What tests should be done in a patient with elevated alkaline phosphatase (ALP) levels?

Diagnostic Workup for Elevated Alkaline Phosphatase

When alkaline phosphatase (ALP) is elevated, the first step is to measure gamma-glutamyl transferase (GGT) to determine whether the source is hepatobiliary (elevated GGT) or non-hepatic such as bone (normal GGT). 1, 2

Initial Laboratory Assessment

Measure GGT concurrently with repeat ALP to confirm the elevation is reproducible and to establish the source. 1 If GGT is elevated, this confirms hepatobiliary origin and you should proceed with liver-focused workup. 1, 2 If GGT is normal or unavailable, obtain ALP isoenzyme fractionation or measure 5'-nucleotidase to determine the percentage derived from liver versus bone. 1, 2

Complete Liver Panel

Obtain the following tests to characterize the pattern of injury: 1, 2

• Total and direct bilirubin to calculate conjugated fraction—elevations suggest more advanced biliary obstruction 1
• ALT and AST to assess for hepatocellular injury component 1
• Albumin to evaluate hepatic synthetic function 1
• Calculate R value: (ALT/ULN)/(ALP/ULN) to classify injury pattern—cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 1

Hepatobiliary Workup (If GGT Elevated)

First-Line Imaging

Obtain abdominal ultrasound as the initial imaging modality to evaluate for: 1, 2

• Dilated intrahepatic or extrahepatic bile ducts
• Gallstones or choledocholithiasis
• Infiltrative liver lesions or masses
• Bile sludge (a precursor to stones) 1

If common bile duct stones are identified on ultrasound, proceed directly to ERCP for both diagnosis and therapeutic stone extraction without further imaging. 1 This should be performed within 24-72 hours to prevent ascending cholangitis and irreversible liver damage. 1

Second-Line Imaging

If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting: 1, 2

• Intrahepatic biliary abnormalities
• Primary sclerosing cholangitis (especially if inflammatory bowel disease is present) 1
• Small duct disease
• Partial bile duct obstruction not visible on ultrasound 1
• Infiltrative diseases (sarcoidosis, amyloidosis, hepatic metastases) 1

Additional Serologic Testing

Based on clinical context, consider: 1

• Antimitochondrial antibody (AMA) if primary biliary cholangitis suspected—diagnosis requires elevated ALP plus positive AMA 1
• ANA, ASMA, and IgG levels if autoimmune hepatitis or overlap syndrome suspected 1
• Viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present 1

Bone Workup (If GGT Normal)

Clinical Assessment

Evaluate for: 1, 2

• Localized bone pain or constitutional symptoms
• History of malignancy
• Fractures or recent trauma 1

Bone-Specific Testing

• Measure bone-specific alkaline phosphatase (B-ALP) if available—this is a sensitive marker for bone turnover and bone metastases 1
• Obtain bone scan only if there is localized bone pain or radiographic findings suggestive of bone pathology 1, 2
• Do NOT obtain bone scan in the absence of symptoms, as this is not recommended 1

Important Bone Considerations

In postmenopausal women, elevated ALP may originate from osteoporosis rather than malignancy, particularly with mild elevations and no symptoms. 1 However, patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center. 1

Severity-Based Approach

The degree of ALP elevation guides urgency: 1, 2

• Mild elevation (<5× ULN): Standard workup as outlined above
• Moderate elevation (5-10× ULN): Expedite workup with imaging and laboratory evaluation 1
• Severe elevation (>10× ULN): Requires urgent evaluation for malignant biliary obstruction, infiltrative disease, or sepsis 1, 2, 3

Critical Clinical Contexts

Sepsis

Extremely high ALP elevations can occur with sepsis (gram-negative, gram-positive, or fungal) and may present with normal bilirubin. 3 This is one of the most common causes of ALP >1,000 U/L in hospitalized patients. 3

Malignancy

Isolated elevated ALP of unclear etiology is most commonly due to underlying malignancy (57% of cases), including infiltrative intrahepatic malignancy, bony metastases, or both. 4 This carries significant prognostic implications, with 47% mortality within an average of 58 months. 4

Inflammatory Bowel Disease

In patients with IBD and elevated ALP, obtain high-quality MRCP to evaluate for primary sclerosing cholangitis. 1 If MRCP is normal but suspicion remains high, consider liver biopsy to diagnose small-duct PSC. 1

Follow-Up Strategy

If initial workup is unrevealing: 1

• Repeat ALP measurement in 1-3 months to assess for persistence or progression
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease
• Consider repeat imaging if ALP remains elevated despite negative initial studies

Common Pitfalls to Avoid

• Do not assume NASH is the cause of ALP elevation ≥2× ULN—NASH typically causes ALT elevation more than ALP 1
• Do not delay ERCP if stones are identified—conservative management carries 25.3% risk of unfavorable outcomes versus 12.7% with active extraction 1
• Do not assume elevated transaminases exclude biliary obstruction—in acute choledocholithiasis, ALT can surpass ALP, mimicking acute hepatitis 1
• Normal CT does not exclude intrahepatic cholestasis—MRI/MRCP is more sensitive for biliary tree evaluation 1
• In children, ALP levels are physiologically 2-3× adult values due to bone growth—measure GGT to confirm bone origin 1