Plasma chromogranin A in patients with inflammatory bowel disease: a possible explanation.

To the Editor: We read with interest the results of the study by Sciola et al. In a large cohort of patients with active ulcerative colitis (UC) or Crohn’s disease (CD), the plasma chromogranin A (CgA) concentration was significantly increased in inflammatory bowel disease (IBD) when compared to controls. This is an important discovery about this enteroendocrine cell (EEC) marker that could have ramifications beyond those described in the study. Active inflammation and not disease-specific pathways seem to drive this response, as plasma CgA was significantly higher in active rather than quiescent disease. This expression was correlated to TNFa expression, the extent of disease, and disease activity but no association was found with IBD type, routine biochemical parameters, or disease activity indices. In addition, the expression at the plasma level was not translated to the tissue level, as immunohistological studies proved inconclusive. A retrospective analysis of all gastrointestinal (GI) carcinoid tumors in the same study has shown that 4.8% of carcinoid patients had IBD. As anticipated, CgA plasma levels are significantly further elevated in patients with GI carcinoid. Consequently, the authors propose that plasma CgA could be a useful clinical tool for suspected carcinoids in IBD. This is a real but rare clinical entity, and very high CgA levels would require investigation. However, based on recent research we suggest that CgA upregulation in IBD has a broader salience than the argyrophil hyperplasia and microcarcinoid/carcinoid pathological literature quoted by the authors. CgA, like synaptophysin, is a general EEC marker. EECs constitute 1% of the cells lining the intestinal lumen and their main function is that of luminal content sensing. EECs control digestion and evoke gut–brain signaling with a central role in the control of food intake. More recent data have identified a role in innate immunity as well, as Toll-like receptors have been described in animal EEC and in a human EEC line, LCC-18. This strongly suggests that EEC upregulation in intestinal inflammation is not a mere bystander of the inflammatory process but actually an integral part of the process, and elevated CgA levels are therefore a putative biomarker of this. Understanding EEC biology in intestinal inflammation is still in its infancy. In humans, EEC upregulation has been shown in patients with intestinal inflammation due to Giardia lamblia. There was a temporal association between plasma CCK levels, enteritis, and hypophagia. Mouse models of intestinal inflammation have also been used to understand EEC physiology. Trichinella spiralis has recently been shown to induce cholecystokinin (CCK) and serotonin (5-HT) cell hyperplasia and hypersecretion in mice. Importantly, reduced food intake during enteritis was significantly improved by the administration of the CCK1 receptor antagonist, loxiglumide. It was also shown that immunocompetence was essential, as mice with severe combined immunodeficiency do not display EEC hyperplasia. Early reports on more specific EEC expression in IBD have echoed these changes. CgA and 5-HT positive cells were increased in both CD and UC, while in Crohn’s colitis only, polypeptide YY (PYY) and pancreatic polypeptide (PP) cells were reduced while enteroglucagon cells were increased. Other emergent data also place EEC in the IBD arena. Phox2b, a neuroendocrine transcription factor colocalized to EECs, has been associated with CD through genome-wide association studies. UbE4A, another protein ascribed through immunohistochemistry to EEC, is a ubiquitination protein that is upregulated in patients with active and stricturing disease. Thus, the growing recent evidence presented here suggests that intestinal inflammation is intrinsically associated with changes in EEC biology, and this would be a very clinically relevant explanation for the increase in plasma CgA noted, without a need to implicate carcinoids. If EEC are further proven to be central to appetite disturbance and to mucosal immunology in IBD, then they may pose novel and tractable therapeutic targets.