Faecal Calprotectin

Calprotectin is a calcium binding protein of the S100 family (S100A8 and S100A9) that makes up about 60% of the cytosolic protein in neutrophils. It is released into the intestinal lumen when neutrophils migrate into inflamed mucosa, and it is stable in stool for several days. It is measured in a small stool sample by quantitative ELISA or immunoturbidimetric assay, reported in microg/g of stool (mg/kg).

The test separates inflammatory bowel disease (IBD: Crohn disease and ulcerative colitis) from functional gut disorders such as irritable bowel syndrome in patients with chronic diarrhoea or abdominal pain. It also monitors disease activity and response to treatment, and predicts relapse. It reduces unnecessary colonoscopy.

IBD affects about 0.5 to 1% of people in Western countries, with a rising incidence in Asia, Africa and Latin America. Peak onset is at 15 to 35 years, with a second smaller peak after 50 years. Irritable bowel syndrome affects 5 to 10% of the population and is far commoner than IBD in primary care.

Indications. Younger adults (under 50 years) with chronic diarrhoea or abdominal pain and no alarm features, to decide who needs colonoscopy, children with chronic abdominal pain or diarrhoea, monitoring of known IBD and prediction of relapse, assessment of mucosal healing, post-operative recurrence of Crohn disease, and suspected NSAID enteropathy.

Specimen. A small random stool sample (about 5 g), collected in a clean container without urine, water or toilet cleaner. It is stable for up to 3 to 7 days at room temperature and longer refrigerated or frozen. Note non-steroidal anti-inflammatory drugs and proton pump inhibitors. A first morning stool is preferred for monitoring, because values vary from day to day.

Ranges vary by assay. In most laboratories:

• Under 50 microg/g: normal, and IBD is very unlikely.
• 50 to 200 microg/g: borderline or mildly raised. Repeat testing after 2 to 4 weeks, review medicines, and consider NSAID effects, infection and early IBD.
• Over 200 microg/g (some use over 250): active intestinal inflammation is likely, and further investigation (colonoscopy) is needed.
• Over 500 microg/g: marked inflammation, with a high likelihood of active IBD.

Diagnostic accuracy. For distinguishing IBD from irritable bowel syndrome in adults, at a threshold of 50 microg/g the sensitivity is about 93% and specificity about 94%, with a negative predictive value over 95% in people under 40 years. In children, the sensitivity is about 97% and specificity about 75%.

Monitoring of known IBD.

• Under 100 to 150 microg/g in a patient in clinical remission suggests mucosal healing and a low risk of relapse.
• A rise over 250 microg/g in remission predicts relapse within 3 to 12 months in about 50 to 80% of cases, and supports treatment adjustment before symptoms.
• Values over 250 microg/g in symptomatic IBD confirm active inflammation and may separate IBD flare from irritable bowel type symptoms.
• A fall of over 50% after starting treatment suggests response.
• After ileocolonic resection for Crohn disease, a value over 100 to 150 microg/g predicts endoscopic recurrence.

Causes of raised faecal calprotectin.

• Inflammatory bowel disease (Crohn disease, ulcerative colitis), microscopic colitis (modest), and diverticulitis.
• Infective gastroenteritis, including Clostridioides difficile, Salmonella, Campylobacter and parasites.
• Colorectal cancer and large polyps (often modest to marked).
• Non-steroidal anti-inflammatory drug enteropathy and proton pump inhibitor use (up to two to threefold).
• Coeliac disease (usually mild), ischaemic colitis, radiation colitis, and necrotising enterocolitis in neonates.
• Cystic fibrosis, cirrhosis with portal hypertension, and autoimmune diseases.
• Gut bleeding, and very high values in infants under 12 months, where values up to 500 microg/g can be normal.

Critical values and findings needing immediate action.

• A value over 500 microg/g with bloody diarrhoea, fever, tachycardia, weight loss or anaemia: urgent assessment for acute severe colitis.
• A raised value with signs of obstruction, perforation or toxic dilatation.
• A raised value with alarm features (rectal bleeding, iron deficiency, weight loss, family history of colorectal cancer): colonoscopy irrespective of the number.
• A raised value in a child with failure to grow, perianal disease or joint symptoms.

Interferences and pitfalls.

• It is a marker of neutrophil inflammation and not specific to IBD. Infection, NSAIDs and cancer raise it.
• A normal result does not exclude microscopic colitis, coeliac disease or isolated small bowel Crohn disease, which can have low values.
• Day-to-day variation is large (up to 40 to 50%), so a single borderline value is repeated.
• Different assays and cut offs are not interchangeable, and the same method is used for monitoring.
• Stool consistency and poor mixing affect extraction in watery stool.
• Delay in transport in hot climates may lower values.
• Bleeding does not explain very high values on its own.
• It must not delay urgent investigation when alarm features are present.

Special groups.

• Children: used to decide which need endoscopy, and normal values are higher under 4 years.
• Infants: high values are physiological in the first year, and the test is of little use.
• Older adults: lower specificity because of NSAIDs, diverticular disease and cancer, so the cut off is read with alarm features.
• Pregnancy: no change in reference limits, and used to monitor IBD.
• Regions: infection is a common cause of a raised value, so stool culture or pathogen testing comes first in endemic areas.

Follow up tests. Repeat faecal calprotectin, stool culture and Clostridioides difficile toxin, ova and parasite examination, full blood count, CRP, ferritin, albumin, coeliac serology, faecal immunochemical test, colonoscopy with biopsy, MR enterography or small bowel capsule endoscopy, and thiopurine metabolites and drug levels in treated IBD.