What causes elevated alkaline phosphatase (ALP) and alanine transaminase (ALT) levels?

Causes of Elevated Alkaline Phosphatase (ALP) and Alanine Transaminase (ALT)

Elevated alkaline phosphatase (ALP) and alanine transaminase (ALT) most commonly indicate liver disease, with the most significant causes being cholestatic disorders, hepatocellular injury, malignancy, and sepsis. 1

Primary Causes of Combined ALP and ALT Elevation

Hepatic Causes

• Cholestatic Liver Disease

  • Extrahepatic biliary obstruction
    • Choledocholithiasis (most common)
    • Malignant obstruction
    • Biliary strictures
  • Intrahepatic cholestasis
    • Primary biliary cholangitis
    • Primary sclerosing cholangitis
    • Drug-induced cholestasis
    • Infiltrative liver diseases 1

• Hepatocellular Injury

  • Occupational chemical exposure
  • Viral hepatitis
  • Drug-induced liver injury
  • Alcoholic liver disease 2

• Infiltrative Liver Diseases

  • Malignant liver metastases (57% of cases with isolated elevated ALP of unclear etiology) 3
  • Sarcoidosis
  • Amyloidosis 1

Non-Hepatic Causes

• Bone Disorders (typically elevate ALP more than ALT)

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

• Systemic Conditions

  • Sepsis (can cause extremely high ALP levels even with normal bilirubin) 4
  • AIDS with opportunistic infections (MAI, CMV) 4

Diagnostic Approach

1. Confirm Hepatic Origin

   • Measure Gamma-Glutamyl Transferase (GGT)
     • Elevated GGT confirms hepatic origin of ALP elevation
     • Normal GGT suggests bone or other tissue source 1

2. Evaluate Pattern of Elevation

   • Predominantly ALP elevation: Suggests cholestatic pattern
   • Predominantly ALT elevation: Suggests hepatocellular pattern
   • Mixed pattern: Consider infiltrative diseases or mixed injury 2

3. Consider Severity

   • Extremely high ALP (>1,000 U/L): Consider sepsis, malignant obstruction, or AIDS 4
   • Mild-moderate elevations: More common in chronic conditions

Special Considerations

• Occupational Exposures: Chemical hepatotoxins can cause acute liver injury with elevated ALT and ALP, often with characteristic patterns of injury 2

• Malignancy: Underlying malignancy is found in 57% of cases with isolated elevated ALP of unclear etiology, with many patients having infiltrative intrahepatic malignancy, bony metastasis, or both 3

• Physiologic Causes: Consider normal physiologic causes such as childhood (bone growth) and pregnancy (placental production) 1

• Rare Scenarios: In rare cases, patients with genetic conditions causing low ALP (hypophosphatasia) may paradoxically show elevated ALP due to concurrent liver disease 5

Clinical Pitfalls to Avoid

1. Don't overlook sepsis as a cause of extremely high ALP, especially when bilirubin is normal 4

2. Don't miss underlying malignancy in patients with persistent unexplained ALP elevation, as this is associated with poor prognosis (47% mortality within an average of 58 months) 3

3. Don't attribute elevations solely to medications without ruling out more serious underlying causes

4. Don't ignore mild elevations, as they may be the first sign of significant disease, particularly in cholestatic processes

5. Don't forget to consider occupational exposures when evaluating liver enzyme abnormalities, especially in patients with relevant work history 2