What does C-reactive protein (CRP) measure in a patient with diarrhea?

What C-Reactive Protein Measures in Diarrhea

C-reactive protein (CRP) measures systemic inflammation to help distinguish organic inflammatory causes of diarrhea (such as inflammatory bowel disease, microscopic colitis, or bacterial infection) from functional non-inflammatory causes (such as irritable bowel syndrome), though it has significant limitations and should not be used as the sole diagnostic test. 1

Biological Mechanism

• CRP is synthesized exclusively by the liver in response to inflammatory cytokines (primarily IL-6, TNF-α, and IL-1β) released during intestinal inflammation. 2
• Production begins 4-6 hours after inflammatory insult, doubles every 8 hours, and peaks at 36-50 hours, making it a marker of the intensity of the inflammatory process. 2
• In gastrointestinal diseases, CRP levels correlate with clinical disease activity, particularly in Crohn's disease, though it is less reliable in ulcerative colitis except in severe, extensive colitis. 3

Diagnostic Performance in Diarrhea

Discriminating Organic from Functional Disease

• At a threshold of 5-6 mg/L, CRP demonstrates only 73% sensitivity and 78% specificity for identifying organic disease causing diarrhea, meaning 27% of patients with inflammatory disease will be missed. 1, 4
• The positive likelihood ratio is only 3.4, indicating patients with elevated CRP are 3.4 times more likely to have organic disease than functional disease. 4, 2
• The negative likelihood ratio of 0.35 is insufficient to confidently rule out organic disease with a normal CRP. 4

Acute Infectious Diarrhea

• In young adults with acute diarrhea, CRP at a cutoff of 3.08 mg/dL demonstrates 82% sensitivity and 85% specificity for distinguishing inflammatory from non-inflammatory diarrhea, with an area-under-the-curve of 0.91. 5
• CRP was the most important predictor of inflammatory diarrhea in multivariate analysis (OR 7.39), superior to other inflammatory markers. 5
• This can aid decisions about initiating empiric antibiotic therapy in the acute setting. 5

Critical Limitations and Pitfalls

Poor Sensitivity for IBD

• The American Gastroenterological Association guidelines explicitly state that CRP has poor sensitivity (only 49-73%) for detecting endoscopically active IBD, with approximately 27-51% of patients with active disease having a normal CRP. 4
• CRP correlates better with endoscopic disease activity in Crohn's disease than ulcerative colitis. 1, 4
• Normal CRP does not exclude microscopic colitis, which requires colonoscopy with biopsy for diagnosis. 4

Non-Specificity

• CRP cannot differentiate between bacterial infection, viral infection, tissue injury, chronic inflammatory conditions, or malignancy without clinical context. 2
• CRP levels are influenced by underlying malignancy, other inflammatory processes, and concurrent systemic conditions, limiting its specificity. 6
• A single CRP measurement, especially at low concentrations, may erroneously classify bacterial infections as viral and delay appropriate treatment. 7

Recommended Clinical Algorithm

First-Line Testing

• Order fecal calprotectin (cutoff 50-60 mg/g) as the first-line test, which has superior sensitivity (81-88%) and specificity (87-96%) compared to CRP. 1, 4
• The positive likelihood ratio for fecal calprotectin is 24.3-30, vastly superior to CRP's 3.4. 4

When to Use CRP

• Use CRP only when fecal calprotectin or fecal lactoferrin testing is unavailable or not covered by insurance. 4
• In emergency settings with suspected IBD, measure CRP alongside complete blood count, electrolytes, liver enzymes, ESR, and serum albumin as part of the initial workup. 1

What NOT to Do

• Never withhold colonoscopy based solely on normal CRP in symptomatic patients with clinical features suggesting IBD, as the false-negative rate is unacceptably high (21-27%). 4
• Never use CRP alone to rule out IBD in patients with chronic diarrhea—the AGA explicitly recommends against this practice (conditional recommendation, low-quality evidence). 4
• Do not rely on CRP to assess treatment response or disease recurrence, as it is not a robust surrogate biomarker for these purposes. 6

Appropriate Use Cases

• CRP is most useful as an adjunct to serial examinations in equivocal presentations when combined with clinical assessment, not as a standalone diagnostic tool. 8
• In patients with known Crohn's disease and moderate to severe symptoms, elevated CRP suggests endoscopic activity and warrants colonoscopy with biopsy. 4
• CRP can help predict prognosis and relapse in patients with established Crohn's disease and may identify patients who respond particularly well to anti-TNF-α biologic agents. 3