What is the appropriate workup for a patient with elevated alkaline phosphatase (ALP) levels?

Workup for Elevated Alkaline Phosphatase

Initial Step: Determine the Source

Measure gamma-glutamyl transferase (GGT) or 5'-nucleotidase concurrently with ALP to confirm whether the elevation is hepatobiliary or non-hepatic in origin. 1 Elevated GGT confirms hepatic origin, while normal GGT suggests bone or other non-hepatic sources. 1

• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone. 1
• Bone-specific alkaline phosphatase (B-ALP) measurement can be useful for suspected bone origin, as B-ALP is a sensitive marker for bone turnover and bone metastases. 1

Severity Classification Guides Urgency

Classify the degree of elevation to determine the pace of workup: 1, 2

• Mild elevation: <5× upper limit of normal (ULN)
• Moderate elevation: 5-10× ULN (requires expedited workup)
• Severe elevation: >10× ULN (requires urgent workup given high association with serious pathology)

If Hepatobiliary Origin (Elevated GGT)

Step 1: Review Medications and Clinical Context

• Perform a thorough medication review, particularly in older patients, as cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years. 1
• Assess for symptoms including right upper quadrant pain, fatigue, nausea, weight loss, jaundice. 1
• Screen for alcohol intake (>20 g/day in women, >30 g/day in men). 1

Step 2: Obtain Complete Liver Panel

• Measure ALT, AST, total and direct bilirubin, albumin. 1, 2
• Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5). 1
• Fractionate total bilirubin to determine the percentage of direct bilirubin, as this helps differentiate between hepatobiliary and bone causes. 1

Step 3: First-Line Imaging - Abdominal Ultrasound

• Perform transabdominal ultrasound as the first-line imaging modality to assess for dilated intra- or extrahepatic ducts, gallstones, infiltrative liver lesions, or masses. 1, 2
• Ultrasound evaluates for choledocholithiasis, which occurs in approximately 18% of adults undergoing cholecystectomy and can significantly impact liver function tests. 1
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP. 1

Step 4: If Ultrasound is Negative but ALP Remains Elevated

• Proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, and small duct disease. 1, 2
• MRCP is particularly useful for identifying choledocholithiasis, biliary strictures, infiltrative diseases (sarcoidosis, amyloidosis, hepatic metastases), and partial bile duct obstruction not visible on CT. 1
• Normal CT does not exclude intrahepatic cholestasis; MRI/MRCP is more sensitive for biliary tree evaluation. 1

Step 5: Consider Specific Etiologies Based on Clinical Context

For patients with inflammatory bowel disease:

• High-quality MRCP is recommended to evaluate for primary sclerosing cholangitis, as elevated ALP in IBD patients should raise suspicion for PSC. 1, 2
• If high-quality MRCP is normal in a patient with IBD and suspected PSC, consider liver biopsy to diagnose small-duct PSC. 1

For autoimmune workup (if indicated):

• Measure ANA, ASMA (anti-smooth muscle antibody), AMA (anti-mitochondrial antibody), and IgG levels if autoimmune liver disease is suspected. 1, 2
• Consider overlap syndromes (AIH/PBC or AIH/PSC) when serum ALP is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment. 1

For viral hepatitis (if risk factors present):

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

Critical pitfall: Do not attribute isolated ALP elevation ≥2× ULN to non-alcoholic steatohepatitis (NASH), as elevation of ALP ≥2× ULN is atypical in NASH, which typically causes ALT elevation more than ALP. 1

If Bone Origin (Normal GGT)

Step 1: Assess Clinical Context

• Evaluate for localized bone pain, recent fractures, or radiographic findings suggestive of bone pathology. 1, 2
• In postmenopausal women, bone metastases are less likely with mild ALP elevation and no symptoms. 1
• Patients under 40 years with suspected bone pathology and elevated ALP may require urgent referral to a bone sarcoma center. 1

Step 2: Obtain Targeted Laboratory Tests

• Check serum calcium, phosphate, and PTH to evaluate for metabolic bone disorders. 2
• Measure 25-hydroxyvitamin D to assess for vitamin D deficiency. 2
• Consider measuring intact FGF23 if X-linked hypophosphatemia (XLH) is suspected, as XLH presents with elevated ALP as a biochemical hallmark, along with hypophosphatemia and elevated FGF23. 1

Step 3: Imaging Based on Clinical Suspicion

• Obtain a bone scan if localized bone pain is present or if there is clinical suspicion of bone metastases (particularly in patients with known malignancy such as renal, breast, bladder, or prostate cancer). 1, 2
• A bone scan is NOT recommended in the absence of elevated ALP with clinical symptoms such as bone pain or radiographic findings. 1
• Consider plain radiographs of symptomatic areas to evaluate for fractures, Paget's disease, or lytic lesions. 1

Step 4: Consider Specific Bone Disorders

• Classical biochemical changes in osteomalacia include hypocalcemia, hypophosphatemia, increased PTH, and elevated bone alkaline phosphatase, though serum calcium and phosphate are often normal. 1
• Serum ALP is a reliable biomarker of rickets activity and osteomalacia in children and adults. 1

Special Populations and Physiologic Causes

Children

• ALP levels are physiologically 2-3× adult values due to bone growth. 1
• Measuring GGT can confirm bone origin in children with elevated ALP. 1
• Transient hyperphosphatasemia (THP) of infants and children is a benign condition requiring no intervention, typically normalizing within 4 months. 3

Pregnancy

• ALP can be elevated in pregnancy due to placental production. 1

Chronic Kidney Disease

• Monitor calcium, phosphate, PTH, and ALP every 12 months in CKD stages 4-5, or more frequently if PTH is elevated. 2
• Elevated ALP in advanced CKD may be partly explained by subclinical liver congestion related to left ventricular diastolic dysfunction and hypervolemia. 4

If Initial Workup is Unrevealing

• Repeat ALP measurement in 1-3 months and monitor closely if ALP continues to rise, as persistent elevation warrants further investigation. 1
• Consider infiltrative non-malignant diseases such as amyloidosis and sarcoidosis in patients with unexplained elevation. 1
• In a retrospective study of 260 patients with isolated elevated ALP of unclear etiology, the most common cause was underlying malignancy (57%), with 61 patients having infiltrative intrahepatic malignancy, 52 having bony metastasis, and 34 having both. 5
• Notably, 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, highlighting the potential clinical significance of this finding. 5

Critical Pitfalls to Avoid

• Do not assume normal CT excludes biliary pathology; proceed to MRCP if clinical suspicion remains high. 1
• Do not overlook medication-induced cholestasis, especially in older patients. 1
• Do not attribute significant ALP elevation to NASH without excluding other causes. 1
• In patients with known liver disease like hypophosphatasia, be aware that ALP levels can transiently increase due to concurrent liver disease (such as alcohol-induced hepatitis), potentially masking the underlying diagnosis. 6
• Using an ALP cutoff of 160 U/L (rather than the upper normal limit) increases sensitivity for detecting liver metastases in patients with colorectal cancer. 7