Evaluation of Elevated Alkaline Phosphatase

  1. Rule Out Physiological Causes:

    • Check for pregnancy or postprandial increase (up to 1.5–2x the upper limit of normal [ULN]).

    • Repeat fasting labs if needed.

  2. Determine the Source:

    • Use gamma-glutamyl transferase (GGT) or 5'-nucleotidase levels.

    • If normal, the alkaline phosphatase is likely of bone origin.

    • If increased, the alkaline phosphatase is likely of hepatobiliary origin.

  3. Bone Origin (if GGT/5'-nucleotidase normal):

    • Evaluate for bone disorders.

  4. Hepatobiliary Origin (if GGT/5'-nucleotidase increased):

    • Perform right upper quadrant (RUQ) ultrasonography:

      • If dilated bile ducts are found:

        • Proceed with MRCP (magnetic resonance cholangiopancreatography) or ERCP (endoscopic retrograde cholangiopancreatography).

      • If no biliary ductal dilatation is found:

        • Check antimitochondrial antibodies (AMA).

  5. AMA Results and Ultrasonography Findings:

    • If AMA positive, or AMA negative with abnormal ultrasonography showing hepatic parenchymal abnormalities:

      • Consider liver biopsy.

    • If AMA negative and ultrasonography is normal:

      • Assess the degree of alkaline phosphatase elevation:

        • If ≥50% elevated:

          • Perform MRCP, ERCP, or liver biopsy.

        • If <50% elevated:

          • Opt for observation.

Differential includes:

1. Extrahepatic Biliary Obstruction

  • Common Causes:

    • Choledocholithiasis (most common)

      • Uncomplicated

      • Complicated (e.g., biliary pancreatitis, acute cholangitis)

  • Malignant Obstruction:

    • Pancreatic cancer

    • Gallbladder cancer

    • Ampulla of Vater malignancy

    • Bile duct carcinoma

    • Metastasis to perihilar lymph nodes

  • Other Causes:

    • Biliary strictures (benign)

    • Primary sclerosing cholangitis with extrahepatic bile duct stricture

    • Complications after invasive procedures

    • Chronic pancreatitis with distal bile duct stricture

    • Biliary anastomotic stricture following liver transplantation

2. Infections

  • Parasitic Infections:

    • Ascaris lumbricoides

    • Liver flukes

  • Other Infections:

    • AIDS cholangiopathy

3. Intrahepatic Cholestasis

  • Primary Diseases:

    • Drug and toxin-induced cholestasis

    • Primary biliary cholangitis

    • Primary sclerosing cholangitis

    • Intrahepatic cholestasis of pregnancy

  • Secondary Conditions:

    • Benign postoperative cholestasis

    • Total parenteral nutrition (TPN)-associated cholestasis

4. Infiltrative Diseases

  • Systemic Diseases:

    • Amyloidosis

    • Lymphoma

    • Sarcoidosis

    • Tuberculosis

  • Local Complications:

    • Hepatic abscess

    • Metastatic carcinoma to the liver

    • Liver allograft rejection

5. Other Cholangiopathies

  • Specific Types:

    • IgG4-related cholangiopathy

    • Ischemic cholangiopathy

    • COVID-19-associated cholangiopathy

6. Alcohol-Associated Liver Diseases

  • Alcohol-associated hepatitis

7. Nonhepatic and Hematologic Causes

  • Sickle cell disease (hepatic crisis)

  • Transient hyperphosphatemia of infancy and childhood