What is the initial approach to work up elevated alkaline phosphatase (ALP) levels?

Workup of Elevated Alkaline Phosphatase

The initial workup of elevated ALP requires first determining whether the elevation is of hepatic or non-hepatic origin by measuring gamma-glutamyl transferase (GGT), followed by targeted imaging and laboratory evaluation based on the source identified. 1, 2

Step 1: Confirm Hepatic vs. Non-Hepatic Origin

• Measure GGT immediately to determine tissue source—elevated GGT confirms hepatobiliary origin, while normal GGT strongly suggests bone or other non-hepatic sources 1, 3, 2
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1, 2
• GGT is found in liver, kidneys, intestine, prostate, and pancreas but critically is NOT found in bone, making it the key discriminator 3, 2

Important caveat: In children, measure GGT rather than relying on total ALP alone, since ALP levels are physiologically elevated due to bone growth 4

Step 2: Classify Severity to Guide Urgency

• Mild elevation: <5× upper limit of normal (ULN) 1, 2
• Moderate elevation: 5-10× ULN—requires expedited workup 1, 2
• Severe elevation: >10× ULN—requires urgent evaluation given high association with serious pathology including malignancy 1, 2

Step 3A: If Hepatobiliary Origin (Elevated GGT)

Obtain Complete Liver Panel

• Measure ALT, AST, total and direct bilirubin, albumin, and prothrombin time 4, 1, 2
• Calculate R value [(ALT/ULN)/(ALP/ULN)] to classify injury pattern: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 1, 2
• Normal albumin and bilirubin suggest preserved hepatic synthetic function 1

Perform Medication Review

• Review ALL medications for drug-induced cholestasis, particularly in older patients where cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years 1, 2

First-Line Imaging: Abdominal Ultrasound

• Perform transabdominal ultrasound to assess for dilated intra- or extrahepatic ducts, gallstones, infiltrative liver lesions, or masses 1, 2
• If ultrasound shows common bile duct stones, proceed directly to ERCP without additional imaging 1, 2
• If ultrasound shows biliary ductal dilatation, proceed to MRI with MRCP to evaluate obstruction etiology 1, 2

Second-Line Imaging: MRI with MRCP

• If ultrasound is negative but ALP remains persistently elevated, proceed to MRI with MRCP—superior for detecting intrahepatic biliary abnormalities 1, 2

Consider Specific Etiologies Based on Clinical Context

For patients with inflammatory bowel disease:

• High-quality MRCP is recommended to evaluate for primary sclerosing cholangitis 1
• If MRCP is normal but suspicion remains high, consider liver biopsy to diagnose small-duct PSC 4, 1

For suspected autoimmune liver disease:

• Measure autoimmune markers: ANA, ASMA, AMA, and IgG levels 1, 2
• Consider overlap syndromes (AIH/PBC or AIH/PSC) when ALP is more than mildly elevated and does not normalize with immunosuppressive treatment 1

For suspected viral hepatitis:

• Obtain viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present 1, 2

For suspected infiltrative disease:

• Consider non-malignant infiltrative diseases (amyloidosis, sarcoidosis) and malignancy (hepatic metastases) 1, 2
• Critical finding: In a recent study, 57% of patients with isolated elevated ALP of unclear etiology had underlying malignancy, with 61 having infiltrative intrahepatic malignancy, 52 having bony metastasis, and 34 having both 5

Assess Alcohol Intake

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

Step 3B: If Non-Hepatic Origin (Normal GGT)

Avoid Unnecessary Hepatic Workup

• Do not pursue extensive hepatobiliary imaging when GGT is normal, as this strongly indicates non-hepatic source 3
• Normal GGT with elevated ALP most commonly indicates bone pathology 3

Consider Common Bone Conditions

• Paget's disease 3, 2
• Osteoporosis and osteomalacia 3, 2
• Bone metastases (particularly in elderly patients or those with known malignancy) 3, 2
• Fracture healing 3

Targeted Bone Workup

• Measure calcium, phosphate, PTH, and vitamin D levels 2
• Assess bone-specific ALP if available 2
• Obtain bone scan if localized bone pain present or if malignancy suspected 1, 3
• In patients with known malignancy history, elevated ALP should prompt evaluation for metastatic disease even if asymptomatic 2
• Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center 1

Special Considerations

• X-linked hypophosphatemia presents with elevated ALP, hypophosphatemia, and elevated FGF23 1
• In postmenopausal women, bone scan is recommended only if clinical symptoms (bone pain) or radiographic findings suggest bone pathology 1

Step 4: Special Populations and Physiologic Causes

Pregnancy

• Mild ALP elevations are physiologically normal during second and third trimester due to placental production 2
• If ALP elevation accompanied by pruritus and bile acids >10 μmol/L, diagnose intrahepatic cholestasis of pregnancy 2

Children

• ALP levels are physiologically higher due to bone growth—use GGT to identify potential biliary disease 4
• Overlap syndrome of autoimmune hepatitis and PSC is significantly more common in children 4

Common Variable Immunodeficiency

• Approximately 40% of CVID patients have abnormal liver function tests, with increased ALP the most frequent abnormality 1

Step 5: Follow-Up for Unrevealing Initial Workup

• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months 1
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease 1
• Persistent elevation warrants further investigation including possible liver biopsy 1

Critical Pitfalls to Avoid

• Don't assume NASH: Elevation of ALP ≥2× ULN is atypical in NASH—consider alternative diagnoses 1
• Don't miss malignancy: 47% of patients with isolated elevated ALP of unclear etiology died within average of 58 months, with malignancy being the most common cause 5
• Don't overlook medications: Drug-induced cholestasis is especially common in older adults and should always be considered 1, 2
• Don't forget physiologic causes: Pregnancy and childhood growth are common benign causes of elevated ALP 4, 2