Why is my C-reactive protein (CRP) level elevated in the absence of signs of infection and with a low fecal calprotectin level, given my history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD)?

Elevated CRP with Low Fecal Calprotectin in PSC-IBD

Your elevated CRP despite low fecal calprotectin and no infection signs is most likely due to ongoing biliary inflammation from your PSC itself, rather than active intestinal IBD inflammation. This dissociation between CRP and fecal calprotectin is well-recognized in PSC-IBD patients and reflects the fact that CRP responds to systemic and hepatobiliary inflammation, while fecal calprotectin specifically measures intestinal mucosal inflammation 1.

Why This Dissociation Occurs

CRP elevation in PSC reflects hepatobiliary disease activity, not just intestinal inflammation. The British Society of Gastroenterology guidelines explicitly recognize that CRP correlates less tightly with intestinal disease activity in IBD patients and can be completely normal even during intestinal flares 1. In your case with PSC, the liver disease itself generates systemic inflammation that elevates CRP independently of bowel activity 1.

Your low fecal calprotectin strongly suggests your intestinal IBD is quiescent. Fecal calprotectin is a more sensitive and specific biomarker for intestinal mucosal inflammation than CRP 1. The 2025 British Society of Gastroenterology guidelines state that fecal calprotectin <100 μg/g correlates with endoscopic remission, and values <150 μg/g make active intestinal inflammation unlikely 1.

Additional Causes to Consider in PSC-IBD

Subclinical intestinal inflammation may be present even without elevated fecal calprotectin. Recent research demonstrates that the vast majority of PSC patients show molecular-level intestinal inflammation with increased IL-17A and IFN-γ expression, even without clinically manifest IBD 2. This subclinical inflammation is typically focused in the distal colon and may not elevate fecal calprotectin sufficiently to cross diagnostic thresholds 2.

Cholangiocarcinoma must be excluded when CRP rises in PSC patients. The Hepatology guidelines emphasize that patients with PSC who show deterioration in constitutional status or liver biochemical parameters should undergo evaluation for cholangiocarcinoma (CCA), which has a 7-9% 10-year cumulative incidence 1. Consider checking:

• CA 19-9 (using cutoff of 130 U/mL for 79% sensitivity and 98% specificity for CCA) 1
• Liver function tests, particularly bilirubin elevation 1
• Cross-sectional imaging (MRI/MRCP) to evaluate for dominant strictures or mass lesions 1

Bacterial cholangitis can elevate both CRP and CA 19-9 without obvious clinical signs. The Hepatology guidelines note that bacterial cholangitis elevates inflammatory markers and can occur with subtle presentations in PSC patients 1.

Clinical Approach Algorithm

Step 1: Assess liver disease activity and exclude malignancy

• Check complete liver biochemistry panel (ALT, AST, ALP, bilirubin, albumin) 1
• Measure CA 19-9 if not recently checked 1
• Consider repeat imaging (MRCP) if dominant stricture or mass is suspected 1

Step 2: Confirm intestinal remission if uncertain

• Your low fecal calprotectin already provides strong evidence of intestinal remission 1
• If fecal calprotectin is borderline (100-150 μg/g), repeat measurement in 3-6 months 1
• Endoscopic assessment is only needed if fecal calprotectin is >150 μg/g or if alarm symptoms develop 1

Step 3: Monitor for disease progression

• Serial CRP measurements can track PSC disease activity over time 3
• The 2019 British Society of Gastroenterology PSC guidelines recommend surveillance colonoscopy every 1-2 years regardless of symptoms due to increased colorectal cancer risk in PSC-IBD 1
• Continue IBD treatment according to standard IBD guidelines, as PSC activity does not dictate IBD therapy changes 1

Critical Pitfalls to Avoid

Do not assume elevated CRP means your IBD is flaring when fecal calprotectin is low. The 2025 British Society of Gastroenterology guidelines specifically state that an unexpectedly raised CRP with no localizing symptoms should prompt fecal calprotectin measurement to validate intestinal disease activity before arranging endoscopy 1. Your low fecal calprotectin already confirms intestinal quiescence.

Do not ignore persistently elevated or rising CRP in PSC. Unlike isolated IBD, PSC patients require vigilance for cholangiocarcinoma development, which can occur at any time and is detected within the first year of PSC diagnosis in approximately 50% of PSC-CCA cases 1.

Recognize that PSC and IBD activity do not correlate. The British Society of Gastroenterology guidelines emphasize there is "at most a weak correlation between activity of PSC and IBD," and treatment of active colitis has no impact on PSC progression 1. Your PSC may be progressing even with quiescent intestinal disease.