What are the causes of an elevated carbohydrate antigen 19-9 (CA 19-9) level?

Causes of Elevated CA 19-9

Malignant Causes

Elevated CA 19-9 is most commonly associated with pancreatic adenocarcinoma, cholangiocarcinoma, and other gastrointestinal malignancies, but benign hepatobiliary conditions—particularly biliary obstruction—are major causes of false-positive elevations. 1

Primary Malignancies

• Pancreatic adenocarcinoma elevates CA 19-9 in up to 85% of patients, making it the most characteristic malignancy associated with this marker 1, 2
• Cholangiocarcinoma (bile duct cancer) causes elevated CA 19-9 in up to 85% of patients, with median levels around 408 U/mL 1, 3
• Colorectal cancer can elevate CA 19-9, though less commonly than pancreaticobiliary malignancies 1, 4
• Hepatocellular carcinoma is associated with CA 19-9 elevation 1
• Gastric cancer can cause elevated levels 4
• Ovarian mucinous neoplasms may significantly elevate CA 19-9, even to levels >10,000 U/mL in benign mucinous cystadenomas 5
• Lung cancer has been reported to elevate CA 19-9 4

Benign Causes

Hepatobiliary Conditions (Most Common Benign Cause)

• Biliary obstruction is the major cause of false-positive CA 19-9 results, occurring in 10-60% of cases 1
• Cholangitis (bacterial or inflammatory) elevates CA 19-9 and must be absent to properly interpret levels 1, 6
• Choledocholithiasis (bile duct stones) causes elevation 1
• Jaundice/hyperbilirubinemia from any cause produces false-positive elevations because CA 19-9 levels correlate directly with bilirubin levels 6
• Hepatic cysts: Up to 50% of patients with simple hepatic cysts or polycystic liver disease have elevated CA 19-9 1
• Severe hepatic injury from any cause can elevate CA 19-9 1

Pancreatic Conditions

• Acute and chronic pancreatitis elevate CA 19-9 1
• Autoimmune pancreatitis can mimic pancreatic cancer clinically with elevated CA 19-9, jaundice, and weight loss—and has been reported after COVID-19 vaccination with levels >12,000 U/mL 1, 7

Other Benign Conditions

• Inflammatory bowel disease is associated with CA 19-9 elevation 1
• Pneumonia and pleural effusion can cause elevation 4
• Renal failure has been associated with elevated levels 4
• Systemic lupus erythematosus (SLE) can elevate CA 19-9 4
• Thyroid disease may cause elevation 2

Critical Diagnostic Considerations

Lewis Antigen Status

• 5-10% of the population is Lewis antigen-negative and cannot produce CA 19-9, making testing completely ineffective in these individuals 1, 2, 6

Threshold Interpretation

• Standard cut-off of 37 U/mL has 79-81% sensitivity and 82-90% specificity for pancreatic cancer diagnosis 2, 8
• Optimized cut-off of 70.5 U/mL improves specificity to 85.9% and PPV to 81.3% for differentiating benign from malignant disease 3
• CA 19-9 >100 U/mL has 75% sensitivity and 80% specificity for cholangiocarcinoma in PSC patients, and increases specificity to 88.9% for pancreatic cancer 1, 8
• CA 19-9 >10,000 U/mL is highly concerning for advanced malignancy (most commonly metastatic pancreatic adenocarcinoma), but can occur in benign ovarian cysts and autoimmune pancreatitis 1, 5, 7

Algorithmic Approach to Elevated CA 19-9

Step 1: Assess for Biliary Obstruction

• Obtain abdominal ultrasound as first-line imaging to assess for biliary obstruction 1
• Check liver function tests and bilirubin—these correlate with CA 19-9 in benign disease 1

Step 2: If Biliary Obstruction Present

• Perform biliary decompression via ERCP with stent placement or percutaneous transhepatic cholangiography 1, 6
• Recheck CA 19-9 after complete biliary decompression 1, 6
• Persistent elevation after decompression strongly suggests malignancy and mandates aggressive investigation with tissue diagnosis 1, 6
• Normalization after decompression indicates benign etiology 1

Step 3: Advanced Imaging

• MRI with MRCP is the optimal investigation for suspected cholangiocarcinoma, providing biliary anatomy and tumor extent 1, 6
• Abdominopelvic CT has 94.1% sensitivity for detecting malignancies causing elevated CA 19-9 1

Step 4: Tissue Diagnosis

• CA 19-9 should never be used alone for diagnosis without confirmatory imaging or biopsy, as it is not tumor-specific 1, 2

Common Pitfalls to Avoid

• Never use CA 19-9 as a screening test in asymptomatic individuals due to inadequate sensitivity and specificity 1, 2
• Never interpret CA 19-9 in the presence of jaundice—measure after biliary decompression when possible 1, 6
• Do not rely solely on CA 19-9 for diagnosis—it does not discriminate between cholangiocarcinoma, pancreatic cancer, gastric cancer, or gallbladder malignancy 1
• Small pancreatic tumors may not elevate CA 19-9, limiting sensitivity for early-stage disease 2
• Different testing methods are not interchangeable—results from one assay cannot be extrapolated to another 1