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

Causes of Elevated Alkaline Phosphatase

Elevated alkaline phosphatase (ALP) levels can result from various hepatobiliary, bone, and systemic conditions, with choledocholithiasis being the most common cause of liver-origin ALP elevation. 1

Hepatobiliary Causes

Cholestatic Conditions

• Extrahepatic biliary obstruction:
  • Choledocholithiasis (most common cause) 1
  • Malignant obstruction (pancreatic cancer, cholangiocarcinoma)
  • 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, 2

Other Hepatic Conditions

• Cirrhosis
• Chronic hepatitis
• Viral hepatitis
• Congestive heart failure (hepatic congestion)
• Ischemic cholangiopathy 1
• Sepsis (can cause extremely high ALP with normal bilirubin) 3

Bone-Related Causes

• Paget's disease
• Bone metastases 1, 2
• Fractures
• Osteomalacia
• Hyperparathyroidism 1
• Growing children (physiologically higher ALP) 1

Other Causes

• Pregnancy (placental production) 1
• Benign familial hyperphosphatasemia (genetic condition) 4
• AIDS-related conditions (MAI infection, CMV infection) 3
• Drug toxicity (e.g., Dilantin) 3
• Lead toxicity 3

Diagnostic Approach

When evaluating elevated ALP, determining the source is critical:

1. Measure gamma-glutamyl transferase (GGT):

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

2. Consider pattern of elevation:

   • Isolated elevated ALP of hepatic origin suggests chronic cholestatic process 1
   • Extremely high ALP (>1000 U/L) is most commonly seen in:
     • Sepsis
     • Malignant obstruction
     • AIDS 3
   • In patients with unclear etiology, malignancy (57%) and bone disease (29%) are most common causes 2

3. Clinical context matters:

   • ALP is physiologically higher in childhood and pregnancy 1
   • In chronic kidney disease, elevated ALP may indicate bone metabolism disorders 1
   • Patients with isolated elevated ALP of unclear etiology have high mortality (47% within ~5 years) 2

Important Caveats

• ALP can be transiently elevated in liver disease even in patients with hypophosphatasia (a condition normally characterized by low ALP) 5
• Bone-specific ALP (B-ALP) can help distinguish bone sources from liver sources 1
• In patients with chronic kidney disease, ALP and PTH measurements together provide better assessment of bone turnover than either alone 1
• Extremely high ALP with normal bilirubin can occur in sepsis 3

Remember that ALP is found in multiple tissues (liver, bone, intestines, kidneys, placenta), making it important to determine the source of elevation through additional testing and clinical correlation.