HOLLYWOOD, FLA. – Patients on angiotensin-receptor blocking therapy who present with severe gastrointestinal symptoms may be experiencing drug-induced enteropathy, Dr. Joseph A. Murray said at the 2013 Advances in IBD meeting.
He discovered the connection in a retrospective analysis of patients after treating two women with collagenous celiac disease whose patient history included olmesartan therapy. "Until a few years ago, I’d never heard of such a thing," he said. "But for a condition like collagenous sprue, which is exceptionally rare, that really got my attention."
Dr. Joseph A. Murray
Olmesartan was implicated in 14 out of 32 cases of refractory idiopathic sprue treated by Dr. Murray at the Mayo Clinic in Rochester, Minn., between 2008 and 2011. "It’s very much less common for other ARBs [angiotensin-receptor blockers] such as valsartan and irbesartan to have a spruelike effect on patients," Dr. Murray said of his clinical experience.
Since he noted the connection, he has successfully treated 22 additional such cases: When all patients were taken off the ARB, their symptoms – particularly their severe diarrhea – resolved, and the patients required no further therapy. They also were all able to return to a diet that contained gluten.
Autoimmune- vs. drug-induced enteropathy
Drug- and autoimmune-induced enteropathy have similar presentations, including severe chronic diarrhea; villous atrophy and collagen deposition with or without intraepithelial lymphocytes; and negative tissue transglutaminase antibodies and endomysial antibodies.
In drug-induced enteropathy, however, laboratory findings will always be seronegative for celiac disease and there will be no response to a gluten-free diet.
Patients taking olmesartan who previously were diagnosed with celiac disease should be retested, as should patients not currently taking olmesertan but who were on the drug at the time they were diagnosed.
In patients with severe diarrhea, olmesartan should be suspected, Dr. Murray said. Diarrhea in drug-induced cases is severe and protracted, with patients experiencing as many as 42 bowel movements a day. Acute renal failure and the need for parenteral nutrition are also possible with this condition, he said.
Clinical presentation
Of the 22 patients (median age, 70 years) treated for drug-induced enteropathy, 13 were women and 21 were non-Hispanic white. Twelve had one or more multiple electrolyte abnormalities, 14 had normocytic normochromic anemia, and 10 were severely hypoalbuminemic.
The amount of ARB prescribed to patients varied from 10 to 40 mg. "Patients had been on olmesartan for at least a year, and even as long as 3 years, before the symptoms started, which often did so abruptly, without explanation."
Prior treatments that had failed in these patients included a gluten-free diet, systemic steroids or budesonide, antidiarrheal agents, pancreatic enzymes, bile acid sequestrants, metronidazole, azathioprine, and octreotide.
In all of the 17 patients who had follow-up biopsies, the villi recovered. Anecdotal reports of four patients who were rechallenged with olmesartan included a full return of the illness, regardless of the period of time that had elapsed.
Possible mechanisms
"We think it’s a cell-mediated immune response, not the classic, ‘I take medication, I get hypersensistivity’ response," Dr. Murray said.
ARBs inhibit transforming growth factor (TGF)-beta, and TGF-beta "is key for regulating the immune response in the gut," he said. However, because TGF-beta also drives collagen formation, that there would be a high number of collagenous sprue cases casts doubt on this as a clear mechanism, he said.
Another possibility Dr. Murray and his associates tested, but rejected, is that a bioactivating hydrolase enzyme activates olmesartan given as a prodrug, in the epithelial tissue of the intestine and liver, creating polymorphisms.
The role of angiotensin receptors in the gut and on lymphocytes has not yet been explained, although there is some similarity to celiac disease where "lots of regulatory T cells in patients "simply don’t work," Dr. Murray said. "We know that these are CD8-positive T cells, so they are cytotoxic, and there are plenty of FOXP3 cells present, and they don’t change when you take them off the drug."
The conference was sponsored by the Crohn’s & Colitis Foundation of America. Dr. Murray had no relevant disclosures.