Explanation of relationship to faecal calprotectin and bowel-related inflammation

Faecal calprotectin is excreted in excess into the intestinal lumen during the inflammatory process and so can act as a marker for inflammatory diseases of the lower gastrointestinal tract. Tests measuring faecal calprotectin can help to distinguish between inflammatory bowel diseases and non-inflammatory bowel diseases (1).

• Calprotectin is a 36-kDa calcium and zinc-binding protein that accounts for about 60% of total proteins in the cytosol fraction in neutrophil granulocytes
  • calprotectin has antimicrobial activity
  • calprotectin is probably involved in the regulation of inflammatory reactions
  • calprotectin is resistant both in vitro and in vivo to enzymatic degradation - levels of calprotectin can be easily measured in the stools
  • calprotectin accounts for 60% of the cytosolic protein in neutrophils, and, to a lesser extent, in monocytes and macrophages, which can be found throughout the human body mainly in plasma, urine, cerebrospinal fluid, faeces, saliva or synovial fluid
  • involved in many physiological functions including cell differentiation, immune regulation, tumourigenesis, apoptosis and inflammation
  • accounts for approximately 60% of total soluble proteins in the cytosol fraction of neutrophils
    • neutrophils are the common effector cells that define acute inflammation in response to a number of factors
      • once the neutrophil migrates to a site of chemoattraction, the contact sets off a cascade of events leading to a respiratory burst, oxygen radical generation, and disintegration of the neutrophil with the release of its cytosolic granules (and calprotectin), which contain a variety of hydrolytic and proteolytic enzymes.
      • thus, the neutrophil deals with the chemoattractant but at the same time causes indiscriminate damage to its surroundings
  • amount of calprotectin reflects the number of participating neutrophils in this inflammation
• calprotectin is highly resistant to degradation by intestinal pancreatic secretions, intestinal proteases, and bacterial degradation, and it is stable in faeces at room temperature for at least a week. In short, the amount of calprotectin in faeces provides a noninvasive quantitative measure of neutrophil flux to the intestine.

Sensitivity and specificity in inflammatory bowel disease (IBD)

• analysis of faecal calprotectin consists of an extraction step followed by quantification by immunoassay
• due to its specificity for gastrointestinal tract inflammation, faecal calprotectin is superior to serum calprotectin (3)
• an abnormal test result simply indicates intestinal inflammation of any cause
  • numerous intestinal diseases and drugs (e.g., NSAIDs, alcohol) are associated with low-grade intestinal inflammation with average calprotectin levels between 50 and 300 mug/mg
  • however, only untreated IBD and certain food infections are associated with very high levels (2)
    • given a degree of clinical disease activity in, for example, Crohn's colitis and small bowel Crohn's disease, it is noteworthy that calprotectin is somewhat lower in the latter
      • due to the fact that the small bowel bacterial load (the main neutrophil chemoattractant) is far less than in the colon and, hence, reflected by a less intense inflammatory response; this is also reflected by histology
  • nearly 99% of patients who have active IBD have elevated faecal calprotectin levels
    • 15% to 20% of patients with IBS have mildly elevated calprotectin levels. (It is important to note that patients with postinfectious or postdiverticulitis IBS-like symptoms may have been included in these studies, and these diseases differ from conventional IBS.)
    • a normal calprotectin level is much more likely to represent IBS (2)
  • additional utility of faecal calprotectin is that changes in its levels are a good indicator of mucosal healing or recurrence of inflammation (3)
    • faecal calprotectin can be used for monitoring of patients with IBD and to identify the patients at risk of relapse
  • FC has a false positive rate of up to 9% based on negative upper and lower gastrointestinal endoscopic findings in patients with elevated FC without taking into account the possibility of significant small bowel pathology (4)

Faecal calprotectin is a poor marker for differentiating colorectal carcinoma from adenoma (3)

• not recommended as a screening marker for colorectal carcinoma in asymptomatic patients

Faecal calprotectin and diagnosis of colorectal cancer

• a study showed (5):
  • elevated pre-diagnostic faecal calprotectin levels were common in patients with colorectal cancer (CRC) in close proximity to diagnosis
  • right-sided localisation and tumour stage were significantly associated with a rise in faecal calprotectin levels

A review notes (6):

• Faecal calprotectin testing
  • is recommended in patients <60 years old with lower gastrointestinal symptoms and normal initial workup to exclude causes of colonic inflammation
  • a normal faecal calprotectin result has a high negative predictive value for inflammatory bowel disease, and prevents unnecessary investigation when the most likely diagnosis is irritable bowel syndrome
  • should not be used in patients older than 60 or if colorectal cancer is suspected
  • is a sensitive marker of intestinal inflammation and may be elevated in conditions other than inflammatory bowel disease, such as diverticulitis and infectious gastroenteritis, or when patients take medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin

References:

1. NICE (October 2013). Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel
2. Bjarnason I. The Use of Fecal Calprotectin in Inflammatory Bowel Disease.Gastroenterol Hepatol (N Y). 2017 Jan; 13(1): 53–56.
3. Pathirana WG et al. Faecal Calprotectin.Clin Biochem Rev. 2018 Aug;39(3):77-90.
4. Van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ. 2010;341:c3369.
5. Blad N, Palmqvist R, Karling P. Pre-diagnostic faecal calprotectin levels in patients with colorectal cancer: a retrospective study. BMC Cancer. 2022 Mar 24;22(1):315.
6. Deputy M, Devanaboina R, Al Bakir I, Burns E, Faiz O. The role of faecal calprotectin in the diagnosis of inflammatory bowel disease. BMJ 2023; 380:e068947 doi:10.1136/bmj-2021-068947.