What is the workup for an elevated alkaline phosphatase (ALP) level?

Workup for Elevated Alkaline Phosphatase

Begin by measuring gamma-glutamyl transferase (GGT) or 5'-nucleotidase to determine whether the ALP elevation originates from the liver or bone, as this single test directs the entire subsequent workup. 1

Initial Laboratory Assessment

Confirm hepatobiliary versus bone origin:

• Elevated GGT confirms hepatobiliary origin; normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation or measure 5'-nucleotidase 1
• Bone-specific ALP (B-ALP) measurement can be useful for suspected bone origin 1

Obtain a complete liver panel including: 1

• ALT, AST, total and direct bilirubin, albumin
• Calculate the R value: (ALT/ULN)/(ALP/ULN) to classify injury pattern 2, 1
  • Cholestatic pattern: R ≤2
  • Mixed pattern: R >2 and <5
  • Hepatocellular pattern: R ≥5

Severity Classification Guides Urgency

Classify ALP elevation to determine workup pace: 1

• Mild: <5× upper limit of normal (ULN)
• Moderate: 5-10× ULN
• Severe: >10× ULN requires expedited workup due to high association with malignant biliary obstruction or infiltrative disease 1, 3

Hepatobiliary Workup (if GGT elevated)

First-line imaging is abdominal ultrasound to evaluate for: 1, 3

• Dilated intrahepatic or extrahepatic bile ducts
• Gallstones or choledocholithiasis (present in ~18% of adults undergoing cholecystectomy) 1
• Infiltrative liver lesions or masses

If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting: 1, 3

• Intrahepatic biliary abnormalities
• Primary sclerosing cholangitis
• Small duct disease
• Choledocholithiasis and biliary strictures

Critical pitfall: Normal CT does not exclude intrahepatic cholestasis; MRI/MRCP is more sensitive for biliary tree evaluation 1

Additional Hepatobiliary Considerations

Review medication history thoroughly, particularly in patients >60 years, as cholestatic drug-induced liver injury comprises up to 61% of cases in this age group 1

Check autoimmune markers if clinically indicated: 1

• ANA, ASMA, AMA, and IgG levels if autoimmune liver disease suspected
• In patients with inflammatory bowel disease and elevated ALP, high-quality MRCP is mandatory to evaluate for primary sclerosing cholangitis 1
• If MRCP is normal in IBD patients with suspected PSC, consider liver biopsy to diagnose small-duct PSC 1

Obtain viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors are present 1

Screen for alcohol intake (>20 g/day in women, >30 g/day in men) 1

Differential Diagnosis for Hepatobiliary Origin

Major causes include: 1

• Cholestatic liver diseases: primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis
• Extrahepatic biliary obstruction: choledocholithiasis, malignant obstruction, biliary strictures
• Infiltrative liver diseases: amyloidosis, hepatic metastases (57% of unexplained isolated ALP elevations are due to malignancy, with 61 patients having infiltrative intrahepatic malignancy in one cohort) 4
• Cirrhosis, chronic hepatitis, congestive heart failure 1

Important caveat: Do not assume NASH is the cause of ALP elevation ≥2× ULN, as NASH typically causes ALT elevation more than ALP 1

Bone Workup (if GGT normal)

Evaluate for bone-specific causes: 1, 3

• Paget's disease
• Bone metastases (52 patients in one cohort had bony metastasis as cause of isolated ALP elevation) 4
• Fractures
• Physiologic causes: childhood growth, pregnancy 1

Obtain bone scan if: 1, 3

• Localized bone pain present
• Radiographic findings suggestive of bone pathology
• Do NOT obtain bone scan in the absence of clinical symptoms or elevated ALP 1

In postmenopausal women: 5

• Elevated ALP is mainly caused by high bone turnover
• Bone metastases are less likely with mild ALP elevation and no symptoms 1
• Bisphosphonate treatment can lower ALP levels and should be reviewed in medication history 1, 6

Urgent referral: Patients under 40 years with suspected bone pathology and elevated ALP may require urgent referral to a bone sarcoma center 1

Follow-Up Strategy

If initial evaluation is unrevealing: 1

• Repeat ALP measurement in 1-3 months
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease
• Persistent elevation warrants further investigation

Critical red flag: 47% of patients with isolated, elevated ALP of unclear etiology died within an average of 58 months in one study, emphasizing the importance of thorough workup 4

Special Clinical Contexts

Wilson disease: Markedly subnormal serum ALP (typically <40 IU/L) alongside Coombs-negative hemolytic anemia and modest aminotransferase elevations suggests Wilson disease; ratio of ALP to total bilirubin <2 strongly suggests this diagnosis 6

Overlap syndromes: Consider AIH/PBC or AIH/PSC when serum ALP is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment 1

Common variable immunodeficiency: Approximately 40% of patients with CVID have abnormalities in liver function tests, with increased ALP the most frequent abnormality 1