significant underlying pathology, particularly malignancy.