Histopathologic and Lymphocyte Subpopulations Evaluation of the Upper Gastrointestinal Tract of Crohn's Disease: A Multicentre Prospective Study (CROHNLY Project)

Inflammatory bowel disease (IBD) comprises a series of disorders of unknown cause, such as ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC), associated with an over-the-top immune response that produces lesions of variable depth and extent in the intestine. They have a chronic course, without cure and with an unpredictable evolution. Clinical symptoms of CD are characterized by malaise, weight loss, fever, diarrhoea, abdominal pain, vomiting, sometimes palpable mass, perianal disease, among others. The disease is most frequently located in the ileocecal area, but all the entire digestive tract from the oral cavity to the rectum may be affected. The involvement of the upper gastrointestinal tract (UGT) (L4) in CD is frequently undiagnosed. From 1-7% of patients with CD refer symptoms or signs that are due to UG involvement. Chronic iron deficient anaemia, in the absence of digestive symptoms, is the only guiding sign that may alert about the diagnosis.

Furthermore, retrospective cohort studies suggest that CD of the UGT is associated with a worse prognosis. The systematic study of the UGT in the initial evaluation of CD at the time of diagnosis is not generally recommended in adulthood, European Crohn's and Colitis Organisation (ECCO) guidelines recommend upper endoscopy only if there are upper digestive symptoms (vomiting, dyspepsia, etc.). In the case of gastroscopy, gastric biopsies have to be performed due to the possible presence of focal active gastritis, which is considered very specific of CD. This statement is based on a limited series of cases published in 1980. On the other hand, systematic performance of duodenal biopsies is not recommended. This fact has caused that the histopathology of duodenal CD is very unknown and the need to perform duodenal biopsies of the UGT is still a matter of debate.

Macro and microscopic findings from the UGT have generally been used to differentiate between UC and CD in cases of IC. Among the macroscopic findings highlight the presence of sores or ulcers and most specific and frequent microscopic findings are granulomas and chronic inflammatory infiltrate respectively. However, it is known that CD can cause lymphocytic infiltration of the duodenal epithelium (duodenal lymphocytosis or lymphocytic enteritis) and villus atrophy. These are findings are characteristically found in celiac disease, and therefore, these histological lesions of the duodenum also propose the differential diagnosis between celiac disease and CD.

In addition, it must be considered that many of the patients with IBD take immunosuppressive for disease control, which have been reported to be the cause of lymphocytic enteritis and duodenal villus atrophy. This proposed drug-induced enteropathy is based only in a few series of cases in the context of treatment with azathioprine and methotrexate. There are no studies systematically evaluate how often these drugs can cause a "sprue like" enteropathy.

The lymphocytic enteritis of celiac disease has been associated with a specific pattern of lymphocyte subpopulations (increase in the percentage of CD3+TCRγẟ+ lymphocytes and decrease in the percentage of CD3-). It is unknown if CD duodenal lymphocytes is associated with a specific CD cytometric pattern. If so, the evaluation of lymphocyte subpopulations could be of great diagnostic aid when considering the differential diagnosis between celiac disease, CD and other forms of duodenal lymphocytosis.