What to do for an adult patient with elevated alkaline phosphatase (ALK phos) and no known medical history?

Workup of Elevated Alkaline Phosphatase

For an adult patient with elevated alkaline phosphatase and no known medical history, immediately measure GGT or obtain ALP isoenzyme fractionation to confirm hepatobiliary origin, then proceed with abdominal ultrasound as first-line imaging if hepatobiliary source is confirmed. 1, 2

Step 1: Determine the Source of ALP Elevation

• Measure GGT concurrently with ALP – elevated GGT confirms hepatobiliary origin, while normal GGT suggests bone or other non-hepatic sources 1, 2
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1
• Alternatively, 5'-nucleotidase can be measured, as elevations generally signal hepatobiliary disease 1, 2

Step 2: Classify Severity to Guide Urgency

• Mild elevation: <5× upper limit of normal (ULN) 1
• Moderate elevation: 5-10× ULN – requires expedited workup 1
• Severe elevation: >10× ULN – requires urgent evaluation due to high association with serious pathology including malignancy and sepsis 1, 3, 4

Step 3: Obtain Complete Liver Panel and Medication Review

• Measure ALT, AST, total and direct bilirubin, albumin, and prothrombin time to assess synthetic function 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
• Review all medications carefully – drug-induced cholestatic liver injury comprises up to 61% of cases in patients ≥60 years 1

Step 4: Hepatobiliary Workup (if GGT elevated)

First-Line Imaging

• Obtain abdominal ultrasound to evaluate for biliary obstruction, dilated ducts, gallstones, and infiltrative liver lesions 1, 2, 5
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP 1

Advanced Imaging if Ultrasound Negative

• Proceed to MRI with MRCP if ALP remains elevated despite negative ultrasound – this is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, small duct disease, and infiltrative processes 1, 2

Serologic Testing

• Obtain viral hepatitis markers (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present 1, 2
• Measure autoimmune markers (ANA, ASMA, AMA) and IgG levels if autoimmune disease suspected 1, 2
• In patients with inflammatory bowel disease, high-quality MRCP is essential to evaluate for primary sclerosing cholangitis 1, 2

Step 5: Bone Workup (if GGT normal)

• Obtain bone-specific alkaline phosphatase (B-ALP) if available 1
• Order bone scan only if localized bone pain, radiographic findings suggestive of bone pathology, or clinical suspicion for metastases 1, 2
• Patients under 40 years with suspected bone pathology may require urgent referral to a bone sarcoma center 1

Step 6: Follow-Up Strategy

• If initial evaluation is unrevealing, repeat ALP measurement in 1-3 months 1
• For asymptomatic patients with mild elevations and intact hepatic function, close clinical follow-up is reasonable if initial studies are negative 2
• Monitor closely if ALP continues to rise, as this may indicate progression of underlying disease 1

Critical Differential Diagnoses by Clinical Context

Most Common Causes in Hospitalized Patients

• Malignancy (57% of cases) – including infiltrative intrahepatic malignancy, bony metastases, or both 6
• Sepsis – can cause extremely high ALP (>1000 U/L) even with normal bilirubin 3, 4
• Biliary obstruction – from choledocholithiasis, malignant obstruction, or strictures 1, 3, 4

Other Important Causes

• Bone disease (29% of cases) – Paget's disease, fractures, metastases 1, 6
• Infiltrative liver diseases – amyloidosis, sarcoidosis, hepatic metastases 1
• Drug-induced cholestasis – especially in older patients 1
• Congestive heart failure 1, 7

Important Clinical Pitfalls

• Do NOT assume NASH is the cause if ALP ≥2× ULN – NASH typically causes ALT elevation more than ALP 1
• Normal CT does not exclude intrahepatic cholestasis – MRI/MRCP is more sensitive for biliary tree evaluation 1
• Transient elevations (normalizing within 1-3 months) are common in hospitalized patients with congestive heart failure or benign bone disease 7
• Persistent elevation (>3 months) usually indicates a clinically significant diagnosis requiring complete evaluation 2, 7
• In patients with sepsis, ALP can be extremely elevated (>1000 U/L) with completely normal bilirubin 3

Prognosis Considerations

• In one study, 47% of patients with isolated elevated ALP of unclear etiology died within an average of 58 months, highlighting the potential clinical significance 6
• If initial ALP is >1.5× normal, there is higher likelihood of persistent elevation (68% vs 41%) 7