Calprotectin Protein Could Be Non-invasive Biomarker for FAP, Study Suggests

Levels of calprotectin, a marker of inflammation, are elevated in the feces of people with familial amyloid polyneuropathy (FAP) who experience gastrointestinal (GI) symptoms, a study suggests.

This finding implicates inflammation as a possible cause of gut symptoms in FAP and supports measuring calprotectin levels in people with intestinal inflammation.

The study, “Fecal calprotectin levels are elevated in transthyretin amyloidosis patients with gastrointestinal manifestations,” was published in the journal Medicine.

FAP, also known as ATTR amyloidosis, is characterized by deposits of misfolded transthyretin (TTR) protein in the body. GI symptoms, such as diarrhea, constipation, weight loss, and nausea, are common in FAP, sometimes even preceding neurological symptoms. However, what causes GI symptoms in FAP is still unclear.

Researchers in Bulgaria hypothesized that GI symptoms in FAP might be associated with increased inflammation in the gut. “The inflammatory hypothesis as a possible cause for GI complications in ATTR amyloidosis has never been addressed,” they wrote.

The “gold standard” for evaluating gut inflammation is an endoscopy with biopsies. However, the procedure is invasive, burdensome to the patient, and expensive, the scientists said. As such, they evaluated levels of calprotectin in feces, as a non-invasive way to assess intestinal inflammation. Calprotectin is a protein released by immune cells called neutrophils during inflammation.

The team measured calprotectin levels in 21 people with FAP (mean age 57 years) and in 42 healthy controls who were matched in terms of age and sex. Most (67%) of the patients carried the Glu89Gln mutation, the most common in Bulgarian FAP patients.

All participants with FAP had GI symptoms: 16 (76%) experienced unintentional weight loss, 14 (67%) had diarrhea, eight (38%) had indigestion, five (24%) had abdominal pain, four (19%) had constipation, and two (9.5%) had alternating diarrhea and constipation.

Mean calprotectin levels were significantly higher in people with FAP than in the controls — 184 micrograms (mcg)/g vs. 40 mcg/g. Patients with diarrhea had higher levels of the protein than those without such complications. Other GI symptoms were not significantly associated with altered calprotectin levels.

Among the FAP patients, 12 (57%) had a polyneuropathy disability score of 1, six (29%) had a score of 2, and three (14%) had a score of 3a. These scores were significantly correlated with calprotectin levels, meaning that individuals with higher protein levels also had more severe neuropathy.

“FC [fecal calprotectin] levels were higher in more advanced stages of the polyneuropathy of the patients, suggesting an increased inflammatory response within the intestines throughout the later stages of the disease,” the researchers wrote. “The most probable explanation of this is due to more intense amyloid deposits in the GI tract.”

Calprotectin levels also significantly correlated with the presence of TTR deposits in the rectum and of neutrophils in the colon.

Statistical analyses determined that a cutoff fecal calprotectin value of 71 microgram (mcg)/g could distinguish between FAP patients with GI symptoms from healthy controls, with an overall accuracy of 97%. The sensitivity (true-positive rate) for this cutoff was 91%, while the specificity, or true-negative rate, was 100%.

“This is the first study describing elevated FC levels in ATTR amyloidosis patients with GI manifestations compared to healthy controls, which suggests an inflammatory component in the pathogenesis of GI complications in this disease,” the scientists wrote.

Beyond understanding the underlying disease mechanisms, the results may aid in the diagnosis of FAP. In particular, gastroenterologists could consider FAP as a possible diagnosis for people with intestinal inflammation without a known cause.

“The presence of elevated FC concentrations could help gastroenterologists to include ATTR amyloidosis in their diagnostic work-up,” the researchers wrote. “Future international studies on bigger cohorts are needed to evaluate the role of FC in the diagnosis of ATTR amyloidosis with GI manifestations.”