What is the workup for an adult patient with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)?

Workup for Elevated Alkaline Phosphatase and Elevated GGT

When both ALP and GGT are elevated together, this confirms a hepatobiliary origin and requires immediate imaging with abdominal ultrasound as the first-line test to evaluate for biliary obstruction, infiltrative liver disease, or parenchymal liver pathology. 1

Initial Confirmation and Severity Assessment

• Confirm the elevation is reproducible by repeating both ALP and GGT within 7-10 days, as cholestatic patterns can fluctuate 2
• Classify the severity to guide urgency: mild elevation (<5× ULN), moderate (5-10× ULN), or severe (>10× ULN), with severe elevations requiring expedited workup due to high association with serious pathology including malignancy 1
• Calculate the R value [(ALT/ULN)/(ALP/ULN)] to confirm cholestatic pattern: R ≤2 indicates cholestatic injury, which is consistent with elevated ALP and GGT 1

Complete the Liver Panel

Obtain the following tests immediately to assess hepatic function and narrow the differential 1:

• Total and direct bilirubin to calculate conjugated fraction—elevations suggest more advanced biliary obstruction or hepatocellular dysfunction
• ALT and AST to assess for hepatocellular injury component
• Albumin to evaluate synthetic function—normal levels suggest preserved hepatic function
• Complete blood count to check for eosinophilia (>5%), which may suggest drug-induced liver injury 2

First-Line Imaging: Abdominal Ultrasound

Proceed immediately to transabdominal ultrasound to evaluate for 1:

• Dilated intrahepatic or extrahepatic bile ducts indicating obstruction
• Cholelithiasis or choledocholithiasis—approximately 18% of adults have common bile duct stones that can cause cholestasis 1
• Masses or infiltrative lesions suggesting malignancy or infiltrative disease
• Liver parenchymal abnormalities including cirrhosis or steatosis

Critical decision point: If ultrasound demonstrates common bile duct stones with obstruction, proceed directly to ERCP for both diagnosis and therapeutic intervention 1

Second-Line Imaging: MRI with MRCP

If ultrasound is negative or non-diagnostic but ALP/GGT remain elevated, proceed to MRI with MRCP, which is superior to CT for detecting 1:

• Intrahepatic biliary abnormalities and small duct disease
• Primary sclerosing cholangitis (PSC), especially if inflammatory bowel disease is present
• Partial bile duct obstruction not visible on ultrasound
• Biliary strictures from malignancy or benign causes
• Infiltrative diseases including hepatic metastases, sarcoidosis, or amyloidosis

Targeted Laboratory Workup Based on Clinical Context

Medication Review (Essential First Step)

• Review all medications thoroughly—cholestatic drug-induced liver injury comprises up to 61% of cases in patients ≥60 years old 1
• Discontinue potential offending agents if identified, with repeat testing in 7-10 days 2

Autoimmune Liver Disease Screening

Check the following if autoimmune etiology is suspected 1:

• Antimitochondrial antibody (AMA) for primary biliary cholangitis (PBC)—diagnosis requires ALP elevation plus positive AMA
• Antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) for autoimmune hepatitis overlap
• IgG levels to assess for autoimmune hepatitis component
• Consider liver biopsy if overlap syndrome suspected (ALP remains elevated despite immunosuppressive treatment) 1

Infectious and Metabolic Causes

• Viral hepatitis serologies (HAV IgM, HBsAg, HBc IgM, HCV antibody) if risk factors present 1
• Assess alcohol intake (>20 g/day in women, >30 g/day in men) as a potential contributor 1
• Screen for metabolic syndrome and evaluate for non-alcoholic fatty liver disease, though ALP ≥2× ULN is atypical for NASH alone 1

Special Population Considerations

If inflammatory bowel disease is present:

• High-quality MRCP is mandatory to evaluate for primary sclerosing cholangitis 1
• If MRCP is normal but suspicion remains high, consider liver biopsy to diagnose small-duct PSC 1
• Monitor for abrupt ALP elevations which may indicate dominant stricture, bacterial cholangitis, or choledocholithiasis requiring ERCP evaluation 1

If patient is on investigational drugs or in clinical trials:

• Use baseline ALP values rather than ULN for monitoring 2
• ALP >2× baseline without alternative explanation should trigger increased monitoring 2
• ALP >3× baseline OR ALP >2× baseline with bilirubin >2× ULN should trigger drug interruption 2

Critical Differential Diagnoses to Consider

The most common causes of combined ALP and GGT elevation include 1, 3, 4:

• Extrahepatic biliary obstruction (choledocholithiasis, malignant obstruction, strictures)—most urgent to identify
• Infiltrative malignancy—57% of isolated elevated ALP cases in one study were due to malignancy, with 47% mortality within 58 months 3
• Primary biliary cholangitis (ALP typically 2-10× ULN with positive AMA)
• Primary sclerosing cholangitis (strongly associated with IBD, ALP typically ≥1.5× ULN)
• Drug-induced cholestatic liver injury—especially in older patients
• Infiltrative non-malignant diseases (sarcoidosis, amyloidosis)
• Sepsis—can cause marked ALP elevation 4

Common Pitfalls to Avoid

• Do not assume NASH is the cause when ALP is ≥2× ULN—this pattern is atypical for NASH, which predominantly elevates ALT 1
• Do not delay imaging in moderate to severe elevations, as malignancy is a common cause requiring urgent diagnosis 3
• Do not overlook Gilbert's syndrome (5-10% of population) as a cause of mild bilirubin elevation—confirm by calculating unconjugated bilirubin fraction (<20-30% conjugated) 2
• Do not stop at normal CT—if ALP remains elevated, proceed to MRI/MRCP as CT is inferior for biliary tree evaluation 1
• Do not forget to fractionate bilirubin to determine direct vs. indirect elevation, which helps differentiate cholestatic from hemolytic causes 1

Follow-Up Strategy

• If initial workup is unrevealing, repeat ALP and GGT in 1-3 months and monitor closely for rising trends 1
• Cholestatic injury improves more slowly than hepatocellular injury—blood tests typically return to baseline within 6 months after removing the offending agent 2
• GGT increases occur earlier and persist longer than ALP in cholestatic disorders, making it useful for monitoring disease progression 2