Carbonic Anhydrase IX: A Marker of Hypoxia Expressed in Active Ulcerative Colitis
Alexander J Carterson, Seymour Rosen, Robert M Najarian. Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA
Background: Hypoxia in the GI tract is generally regarded as the diminishment or abolition of blood flow resulting, in its acute phase, in frank infarction that is easily identified histologically. Currently, recognition is being given to a more localized hypoxia within the intestinal mucosa which may be present in normal physiologic states, but can be augmented by inflammatory processes such as inflammatory bowel disease. Hypoxia-inducible factor 1α is upregulated in hypoxic states and its closely allied gene target, carbonic anhydrase IX (CAIX) is present at low intensity in normal intestinal crypt epithelium.
Design: Using immunohistochemistry, we investigated whether hypoxia, as indicated by the presence of CAIX-positive colonic crypt epithelium, plays a contributory role in active ulcerative colitis (UC). Distal colonic biopsies in successive cases of symptomatically-active UC were examined (n=20), with UC surveillance biopsies in asymptomatic patients (n=14) used as “controls”. CAIX expression was quantitated by evaluating the number of CAIX-positive epithelial cells/100 crypts and the number of positively-stained epithelial cells/individual crypt.
Results: 2642 crypts were examined overall (1478 in the surveillance UC and 1164 in the active UC groups), with 160 and 326 crypts demonstrating positive staining with CAIX, respectively. For every 100 individual crypts examined in surveillance cases, 12 crypts showed positivity with 0.5±0.1 CAIX-positive epithelial cells identified per crypt. In contrast, within the active UC cases, 34 crypts showed positivity per 100 crypts examined (p=0.001) and contained 2.5±0.7 CAIX-positive epithelial cells/crypt (p=0.01). Immunoreactivity was most intense in areas of greatest inflammation; however, foci with limited inflammation exhibited prominent epithelial positivity as well. Therefore, in the material examined, there was a distinct increase in CAIX expression, both in terms of individual crypt upregulation and the extent of mucosal staining in patients with active UC versus asymptomatic patients biopsied at surveillance colonoscopy.
Conclusions: These findings show that CAIX is consistently expressed in active UC. CAIX upregulation in the colonic mucosa may be an adaptive mechanism aimed at preservation of tissue viability during hypoxic stress. These studies suggest a role for hypoxia in active IBD, supporting studies that have shown that ameliorating hypoxia reduces such injury in experimental models. Further work to investigate the role of hypoxia in IBD and its contributory effects is needed.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 90, Monday Morning