What are the causes of elevated Carbohydrate Antigen 19-9 (CA 19.9)?

Causes of Elevated CA 19-9

CA 19-9 is commonly elevated in pancreatic cancer but can also be significantly elevated in many benign conditions including cholestasis, cholangitis, inflammatory conditions of the hepatobiliary system, and other non-malignant diseases. 1

Malignant Causes of Elevated CA 19-9

• Pancreatic cancer - Most common malignant cause, with CA 19-9 being the most sensitive marker for pancreatic ductal adenocarcinoma 1
• Biliary tract cancers - Including cholangiocarcinoma 2
• Colorectal cancer 2
• Gastric cancer 2
• Hepatocellular carcinoma 1
• Ovarian cancer 1, 2
• Lung cancer 2

Benign Causes of Elevated CA 19-9

Hepatobiliary and Pancreatic Conditions

• Cholestasis/Biliary obstruction - Can cause markedly elevated levels even in patients with history of pancreatic cancer 3
• Cholangitis - Inflammation of bile ducts can significantly raise CA 19-9 3
• Chronic cholecystitis 4
• Pancreatitis - Both acute and chronic forms 2
• Autoimmune pancreatitis - Can cause extremely high levels (>12,000 U/mL) 5
• Biliary hamartomas 4

Other Benign Conditions

• Hepatic and renal cysts 4
• Hepatic steatosis 4
• Pneumonia and pleural effusion 2
• Renal failure 2
• Systemic lupus erythematosus (SLE) 2
• Thyroid disease 1
• Post-COVID-19 vaccination - Recent evidence shows possible extreme elevations 5

Important Clinical Considerations

Interpretation Pitfalls

1. Lewis antigen status - Approximately 5% of the population are Lewis antigen-negative (genotype Lewis a-b-) and cannot produce CA 19-9, making testing ineffective in these individuals 1

2. Degree of elevation - While higher levels (>1000 U/mL) are more commonly associated with malignancy, even extremely high levels can occur in benign conditions:

   • Benign conditions typically have lower CA 19-9 levels than malignant conditions, but there is significant overlap 2
   • Cases with CA 19-9 >12,000 U/mL have been reported in autoimmune pancreatitis following COVID-19 vaccination 5

3. Persistent elevation - Long-term elevation without evidence of malignancy can occur:

   • Multiple studies document persistent CA 19-9 elevation for years (2-7 years) without development of malignancy 6, 4

Clinical Approach to Elevated CA 19-9

1. Interpret in clinical context - CA 19-9 should never be used alone for diagnosis 1, 2

2. Consider common benign causes first - Especially hepatobiliary conditions and inflammatory processes 3, 2

3. Imaging correlation is essential - CA 19-9 should be interpreted alongside appropriate imaging studies 1

4. Remember limitations:

   • Not recommended as a screening test due to inadequate sensitivity and specificity 1
   • Cannot determine operability of pancreatic cancer alone 1
   • Cannot provide definitive evidence of disease recurrence without confirmation by imaging or biopsy 1

5. Consider genetic factors - Testing is not useful in Lewis antigen-negative individuals 1

CA 19-9 remains an important marker for monitoring response to treatment in known pancreatic cancer, but its elevation should always be interpreted cautiously given the wide range of potential benign and malignant causes.