What is the appropriate work‑up for a patient with an elevated alkaline phosphatase level while alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are normal?

Workup for Elevated Alkaline Phosphatase with Normal ALT and AST

Order gamma-glutamyl transferase (GGT) immediately to confirm whether the elevated alkaline phosphatase originates from the liver or from bone, as this single test will direct your entire diagnostic pathway. 1

Initial Diagnostic Step: Confirm Hepatic Origin

• Measure GGT concurrently with repeat ALP—elevated GGT confirms hepatobiliary 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
• In postmenopausal women, elevated ALP frequently originates from high bone turnover rather than liver disease, making GGT measurement essential to avoid unnecessary hepatobiliary workup 2

If GGT is Elevated (Hepatobiliary Origin Confirmed)

Complete the Hepatobiliary Laboratory Panel

• Obtain total and direct bilirubin to calculate conjugated fraction—elevations suggest biliary obstruction or hepatocellular dysfunction 1
• Measure ALT and AST to calculate the R-value: (ALT/ULN) ÷ (ALP/ULN)—an R ≤2 defines cholestatic injury, R >2 and <5 indicates mixed injury, and R ≥5 suggests hepatocellular injury 1
• Check albumin and INR to assess synthetic liver function 1
• Order viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV) if risk factors are present 1

Obtain First-Line Imaging

• Perform abdominal ultrasound as the initial imaging modality to evaluate for dilated intra- or extrahepatic ducts, gallstones, infiltrative liver lesions, or masses 1
• Ultrasound reliably identifies biliary obstruction, choledocholithiasis, and focal lesions 1

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, small-duct disease, and partial bile duct obstruction 1
• MRCP demonstrates 86% sensitivity and 94% specificity for diagnosing primary sclerosing cholangitis 1

Check Autoimmune Markers

• Measure antimitochondrial antibody (AMA)—positive AMA plus elevated ALP essentially confirms primary biliary cholangitis 1
• If AMA is negative, check ANA with sp100/gp210 subtyping, as these support PBC variants 1
• Obtain anti-smooth muscle antibody (ASMA) and quantitative IgG if autoimmune hepatitis overlap syndrome is suspected 1

Consider Specific Cholestatic Diagnoses

• Primary biliary cholangitis (PBC): Diagnosis requires elevated ALP plus positive AMA (or ANA sp100/gp210 if AMA-negative); treat with ursodeoxycholic acid 13–15 mg/kg/day 1
• Primary sclerosing cholangitis (PSC): 50–80% have inflammatory bowel disease; MRCP shows characteristic "beading" of bile ducts; if MRCP is normal but suspicion remains high, consider liver biopsy for small-duct PSC 1
• Drug-induced cholestasis: Review all medications, including over-the-counter drugs and supplements—older patients (≥60 years) are particularly prone, with cholestatic DILI comprising up to 61% of cases in this age group 3, 1

Severity-Based Urgency

• Mild elevation (<5× ULN): Systematic outpatient workup as outlined above 1
• Moderate elevation (5–10× ULN): Expedite imaging and laboratory evaluation 1
• Severe elevation (>10× ULN): Requires urgent workup due to high association with serious pathology such as sepsis, malignant obstruction, or complete biliary blockage 1, 4

If GGT is Normal (Non-Hepatic Origin)

Evaluate for Bone Disease

• Assess for bone-related symptoms: localized bone pain, fractures, or constitutional symptoms 1
• Order bone scan only if symptomatic (localized pain or suspected metastases)—in asymptomatic patients, the likelihood of a positive bone scan is <5% 1
• Consider bone-specific ALP measurement, which is a sensitive marker for bone turnover and metastases 1
• In postmenopausal women, elevated ALP is commonly due to high bone turnover; bisphosphonate treatment lowers ALP levels, confirming bone origin 2

Consider Physiologic Causes

• ALP levels are physiologically 2–3× adult values in children due to bone growth 1
• Pregnancy causes mild ALP elevation in the second and third trimesters due to placental production 1

Rule Out Other Non-Hepatic Sources

• Intestinal ALP can be elevated after fatty meals or in patients with inflammatory bowel disease 1
• Renal osteodystrophy in chronic kidney disease: Measure intact PTH—elevated PTH plus elevated ALP strongly suggests high-turnover bone disease 1

Critical Pitfalls to Avoid

• Do not assume normal ultrasound excludes significant biliary pathology—intrahepatic cholestasis, primary sclerosing cholangitis, and small-duct disease require MRCP for diagnosis 1
• Do not attribute isolated ALP elevation ≥2× ULN to nonalcoholic steatohepatitis (NASH)—NASH typically elevates ALT more than ALP 1
• Do not delay MRCP while awaiting serology results—order both concurrently to expedite diagnosis 1
• Do not overlook medication review, particularly in older patients—cholestatic drug-induced liver injury is common and often reversible 3, 1
• Do not miss malignancy—in a retrospective cohort of 260 patients with isolated elevated ALP of unclear etiology, 57% had underlying malignancy (intrahepatic infiltration, bone metastases, or both) 5

Monitoring and Referral

• Repeat ALP and GGT in 7–10 days to confirm reproducibility and direction of change 1
• Refer to hepatology urgently if MRCP reveals a dominant stricture, mass lesion suggestive of cholangiocarcinoma, or if ALP continues to rise despite initial workup 1
• Consider hepatology referral if ALP remains elevated ≥6 months without identified cause 1